WO2017108917A1

WO2017108917A1 - Pharmaceutical compositions for use in the treatment of chronic obstructive pulmonary disease

Info

Publication number: WO2017108917A1
Application number: PCT/EP2016/082124
Authority: WO
Inventors: Gonzalo De Miquel Serra
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2015-12-22
Filing date: 2016-12-21
Publication date: 2017-06-29
Anticipated expiration: 2018-06-22
Also published as: TW201735914A

Abstract

Disclosed are pharmaceutical compositions for inhalation comprising a combination of a long-acting muscarinic antagonist and a long-acting beta-2 agonist, such as 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, for use in the treatment of chronic obstructive pulmonary disease (COPD), wherein the use is for the relief of COPD symptoms, when needed.

Description

PHARMACEUTICAL COMPOSITIONS FOR USE IN THE TREATMENT

OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

FIELD

This specification describes pharmaceutical 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

(COPD), and in particular for use in the relief of COPD symptoms when needed.. In particular, 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.

BACKGROUND

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. The treatment of COPD on a

maintenance basis may typically be provided by treatment with a LAMA, such as tiotropium, umeclidinium, glycopyrronium or aclidinium. More recent advances have seen the indication of fixed dose LAMA/LABA combinations, such as the combination of umeclidinium and vilanterol (Anoro™), the combination of glycopyrronium and indacaterol (Ultibro™), the combination of tiotropium and olodaterol (Stiolto™), the combination of glycopyrronium and formoterol (Bevespi Aerosphere™) and the combination of aclidinium and formoterol (Duaklir™). Currently, Anoro™, Ultibro™ and Stiolto are all indicated for once-daily maintenance treatment of COPD. Bevespi Aerosphere™ and Duaklir™ are indicated for twice-daily maintenance treatment of COPD.

However, notwithstanding the availability of such treatment options, COPD remains a poorly understood and frequently poorly treated disease. In particular, many patients who are receiving maintenance treatment for COPD nevertheless suffer from occasional exacerbations.

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.

Increased COPD symptoms (including dyspnea, chronic cough and sputum production) are predictive of COPD exacerbations, hospitalizations, and a faster disease progression (Elwing J, Panos RJ, Int. J. Chron. Obstruct. Pulmon. Dis., 2008, 3, 55-70). 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). Furthermore, as COPD progresses, exacerbations become more frequent (Global Initiative for Chronic Obstructive Lung Disease (GOLD) Executive and Science Committees, GOLD Executive Summary updated 2009). COPD patients who experience greater variability in symptoms also tend to suffer more frequent exacerbations, have a lower health-related quality of life, and utilize respiratory care resources more frequently (Kessler R, et al, Eur. Respir. J., 2011, 37, 264-725).

Current COPD treatments utilise regular maintenance treatment to attempt to allow patients to reach the lowest possible level of symptom intensity without significant symptomatic variations. However, patients may be able to identify the periods in which their symptoms are more frequent or are more severe. During these times it may be desirable to have more effective treatment options which would allow patients to better address variations in their COPD symptoms.

In asthma, the inflammatory and reversible nature of the disease has enabled such a symptom-centric focus. For example, in asthma a fixed dose combination of budesonide (an inhaled corticosteroid) and formoterol (a long-acting beta-2 agonist) (for example SYMBICORT^®) is used for maintenance treatment and for symptomatic relief when needed, to better control asthma related symptoms and asthma fluctuations. This is the so called SYMBICORT Maintenance And Reliever Therapy (SMART™).

However, for COPD, all current treatment options are based upon the consideration of COPD as a stable and poorly reversible condition with few and limited symptomatic fluctuations over time. This approach to COPD treatment, coupled with the limited response of COPD inflammation to inhaled corticosteroids, has strongly prejudiced against any dosing approach to the treatment of COPD other than maintenance treatment. Current medical guidelines, for example the GOLD treatment guidance and treatment guidance from the American Thoracic Society (ATS) and the European Respiratory Society (ERS), all recommend the use of LAM As and LAB As on a maintenance basis. Accordingly, although various fixed dose LAMA/LABA combinations have been indicated for the treatment of COPD, they are all are indicated for maintenance treatment only.

