WO2015091288A1

WO2015091288A1 - Aclidinium for use in the treatment of cough

Info

Publication number: WO2015091288A1
Application number: PCT/EP2014/077625
Authority: WO
Inventors: Diana JARRETA FERNANDEZ; Maria Esther Garcia Gil
Original assignee: Almirall S.A.
Priority date: 2013-12-19
Filing date: 2014-12-12
Publication date: 2015-06-25
Also published as: UY35899A; TW201605440A; AR098866A1

Abstract

The present invention provides aclidinium or any of its steroisomers or mixture of stereoisomers, or a pharmaceutically acceptable salt or solvate thereof, for the treatment of cough.

Description

ACLIDINIUM FOR USE IN THE TREATMENT OF COUGH

Field of the Invention

The invention relates to a novel use of aclidinium, which can be advantageously used for the treatment of cough.

Background of the Invention

Cough is an airway defensive reflex facilitating clearance of accumulated secretions and protecting airways and lungs from aspiration, inhaled particulates and irritants. However, when associated with disease, cough is one of the most common symptoms for which patients seek medical attention from primary care physicians and pulmonologists, probably because cough can so profoundly and adversely affect the quality of patients' lives (French CL et al., Arch Inter Med. 1998; 158:1657-1661 ).

Cough can be divided into three categories: acute, defined as lasting less than three weeks; subacute, lasting three to eight weeks; and chronic, lasting more than eight weeks (Irwin RS et al., New England Journal of Medicine 2000; 343(23):1715-1721 ).

Acute cough is most frequently associated with upper respiratory tract infections (URTI) such as the common cold, acute bacterial sinusitis, pertussis, exacerbations of chronic obstructive pulmonary disease (COPD), allergic rhinitis, and rhinitis due to environmental irritants. Both prescription and over the counter (OTC) medication are commonly used to treat acute cough with limited success (Dicpinigaitis PV et al., Cough 2009, 5:1 1 ).

Chronic cough is a common symptom of respiratory conditions such as postnasal-drip syndrome from conditions of the nose and sinuses (non-allergic rhinitis, allergic rhinitis, vasomotor rhinitis, chronic bacterial sinusitis), asthma, gastroesophageal reflux disease, chronic bronchitis due to cigarette smoking or other irritants, bronchiectasis, eosinophilic bronchitis or the use of an angiotensin-converting-enzyme inhibitor. Most OTC cough medicines are short-acting syrups in two basic categories: antitussives (cough suppressants) and expectorants. Suppressants attempt to dampen the cough reflex to normal levels when its intensity is in excess of what is required to defend the airways. The most commonly used OTC suppressant is dextromethorphan, which is considered generally safe at recommended doses. However, it can cause hallucinations when taken in large doses.

Expectorants may be useful in cases of excessive mucus production, by increasing the volume of mucus and facilitating the removal of secretions by ciliary transport and/or cough.

Many OTC products offer combinations of centrally acting cough suppressants (e.g., dextromethorphan) and expectorants (e.g., guaifenesin), as well as combinations of either drug with analgesics, decongestants, and/or antihistamines.

Prescription cough remedies usually contain higher doses of cough suppressant than expectorant agents, and are typically prescribed when OTC remedies have failed to relieve disruptive cough symptoms. Some studies have investigated the potential effects of anticholinergic agents on cough, but with inconsistent results. Thus, while ipratropium (a short acting antimuscarinic antagonist) was found effective in reducing cough associated with upper respiratory tract infection in non-smoking patients (Holmes PW et al., Respiratory Medicine 1992; 86(5): 425-429), oxitropium (another short acting antimuscarinic antagonist) was not an effective therapy of this type of cough (Lowry R et al., Br J din Pharmac 1994; 37: 187- 191 ).

On the other hand, tiotropium (a long acting antimuscarinic antagonist) was found to inhibit cough reflex sensitivity to capsaicin in non-smoker patients with acute viral upper respiratory tract infection (Dicpinigaitis PV et al., Lung 1998; 186(6): 369-374). In another study, tiotropium was capable of attenuating capsaicin induced cough in guinea pigs; and caused a concentration dependant inhibition of capsaicin responses in guinea pig and human vagus while glycopyrrolate (another long acting antimuscarinic antagonist) did not (Bonvini SJ et at,, American Journal of Respiratory and Critical Care Medicine 2013, 187: Meeting Abstracts, A4932)

There is a need for effective and safe therapies for cough, in particular for acute, subacute, and chronic cough.

