WO2020240350A1

WO2020240350A1 - An inhalable fixed dose powder composition comprising glycopyrronium, formoterol and fluticasone propionate

Info

Publication number: WO2020240350A1
Application number: PCT/IB2020/054774
Authority: WO
Inventors: Sunil Chaudhari; Ganesh JADHAV; Girish TRIVEDI; Monika TANDON; Rahul KODGULE; Sushrut Kulkarni
Original assignee: Glenmark Pharmaceutical Limited
Priority date: 2019-05-24
Filing date: 2020-05-20
Publication date: 2020-12-03
Also published as: ZA202108150B; MX2021014343A; CO2021017397A2

Abstract

The present invention relates to an inhalable fixed dose dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and fluticasone, or a pharmaceutically acceptable salt or ester thereof, such as fluticasone propionate. Preferably, the present invention relates to an inhalable dry powder composition comprising an effective amounts of glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt, fluticasone propionate and lactose. The present invention also relates to a process of preparing such compositions and to their use in the treatment of respiratory diseases in a subject in need thereof by inhalation administration of such dry powder compositions.

Description

AN INHALABLE FIXED DOSE POWDER COMPOSITION COMPRISING GLYCOPYRRONIUM, FORMOTEROL AND FLUTICASONE PROPIONATE

PRIORITY DOCUMENTS

This patent application claims priority to Indian Provisional Patent Application Nos. 201921020572 (filed on May 24, 2019), 201921023615 (filed on June 14, 2019), and 201921029676 (filed on July 23, 2019), the contents of each of which are incorporated by reference herein.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to an inhalable fixed dose dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and fluticasone propionate. In a preferred embodiment, the inhalable dry powder composition comprises glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt, fluticasone propionate and lactose. The present invention also relates to a process of preparing such compositions and to their use in the treatment of respiratory diseases in a subject in need thereof by inhalation administration of such dry powder compositions.

BACKGROUND OF THE INVENTION

Respiratory disorders related to airway inflammation include a number of lung diseases such as chronic obstructive pulmonary disease (COPD) and asthma.

Asthma is a disease characterized by an increased responsiveness of the trachea and bronchi to various stimuli, and manifested by widespread narrowing of the airways that changes in severity either spontaneously or as a result of treatment. The events leading to airway obstruction in asthma include edema of airway walls, infiltration of inflammatory cells into the lung, production of various inflammatory mediators and increased mucous production.

Current therapies for the treatment of asthma include bronchodilator drugs, corticosteroids and leukotriene antagonists. Bronchodilator drugs dilate the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lungs. Corticosteroids are effective at reducing asthma symptoms by blocking the body's inflammatory response. The leukotriene antagonists have limited efficacy, with only a small increase in pulmonary function demonstrated in clinical trials.

COPD is a term used to classify two major airflow obstruction disorders: chronic bronchitis and emphysema. Chronic bronchitis is an inflammation of the bronchial airways. Emphysema is an inflammation of the alveoli, or air sacs in the lungs. Emphysema has a number of causes, including smoking, exposure to environmental pollutants, alpha-one antitrypsin deficiency, and aging. COPD is a disease of the respiratory apparatus, characterized by an irreversible obstruction of the airways, of a degree that varies according to its severity.

Glycopyrronium is a long acting muscarinic antagonist (LAMA). Its chemical name is 3- (2-cyclopentyl-2-hydroxy-2-phenylacetoxy)- 1 , 1 -dimethylpyrrolidinium. It has the following structure:

(Glycopyrronium)

Glycopyrronium bromide (also known as Glycopyrrolate) is currently approved in Europe as dry powder inhaler Seebri Breezhaler^® (Novartis) which is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. Seebri Breezhaler is presented as an inhalation powder in hard capsules. Each capsule contains 63 meg of glycopyrronium bromide, equivalent to 50 meg of glycopyrronium. The FDA approved Seebri™ Neohaler^® (glycopyrrolate) inhalation powder 15.6 meg as a stand-alone monotherapy for maintenace treatment of COPD. Seebri™ Neohaler and Seebri Breezhaler^® contain lactose and magnesium stearate as inactive ingredients. Glypyrrolate is available in combination with indacaterol maleate under the brand name Utibron Neohaler^® as a powder for inhalation for the long-term, maintenance treatment of airflow obstruction in patients with COPD.

Formoterol (N-[2-hydroxy-5-[ l-hydroxy-2-[ l-(4-methoxyphenyl) propan-2-ylamino] ethyljphenyljformamide) is a long-acting Pi-agonist (LABA). Formoterol fumarate is sold as Foradil^®, which is indicated for maintenance treatment of asthma. Foromoterol fumarate is sold as Perforomist inhalation solution which is indicated for maintenance treatment of bronchoconstriction in patients with COPD.

(Formoterol)

It is commercially available in U.S. as a metered dose inhaler marketed as Symbicort^® and Dulera^® in combination with budesonide and mometasone respectively. It is also commercially available in U.S. as a nebuliser and as a dry powder inhaler.

Fluticasone propionate is an inhaled corticosteroid (ICS) used to treat asthma and allergic rhinitis. The chemical name for fluticasone propionate is S-(fhroromethyl)-6a,9-difluoro-l 1 b, 17-dihydroxy- 16a-methyl-3-oxoandrosta- 1 ,4-diene- 17P-carbothioate, 17-propanoate. It has the following structure.

(Fluticasone propionate)

GlaxoSmithKline currently markets fluticasone propionate inhalation powder as FLOVENT^® Diskus (USA) for maintenance treatment of asthma. FLONASE^® (USA), an aqueous suspension of fluticasone propionate, is used for the temporary relief of symptoms of hay fever or other upper respiratory allergies. GlaxoSmithKline also currently markets ADVAIR^® DISKUS (a combination of fluticasone propionate and salmeterol xinafoate). Fluticasone propionate is also available in combination with formoterol fumarate as a metered dose inhalation suspension (FLUTIFORM^® in EU) for the treatment of asthma and as a dry powder inhalation capsule (AVESSA, MAXIFLO in India) for the treatment of asthma and COPD.

International Publication No. WO 01/76575 describes a pharmaceutical composition for pulmonary delivery comprising glycopyrrolate in a controlled release formulation. International Publication No. WO 2005/107873 relates to the use of glycopyrronium in the treatment of childhood asthma.

International Publication No. WO 2005/105043 relates to a dry powder composition comprising glycopyrronium, and methods for producing the same.

International Publication Nos. WO 2011/076841 and WO 2011/076843 discloses aerosol solution formulations comprising glycopyrronium as chloride and bromide salt respectively and formoterol or a salt thereof dissolved in a mixture of HFA propellant and a co-solvent.