Consequently, COPD patients who require additional therapy on top of these maintenance treatments in order to treat fluctuations in their COPD symptoms would tend to rely upon the use of short-acting beta-2 agonists (SAB As), such as salbutamol/albuterol, fenoterol or terbutaline, or short-acting muscarinic antagonists (SAMAs), such as ipratropium. However, there is very little evidence supporting the clinical efficacy of SABAs or SAMAs on COPD-related symptoms (such as dyspnea, cough or mucus production), or on improvements in COPD-related quality of life, or in the prevention of COPD exacerbations.

Therefore, a change in approach to the treatment of COPD to one which focuses on the relief and control of symptoms, and not only on lung function, may prove to be beneficial. There is therefore a need to find an alternative method of treating COPD which would provide the patient with one or more of:

1) better control during periods of increased COPD symptoms 2) better control of COPD progression

3) a reduction in the number of exacerbations

4) a reduction in the severity of symptoms of exacerbations; and

5) a reduction in the incidence of clinically important deteriorations.

SUMMARY

The present specification describes pharmaceutical compositions for use in the treatment of COPD, for symptomatic relief, when needed, and in addition to maintenance treatment.

In particular, the present specification 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

(ii) a second active ingredient which is a long-acting beta-2 agonist or a pharmaceutically acceptable salt thereof;

for use in the treatment of COPD, wherein the use is in addition to maintenance treatment and is for the relief of COPD symptoms, when needed.

The present specification further relates, in part, to a pharmaceutical composition for inhalation comprising, in admixture:

for use in the treatment of COPD, wherein the use is in addition to maintenance treatment and is for the relief of COPD symptoms, when needed, and wherein said use results in one of more of:

1) better control during periods of increased COPD symptoms

2) better control of COPD progression

3) a reduction in the number of exacerbations; and

4) a reduction in the severity of symptoms of exacerbations.

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

for use in the treatment of COPD, wherein the use is in addition to maintenance treatment and is for the relief of COPD symptoms, when needed, and wherein said use results in a reduction in the incidence of clinically important deteriorations (CID).

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.

DETAILED DESCRIPTION

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. 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

pharmaceutically acceptable anion of a mono or polyvalent acid. The different salts of 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. "Duaklir™" or "Duaklir Genuair™" 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. 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

3 [(cyclopentylhydroxyphenylacetyl)oxy]- 1 , 1 -dimethyl pyrrolidinium bromide.

"Glycopyrronium/formoterol" refers to a fixed dose combination of

glycopyrronium or a pharmaceutically acceptable salt thereof and formoterol or a pharmaceutically acceptable salt thereof. A particular form of glycopyrronium/formoterol 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. "Bevespi Aerosphere™" is a fixed dose combination of glycopyrronium bromide and formoterol fumarate dihydrate.

"Clinically important deterioration (CID)" refers to the composite index, known to those skilled in the art, whereby a CID is deemed to have occurred if one of the following are measured: a reduction from baseline in FEV1 (forced expiratory volume in 1 second) of over lOOmL, an increase from baseline of more than 4 points in the Saint George's Respiratory Questionnaire (SGRQ), or one or more COPD exacerbations. Alternatively, as the skilled person will be aware, a CID can also be measured using different combinations of the above CID individual components together with additional individual symptomatic endpoints (such as a reduction from baseline of more than 1 point in the

Transitional Dyspnea Index score, or a decrease from baseline of more than 2.0 points in the COPD Assessment Questionnaire (CAT)).

"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

questionnaires known to those skilled in the art. 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.

"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.

"Formoterol" 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. Typically formoterol is administered in the form of a pharmaceutically acceptable salt. The different salts of formoterol 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, 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. More typically, 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. For example, 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

Characteristics or Prescribing Information Leaflet. By way of illustration only,

maintenance treatment includes the once-daily posology currently indicated for the combinations of umeclidinium and vilanterol (Anoro™), of glycopyrronium and indacaterol (Ultibro™), and of tiotropium and olodaterol (Stiolto™), and the twice-daily posology currently indicated for the combination of glycopyrronium and formoterol (Bevespi Aerosphere™) and aclidinium and formoterol (Duaklir™).