It has now surprisingly been found that aclidinium has significant efficacy in the treatment of cough. Aclidinium has the chemical name 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3- phenoxypropyl)-1 -azoniabicyclo[2.2.2] octane and was first disclosed in WO 01/041 18. It is a long-acting muscarinic receptor antagonist approved in 2012 by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the maintenance treatment to relieve respiratory symptoms in patients with COPD.

Pharmaceutical compositions comprising aclidinium are described in EP2100598A1 and in EP2100599A1.

Summary of the Invention

The present invention provides aclidinium or any of its steroisomers or mixture of stereoisomers, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cough. Preferably, aclidinium is in the form of a salt with an anion X^". Most preferably, the anion X^" is bromide.

Typically, the invention relates to aclidinium for use in the treatment of cough, wherein the cough is acute cough, subacute cough or chronic cough.

Preferably, the invention relates to aclidinium for use in the treatment of cough, wherein the cough is associated with upper respiratory tract infections (URTI), acute bacterial sinusitis, chronic bacterial sinusitis, pertussis, chronic obstructive pulmonary disease (COPD), non-allergic rhinitis, allergic rhinitis, rhinitis due to environmental irritants, asthma, gastroesophageal reflux disease, chronic bronchitis, bronchiectasis, eosinophilic bronchitis or the use of an angiotensin-converting-enzyme inhibitor. In a particular embodiment, the invention relates to aclidinium for use in the treatment of cough in smoker patients, in particular when these patients suffer from chronic obstructive pulmonary disease or asthma.

In a particular embodiment, the invention relates to aclidinium, preferably aclidinium bromide, for use in the treatment of cough, wherein the cough is associated with upper respiratory tract infections (such as the common cold), acute bacterial sinusitis, chronic bacterial sinusitis, pertussis, non-allergic rhinitis, allergic rhinitis, rhinitis due to environmental irritants, gastroesophageal reflux disease (GERD), bronchiectasis, eosinophilic bronchitis or the use of an angiotensin-converting-enzyme inhibitor.

In another particular embodiment, the invention relates to aclidinium, preferably aclidinium bromide, for use in the treatment of cough in patients suffering from chronic obstructive pulmonary disease (including chronic bronchitis and/or emphysema) or asthma; preferably when these patients are smokers.

In one embodiment, aclidinium is administered as a pharmaceutical composition suitable for inhalation, preferably in the form of a dry powder. The composition can be administered by means of any inhaler device, preferably via a dry powder inhaler, more preferably via a breath-activated, multi-dose, dry powder inhaler.

Typically, a dry powder formulation comprises a pharmaceutically acceptable carrier selected from mono-, di- or polysaccharides and sugar alcohols. Preferably, the carrier is lactose, more preferably lactose monohydrate, even more preferred alpha-lactose monohydrate.

In a particular embodiment, aclidinium is administered at least once a day, preferably in the morning or in the evening. More preferably aclidinium is administered twice daily, i.e. two oral inhalations per day. In a most preferred embodiment aclidinium is administered twice daily, one in the morning and another one in the evening. The effective dose of aclidinium to be used per inhalation is the equivalent to a metered nominal dose from 100 to 1000 micrograms of aclidinium bromide per inhalation in a dry powder for inhalation, more preferably 200 or 400 micrograms of aclidinium bromide per inhalation. In a most preferred embodiment the effective dose of aclidinium is the equivalent to a metered nominal dose of 400 micrograms of aclidinium bromide per inhalation.

In a particular embodiment, the effective dose of aclidinium to be used per inhalation is the equivalent to a metered nominal dose of 400 micrograms of aclidinium bromide per inhalation and/or a metered nominal dose of 343 micrograms of aclidinium per inhalation.

In another particular embodiment, the effective dose of aclidinium to be used per inhalation is the equivalent to a delivered dose (the dose leaving the mouthpiece of the inhaler device) of 375 micrograms of aclidinium bromide per inhalation and/or a delivered dose of 322 micrograms of aclidinium per inhalation. The delivered dose can be measured using standard techniques known to those skilled in the art.

