AU2013100009B4 - Treatment of chronic obstructive pulmonary disease - Google Patents

Abstract

C:NPorbl\DCC\DAR\484T87_ 1. DOC-4/0 1/20 L3 Treatment of chronic obstructive pulmonary disease A method of treating a subject affected by chronic obstructive pulmonary disease. The method comprising administering to the subject a unit dosage form of a dry powder formulation of glycopyrronium bromide.

Description

C NRPonblOCCDAR\4840087_ .DOC-4/l1/2013 TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE Field of the invention The invention relates to a method of treating a subject affected by chronic obstructive pulmonary disease that involves administering to the subject a unit dosage form of a dry powder formulation of glycopyrronium bromide. Background Glycopyrronium bromide is the international non-proprietary name INN) for the compound whose chemical name is 3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1 dimethylpyrrolidinium bromide. It has the following chemical structure:

ON

3 OH The United States Adopted Name (USAN) for glycopyrronium bromide is glycopyrrolate. Alternative chemical names include (i) pyrrolidinium, 3-[(cyclopentylhydroxyphenylacetyl) oxy]-1, 1 -dimethyl bromide, (ii) 3-hydroxy-1, 1 -dimethylpyrrolidinium bromide a-cyclopentyl mandelate, (iii) 1-methyl-3-pyrrolidyl a-cyclopentylmandelate methobromide, and (iv) 1 methyl-3-pyrrolidyl a-phenyl-a-cyclopentylglycolate methobromide. The molecular formula is C 19

H

2 aBrNO 3 . The molecular weight is 398.33. The Chemical Abstracts number is 596 51-0. Glycopyrronium bromide is an antimuscarinic agent that had been formulated as a liquid formulation and marketed as ROBINUL@ injection as(i) a preoperative antimuscarinic to reduce salivary, tracheobronchial and pharyngeal secretions, and to reduce the acidity and volume of the gastric contents, (ii) a preoperative or intra-operative antimuscarinic to attenuate or prevent intraoperative bradycardia associated with the use of suxamethonium or due to cardiac vagal reflexes, and (iii) to protect against the peripheral muscarinic C:NRPortbWDCC\ARR4840087_I DOC-4OIU2013 -2 actions (e.g. bradycardia and excessive secretions) of anticholinesterases such as neostigmine or pyridostigmine given to reverse neuromuscular blockade produced by non depolarising muscle relaxants. ROBINUL® injection is supplied as a clear, colourless sterile solution that is contained in an ampoule. Typically a doctor injects the contents of the ampoule into the vein or muscle of the patient receiving the treatment. United States patent US 2956062(A H Robins) discloses glycopyrrolate and a process for its preparation. Schroeckenstein et al, J. Allergy Clin.lmmunol., 1988; 82(1): 115-119,discloses the use of glycopyrrolate in an aerosol formulation for treating asthma. A single administration of the metered-dose glycopyrrolate aerosol achieved bronchodilation over a 12 hour period. Leckie et al., Exp. Opin. Invest. Drugs, 2000; 9(1): 3-23, is a review of therapies for chronic obstructive pulmonary disease (COPD). Glycopyrrolate is mentioned as a possible drug treatment. However, there is no reference to its level of activity or to the duration at which it exerts its therapeutic effect. Skorodin, Arch Intern. Med, 1993; 153: 814-828, discloses the use of glycopyrrolate in an aerosol formulation for the treatment of asthma and COPD. It states, in general, that quaternary ammonium anticholinergic compounds have a duration of action of 4 to 12 hours. A dose of between 0.2 to 1.0 mg of glycopyrrolate is recommended at 6 to 12 hour intervals. International patent application WO 2001-76575 (Arakis) discloses a pharmaceutical composition for pulmonary delivery that comprises glycopyrrolate in a controlled release formulation that is suitable for treating respiratory diseases, including COPD. International patent application WO 2005-105043 (Vectura) discloses dry powder pharmaceutical compositions that comprise glycopyrronium salts, for example glycopyrrolate. The compositions exhibit improved stability over time. International patent application WO 2005-113042 (Novartis) discloses an inhaler device that is suitable for delivering powdered medicaments. The device is known as the C:\NRPonbl\DCC\DARW4840087_.DOC-4/0Oj 13 -3 BREEZHALER® inhalation device. International patent application WO 2010-115937 (Novartis) discloses a process for preparing pyrrolidinium salts, including glycopyrronium bromide. Statement of the invention The present invention provides a method of treating a subject affected by chronic obstructive pulmonary disease, said method comprising administering to the subject a unit dosage form of a dry powder formulation, said unit dosage form comprising a capsule that contains: (a) 0.01 to 0.5 mg glycopyrronium bromide; (b) 0.01 to 0.1 mg magnesium stearate; and (c) 20 to 30 mg lactose. In a preferred embodiment of the present invention the unit dosage form comprises a capsule that contains: (a) 0.05 to 0.08 mg glycopyrronium bromide; (b) 0.02 to 0.05 mg magnesium stearate; and (c) 24.5 to 25.5 mg lactose monohydrate. In an especially preferred embodiment of the present invention the unit dosage form comprises a capsule that contains: (a) 0.063 mg glycopyrronium bromide; (b) 0.04 mg magnesium stearate; and (c) 24.9 mg lactose monohydrate. Preferably the glycopyrronium bromide and the magnesium stearate are present as a co micronised mixture. Preferably the unit dosage form is administered to the subject once a day. Preferably the capsule is composed of hypromellose.