"When needed" refers to the administration of a given therapy outside of maintenance treatment and which is given in response to an increase in symptoms, either an increased frequency of symptoms, or an increased severity of symptoms, or both, and which is given to relieve said symptoms. In particular, reference herein to the use of a COPD therapy "when needed" refers to the use of that therapy by the patient in addition to their maintenance treatment and in response to a perceived increase in the regularity or severity of his or her COPD symptoms. For the avoidance of doubt, reference to the use of the pharmaceutical compositions described herein "in addition to maintenance treatment" refers to the use of such pharmaceutical compositions on top of, or supplemental to, any maintenance treatment already used by a patient. The pharmaceutical compositions used by a given patient when needed may be the same as, or may be different to, the

pharmaceutical compositions used by that patient for maintenance treatment. A number of fixed dose LAMA/LABA combinations have recently been indicated for COPD, such as the combination of umeclidinium and vilanterol (Anoro™), the combination of glycopyrronium and indacaterol (Ultibro™), the combination of tiotropium and olodaterol (Stiolto™), the combination of glycopyrronium and formoterol (Bevespi Aerosphere™), and the combination of aclidinium and formoterol (Duaklir™). However, each of these combinations have been indicated for maintenance treatment only. Dosing regimens in which fixed dose LAMA/LABA combinations are used by the patient when needed, outside of maintenance treatment, are currently not recommended.

However, notwithstanding the significant improvements shown by the use of fixed dose LAMA/LABA combinations as maintenance treatment, many patients nevertheless experience variations in the frequency and severity of their COPD symptoms, and many patients progress to suffer an exacerbation.

In accordance with the present disclosure, we have now found that the

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

deterioration.

According to the present disclosure, 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. The improved control of symptoms as provided by such additional doses of a LAMA/LABA combination (such as 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

Accordingly, in one aspect there is provided a pharmaceutical composition for inhalation comprising, in admixture:

(i) a first active ingredient which is aclidinium or a pharmaceutically acceptable salt thereof; and

(ii) a second active ingredient which is formoterol or a pharmaceutically acceptable salt thereof;

In a further aspect, the first active ingredient is glycopyrronium or a

pharmaceutically acceptable salt thereof.

In a further aspect there is provided a pharmaceutical composition for inhalation comprising, in admixture:

for use in the treatment of COPD, wherein the use is 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:

1) better control during periods of increased COPD symptoms

2) better control of COPD progression

3) a reduction in the number of exacerbations; and

4) a reduction in the severity of symptoms of exacerbations. In a further aspect there is provided a pharmaceutical composition for inhalation comprising, in admixture:

1) better control during periods of increased COPD symptoms

2) better control of COPD progression

3) a reduction in the number of exacerbations; and

4) a reduction in the severity of symptoms of exacerbations.

In a further aspect, the first active ingredient is glycopyrronium or a

pharmaceutically acceptable salt thereof.

for use in the treatment of COPD, wherein the use is 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).

In a further aspect, the first active ingredient is glycopyrronium or a

pharmaceutically acceptable salt thereof.

Methods of treating COPD

In a further aspect there is provided 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:

wherein the pharmaceutical composition is administered in addition to maintenance treatment and is for the relief of COPD symptoms, when needed.

In a further aspect, the first active ingredient is glycopyrronium or a

pharmaceutically acceptable salt thereof.

(ii) 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:

1) better control during periods of increased COPD symptoms

2) better control of COPD progression

3) a reduction in the number of exacerbations; and

4) a reduction in the severity of symptoms of exacerbations.

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:

1) better control during periods of increased COPD symptoms

2) better control of COPD progression

3) a reduction in the number of exacerbations; and

4) a reduction in the severity of symptoms of exacerbations.

In a further aspect, the first active ingredient is glycopyrronium 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 a reduction in the incidence of clinically important deteriorations (CID).

In a further aspect, the first active ingredient is glycopyrronium or a

pharmaceutically acceptable salt thereof.

The current safety margins and exposures would suggest that the maximum number of daily doses of aclidinium/formoterol or of glycopyrronium/formoterol would not be limited by the safety margin of the LAMA component. Any limit on the number of daily doses is considered more likely to be determined by the safety margin of the formoterol component.

Accordingly, in a further aspect the pharmaceutical compositions described herein are administered when needed in total no more than four times a day. In a further aspect, the compositions described herein are administered when needed in total no more than two times a day. In a further aspect, the compositions described herein are administered when needed in total no more than once a day. In another aspect, the compositions described herein are administered when needed no more than twice within any 12-hour time period. In a further aspect, the compositions described herein are administered when needed no more than once within any 12-hour time period.