International Publication No. WO 2010/138868 relates to a pharmaceutical composition comprising a suspension medium including a propellant, a long-acting muscarinic antagonist, a long-acting beta-2 adrenergic receptor agonistand respirable suspending particles to form co suspension.

International Publication No. WO 2005/110402 relates to a combination of glycopyrrolate and beta-2 adrenoceptor agonists for the treatment of inflammatory or obstructive airways diseases.

European Publication No. EP 2749280-A2 relates to a pharmaceutical composition for inhalation comprising glycopyrronium in combination with a beta2-agonist, such as formoterol, and optionally one or more inhaled corticosteroids.

A study published by Reisner {Am. J. Respir. Crit. Care Med., 2011, 183:A6453) involved treatment with a combination of glycopyrrolate and formoterol fumarate delivered via a metered dose inhaler (MDI) in the treatment of COPD in patients.

International Publication No. WO 2016/071862 describes an inhalable powder composition comprising glycopyrronium and its salts and lactose.

International Publication No. WO 2017/077488 describes an inhalable powder composition comprising glycopyrronium or its pharmaceutically acceptable salt formoterol or its pharmaceutically acceptable salt, and lactose.

There is a need for improved treatments for respiratory diseases such as asthma and

COPD.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to an inhalable fixed dose dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and fluticasone propionate, and optionally a pharmaceutically acceptable carrier. In one embodiment, the weight ratio of (a) glycopyrronium or its salt, (b) formoterol or its salt, and (c) fluticasone propionate ranges from 0.8-2.5: 1: 15-25.

In an embodiment, the inhalable fixed dose dry powder composition further comprises a pharmaceutically acceptable carrier selected from lactose, mannitol, trehalose, sucrose, and any mixture thereof. The composition may be free of hydrophobic excipients and/or propellants. In one embodiment, the composition is free of both hydrophobic excipients and propellants.

In an embodiment, there is provided an inhalable fixed dose dry powder composition comprising glycopyrronium bromide, formoterol fumarate, fluticasone propionate and lactose.

In one preferred embodiment, the pharmaceutically acceptable carrier is lactose monohydrate.

In an embodiment of any of the compositions described herein, the pharmaceutically acceptable carrier is an admixture of lactose particles comprising: (i) about 0.1 to about 10% w/w of fine particles of lactose having a particle size D90 less than about 50 pm, such as less than about 30 pm or less than about 20 pm; and (ii) about 90 to about 99.9 % w/w of particles of coarse lactose having a particle size D90 more than about 80 pm, such as more than about 150 pm, or more than about 160 pm, such as between about 150 pm and about 200 pm, based upon 100% total weight of lactose particles. In one embodiment, the weight ratio of fine lactose particles to coarse lactose particles ranges from about 1: 100 to about 1:7, for example, from about 1: 100 to about 1: 10, from about 1 :50 to about 1 : 10, or from about 1 : 15 to about 1:40.

One embodiment is an inhalable fixed dose dry powder composition comprising glycopyrronium bromide, formoterol fumarate, fluticasone propionate, and an admixture of fine lactose (e.g., lactose monohydrate) and coarse lactose (e.g., lactose monohydrate), where

(i) the ratio of (a) glycopyrronium or its salt, (b) formoterol or its salt, and (c) fluticasone propionate ranges from 0.8-2.5: 1: 15-25,

(ii) the fine lactose has a D50 of from about 2pm to about 20 pm and/or a D90 from about 4 pm to about 50 pm,

(iii) the coarse lactose has a D50 of from about 80 pm to about 130 pm and/or a D90 from about 150 to about 200 pm,

(iv) the composition is free or substantially free of hydrophobic excipients and/or propellants, and (v) the composition (e.g., when incorporated into a sealed capsule comprised of hydroxypropyl methylcellulose), when tested for aerodynamic particle size distribution (APSD) (e.g., using an Andersen Cascade Impactor apparatus), results in a fine particle mass for (a) glycopyrronium bromide of from about 2 pg to about 6 pg (e.g., from about 2 to about 5 pg), (b) formoterol fumarate of from about 2 pg to about 6 pg (e.g., from about 2 to about 5 pg), and (c) fluticasone propionate of from about 45 pg to about 70 pg. In a preferred embodiment, the fine lactose has a D50 of from about 2 pm to about 10 pm (e.g., a D50 of from about 3 to about 7 pm) and/or a D90 of from about 5 pm to about 20 pm (e.g., a D90 of form about 7 to about 15 pm). In another preferred embodiment, the fine lactose has a D50 of not more than 5 pm and/or a D90 of not more than 10 pm. In yet another preferred embodiment, the coarse lactose has a D50 of from about 95 pm to about 125 pm and/or a D90 from about 160 pm to about 190 pm. In one embodiment, the weight ratio of fine lactose particles to coarse lactose particles ranges from about 1 : 100 to about 1:7, for example, from about 1: 100 to about 1: 10, from about 1:50 to about 1 : 10, or from about 1 : 15 to about 1 :40.

In one preferred embodiment, the composition, when tested for APSD (e.g., using an Andersen Cascade Impactor apparatus) after 3 months of storage at 30° C and 75% relative humidity (e.g., in a sealed capsule comprised of hydroxypropyl methylcellulose), results in a fine particle mass for (a) glycopyrronium bromide of from about 2 pg to about 5 pg, (b) formoterol fumarate of from about 2 pg to about 5 pg, and (c) fluticasone propionate of from about 45 pg to about 70 pg, such as from about 45 pg to about 60 pg.

In one preferred embodiment, the composition, when tested for APSD (e.g., using an Andersen Cascade Impactor apparatus) after 3 months of storage at 40° C and 75% relative humidity (e.g., in a sealed capsule comprised of hydroxypropyl methylcellulose), results in a fine particle mass for (a) glycopyrronium bromide of from about 2.5 pg to about 4.5 pg, (b) formoterol fumarate of from about 2.5 pg to about 4.5 pg, and (c) fluticasone propionate of from about 45pg to about 60 pg.

In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt, fluticasone propionate and lactose, wherein said composition is free from a hydrophobic excipient. In one embodiment, the composition is free of hydrophobic excipients. In an embodiment, the hydrophobic excipient is selected from metal stearates (such as, but not limited to magnesium stearate, calcium stearate and combinations thereof), amino acids, peptides, phospholipids, and any combination of any of the foregoing.

In another embodiment, there is provided an inhalable fixed dose dry powder composition consisting of an effective amount of glycopyrronium or its pharmaceutically acceptable salt, an effective amount of formoterol or its pharmaceutically acceptable salt, an effective amount of fluticasone propionate and lactose.