C:\NRParbl\CCDAR\440087_L.DOC-4/01/2013 -4 The term "dosage form" as used herein means the form of physical state in which a therapeutically active ingredient is dispensed for use. For example, a dry powder formulation. The term "unit dosage form" as used herein means the form in which the desired dosage of a therapeutically active ingredient is intended to be administered as a single dose. For example, a capsule that contains the desired dosage of a therapeutically active ingredient. The term "chronic obstructive pulmonary disease" or "COPD" as used herein is a common preventable and treatable disease that is characterised by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles of gases, most commonly tobacco smoke. COPD includes chronic bronchitis and emphysema. Characteristic symptoms of the disease include dyspnea, chronic cough and chronic sputum production. Throughout this specification and in the claims that follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. Detailed description of the invention The present invention relates to a method of treating a subject affected by chronic obstructive pulmonary disease that involves administering to the subject by inhalation a unit dosage form of a dry powder formulation of glycopyrronium bromide. The unit dosage form comprises a capsule that contains glycopyrronium bromide, magnesium stearate and lactose. Chronic obstructive pulmonary disease (COPD) has a significant impact on society causing considerable morbidity and mortality. The Australian Lung Foundation estimates about 2.1 million Australians have some form of COPD. This represents about one in five Australians aged 40 or over. It has been estimated that 1.2 million Australians have at least Stage 11 COPD, at which point breathlessness may be affecting their daily lives.