It is anticipated that a patient who uses the compositions of the present disclosure when needed, as described herein, will do so for a limited period of time before having his or her treatment options reassessed. In a further aspect, therefore, the use of the

pharmaceutical compositions when needed, as described herein, 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.

Glycopyrronium/formoterol is currently indicated in the form of glycopyrronium bromide/formoterol fumarate dihydrate. In a further aspect, therefore, the compositions described herein comprise glycopyrronium in the form of glycopyrronium bromide. In a further aspect, the compositions described herein comprise formoterol in the form of formoterol fumarate. In a further aspect, the compositions described herein comprise formoterol in the form of formoterol fumarate dihydrate.

Aclidinium/formoterol is currently indicated in the form of aclidinium

bromide/formoterol fumarate dihydrate. In a further aspect, therefore, the compositions described herein comprise aclidinium in the form of aclidinium bromide. In a further aspect, the compositions described herein comprise formoterol in the form of formoterol fumarate. In a further aspect, the compositions described herein comprise formoterol in the form of formoterol fumarate dihydrate.

Aclidinium/formoterol and glycopyrronium/formoterol are currently indicated for administration via the inhaled route. In one aspect, administration may be by oral inhalation. In another aspect inhalation may be by intra-nasal inhalation. 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.

Accordingly, in a further aspect, the compositions of the present disclosure are

administered via the inhaled route, using a suitable inhaler. In another aspect, the inhaler is a metered dose inhaler or a dry powder inhaler. In a further aspect, the compositions described herein are administered via a dry powder inhaler. In a further aspect, the compositions described herein are administered via a breath-activated, multidose, dry powder inhaler. In a further aspect, the compositions described herein are administered via the Genuair/Pressair device. In a further aspect, the compositions described herein are administered via a metered dose inhaler, such as a pressurised metered dose inhaler (pMDI). Pharmaceutical compositions comprising aclidinium/ formoterol

Where the first active ingredient is aclidinium, each administration of the compositions of the present disclosure comprises a single actuation of the inhaler. In a further aspect, therefore, where the first active ingredient is aclidinium, 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. In another aspect, where the first active ingredient is aclidinium, 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. In another aspect, where the first active ingredient is aclidinium, no more than two actuations are administered for use when needed at any one time.

Typically, the metered (or nominal) dose of aclidinium/formoterol per actuation of the inhaler comprises about 343 μg of aclidinium (equivalent to about 400 μg of aclidinium bromide) and about 12 μg of formoterol fumarate dihydrate. The metered (or nominal) dose is the maximum theoretical dose of the inhaler per actuation. Typically, the delivered dose of aclidinium/formoterol per actuation of the inhaler comprises about 340 μg of aclidinium (equivalent to about 396 μg of aclidinium bromide) and about 1 1.8 μg 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 μg of aclidinium" refers to a dose of 343 μg of aclidinium subject to variation within the normal limits of acceptance for the delivery system, such as 223-463 μg of aclidinium (plus/minus 35%), 257-429 μg of aclidinium (plus/minus 25%), 292-394 μg of aclidinium (plus/minus 15%) or 309-377 μg of aclidinium (plus/minus 10%). A metered dose of "about 12 μg of formoterol fumarate dihydrate" refers to a dose of 12 μg of formoterol fumarate dihydrate subject to variation within the normal limits of acceptance for the delivery system, such as 7.8-16.2 μg of formoterol fumarate dihydrate (plus/minus 35%), 9-15 μg of formoterol fumarate dihydrate (plus/minus 25%), 10.2-13.8 μg of formoterol fumarate dihydrate (plus/minus 15%) or 10.8-13.2 μg of formoterol fumarate dihydrate (plus/minus 10%). Similarly, a delivered dose of "about 340 μg of aclidinium" and a delivered dose of "about 11.8 μ 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.

Accordingly, in a further aspect, the compositions described herein comprise a delivered dose of about 340 μg of aclidinium per administration. In another aspect, the aclidinium is in the form of aclidinium bromide and the delivered dose of aclidinium bromide is about 396 μg per administration. In a further aspect the compositions described herein comprise a delivered dose of about 11.8 μ of formoterol fumarate dihydrate per administration.