In another embodiment, there is provided a process for preparing an inhalable fixed dose dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and fluticasone propionate. In one embodiment, the process comprises:

(i) mixing glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and fluticasone propionate with fine lactose (e.g., lactose monohydrate), for example, (a) having a D90 particle size less than about 50 pm, and/or (b) a D50 of from about 2pm to about 20 pm and/or a D90 from about 4 pm to about 50 pm; and

(ii) blending the mixture of step (i) with coarse lactose (e.g., lactose monohydrate) having (a) a D90 particle size of more than about 150 pm, and/or (b) a D50 of from about 80 pm to about 130 pm and/or a D90 from about 150 to about 200 pm.

In another embodiment, there is provided a process for preparing an inhalable fixed dose dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and fluticasone propionate, wherein said process comprises:

(i) mixing glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and fluticasone propionate with fine lactose (e.g., lactose monohydrate), for example, (a) having a D90 particle size less than about 50 pm, preferably less than about 30 pm, more preferably less than about 20 pm, and/or (b) a D50 of from about 2 pm to about 20 pm and/or a D90 from about 4 pm to about 50 pm.

(ii) blending the mixture of step (i) with coarse lactose (e.g., lactose monohydrate) having (a) a D90 particle size of more than about 150 pm, preferably more than about 160 pm, and/or (b) a D50 of from about 80 mih to about 130 mih and/or a D90 from about 150 to about 200 mpi.

(ii) blending mixture of step (i) with coarse lactose (e.g., lactose monohydrate) having (a) a D90 particle size of about 150 pm to about 200 pm, and/or (b) a D50 of from about 80 pm to about 130 pm and/or a D90 from about 150 to about 200 pm.

(i) mixing glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and fluticasone propionate with particles of lactose having a D50 less than about 30 pm (e.g., a D50 of from about 2 pm to about 20 pm);

(ii) blending the mixture obtained in step (i) with lactose having a D50 of about more than about 80 pm (e.g., lactose having (a) a D90 particle size of more than about 150 pm, and/or (b) a D50 of from about 80 pm to about 130 pm and/or a D90 from about 150 to about 200 pm).

The weight ratio of fine lactose particles to coarse lactose particles may be the same as that described above.

In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising (a) glycopyrronium or its salt in an amount of about 5 meg to about 25 meg, (b) formoterol or its salt in an amount of about 5 meg to about 50 meg (c) fluticasone propionate in an amount of about 50 meg to about 500 meg and (d) lactose, wherein said composition is free from hydrophobic excipient. In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising (a) glycopyrronium or its salt in an amount of about 5 meg to about 50 meg, (b) formoterol or its salt in an amount of about 5 meg to about 50 meg (c) fluticasone propionate in an amount of about 50 meg to about 500 meg and (d) lactose (e.g., lactose monohydrate) (such as a mixture of fine lactose and coarse lactose as described above), wherein the composition is free from hydrophobic excipient.

In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising, per actuation, (a) glycopyrronium in an amount of about 12.5 meg, (b) formoterol fumarate dihydrate in an amount of about 12 meg (c) fluticasone propionate in an amount of about 250 meg and (d) lactose, wherein said composition is prepared by process which comprises:

(i) mixing glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and fluticasone propionate with fine lactose (as described above) (such as particles of lactose having a D90 particle size less than about about 50 pm);

(ii) blending mixture of step (i) with coarse lactose (as described above) (such as particles of lactose having a D90 particle size of more than about 150 pm); and

(iii) filling the final blend of step (ii) in capsule / blister or suitable pack.

In an embodiment of any of the compositions described herein, the composition has a fine particle mass having a particle size less than about 50 pm in the range of about 5% to about 30% and/or a coarse particle mass having a particle size more than about 80 pm is in the range of about 20% to about 90% w/w.

Preferably, any of the compositions described herein is filled in a capsule made up of gelatin or HPMC having a reduced moisture content less than 15% w/w or less than 10% w/w.

Alternately, any of the compositions described herein can be filled, either as discrete dosage units, in a blister or a sachet or in a reservoir for multiple use.

In another aspect, the present invention relates to a method of treating a respiratory disease (such as COPD or asthma) in a subject in need thereof, comprising inhalation administration of any of the compositions described herein, such as, for example, a pharmaceutical composition comprising an effective amount of glycopyrronium bromide, an effective amount of formoterol fumarate dihydrate, an effective amount of fluticasone propionate and optionally a pharmaceutical carrier, wherein said composition is free of hydrophobic excipients.

In an embodiment of any of the methods described herein, the respiratory disease is COPD and/or asthma.

In an embodiment of any of the methods described herein, the present dry powder inhalation composition is administered to a subject in need thereof by the inhalation route using a suitable dry powder inhaler.

In an further embodiment, the dry powder inhaler is selected from a single dose capsule device or a multiple dose inhaler device.

In a further embodiment, the present invention relates to the use of an inhalable fixed dose dry powder composition according to any of the embodiments described herein, such as, for example, a pharmaceutical composition comprising an effective amount of glycopyrronium bromide, an effective amount of formoterol fumarate dihydrate and an effective amount of fluticasone propionate for the treatment of a respiratory disease (e.g., COPD and/or asthma) in a subject in need thereof.

In an embodiment, for any of the methods described herein, the fixed dose combination of glycopyrronium bromide, formoterol fumarate dihydrate and fluticasone propionate provides a faster relief of symptoms associated with respiratory diseases in particular COPD, and provides better therapeutic value when compared to a dual combination therapy with formoterol fumarate and fluticasone propionate upon administration by inhalation.

Another embodiment is a method of improving lung function in a subject having a respiratory disease by inhalation administration of a composition according to any of the embodiments described herein, such as, for example, a pharmaceutical composition comprising comprising an effective amount of glycopyrronium bromide, an effective amount of formoterol fumarate dihydrate and an effective amount of fluticasone propionate.

In one embodiment of any of the methods described herein, such as a method of treating respiratory disease, the method includes inhalation administration of a composition comprising glycopyrronium or its salt, formoterol or its salt, and fluticasone propionate in a weight ratio ranging from about 1:0.1 : 10 to about 1:2:200, or from about 1:0.5: 100 to about 1: 1 :50. In one embodiment, the ratio of (a) glycopyrronium or its salt, (b) formoterol or its salt, and (c) fluticasone propionate ranges from 0.8-2.5: 1: 15-25. Any of the compositions described herein may comprise an effective amount of glycopyrronium or its salt, an effective amount of formoterol or its salt, and an effective amount of fluticasone propionate for administration by inhalation to a subject in need thereof at least once daily or at least twice daily.

Yet another embodiment is a method of improving forced vital capacity (FVC) and trough forced expiratory volume (FEV1) of lungs in a subject having a respiratory disease by inhalation administration of any of the compositons described herein, such as a dry powder composition comprising an effective amount of glycopyrronium or its salt, an effective amount of formoterol or its salt and an effective amount of fluticasone propionate.