In another particular embodiment, the effective dose of aclidinium to be used per inhalation is the equivalent to a fine particle dose (fine particle dose = μg

aclidinium/aclidinium bromide in the delivered dose below a cut off aerodynamic threshold of 5 micrometer) of 100-190 (preferably 1 10-180) micrograms of aclidinium bromide per inhalation and/or a fine particle dose of 86-163 (preferably 94-155) micrograms of aclidinium per inhalation. The fine particle dose can be measured using standard techniques known to those skilled in the art.

In another particular embodiment, aclidinium for use in the treatment of cough is coadministered with a therapeutically effective amount of one or more other therapeutic agents selected from cough suppressants (antitussives), antihistamines, expectorants, decongestants, analgesics, antipyretics, antibiotics, local anaesthetics, corticosteroids and bronchodilators.

The invention further provides a pharmaceutical composition comprising aclidinium and a therapeutically effective amount of one or more other therapeutic agents selected from cough suppressants (antitussives), antihistamines, expectorants, decongestants, analgesics, antipyretics, antibiotics, local anaesthetics, corticosteroids and

bronchodilators for use in the treatment of cough. The invention further provides the use of aclidinium, in the manufacture of a medicament for use in the treatment of cough.

The invention further provides a method for treating cough comprising administering to a patient in need thereof an effective amount of aclidinium, as defined above.

Detailed description of the invention

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. More typically, X is an anion derived from an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid, or an organic acid such as methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid or maleic acid. Most preferably aclidinium is in the form of aclidinium bromide.

Aclidinium bromide is a white powder with a molecular formula of C₂₆H₃oN0₄S₂Br and a molecular mass of 564.56. It is very slightly soluble in water and ethanol and sparingly soluble in methanol. The compound of the invention may exist in both unsolvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising a compound of the invention and an amount of one or more pharmaceutically acceptable solvent molecules. The term hydrate is employed when said solvent is water. Examples of solvate forms include, but are not limited to, compounds of the invention in association with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. It is specifically contemplated that in the present invention one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate. The words "treatment" and "treating" are to be understood as embracing amelioration of symptoms of a disease or condition and/or elimination or reduction of the cause of the disease or condition and/or prevention of the appearance of the disease or its symptoms. In this particular case, "treatment" of cough means reducing the frequency of cough events and/or reducing the severity of the cough events (relative to the non- treated conditions). This term refers to both treatment by prevention and

treatment/suppression of cough episodes.

The term "therapeutically effective amount" refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.

The term "patient" refers to a human (including adults and children) or other mammal. In a preferred embodiment, "patient" refers to a human. The term "smoker" refers to a human (in particular an adult) who smokes, i.e. who inhales the smoke of burning tobacco encase in cigarettes, pipes and cigars.

Aclidinium can be co-administered with a therapeutically effective amount of one or more other therapeutic agents (e.g. any other OTC drug or prescription medicine) selected from cough suppressants (antitussives), antihistamines, expectorants, decongestants, analgesics, antipyretics, antibiotics, local anaesthetics, corticosteroids and

bronchodilators.

In particular, aclidinium can be co-administered with a therapeutically effective amount of one or more other therapeutic agents (e.g. any other OTC drug or prescription medicine) selected from other cough suppressants (antitussives; e.g. dextromethorphan, codeine, dihydrocodeine, hydrocodone, clobutinol, chlophendianol, pentoxyverine, benzonatate), antihistamines (e.g. brompheniramine, chlorpheniramine, desloratidine,

dexbrompheniramine, diphenhydramine, promethazine, triprolidine, promethazine), expectorants (e.g. guaifenesin), decongestants (e.g. pseudoephedrine, phenylephrine), analgesics/antipyretics (e.g. acetaminophen, NSAIDs), antibiotics, local anaesthetics (e.g. proparacaine, procaine, tetracaine, hexylcaine, bupivacaine, lidocaine, benoxinate, mepivacaine, prilocaine, mexiletene, vadocaine, etidocaine), corticosteroids, or bronchodilators. Alternatively, the second therapeutic agent can be a substance obtained or extracted from a natural source (e.g. Echinacea, tea tree oil, turmeric, menthol) or any other substance alleged to promote recovery from respiratory infections or relieve their symptoms (e.g. zinc, vitamin C). The invention is also directed to a pharmaceutical composition comprising aclidinium and a therapeutically effective amount of one or more other therapeutic agents selected from cough suppressants (antitussives), antihistamines, expectorants, decongestants, analgesics, antipyretics, antibiotics, local anaesthetics, corticosteroids and

bronchodilators for use in the treatment of cough.