In a further aspect, the compositions described herein comprise a metered dose of about 343 μg of aclidinium per administration. In another aspect, the aclidinium is in the form of aclidinium bromide and the metered dose of aclidinium bromide is about 400 μg per administration. In a further aspect the compositions described herein comprise a metered dose of about 12 μ of formoterol fumarate dihydrate per administration.

The compositions described herein are administered for use when needed in a total of no more than four actuations per day. In a further aspect, therefore, the compositions described herein comprise a total delivered daily dose of aclidinium for use when needed of no more than about 1360 μg. In another aspect, 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 μg. In another aspect, 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 μg. A delivered dose of "about 1360 μg^,, of aclidinium" or "about 1584 μg^,, of aclidinium bromide or "about 47.2 μg^,, 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.

In a still further aspect, the compositions described herein comprise a total metered daily dose of aclidinium for use when needed of no more than about 1372 μg. In another aspect, 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 μg. In another aspect, 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 μg. A metered dose of "about 1372 μ^' of aclidinium" or "about 1600 μ " of aclidinium bromide or "about 48 μ " 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.

Pharmaceutical compositions comprising glycopyrronium/formoterol

Where the first active ingredient is glycopyrronium, each administration of the compositions of the present disclosure comprises two actuations of the inhaler. In a further aspect, therefore, where the first active ingredient is glycopyrronium, 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. In another aspect, where the first active ingredient is glycopyrronium, 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. In another aspect, where the first active ingredient is glycopyrronium, no more than four actuations are administered for use when needed at any one time.

Typically, the metered (or nominal) dose of glycopyrronium/formoterol per actuation of the inhaler comprises about 8.3 μg of glycopyrronium (equivalent to about 10.3 μg of glycopyrronium bromide) and about 5.8 μg of formoterol fumarate dihydrate. The metered (or nominal) dose is the maximum theoretical dose of the inhaler per actuation. Typically, the delivered dose of glycopyrronium/formoterol per actuation of the inhaler comprises about 7.2 μg of glycopyrronium (equivalent to about 9.0 μg of glycopyrronium bromide) and about 5.0 μg 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 μg of glycopyrronium" refers to a dose of 8.3 μg of glycopyrronium subject to variation within the normal limits of acceptance for the delivery system, such as 5.4-11.2 μg of glycopyrronium (plus/minus 35%), 6.2-10.4 μg of glycopyrronium (plus/minus 25%), 7.1-9.5 μg of glycopyrronium (plus/minus 15%) or 7.5- 9.1 μg of glycopyrronium (plus/minus 10%). A metered dose of "about 5.8 μg of formoterol fumarate dihydrate" refers to a dose of 5.8 μg of formoterol fumarate dihydrate subject to variation within the normal limits of acceptance for the delivery system, such as 3.8-7.8 μg of formoterol fumarate dihydrate (plus/minus 35%), 4.4-7.3 μg of formoterol fumarate dihydrate (plus/minus 25%), 4.9-6.7 μg of formoterol fumarate dihydrate

(plus/minus 15%) or 5.2-6.4 μg of formoterol fumarate dihydrate (plus/minus 10%).

Similarly, a delivered dose of "about 7.2 μg of glycopyrronium" and a delivered dose of "about 5.0 μg 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.

Accordingly, in a further aspect, the compositions described herein comprise a delivered dose of about 7.2 μg of glycopyrronium per actuation of the inhaler. In another aspect, the glycopyrronium is in the form of glycopyrronium bromide and the delivered dose of glycopyrronium bromide is about 9.0 μg per actuation. In a further aspect the compositions described herein comprise a delivered dose of about 5.0 μg of formoterol fumarate dihydrate per actuation.

In a further aspect, the compositions described herein comprise a metered dose of about 8.3 μg of glycopyrronium per actuation of the inhaler. In another aspect, the glycopyrronium is in the form of glycopyrronium bromide and the metered dose of glycopyrronium bromide is about 10.3 μg per actuation. In a further aspect the

compositions described herein comprise a metered dose of about 5.8 μg of formoterol fumarate dihydrate per actuation.

Each administration of glycopyrronium/formoterol comprises two actuations of the inhaler. In a further aspect, therefore, the compositions described herein comprise a delivered dose of about 14.4 μg of glycopyrronium per administration. In another aspect, the glycopyrronium is in the form of glycopyrronium bromide and the delivered dose of glycopyrronium bromide is about 18.0 μg per administration. In a further aspect the compositions described herein comprise a delivered dose of about 10.0 μg of formoterol fumarate dihydrate per administration.