A further embodiment is a method of improving FVC or FEV of lungs in a subject having a respiratory disease in the span of at least about 4 weeks, such as at least about 8 weeks or at least about 12 weeks, when measured using a spirometry, such as FEV1 or FVC.

In an embodiment, the subject suffering from respiratory disease experiences a clinically meaningful improvement in the FEV1 or FVC (Guidelines of American Thoracic Society and European Respiratory Journal, 2005, Standardisation of Spirometry) value of at least about 30 mF, such as at least about 40 mF or at least about 50 mF, compared to baseline in the span of at least about 4 weeks, such as at least about 8 weeks or at least about 12 weeks, when measured using a spirometry technique.

In another embodiment, any of the compositions described herein improves the trough FEV1 or FVC volume at least by about 3%, at least by about 5% or at least by about 6% in a subject suffering from respiratory disease that is under dual combination therapy of formoterol or its salt and fluticasone or its ester or salt as compared to baseline in the span of at least about 4 weeks, at least about 8 weeks or at least about 12 weeks when measured using a spirometry technique.

In a further embodiment, any of the compositions described herein improves the trough FEV1 or FVC volume at least by about 5%, at least by about 10% or at least by about 15% in a subject suffering from respiratory disease that is previously untreated and is now in need of such therapy as compared to baseline in the span of at least about 8 weeks or at least about 12 weeks when measured using a spirometry technique. In an embodiment, any of the compositions described herein has a synergistic effect when used in any of the methods described herein. In a further embodiment, any of the compositions described herein is synergistic.

In one embodiment, the any of the methods described herein provides relief, e.g., relief from symptoms of COPD and/or asthma, within about 30 minutes, within about 15 minutes or within about 10 minutes.

In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising (a) glycopyrronium in an amount of about 25 meg, (b) formoterol fumarate dihydrate in an amount of about 12 meg (c) fluticasone propionate in an amount of about 100 to about 400 meg (e.g., about 100 meg or about 250 meg) and (d) lactose, wherein the composition is free from hydrophobic excipient. In a preferred embodiment the composition includes fine lactose and coarse lactose as described above. The weight ratio of fine lactose to coarse lactose may be as described above.

Another preferred embodiment is a method of treating a respiratory disorder comprising inhalation administration of a fixed dose dry powder composition comprising about 12.5 meg or 25 meg of glycopyrronium, about 12 meg of formoterol fumarate and about 250 meg of fluticasone propionate at least once or at least twice daily, for at least about 4 weeks, at least about 8 weeks or at least about 12 weeks to obtain a clinically meaningful improvement in FEV1 and FVC values by at least 30 mL, at least about 40 mL or at least about 50 mL.

In an embodiment, any of the compositions described herein is administered via a suitable single dose inhaler capable of delivering about 12.5 meg or 25 meg of glycopyrronium, about 12 meg of formoterol fumarate and about 250 meg of fluticasone propionate upon actuation of the device.

In another aspect, the dry powder compositions described herein may be administered using an inhaler device. The inhaler device comprises a medicament chamber for holding a capsule, a rotatable mouthpiece and a piercing means for perforating the capsule. The dry powder composition is contained in a capsule, which is placed in the medicament chamber. In one embodiment, the dry powder composition comprises glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt, fluticasone propionate and an admixture of fine particles of lactose (e.g., lactose monohydrate) (e.g., having a D50 less than 30mhi) and coarse particles of lactose (e.g., lactose monohydrate) (e.g., having a D50 more than about 80 pm). The weight ratio of fine particles to coarse particles may be as described above.

In another embodiment, there is provided a pharmaceutical kit composition for inhalation comprising:

(a) a dry powder inhalation composition as described herein (e.g., a composition comprising glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt, fluticasone propionate and lactose monohydrate, wherein the composition comprises an admixture of fine particles of lactose having a D50 less than about 30pm and coarse particles of lactose having a D50 of more than about 80 pm), wherein the composition is filled in a capsule; and

(b) a single dose dry powder inhaler device comprising a lower housing member having a medicament chamber for receiving the capsule, a rotatable mouthpiece that can be engaged with the lower housing member, and an appropriate piercing means for the capsule.

Yet another embodiment is a method of administering a dry powder inhalation composition according to any of the embodiments described herein with an inhaler as described above. The method comprises:

i. opening a mouthpiece in the inhaler to access a capsule chamber,

ii. loading a capsule with a composition according to any of the embodiments described herein into the capsule chamber,

iii. locking the mouthpiece on the inhaler body,

iv. actuating push button(s) to pierce the capsule; and

v. inhaling.

Another embodiment is a drug product comprising a dry powder inhaler device for administration of a dry powder composition, wherein the inhaler device is as described above and the dry powder composition is as described herein. The dry powder composition may comprise glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt, fluticasone propionate and lactose monohydrate (preferably an admi ture of coarse lactose monohydrate and fine lactose monohydrate). The inhaler device has a medicament chamber for holding a capsule comprising a composition according to any of the embodiments described herein, a rotatable mouthpiece and a piercing means for perforating the capsule. In an embodiment of the present invention, the method of using a fixed dose inhalable dry powder composition according to any of the embodiments described herein results in a reduction in the use of rescue medication from about 10% to about 30% or about 30% to about 50%.

In another embodiment of any of the methods described herein, the composition comprises a fixed dose combination of glycopyrronium bromide, formoterol fumarate dihydrate and fluticasone propionate, wherein the composition provides an improvement in lung function of patients within about 30 minutes, about 45 minutes or about 60 minutes.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 represents a clinical study flow chart showing the scheduled visits for patients.

Figure 2 is a Plot of Feast Square Means ± SE of Change from Baseline of Trough FEV 1 (F) with MMRM Full Analysis Set.

Figure 3 is a Plot of Feast Square Means ± SE of Change from Baseline in Trough FEV 1 (F) with ANCOVA and FOCF Full Analysis Set.

Figure 4 is a Plot of Feast Square Means ± SE of Change from Baseline in Post-dose FEV 1 (F) with MMRM Full Analysis Set.

Figure 5 is a Plot of Feast Square Means ± SE of Change from Baseline in Trough FVC (F). Figure 6 is a Plot of Feast Square Means ± SE of Change from baseline in modified Medical Research Council (mMRC) score Full Analysis Set.

Figure 7 is a longitudinal cross-section view of an inhaler device having two piercing systems, with a capsule arranged therein in a non-perforated condition.

DETAIFED DESCRIPTION OF THE INVENTION

The terms used herein are defined as follows. If a definition set forth in the present application and a definition set forth later in a non -provisional application claiming priority from the present provisional application are in conflict, the definition in the non-provisional application shall control the meaning of the terms. The term singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes a single excipient as well as two or more different excipients, and the like.