CANIUortbhDCC\DARM44007_l.DDC-410aI03 -5 Many of those will not know they have COPD and are therefore not taking steps to manage their disease. Some mistakenly assume their breathlessness is solely a symptom of ageing, lack of fitness or asthma. Some recognise their breathlessness is a result of cigarette smoking but do not seek medical advice as they do not want to be confronted with being advised to stop smoking. COPD is the second most common cause of avoidable hospital admissions in Australia. It is the fourthmost common cause of death in Australia and has been predicted to be the third by 2020. The Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) recommends the use of long-acting bronchodilators as first-line maintenance therapy for patients with moderate to severe COPD, however there are limited therapeutic options to improve lung function, reduce symptoms and control exacerbations with a convenient once daily dosing regimen. Novartis has collaborated with Sosei Co. Limited of Japan and Vectura Group plc. to develop an inhalable dry powder of glycopyrronium bromide that is administered by a low resistance single dose dry powder inhaler called the BREEZHALER® device as a long term once-daily maintenance bronchodilator treatment in patients who have COPD. Studies show glycopyrronium bromide has a fast onset of action, it provides sustained 24 hour bronchodilation, it improves exercise tolerance and it reduces the rate of exacerbations. The fast of action means patients fell better shortly after taking their medicine. It also reinforces trust and encourages compliance. Sustained 24-hour bronchodilation means the patients can take their medicine once-a-day to manage their disease for the next 24 hours. It is much more convenient for patients than taking bronchodilators with a shorter duration of action that need to be taken twice, three or even four times each day. Improving convenience is understood to encourage patients to comply with their treatment instructions. Improving exercise tolerance means patients can do more for longer. Reducing the rate of exacerbations means patients less frequently experience an increase in severity of their disease or any of its symptoms, which includes episodes that might require the patient to receive treatment in a hospital i.e. patients manage their disease better. The clinical benefits of once-daily glycopyrronium bromide are described in more detail by Charlotte Suppli Ulrik in International Journal of COPD, CANRIonbDCC\DAR\4!400871.DOC-W 1,2013 -6 2012, Volume 7, pages 2012 673-678, the contents of which is incorporated herein by reference. The unit dosage form of a dry powder formulation of the method of the present invention contains 0.01 to 0.5 mg glycopyrronium bromide, preferably 0.05 to 0.08 mg glycopyrronium bromide, more preferably 0.06 to 0.07 mg glycopyrronium bromide, but especially about 0.063 mg glycopyrronium bromide, more especially 0.0625 mg glycopyrronium bromide. Glycopyrronium bromidehas two stereogenic centres and hence exists in four isomeric forms or enantiomers/stereoisomers/diastereomers, namely (3R,2'R)-, (3S,2'R)-, (3R,2'S) and (3S,2'S)-3-[(cyclopentyl-hydroxyphenylacetyl)-oxy]-1,1-dimethylpyrrolidinium bromide. In a preferred embodiment, glycopyrronium bromide is present as a racemic mixture of (3S,2'R)- and (3R,2'S)-3-[(cyclopentyl-hydroxyphenylacetyl)-oxy]-1, 1 dimethylpyrrolidinium bromide. Such a racemic mixture can be prepared by the process disclosed in United States patent US 2,956,062 however it is preferably prepared by the process disclosed in Australian patent application AU 2010233772 (derived from the Applicant's international patent application WO 2011/145051), the contents of which is incorporated herein by reference. In other preferred embodiments glycopyrronium bromide is present as a substantially pure single enantiomer of glycopyrronium bromide. Such single enantiomers glycopyrronium bromide can be prepared by the processes disclosed in United States patent US 6307060, the contents of which is incorporated herein by reference. (DH O , 60 rBr [S, R]-diastereomer [R, S]-diastereomer C:\NRortbflDCC\DAR\484087_L.DOC-4O/U203 -7 0 \,Br 0 Br [R, RJ- diastereomer [S, S- diastereorner The unit dosage form of a dry powder formulation of the method of the present invention contains 0.01 to 0.1 mg magnesium stearate, preferably 0.02 to 0.05 mg magnesium stearate, more preferably 0.03 to 0.04 mg magnesium stearate, but especially about 0.04mg magnesium stearate, more especially 0.0375 mg magnesium stearate. Magnesium stearate is a force control agent/lubricant whose presence leads to a general improvement in the inhalable fine particle fraction in dry powder glycopyrronium bromide formulations. It stabilizes the drug substance by suppressing or slowing down undesirable agglomeration and aggregation. It also enhances the dosing efficiency of inhalable dry powder glycopyrronium bromide formulations by improving powder flowability. In preferred embodiments the crystalline glycopyrronium bromide is co-micronised with magnesium stearate as this has been found to reduce the tendency for the micronised glycopyrronium bromide to agglomerate. This minimises dosing and delivery problems downstream. It also enhances the physical stability of the micronised glycopyrronium bromide. Lactose is admixed to give a dry powder formulation of glycopyrronium bromide. Such a process is described in international patent application WO 2008-000482, the contents of which is incorporated herein by reference. The unit dosage form of a dry powder formulation of the method of the present invention contains 20 to 30 mg lactose (e.g. lactose monohydrate or anhydrous lactose, preferably lactose monohydrate), preferably 24.5 to 25.5 mg lactose (e.g. lactose monohydrate or anhydrous lactose, preferably lactose monohydrate), more preferably 24.8 to 25.0 mg lactose (e.g. lactose monohydrate or anhydrous lactose, preferably lactose monohydrate), but especially about 25 mg lactose (e.g. lactose monohydrate or anhydrous lactose, preferably lactose monohydrate), more especially 24.9 mg lactose (e.g. lactose C:WRPorib1DCCAR\484DD711OC-4/0 2013 -8 monohydrate or anhydrous lactose, preferably lactose monohydrate). Lactose is a natural disaccharide, obtainable from milk, which consists of one glucose and one galactose moiety. It is often used as a carrier for inhalable dry powder formulations, typically in the form of lactose monohydrate or anhydrous lactose. The lactose is preferably lactose monohydrate, especially crystalline lactose monohydrate. The unit dosage form of a dry powder formulation of the method of the present invention is a capsule that contains the aforementioned glycopyrronium bromide, magnesium stearate and lactose. Capsules for containing inhalable dry powder formulations can be made of a variety of materials, typically including gelatin or a synthetic polymer. The capsule of the unit dosage form of the method of the present invention is preferably hydroxypropyl methylcellulose (HPMC), also known as hypromellose. Hypromellose capsules have a lower intrinsic moisture content than gelatin capsules. Varying moisture content in hypromellose capsules has much less effect on the stability and brittleness of the capsule shell than with gelatin capsules. The dry powder formulation is moisture sensitive so hypromellose capsules help to maintain the physical stability of the active ingredient. For reasons provided below, the capsule is preferably substantially transparent. 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 optimises product stability. In preferred embodiments the peel foil is alu-alu blister material. The capsule of the unit dosage form of the method of the present invention is intended to be used in conjunction with a dry powder inhalation device. The device is preferably a low resistance device that is easy for patients to use. Preferred devices include single dose dry powder inhalers. A preferred such device is the BREEZHALERDsingle dose dry powder inhaler that is described in Australian patent AU 2005245095, which was derived from international patent application W02005/113042. Another preferred device is the AEROLIZERDsingle dose dry powder inhaler that is described in European patent EP 1270034 B1. In both devices the capsule is loaded into a capsule chamber, the patient depresses a pair of push-buttons that cause sharpened and spring-urged pins to pierce the capsule with minimal resistance. When the patient releases pressure on the push buttons, the pins retract, leaving apertures in the ends of the capsule through which the C:\RPortbnDCCOAR\440087_1.DOC-4/01/2013 -9 dry powder formulation of glycopyrronium bromide is capable of being removed. The patient inserts the mouthpiece of the inhaler in his mouth, seals his lips (and perhaps teeth) around the mouthpiece and inhales quickly and deeply. This action draws surrounding air into the inhaler, through air inlets provided. Air passages are positioned substantially tangentially with respect to the capsule chamber so that the rush or air forms a vortex within the device. That vortex draws the dry powder out of the capsule, through the mouthpiece and into the patient's lungs. A perforated plate located at the base of the mouthpiece prevents the capsule from leaving the device (and being swallowed by the patient). The patient can open the inhaler to remove the spent capsule. The inhaler is then ready to be reloaded with a fresh capsule, when needed. A useful feature of the BREEZHALER@ and AEROLIZER® devices is the capsules can be heard as they spin inside the devices. This provides the patient with an auditory cue that the dry powder formulation is being inhaled. This is important as some patients have been known when using other inhalation devices to take additional doses if they are not sure they have inhaled their medicine. As mentioned above the capsule is preferably substantially transparent. This provides the patient with a visual cue that the dry powder formulation has been being inhaled. In its simplest form, a system or a kit for treating a subject affected by chronic obstructive pulmonary disease comprises an inhalation device and a unit dosage form of a dry powder formulation of glycopyrronium bromide. In preferred embodiments the system or kit comprises a plurality of unit dosage forms, packaged in one or more blisters, and an inhalation device. The kit is preferably packaged in a carton. An especially preferred such system or kit comprises (a) either five blisters that each store six unit dosage forms, or three blisters that each store ten unit dosage forms of the dry powder formulation of glycopyrronium bromide, and (b) a BREEZHALER® inhalation device. The kit is preferably packaged in a carton that is provided to the patient to provide a month's supply of medicine.