In a further aspect, the compositions described herein comprise a metered dose of about 16.6 μg of glycopyrronium per administration. In another aspect, the glycopyrronium is in the form of glycopyrronium bromide and the metered dose of glycopyrronium bromide is about 20.6 μg per administration. In a further aspect the compositions described herein comprise a metered dose of about 11.6 μg of formoterol fumarate dihydrate per administration.

The 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. In a further aspect, therefore, the compositions described herein comprise a total delivered daily dose of glycopyrronium for use when needed of no more than about 57.6 μg. In another aspect, 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 μg. In another aspect, 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 μg. A delivered dose of "about 57.6 μg" of aclidinium" or "about 72.0 μ£' of glycopyrronium bromide or "about 40 μg" 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.

In a still further aspect, the compositions described herein comprise a total metered daily dose of glycopyrronium for use when needed of no more than about 66.4 μg. In another aspect, the 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 μg. In another aspect, 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 46.4 μg. A metered dose of "about 66.4 μg" of glycopyrronium" or "about 82.4 μg" of glycopyrronium bromide or "about 46.4 μg" 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.

Formulations for inhalation

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 μιη, for example 2-5 μιη. Particles having a size above 10 μιη are generally too large when inhaled to reach the small airways. To achieve these particle sizes 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.

Achieving a high dose reproducibility with micronised powders is difficult because of poor flowability and a tendency to agglomerate. Furthermore, 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). When the excipient is 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 μιη, for example 90-150 μιη. 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. Hence the average particle size is generally referred to in the art as equivalent d50. To characterise a particle size diameter, 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. In one aspect, the lactose particles for use in formulations described herein have a dlO of 90-160 μαι, a d50 of 170-270 μαι, and a d90 of 290-400 μιη.

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. Typically, 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. Typically, the ratio by weight of lactose particles to formoterol (such as in the form of formoterol fumarate dihydrate) is 500: 1 to 2000: 1, for example 750: 1 to 1500: 1, such as 900: 1 to 1000: 1.

In one aspect, the compositions described herein are administered in the form of a dry powder formulation of aclidinium bromide in admixture with formoterol fumarate dihydrate and lactose. In a further aspect, the lactose is lactose monohydrate. In a still further aspect, the lactose is alpha-lactose monohydrate. In a further aspect, the aclidinium particles have an average particle size of from 2-5 μιη in diameter, such as between 0.01 and 3μιη in diameter. In a further aspect, the lactose particles have a dlO of 90-160 μιη, a d50 of 170-270 μιη, and a d90 of 290-400 μιη. In a still further aspect, 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.

When administered in the form of an aerosol, the compositions described herein must be suitably formulated. In one aspect, therefore, the compositions described herein comprise a formulation suitable for inhalation via a metered dose inhaler (MDI).

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 μιη, for example 2-5 μιη. 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. In particular, 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. Examples of 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. Generally, the suspending particles are sized within a respirable range, for example between 0.75 and 5 um, such as between 1 and 3 μιη. In particular, 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.

In one aspect, therefore, the compositions described herein are administered in the form of an MDI formulation of glycopyrronium bromide in admixture with formoterol fumarate dihydrate. In a further aspect, the compositions comprise a suspension medium such as an HFA propellant, for example HFA-134a. In a further aspect, the compositions comprise suspending particles, such as a phospholipid, for example DSPC. In a further aspect, the suspending particles further comprise a metal salt, such as a calcium salt, e.g. calcium chloride. In a further aspect the suspending particle is in the form of a perforated microstructure. In a still further aspect, the glycopyrronium particles have an average particle size of from 2-5 μιη in diameter, such as between 0.01 and 3μιη in diameter. In a still further aspect, the suspending particles have an average size of from 0.75 to 5 μτη, such as between 1 and 3 μιη. Uses of the pharmaceutical compositions

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. In one aspect, therefore, the use of the compositions as described herein results in the relief of COPD symptoms compared with maintenance treatment. In another aspect, use of the compositions as described herein results in a reduction in the severity of COPD symptoms compared with maintenance treatment. In another aspect, the use of the compositions as described herein results in a reduction in the frequency of COPD symptoms compared with maintenance treatment.