The term "glycopyrronium" is used in a broad sense to include not only "glycopyrronium" per se but also its pharmaceutically acceptable salts. The two terms glycopyrronium or its pharmaceutically acceptable salt are being used interchangeably. Glycopyrrolate is a quaternary ammonium salt. Suitable counter ions are pharmaceutically acceptable counter ions including, for example, fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl-acetate or triphenylacetate, o- hydroxybenzoate, p-hydroxybenzoate, l-hydroxynaphthalene-2-carboxylate, 3- hydroxynaphthalene-2-carboxylate, methane-sulfonate and benzenesulfonate. A particularly preferred salt of glycopyrrolate is glycopyrronium bromide. Glycopyrrolate has two centers of asymmetry (chiral centers), and can exist in four stereoisometric forms, namely (3R, 2'R)-, (3S, 2'R)-, (3R, 2'S)- and (3S, 2'S).

By“salt” or“pharmaceutically acceptable salt”, it is meant those salts and esters which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use.

Representative acid additions salts include, for example, the hydrochloride, furoate, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, and lauryl sulphate salts. Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts.

The term "formoterol" is used in a broad sense to include not only "formoterol" per se but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable esters, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complex, pharmaceutically acceptable co-crystals etc. Formoterol salts include, for example, acid addition salts such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid and p-toluenesulfonic. Preferably the formoterol salt used in the presently claimed compositiosn and methods is formoterol tartrate or formoterol fumarate, more preferably formoterol fumarate dihydrate.

The term "effective amount" or "therapeutically effective amount" denotes an amount of an active ingredient that, when administered to a subject for treating a respiratory disease, produces an intended therapeutic benefit in a subject.

The term“active ingredient” (used interchangeably with“active” or“active substance” or “active agent” or“drug”) as used herein includes glycopyrronium or a salt thereof, formoterol or a salt thereof, and fluticasone or an ester or salt thereof. Preferably, the active ingredients include glycopyrronium bromide, formoterol fumarate dihydrate and fluticasone propionate.

The term“treating” or“treatment” as used herein also covers the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder, such as one modulated by glycopyrronium or its pharmaceutically acceptable salt in a mammal.

The term "subject" includes mammals like humans and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife). Preferably, the subject is a human.

The term "synergistic" or“synergy”, as used herein, refers to a combination exhibiting an effect greater than that would be expected from the sum of the effects of the individual components of the combination when administered alone. The term "synergistic" or“synergy” with regard to the combination of glycopyrronium (or its salt), formoterol (or its salt) and fluticasone (or its ester or salt) which is used in the treatment respiratory diseases (for example, in the form of a pharmaceutical composition, a combination product or a kit according to the invention) refers to an efficacy for the treatment of the respiratory diseases that is greater than that would be expected from the sum of their individual effects. The advantages for the synergistic combinations of the present invention include, but are not limited to, lowering the required dose of one or more of the active ingredients of the combination, reducing the side effects of one or more of the active compounds of the combination and/or rendering one or more of the active ingredients more tolerable to the subject in need of treatment of the respiratory diseases. By“pharmaceutically acceptable excipients,” it is meant any of the components of a pharmaceutical composition other than the actives and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.

As used herein, the term "average particle size" (or synonymously, "mean particle size") refers to the distribution of particles, wherein about 50 volume percent of all the particles measured have a size less than the defined average particle size value and about 50 volume percent of all measurable particles measured have a particle size greater than the defined average particle size value. This can be identified by the term "D50" or“d(0.5)”. Similarly, D90 value relates to about 90 volume percent of all the particles measured have a size less than the defined particle size value (also referred to as“D90 particle size’). The particle size can be measured using various techniques like laser diffraction, photon correlation spectroscopy (PCS) and Coulter’s principle. Unless specified otherwise, the particle size is measured by laser diffraction.

The fine particle mass (FPM) test is conducted using a validated multistage impactor or impinger method, or a suitably validated alternative. It is considered acceptable to set upper and lower limits on the results of pooled stages corresponding to a particle size distribution of less than 5 micrometer, although alternative limits may be found acceptable with adequate justification. The drug mass is reported rather than the percentage of emitted dose (or other derived parameter).

The Mass Median Aerodynamic Diameter (MMAD) is defined as the diameter at which 50% of the particles by mass are larger and 50% are smaller.

The Carr index and Hausner ratio are frequently used in as an indication of the flowability of a powder. The Carr index and Hausner ratio can be determined using Tap Density Apparatus. The bulk density and tap density of the powder composition can be determined by Tap density apparatus.

As used herein, the term“respiratory disorder” includes, but is not limited to, asthma, emphysema, bronchitis, COPD, sinusitis, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), irritant induced asthma, occupational asthma, sensory hyper-reactivity, airway (or pulmonary) inflammation, multiple chemical sensitivity, and aid in smoking cessation therapy.

As used herein, the term “asthma” includes, e.g., acute asthma, chronic asthma, intermittent asthma, mild persistent asthma, moderate persistent asthma, severe persistent asthma, chronic persistent asthma, mild to moderate asthma, mild to moderate persistent asthma, mild to moderate chronic persistent asthma, allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, nocturnal asthma, bronchial asthma, exercise induced asthma, occupational asthma, seasonal asthma, silent asthma, gastro-esophageal asthma, idiopathic asthma and cough variant asthma.

As used herein, the term“improving lung function” or“improvement in lung function” refers to enhancing or improving the declined lung function in a subject having a respiratory disorder by one or more of the following mechanisms, including, but not limited to, inhibiting bronchoconstriction, preventing bronchoconstriction, inducing bronchodilation, reducing airway hyper-reactivity/responsiveness by suppression of airway inflammation or reducing exacerbations in the subject.

Lung function generally means how well one’s lungs work. Various tests are used to assess the lung function in human. For example, spirometry, which is the most commonly used lung function test, specifically measures the amount (volume) and/or speed (flow) of air that can be inhaled and exhaled. Typically, spirometric measurements involve determination of certain functional parameters such as forced expiratory volume (FEV), forced vital capacity (FVC), forced expiratory flow, peak expiratory flow, and the like.

As used herein, the term“FEV 1” refers to an amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation by a subject.

As used herein, the term“FVC” refers to is the total amount of air exhaled after taking the deepest breath possible during the FEV test. Because respiratory disease causes the air in lungs to be exhaled at a slower rate and in smaller amounts compared to a normal, healthy person, measuring how well the patient can forcibly exhale air can help determine the lung functioning.

In an embodiment, the inhalable dry powder composition of the present invention has a bulk density in the range of about 0.3 g/ml to about 1 g/ml and/or a tapped density in the range of about 0.5 g/ml to about 1.25 g/ml.