C:\NRPortbADCCMAR\4840087_ DOC-4/0112013 - 10 In further aspects the invention provides: 1. A method of treating a subject affected by chronic obstructive pulmonary disease, said method comprising administering to the subject a unit dosage form of a dry powder formulation, said unit dosage form comprising a capsule that contains: (a) glycopyrronium bromide; (b) magnesium stearate; and (c) lactose. 2. A method as defined in point 1, wherein the unit dosage form comprises a capsule that contains: (a) 0.01 to 0.5 mg glycopyrronium bromide; (b) 0.01 to 0.1 mg magnesium stearate; and (c) 20 to 30 mg lactose. 3. A method as defined in point 1, wherein the unit dosage form comprises a capsule that contains: (a) 0.05 to 0.08 mg glycopyrronium bromide; (b) 0.02 to 0.05 mg magnesium stearate; and (c) 24.5 to 25.5 mg lactose. 4. A method as defined in point 1, wherein the unit dosage form comprises a capsule that contains: (a) 0.06 to 0.07 mg glycopyrronium bromide; (b) 0.03 to 0.04 mg magnesium stearate; and (c) 24.8 to 25.0 mg lactose. 5. A method as defined in point 1, wherein the unit dosage form comprises a capsule that contains: (a) 0.063 mg glycopyrronium bromide; (b) 0.04mg magnesium stearate; and (c) 24.9 mg lactose.