In one aspect, the use of the 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.

In another aspect, the use of the 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.

In another aspect, the use of the 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%.

In a further aspect, the use of the 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.

In another aspect, 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%. In a further aspect, 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. In particular, 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).

Accordingly, in one aspect, the use of the 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. In a further aspect the exacerbations are moderate or severe exacerbations.

In one aspect, 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.

In another aspect, 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. In another aspect, 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.

Use of the pharmaceutical compositions when needed according to the present disclosure may result in the reduction in the incidence of clinically important deteriorations (CID). In one aspect, therefore, the administration of the composition provides a reduction in the incidence of clinically important deteriorations suffered by a COPD patient compared with maintenance treatment.

In another aspect, the administration of the composition provides an additional reduction in the percentage of patients experiencing a CID compared with

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.

In another aspect, 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%>. In a further aspect, the

administration of the 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.

Use of the pharmaceutical 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:

1) Inspiratory Capacity (IC)

2) Functional Residual Capacity (FRC)

3) Residual Volume (RV)

3) trough and peak Forced Expiratory Volume in one second (FEV1)

4) use of rescue medication; and

6) SGRQ.

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. Accordingly, in one aspect the maintenance treatment is a LABA, such as formoterol, arformoterol, vilanterol, indacaterol, salmeterol or olodaterol. In another aspect the maintenance treatment is a LAMA, such as aclidinium, tiotropium, umeclidinium or glycopyrronium. In another aspect the maintenance treatment is an ICS, such as budesonide or fluticasone. In another aspect, 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.

Throughout this specification, where reference is made to 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) then an additional aspect of the disclosure is the said pharmaceutical

composition 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). A still further aspect of the disclosure is the said pharmaceutical composition in which a third active ingredient is present. In another aspect, the third active ingredient is 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.

Furthermore, throughout this specification, where reference is made to a

pharmaceutical composition for use in the treatment of COPD, the n 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.

Furthermore, throughout this specification, where reference is made to a

pharmaceutical composition for use in the treatment of COPD, then 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. The pharmaceutical compositions described in the present disclosure are further illustrated in the following Examples. These Examples are given by way of illustration only and are non-limiting.

EXAMPLES

Example 1 : Preparation of Duaklir Genuair™

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 μιη, a d50 of 170-270 μιη and a d90 of 290-400 μ, was prepared.

Formoterol fumarate dihydrate (0.08 kg) and alpha-lactose monohydrate (75.458 kg) were blended in a Bohle blender, the mixture was sieved through a sieving-machine Bohle BTS and blended again. Aclidinium bromide (2.462 Kg) was added and the mixture blended in a Bohle blender, then sieved through a sieving-machine Bohle BTS. Finally, the mixture was blended again in a Bohle blender.

Genuair™ (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 Genuair™ provided a metered dose of 12 mg of the composition described above.

The mean delivered dose per actuation (per inhalation) was 340 μg aclidinium (aclidinium free ammonium cation), which corresponds to 396 μg 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 μg aclidinium (aclidinium free ammonium cation), which corresponds to 337-455 μg aclidinium bromide. The mean delivered dose per actuation (per inhalation) was 11.8 μg formoterol fumarate dihydrate. The accepted variance was 10-13.6 μg formoterol fumarate dihydrate.

Example 2: Preparation of Bevespi Aerosphere™

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 μg glycopyrronium (glycopyrronium free ammonium cation), which corresponds to 9.0 μg 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 μg glycopyrronium (glycopyrronium free ammonium cation), which corresponds to 6.8-11.3 μg glycopyrronium bromide. The mean delivered dose per actuation (per inhalation) was 5.0 μg formoterol fumarate dihydrate. The accepted variance was 3.8-6.3 μg 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 μg) when needed in order to relieve those symptoms. 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. The maximum total daily metered dose of aclidinium bromide/formoterol fumarate dihydrate taken by the patient when needed, in addition to maintenance treatment, is 1600/48 μg. 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

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 μg, total delivered dose per administration of 18.0/10.0 μg). 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. The maximum total daily delivered dose of glycopyrronium bromide/formoterol fumarate dihydrate taken by the patient when needed, in addition to maintenance treatment, is 72/40 μg. 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.