In another embodiment, any of the dry powder compositions described herein has a Hausner ratio in the range of about 1 to about 2, preferably a Hausner ratio in the range of about 1.25 to about 1.75 and more preferably a Hausner ratio in the range of about 1.30 to about 1.65. In another embodiment, any of the dry powder compositions described herein has a Carr index in the range of about 20% to about 45% and more preferably a Carr index in the range of about 22% to about 40%.

The pharmaceutical compositions of any of the embodiments described herein may optionally comprise one or more pharmaceutically acceptable excipients.

Any of the inhalable pharmaceutical dry powder compositions described herein may contain one or more pharmaceutically acceptable excipients. Examples of such excipients include, but are not limited to, diluents, solvents, and the like.

The pharmaceutically acceptable diluents suitable for use in the invention may be selected from, but not limited to, lactose, mannitol, sucrose, trehalose, cyclodextrin, and mixtures thereof. Preferably, the pharmaceutically acceptable diluent is lactose. V arious grades of lactose are available for use in dry powder compositions and may be selected from Respitose^® SV010, Respitose^® SV003, Respitose^® ML006, InhaLac 70, InhaLac 230, InhaLac 500, Lactose Monohydrate Inhalation 40M, Lactose Anhydrous 120M, Lactohale^® 300, and the like.

Examples of suitable solvents include, but are not limited to, water, propylene glycol, ether, petroleum ether, alcohols, e.g. methanol, ethanol, isopropyl alcohol and higher alcohols; alkanes, e.g. pentane, hexane and heptane; ketones, e.g. acetone and methyl ethyl ketone; and the like, and mixtures thereof.

In an embodiment, there is provided an inhalable fixed dose dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt, and fluticasone propionate and lactose, wherein said composition is free from a hydrophobic excipient.

In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt, fluticasone propionate and lactose.

In one embodiment of the present invention, any of the inhalable pharmaceutical dry powder compositions described herein is free from a hydrophobic excipient.

In one embodiment of the present invention, any of the inhalable pharmaceutical dry powder compositions described herein is not prepared by co-milling or co-micronization process. In another embodiment, the glycopyrronium or pharmaceutically acceptable salt thereof is not co-micronized with lactose (such as lactose monohydrate).

In an embodiment, all the drugs or active ingredients present in any of the inhalable pharmaceutical dry powder compositions described herein are in micronized form. The D50 of each drug is not more than 5 pm, preferably not more than 4 pm and/or D90 of each drug is not more than 10 pm, preferably not more than 6 pm.

In an embodiment, the inhalable fixed dose dry powder composition comprises glycopyrronium or its pharmaceutically acceptable salt in the range of about 0.01% w/w to about 10% w/w or from about 0.05% w/w to about 5% w/w, formoterol its pharmaceutically acceptable salt in the range of about 0.01% w/w to about 10% w/w or from about 0.05% w/w to about 5% w/w, fluticasone propionate in the range of 0.05% w/w to about 10% w/w or from about 0.1% w/w to about 5% w/w and lactose in the range of about 90% w/w to about 99.9% w/w of total weight of inhalation composition, wherein the composition is free from a hydrophobic excipient.

In an embodiment, any of the inhalable pharmaceutical dry powder compositions described herein has a D50 value less than about 120 pm or less than about 100 pm.

In an embodiment, any of the inhalable pharmaceutical dry powder compositions described herein has a D90 value about 120 pm to about 200 pm or about 150 pm to about 180 pm.

In an embodiment, any of the inhalable fixed dose dry powder compositions of the present invention comprising glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt, fluticasone propionate and lactose is stable for a period of about 3 months or about 6 months or about 1 year or about 2 years or about 3 years when stored at temperature and humidity preferable for storage of dry powder inhalation composition, such as, for example, 25 °C and about 60% relative humidity (RH), or about 30 °C and about 65% RH, or about 40 °C and about 75% RH.

In an embodiment, the stability of the composition is indicated by consistent dispersability of powdered inhalable composition over a period of time during storage which is determined using Anderson cascade impactor.

The indicative measures for stability includes fine particle dose (FPD), fine particle fraction (FPF), Mass Median aerodynamic diameter (MMAD), delivered dose (DD) and assay of drug. In an embodiment of the present invention, any of the inhalable fixed dose dry powder compositions described herein has a fine particle mass having particle size less than about 50 pm in the range of about 5% to about 30% and/or a coarse particle mass having particle size more than 80 pm is in the range of about 20% to about 90% w/w.

In an embodiment, the MMAD of any of the inhalable fixed dose dry powder compositions described herein is in the range from about 1pm to about 5pm.

In an embodiment, any of the inhalable fixed dose dry powder compositions described herein may be further filled into a capsule for inhalation or may be processed into a lightly compressed tablet or powder agglomeration which can be easily crushed to obtain a powder for inhalation. Preferably, the composition is filled in a capsule made up of gelatin or HPMC having a reduced moisture content less than about 15% w/w or less than about 10% w/w.

In another embodiment, the composition can be filled, either as discrete dosage units, in a blister or a sachet or in a reservoir for multiple use.

In an embodiment, the present invention relates to a method of treating a respiratory disease in a subject in need thereof, comprising inhalation administration of a pharmaceutical composition comprising an effective amount of glycopyrronium bromide, an effective amount of formoterol fumarate dihydrate, an effective amount of fluticasone propionate and, optionally, a pharmaceutically acceptable carrier, wherein said composition is free from a hydrophobic excipient.

In an embodiment, the present dry powder inhalation composition is administered to a subject in need thereof by the inhalation route using a suitable dry powder inhaler.

In an further embodiment, the dry powder inhaler is selected from a single dose capsule device and a multiple dose inhaler device.

In a further embodiment, the present invention relates to the use of an inhalable fixed dose dry powder composition comprising an effective amount of glycopyrronium bromide, an effective amount of formoterol fumarate dihydrate and an effective amount of fluticasone propionate for the treatment of a respiratory disease in a subject in need thereof.

In an embodiment of the present invention, the respiratory disease is COPD and / or asthma.

In an embodiment, the fixed dose combination of glycopyrronium bromide, formoterol fumarate and fluticasone propionate provides a faster relief of symptoms associated with respiratory diseases, in particular COPD, and provides better therapeutic value when compared to dual combination therapy with formoterol fumarate and fluticasone propionate upon administration by inhalation.

In an embodiment, the inhalation administration of said pharmaceutical composition provide relief within about 30 minutes, about 15 minutes or about 10 minutes.

Another embodiment is a method of improving lung function in a subject having a respiratory disease by inhalation administration of pharmaceutical composition comprising comprising effective amount of glycopyrronium bromide, effective amount of formoterol fumarate and effective amount of fluticasone propionate.