Alternatively, the second therapeutic agent can be a substance obtained or extracted from a natural source (e.g. Echinacea, tea tree oil, turmeric, menthol) or any other substance alleged to promote recovery from respiratory infections or relieve their symptoms (e.g. zinc, vitamin C). Aclidinium for use in the present invention may be administered by any suitable route to provide local antimuscarinic action. It is preferably administered by inhalation, e.g., as a powder, spray, or aerosol, preferably as a dry powder. Pharmaceutical compositions comprising aclidinium may be prepared using conventional diluents or excipients and techniques known in the galenic art.

Medicaments for administration in a dry powder for inhalation desirably have a controlled particle size. The optimum particle size for inhalation into the bronchial system is usually 1-10 μηι, preferably 2-5μηι. Particles having a size above 20 μηι are generally too large when inhaled to reach the small airways. To achieve these particle sizes the particles of the active ingredient as produced may be size reduced by conventional means, e.g. by micronisation or supercritical fluid techniques. The desired fraction may be separated out by air classification or sieving. Preferably, the particles will be crystalline.

Achieving high dose reproducibility with micronised powders is difficult because of their poor flowability and extreme agglomeration tendency. To improve the efficiency of dry powder compositions, the particles should be large while in the inhaler, but small when discharged into the respiratory tract. Thus, an excipient, for example a mono-, di- or polysaccharide or sugar alcohol, such as lactose, mannitol or glucose is generally employed. The particle size of the excipient will usually be much greater than the inhaled medicament within the present invention. When the excipient is lactose it will typically be present as lactose particles, preferably crystalline alpha lactose monohydrate, e.g. , having an average particle size range of 20-1000 μηι, preferably in the range of 90-150 μηι. In one embodiment, the lactose particles for use in formulations of the invention have a d10 in the range of 90 - 160 μηι, a d50 in the range of 170 - 270 μηι, and d90 in the range of 290 - 400 μΐτι.

Suitable lactose materials for use in the present invention are commercially available, e.g., from DFE Pharma (Respitose® ML001 , Respitose® ML006, Respitose® SV003, Respitose® SV010, Lactohale® 100, Lactohale® 200, Lactohale® 201 , Lactohale® 300) or Meggle (lnhalac® 70, lnhalac® 120, lnhalac® 230, lnhalac® 250, lnhalac® 400, PrismaLac® 40, Capsulac® 60, Capsulac® 60 INH, SacheLac® 80, SpheroLac® 100) or Sheffield Bio-Science (Monohydrate inhalation 120 M, Monohydrate inhalation 80 M, Monohydrate inhalation 40 M, Anhydrous inhalation 40 M, Monohydrate inhalation 120 MS, Anhydrous inhalation 120 MS).

The ratio between the lactose particles and aclidinium by weight will depend on the inhaler device used, but is typically, e.g. , 5: 1 to 200: 1 , preferably 25: 1 to 150: 1 , more preferably 30: 1 to 70: 1 , even more preferably 30: 1 to 35: 1.

In a preferred embodiment, the aclidinium is administered in the form of a dry powder formulation of aclidinium bromide in admixture with lactose, in a ratio by weight of aclidinium to lactose of 1 :50 to 1 : 150, suitable for administration via a dry powder inhaler, wherein the aclidinium particles have an average particle size of from 2 to 5 μηι in diameter, e.g., less than 3 μηι in diameter, and the lactose particles have have a d10 of 90 - 160 μηι, a d50 of 170 - 270 μηι, and d90 of 290 - 400 μνη.

In a particular preferred embodiment, the aclidinium is administered in the form of a dry powder formulation of aclidinium bromide in admixture with lactose, in a ratio by weight of aclidinium to lactose of 1 :25 to 1 : 150 (preferably 1 :25 to 1 :70, more preferably 30: 1 to 70:1 , even more preferably 30: 1 to 35: 1 ), suitable for administration via a dry powder inhaler, wherein the aclidinium particles have an average particle size of from 2 to 5 μηι in diameter, e.g., less than 3 μηι in diameter, and the lactose particles have have a d10 of 90 - 160 μηι, a d50 of 170 - 270 μηι, and d90 of 290 - 400 μηι.