CRPrIbMl\CC\DAR484008 7_.DOC-/I/20W13 - 11 6. A method as defined in any one of points 1 to 5, wherein the lactose is lactose monohydrate. 7. A method as defined in any one of points 1 to 5, wherein the lactose is anhydrous lactose. 8. A method as defined in any one of the preceding points, wherein the glycopyrronium bromide and the magnesium stearate are present as a co-micronised mixture. 9. A method as defined in any one of the preceding points, wherein the glycopyrronium bromide and the magnesium stearate are present as a co-micronised mixture admixed with the lactose. 10. A method as defined in any one of the preceding points, wherein the capsule is composed of hypromellose. 11. A method as defined in any one of the preceding points, wherein the unit dosage form is administered to the subject once-a-day. 12. A method as defined in any one of points 1 to 10, wherein the unit dosage form is administered to the subject twice-a-day.

C:\NRPortblCCMAR\4840D87_.LDOC-4/1ZO 13 - 12 The invention will now be described with reference to the following specific embodiments: Example 1 Unit dosage form of a dry powder formulation of glycopyrronium bromide Glycopyrronium bromide was prepared using the process described in Australian patent application AU 2010233772. This drug substance comprised a 1:1 racemic mixture of (3S,2'R)- and (3R,2'S)-3-[(cyclopentyl-hydroxyphenylacetyl)-oxy]-1,1 dimethylpyrrolidinium bromide. A dry powder formulation of glycopyrronium bromide was prepared using the process described in international patent application WO 2008-000482. This involved co micronising the glycopyrronium bromide with magnesium stearate and admixing lactose monohydrate. Hydroxypropyl methylcellulose (HPMC) capsules, Size 3, supplied by Qualicaps Inc, were filled with the dry powder formulation to give a unit dosage form of the dry powder formulation of glycopyrronium bromide. Each capsule contained: (a) 0.0625 mg glycopyrronium bromide; (b) 0.0375 mg magnesium stearate. (c) 24.900 mg lactose monohydrate; and This gave each capsule a total capsule fill weight of approximately 25 mg. The glycopyrronium bromide content corresponds to 0.05 mg (50 pg) of glycopyrronium (i.e. this excludes the bromide counterion) per capsule. The mass of each HMPC capsule shell was approximately 49.0 mg, which gave a total mass for the capsule of 74.0 mg.

C:\Nortb\DCC\DAR\484D087_ILDDC-4/01/2013 - 13 Example 2 System for delivering glycopyrronium bromide by pulmonary inhalation A system for delivering glycopyrronium bromide by pulmonary inhalation was prepared by providing a carton that contains a BREEZHALER@ inhalation device together with five peel foil blisters that each contains six unit dosage forms of Example 1. The BREEZHALER® inhalation device is a single use dry powder inhalation device that is described in Australian patent AU 2005245095. The device is available in Australia as the inhalation device for ONBREZ@ BREEZHALER@ indacaterol maleate capsules. The peel foil of the blisters is alu-alu blister material. Five blister packs and the BREEZHALER@ inhalation device comprise a kit that was provided for a month's supply of medicine. The kit was packaged in a carton. In use, the BREEZHALER® inhalation device delivered a dose of approximately 44 pg of glycopyrronium to the patient by pulmonary inhalation, from a measured dose of approximately 50 pg glycopyrronium. In an alternative system, a carton contained a BREEZHALER® inhalation device together with three peel foil blisters that each contains ten unit dosage forms of Example 1.