In one embodiment, the method of treating respiratory disease includes inhalation administration of aforementioned composition comprising of glycopyrronium or its salt, formoterol or its salt, and fluticasone or its ester or salt in the weight ratio ranges from about 1:0.1: 10 to about 1 :2:200, or from about 1:0.5: 100 to about 1 : 1:50. In one embodiment, the ratio of (a) glycopyrronium or its salt, (b) formoterol or its salt, and (c) fluticasone propionate ranges from 0.8-2.5: 1 : 15-25.

Yet another embodiment is a method of treating a respiratory disease, such as COPD or asthma, in a subject in need thereof comprising inhalation administration of pharmaceutical composition comprising an effective amount of glycopyrronium bromide, an effective amount of formoterol fumarate and an effective amount of fluticasone propionate, wherein the weight ratio of glycopyrronium bromide, formoterol fumarate and fluticasone propionate ranges from about 1:0.1: 10 to about 1 :2:200, or from about 1:0.5: 100 to about 1: 1:50. For example, the weight ratio of glycopyrronium bromide and formoterol fumarate may be about 1:0.1, about 1:0.2, about 1:0.5, about 1:0.8, about 1:0.9, about 1 : 1, about 1:2, about 1: 10, about 1 :20, about 1:50, the weight ratio of formoterol fumarate and fluticasone propionate may be about 1 : 1, about 1 :2, about 1 :5, about 1: 10, about 1 : 15, about 1:20, about 1 :50, about 1:70, about 1: 100, about 1:200, and/or the weight ratio of glycopyrronium bromide and fluticasone propionate may be about 1 : 1, about 1:2, about 1:5, about 1 :8, about 1 : 10, about 1: 15, about 1:20, about 1 :50, about 1: 100, about 1:200.

The pharmaceutical compositions described herein may comprise an effective amount of glycopyrronium or its salt, an effective amount of formoterol or its salt, and an effective amount of fluticasone or its salt for administration by inhalation to a subject in need thereof atleast once daily or atleast twice daily.

Yet another embodiment is a method of reducing eosinophil or neutrophil count and/or increasing FEV1 in a subject having a respiratory disease comprising administering to the subject by inhalation a pharmaceutical composition comprising effective amount of glycopyrronium or its salt, an effective amount of formoterol or its salt and an effective amount of fluticasone propionate, according to any of the embodiments described herein.

A further embodiment is a method of reducing eosinophil or neutrophil count and/or increasing FEV1 in a subject having a respiratory disease in the span of at least 4 weeks, at least 8 weeks or at least 12 weeks when measured using a spirometry technique, the method comprising administering a composition according to any of the embodiments described herein.

Yet another embodiment is a method of improving forced vital capacity (FVC) of lungs in a subject having a respiratory disease comprising administering an effective amount of glycopyrronium or its salt, an effective amount of formoterol or its salt and an effective amount of fluticasone propionate, according to any of the embodiments described herein.

A further embodiment is a method of improving FVC of lungs in a subject having a respiratory disease in the span of at least 4 weeks or at least 8 weeks or at least 12 weeks when measured using a spirometry such as FEV1 or FVC, the method comprising administering a composition according to any of the embodiments described herein.

In an embodiment, the subject suffering from respiratory disease experiences a clinically meaningful improvement in the FEV 1 value of at least about 30 mF, at least about 40 mF or at least about 50 mF compared to baseline in the span of at least about 4 weeks, at least about 8 weeks or at least about 12 weeks when measured using a spirometry technique.

In an embodiment, the subject suffering from respiratory disease experiences a clinically meaningful improvement in the FVC (Guidelines of American Thoracic Society and European Respiratory Journal, 2005, Standardisation of Spirometry) and lung function value of at least about 30 mF, at least about 40 mF or at least about 50 mF compared to baseline in the span of at least about 4 weeks, at least about 8 weeks or at least about 12 weeks when measured using a spirometry technique.

In another embodiment, the composition improves the trough FEV1 volume at least by about 3%, at least by about 5% or at least by about 6% in a subject suffering from respiratory disease and is under dual combination therapy of formoterol or its salt and fluticasone or its ester or salt as compared to baseline in the span of at least about 4 weeks, at least about 8 weeks or at least about 12 weeks when measured using a spirometry technique.

In a further embodiment, the composition improves the trough FEV 1 volume at least by about 5%, at least by about 10% or at least by about 15% in a subject suffering from respiratory disease and who is previously untreated and is now in need of such a therapy as compared to baseline in the span of at least about 8 weeks or at least about 12 weeks when measured using a spirometry technique.

In another embodiment, the composition improves the trough FVC at least by about 3% at least by about 5% or at least by about 6% in a subject suffering from respiratory disease and is under dual combination therapy as compared to baseline in the span of at least about 4 weeks, at least about 8 weeks or at least about 12 weeks when measured using a spirometry technique. In a further embodiment, the composition improves the trough FVC volume at least by about 5%, at least by about 10% or at least by about 15% in a subject suffering from respiratory disease who is previously untreated and is now in need of such a therapy as compared to baseline in the span of at least 8 weeks or at least 12 weeks when measured using a spirometry technique.

In an embodiment, the compositions described herein have a synergistic effect. In a further embodiment, the combinations described herein are synergistic.

In one embodiment, the methods described herein provide relief within about 30 minutes, within about 15 minutes or within about 10 minutes.

In a further embodiment, the present invention relates to use of an effective amount of glycopyrronium bromide; formoterol fumarate dihydrate, fluticasone propionate in the inhalable pharmaceutical dry powder composition of the present invention for the treatment of respiratory disorders in a subject.

Another preferred embodiment is a method of treating a respiratory disorder comprising inhalation administration of the fixed dose dry powder composition comprises about 12.5 meg or 25 meg of glycopyrronium, about 12 meg of formoterol fumarate and about 250 meg of fluticasone propionate at least once or at least twice daily, for at least about 4 weeks, at least about 8 weeks or at least about 12 weeks to obtain a clinically meaningful improvement in FEV1 and FVC values by at least about 30 mF, at least about 40 mF or at least about 50 mF. In an embodiment, the composition is administered via suitable single dose inhaler capable of delivering 12.5 meg or 25 meg of glycopyrronium, 12 meg of formoterol fumarate and 250 meg of fluticasone propionate upon actuation of the device.

The inhaler shown in Figure 7 comprises a body portion 1 and a mouthpiece 2. The mouthpiece 2 has an ellipsoidal tubular portion, with walls 5 and an inhalation passage 4. The mouthpiece 2 is connected to the body portion 1 by means of a pivot pin (not specifically shown) projecting from the flange 3 of the mouthpiece 2, which can fit into a hole (not specifically shown) in the body portion 1. The inhaler mouthpiece 2 can be locked in its closed condition by a snap type of locking means.