The invention is also directed to a pharmaceutical composition comprising aclidinium for use in the treatment of cough, wherein the composition is the in the form of a dry powder formulation of aclidinium bromide in admixture with lactose, in a ratio by weight of aclidinium to lactose of 1 :25 to 1 :150 (preferably 1 :25 to 1 :70, more preferably 30: 1 to 70:1 , even more preferably 30:1 to 35:1 ), suitable for administration via a dry powder inhaler, wherein the aclidinium particles have an average particle size of from 2 to 5 μηι in diameter, e.g., less than 3 μηι in diameter, and the lactose particles have have a d10 of 90 - 160 μηι, a d50 of 170 - 270 μηι, and d90 of 290 - 400 μηι.

Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator. Each capsule or cartridge may generally contain between 0.001 -200 mg, more preferably 0.01-100 mg of active ingredient or the equivalent amount of a pharmaceutically acceptable salt thereof. Alternatively, the active ingredient (s) may be presented without excipients. Packaging of the formulation may be suitable for unit dose or multi-dose delivery. In the case of multi- dose delivery, the formulation can be pre-metered or metered in use. Dry powder inhalers are thus classified into three groups: (a) single dose, (b) multiple unit dose and (c) multi dose devices. In one embodiment, aclidinium can also be administered via single dose dry powder inhalers such as the devices described in WO 2005/1 13042 or in EP1270034. These devices are low resistance unit dosage form inhalers. The unit dosage form of the dry powder formulation are capsules typically made of gelatin or a synthetic polymer, preferably hydroxypropyl methyl cellulose (HPMC) , also known as hypromellose. The hypromellose capsules are preferably packaged in a blister. The blister is preferably a peel foil blister that allows patients to remove capsules stored therein without damaging them and optimizes product stability. In another embodiment, aclidinium is administered via a breath-activated, multi-dose, dry powder inhaler, which delivers up to 200 metered doses from a non-removable cartridge. An especially preferred inhaler device for this purpose is Genuair® (also marketed as Pressair®), (formerly known as Novolizer SD2FL), or as described in WO 97/00703, WO 03/000325 or WO 2006/008027 the contents of which applications are incorporated herein by reference. Genuair® is also described in H. Chrystyn et al. Int J Clin Pract, March 2012, 66, 3, 309-317 (first published online on 16 February 2012); and in H.

Magnussen et al. Respiratory Medicine (2009) 103, 1832-1837. Another breath- activated, multi-dose, dry powder inhaler suitable for the administration of aclidinium is Novolizer®, which is described in C. Fenton et al., Drugs 2003; 63 (22): 2437-2445; and D. Kohler, Respiratory Medicine (2004) Supplement A, S17-S21.

Aclidinium is preferably administered with the Genuair® (also marketed as Pressair®) device.

The following examples are given in order to provide a person skilled in the art with a sufficiently clear and complete explanation of the present invention, but should not be considered as limiting of the essential aspects of its subject, as set out in the preceding portions of this description.

EXAMPLES Example 1

In a Phase III randomized, double-dummy, placebo and active comparator-controlled, multicentre, patients with moderate to severe COPD were treated with aclidinium or placebo, and with tiotropium or placebo for 6 weeks. Patients were randomized to receive aclidinium bromide 400 μg (Eklira®; metered dose; equivalent to aclidinium 322 μg delivered dose; each metered dose contains 12.6 mg of lactose monohydrate) twice-daily (in the morning, 9 am ± 1 hour, and in the evening, 9 pm ± 1 hour) via the Genuair® multi-dose dry powder inhaler, tiotropium 18 μg

(Spiriva®) once daily in the morning via the HandiHaler®, or placebo for 6 weeks. Two Genuair® inhalers (pre-loaded with 1 month's supply [60 doses] of either aclidinium or matched placebo) and one HandiHaler (with 60 capsules of tiotropium or matched placebo) were supplied. Patients were instructed to use both inhalers each morning (9:00 ± 1 hour) and Genuair® only each evening (21 :00 ± 1 hour).

Results are displayed in Table 1.