Claims

1. 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

(ii) a second active ingredient which is long-acting beta-2 agonist or a

pharmaceutically acceptable salt thereof;

2. A pharmaceutical composition for inhalation according to claim 1, wherein the use results in one of more of:

1) better control during periods of increased COPD symptoms

2) better control of COPD progression

3) a reduction in the number of exacerbations; and

4) a reduction in the severity of symptoms of exacerbations.

3. A pharmaceutical composition for use according to claim 2, wherein the exacerbations are moderate or severe COPD exacerbations.

4. A pharmaceutical composition according to claim 1, wherein the use results in a reduction in the incidence of clinically important deteriorations.

5. A pharmaceutical composition according to any one of claims 1 to 4, 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.

6. A pharmaceutical composition for use according to claim 5, wherein each administration of the pharmaceutical composition comprises a delivered dose of about 340 μg of aclidinium.

7. A pharmaceutical composition for use according to claim 5 or claim 6, wherein the total daily delivered dose of aclidinium for use when needed is no more than about 1360 μg.

8. A pharmaceutical composition for use according to claim 5, wherein the aclidinium is in the form of aclidinium bromide.

9. A pharmaceutical composition for use according to any one of claims 5 to 8, wherein each administration of the pharmaceutical composition comprises a delivered dose of about 396 μg of aclidinium bromide.

10. A pharmaceutical composition for use according to any one of claims 5 to 9, wherein the total daily delivered dose of aclidinium bromide for use when needed is no more than about 1584 μg.

11. A pharmaceutical composition for use according to any one of claims 1 to 10, wherein the second active ingredient is formoterol fumarate dihydrate.

12. A pharmaceutical composition for use according to claim 11, wherein each administration of the pharmaceutical composition comprises a delivered dose of about 11.8 μg of formoterol fumarate dihydrate.

13. A pharmaceutical composition for use according to claim 11 or claim 12, wherein the total daily delivered dose of formoterol fumarate dehydrate for use when needed is no more than about 47.2 μg.

14. A pharmaceutical composition for use according to any one of claims 1 to 13, wherein each administration comprises a single actuation of an inhaler.

15. A pharmaceutical composition for use according to claim 14, wherein the total number of actuations per day for use when needed is no more than four.

16. A pharmaceutical composition for use according to any preceding claim, wherein the pharmaceutical composition is administered using a dry powder inhaler.

17. A pharmaceutical composition for use according to any preceding claim, wherein the pharmaceutical composition further comprises lactose monohydrate.

18. A pharmaceutical composition according to any one of claims 1 to 4, 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.

19. A pharmaceutical composition for use according to claim 18, wherein each administration of the pharmaceutical composition comprises a delivered dose of about 14.4 μg of glycopyrronium.

20. A pharmaceutical composition for use according to claim 18 or claim 19, wherein the total daily delivered dose of glycopyrronium for use when needed is no more than about 57.6 μg.

21. A pharmaceutical composition for use according to claim 18, wherein the glycopyrronium is in the form of glycopyrronium bromide.

22. A pharmaceutical composition for use according to any one of claims 18 to 21, wherein each administration of the pharmaceutical composition comprises a delivered dose of about 18 μg of glycopyrronium bromide.

23. A pharmaceutical composition for use according to any one of claims 18 to 22, wherein the total daily delivered dose of glycopyrronium bromide for use when needed is no more than about 72 μg.

24. A pharmaceutical composition for use according to any one of claims 18 to 23, wherein the second active ingredient is formoterol fumarate dihydrate.

25. A pharmaceutical composition for use according to claim 24, wherein each administration of the pharmaceutical composition comprises a delivered dose of about 10 μg of formoterol fumarate dihydrate.

26. A pharmaceutical composition for use according to claim 24 or claim 25, wherein the total daily delivered dose of formoterol fumarate dihydrate for use when needed is no more than about 40 μg.

27. A pharmaceutical composition for use according to any one of claims 18 to 26, wherein each administration comprises two actuations of an inhaler.

28. A pharmaceutical composition for use according to claim 27, wherein the total number of actuations per day for use when needed is no more than eight.

29. A pharmaceutical composition for use according to any one of claims 18 to 28, wherein the pharmaceutical composition is administered using a metered dose inhaler.

30. A pharmaceutical composition for use according to any one of claims 18 to 29, wherein the pharmaceutical composition further comprises a phospholipid.