C:\NRPoLbl\CC\DAR\4g40087_1.DOC-4/Oi/2013 -14 Example 3 Clinical performance of the dry powder formulation of glycopyrronium bromide A pooled analysis of two studies (GLOW1 and GLOW2) assessed the efficacy of unit dosage forms of a dry powder formulation of glycopyrronium bromide of Example 1 v placebo and open-label tiotropium bromide when administered once-daily using the BREEZHALER® inhalation device. Tiotropium bromide is a long-acting muscarinic antagonist. It is the active ingredient of SPIRIVA® HANDIHALER® tiotropium bromide inhalation powder that is marketed by Boehringer Ingelheim and Pfizer to treat patients who have COPD. In the studies the efficacy of glycopyrronium (GLY) 50pg QD vs placebo (PBO) and open label tiotropium 18 pg QD (TIO) was assessed over 26 to 52 weeks in patients who have COPO. The assessments were made with respect to exacerbations, symptoms (as determined by the transition dyspnea index (TDI)) and health status (as determined by St George's Respiratory Questionnaire (SGRQ)). 1854 patients were analysed (GLY =1059, TIO=267, PBO=528). GLY statistically significantly prolonged the time to first moderate/severe exacerbation vs PBO (Wk 26: hazard ratio [HR] 0.64; Wk 52: HR 0.67, both p<0.001), which was comparable to TIO (Wk 26: HR 0.70, p=0.026; Wk 52: HR 0.61, both p<0.001). GLY had a statistically significantly lower rate of moderate/severe exacerbations vs PBO (Wk 26: rate ratio [RR] 0.66; Wk 52: RR 0.66; both p<0.005), while TIO was not significantly different from PBO (Wk 26; RR 0.74, p=O.085 and Wk 52: RR 0.80, p=0.179). Treatment difference in TDI total score was significant for GLY (Wk 26: 0.93 and Wk 52: 0.57) and TIC (Wk 26: 1.05 and Wk 52: 0.66) vs PBO, all p<0.05. SGRQ score (LS Mean [SE]) was significant for GLY (Wk 26; -3.07 [0.683] and Wk 52; -3.32 [1.004]; p<0.001) and TIO (Wk 26; -2.43 [1.014] and Wk 52; -2.84 [1.155]; p<0.05) vs PBO. These results showed that GLY once daily significantly reduced COPD exacerbations and improved symptoms vs PBO over 52 wks. Overall, the effects of GLY were similar to tiotropium.

C:UNPortbIWCCDAR\4840087_I.DOC-4OL/2013 - 15 These and other clinical benefits of once-daily glycopyrronium bromide are described in more detail by Charlotte Suppli Ulrik in International Journal of COPD, 2012, Volume 7, pages 2012 673-678.

Claims (5)

1. A method of treating a subject affected by chronic obstructive pulmonary disease, said method comprising administering to the subject a unit dosage form of a dry powder formulation, said unit dosage form comprising a capsule that contains: (a) 0.05 to 0.08 mg glycopyrronium bromide; (b) 0.02 to 0.05 mg magnesium stearate; and (c) 24.5 to 25.5 mg lactose monohydrate.

2. A method according to claim 1, wherein the unit dosage form comprises a capsule that contains: (a) 0.06 to 0.07 mg glycopyrronium bromide; (b) 0.03 to 0.04 mg magnesium stearate; and (c) 24.8 to 25.0 mg lactose monohydrate.

3. A method according to claim 2, wherein the unit dosage form comprises a capsule that contains: (a) 0.063 mg glycopyrronium bromide; (b) 0.04mg magnesium stearate; and (c) 24.9 mg lactose monohydrate.

4. A method according to any one of claims 1 to 3, wherein the glycopyrronium bromide and the magnesium stearate are present as a co-micronised mixture.

5. A method according to any one of claims 1 to 4, wherein the unit dosage form is administered to the subject once a day.