Table 1. Change from baseline in percentage (%) of mornings with cough (Least

Squares Mean) in smoker patients

n=number of patients in the analysis

*p < 0.05 for aclidinium vs. placebo

As it can be observed in Table 1 , after 6 weeks of treatment, 400 micrograms of aclidinium bromide per inhalation twice-daily showed statistically significant reduction in the adjusted mean change from baseline compared to placebo in percentage of mornings with cough (p< 0.05 versus placebo). Although tiotropium also showed a numerical reduction in the percentage of mornings with cough vs placebo, the reduction was not statistically significant. In addition, the reduction in the percentage of mornings with cough for aclidinium is numerical lower than the reduction obtained with tiotropium.

These phase III results demonstrate a remarkable and statistically significant improvement in reducing the percentage (%) of mornings with cough in patients treated with aclidinium, while in the case of patients treated with tiotropium, the reference standard anticholinergic agent, the reduction was not statistically significant.

Claims

1. Aclidinium or any of its steroisomers or mixture of stereoisomers, or a

pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cough.

2. Aclidinium for use according to claim 1 , wherein aclidinium is in the form of aclidinium bromide.

3. Aclidinium for use according to claim 1 or 2, wherein the cough is acute cough, subacute cough or chronic cough.

4. Aclidinium for use according to any one of the preceding claims, wherein the cough is associated with upper respiratory tract infections (URTI), acute bacterial sinusitis, chronic bacterial sinusitis, pertussis, chronic obstructive pulmonary disease (COPD), non-allergic rhinitis, allergic rhinitis, rhinitis due to environmental irritants, asthma, gastroesophageal reflux disease, chronic bronchitis, bronchiectasis, eosinophilic bronchitis or the use of an angiotensin-converting-enzyme inhibitor.

5. Aclidinium for use according to any one of claims 1 to 3, wherein the cough is associated with upper respiratory tract infections (such as the common cold), acute bacterial sinusitis, chronic bacterial sinusitis, pertussis, non-allergic rhinitis, allergic rhinitis, rhinitis due to environmental irritants, gastroesophageal reflux disease (GERD), bronchiectasis, eosinophilic bronchitis or the use of an angiotensin-converting-enzyme inhibitor.

6. Aclidinium for use according to any one of claims 1 to 3, in patients suffering from chronic obstructive pulmonary disease (including chronic bronchitis and/or emphysema) or asthma; preferably when these patients are smokers.

7. Aclidinium for use according to any one of the preceding claims, wherein aclidinium is in the form of a dry powder formulation suitable for inhalation.

8. Aclidinium for use in a dry powder formulation according to claim 7, providing a metered nominal dose of aclidinium equivalent to from 100 to 1000 micrograms of aclidinium bromide per inhalation; preferably 200 or 400 micrograms of aclidinium bromide.

9. Aclidinium for use in a dry powder formulation according to claim 7, providing a metered nominal dose of aclidinium equivalent to 400 micrograms of aclidinium bromide per inhalation and/or a metered nominal dose of 343 micrograms of aclidinium per inhalation.

10. Aclidinium for use in a dry powder formulation according to claim 7, providing a delivered dose of aclidinium equivalent to 375 micrograms of aclidinium bromide per inhalation and/or a delivered dose of 322 micrograms of aclidinium per inhalation.

1 1 . Aclidinium for use according to any one of claims 7 to 10, wherein aclidinium is administered one or more times per day, preferably twice daily.

12. Aclidinium for use according to any preceding claim, wherein aclidinium is coadministered with a therapeutically effective amount of one or more other therapeutic agents selected from cough suppressants (antitussives), antihistamines, expectorants, decongestants, analgesics, antipyretics, antibiotics, local anaesthetics, corticosteroids and bronchodilators.

13. Pharmaceutical composition comprising aclidinium and a therapeutically effective amount of one or more other therapeutic agents selected from cough suppressants (antitussives), antihistamines, expectorants, decongestants, analgesics, antipyretics, antibiotics, local anaesthetics, corticosteroids and bronchodilators for use in the treatment of cough.

14. Use of aclidinium, as defined in any preceding claims, in the manufacture of a medicament for use in the treatment of cough.

15. A method for treating cough comprising administering to a patient in need thereof an effective amount of aclidinium, as defined in any preceding claim.