The inhaler body 1 is provided with a medicament chamber 14 for the capsule, the chamber being upward opened and communicating with the outside through a perforated plate or grid 7, included in the inhaler mouthpiece 2 at the flange 3 and designed for separating the medicament chamber 14 from the duct 6 of the mouthpiece. A capsule 12 can be placed in the chamber 14. The perforating means comprise a pair of perforating needles 10 which can transversely slide as counter-urged by the coil springs 9; each coil spring coaxially encompassing the perforating needle 10 and operating between a respective abutment element 8, rigid with the inhaler body 1 , and a hollow push-button element 11.

The operation of the inhaler device may be as follows.

A capsule is placed in the medicament chamber 14 and the mouthpiece 2 is locked on the inhaler body 1. By pressing the push-button elements 11, the perforating needles 10 will perforate the capsule 12, thereby its contents, will be released in the capsule chamber. By applying suction on the mouthpiece 2, an air flow will be generated which, coming from the outside, will enter the medicament chamber through the holes 13, thereby mixing with the capsule contents and, passing through the grid 7 and duct 6, will allow the products to be inhaled.

The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention. EXAMPLES

For this invention to be better understood, the following examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any manner.

The aerodynamic particle size distribution (APSD) was determined below using an Anderson Cascade Impactor Apparatus as follows:

1. Prepare mobile phase, buffer solution, standard solution, diluent and sample solution.

2. Set up Anderson cascade impactor at the flow rate of 90 L/min for preparation of samples followed by calibration of apparatus. Once critical flow is achieved, take capsule inside the inhaler and pierce it. With the pump in running mode and the 2 -way solenoid valve closed, locate the mouthpiece of the inhaler in the mouthpiece adapter. Discharge the powder into the impactor by opening the solenoid valve for the required time, T (2.7 sec ± 5%). Repeat the discharge sequence for 9 times.

3. Dismantle the apparatus and carefully wash each stage with diluent.

4. Inject an equal volume of diluent as a blank, standard solution and sample solution into an equibrated HPLC and record the chromatograms and measure the response of the principal peaks.

5. Aerodynamic particle size distribution (APSD) values are measured which gives value of fine particle mass (FPM), delivered dose (DD), fine particle fraction (FPF), and mass median aerodynamic diameter (MMAD).

(A) Composition:

EXAMPLES: (1-3) Dry powder fixed dose inhalable composition comprising glycopyrronium bromide, formoterol fumarate dihydrate and fluticasone propionate

Manufacturing process:

1. Mix glycopyrronium bromide, formoterol fumarate dihydrate and fluticasone propionate with fine grade lactose monohydrate having average particle size less than about 30 pm (e.g., a D50 of not more than 5 pm and a D90 of not more than 10 pm). The D50 of each active ingredient was not more than 5 pm, preferably not more than 4 pm and/or D90 of each active ingredient was not more than 10 pm, preferably not more than 6 pm.

2. Blend the mixture obtained in step (1) with coarse lactose monohydrate having average particle size in the range of about more than about 80 pm (e.g, a D50 of 95-125 pm, and a D90 of 160-190 pm).

3. Fill the blend of step (2) in a capsule or blister.

Stability Studies:

Table 1 Stability data of finalized composition (Example 2) stored at 30°C / 75% RH:

Table 2 Stability data of finalized composition (Example 2) stored at 40°C / 75% RH:

(B) Method of Treatment:

1. Protocol A randomized, double-blind, clinical trial to assess the efficacy and safety of a fixed dose combination dry powder of glycopyrronium bromide in an amount equivalent to glycopyrronium 12.5 pg / formoterol fumarate (FF) 12 pg / fluticasone propionate (FP) 250 pg to be administered by a dry powder inhaler in comparison with a dry powder of glycopyrronium 50 pg co administered with a fixed dose dry powder combination of formoterol fumarate 12 pg/ fluticasone propionate 250 pg in patients with chronic obstructive pulmonary disease.

2. Patient Population

Male and female subjects, 40 to 75 years of age (inclusive of both), with a primary clinical diagnosis of COPD, a post-bronchodilator forced expiratory volume in 1 second (FEV 1 yforced vital capacity (FVC) ratio of < 0.70, a history of > 2 COPD exacerbations in the ast 1 year and having significant symptom level with mMRC score > 2 and currently receiving inhaled corticosteroid (ICS), long-acting b2 agonist (LABA) (as a free or fixed combination) or long-acting muscarinic antagonist (LAMA) in inhaled form in any combination (except the 3 together) were included in the study.

3. Study design including flow chart of the study

This is a phase 3 multi-center, randomized, double-blind, parallel group, non-inferiority study to evaluate the efficacy, safety, and tolerability of triple therapy i.e. FDC DPI of glycopyrronium 12.5 pg/ formoterol fumarate 12 pg/ fluticasone propionate 250 pg (G12.5/FF12/FP250 or G/FF/FP as a Test Product (T)) in comparison to the reference group, DPI of glycopyrronium 50 pg co-administered with FDC DPI of formoterol fumarate 12 pg/fluticasone propionate 250 pg (G50+FF12/FP250 or G+FF/FP) in subjects with COPD. The study population consisted of eligible male and female subjects in the age range of > 40 and < 75 years with post- bronchodilator ratio of forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) of < 0.70 and post-bronchodilator FEV1 >3 0% predicted and < 80% predicted at screening visit and having significant symptoms (modified Medical Research Council, mMRC score >2) and having history of 2 or more exacerbations in last one year (Group D COPD patients). Patients satisfying eligibility criteria at the screening visit were asked to stop all the current medications for the treatment of COPD and had received an open label fixed dose combination of dry powder inhaler (DPI) formoterol fumarate 12 pg/ fluticasone propionate 250 mg (FF/FP) 1 inhalation twice daily during 2 weeks of run-in period. Patient’s symptoms, rescue medication use and compliance with run-in medication were monitored using subject diary. After the run-in period, subjects with > 80% compliance with the diary and ICS/LABA at randomization visit (visit 2) were randomized in the ratio of 1 : 1 to the dry powder fixed dose combination (FDC) DPI inhaler of G12.5/ FF12/FP250 or G/FF/FP one inhalation twice daily or DPI Glycopyrronium 50pg (G) once daily co-administered with FDC DPI FF12/FP250 twice daily (G50+FF12/FP250 or G+FF/FP as a Reference product (R)) for a period of 12 weeks of treatment in blinded form.

On day 1, pre-dose spirometry was performed and the subject was dosed under the supervision of the investigator. On day 2, spirometry for trough FEV 1 was performed. Follow up visit (visit 7) was 2 weeks after the end-of-treatment visit. During the entire study, patients used pMDI salbutamol as rescue medication.

Spirometry: At screening spirometry was performed pre-bronchodilator and 15 minutes after administration of 4 puffs of salbutamol 100 pg using MDI with spacer. Spirometry was performed at -45 min and -15 min before dosing at randomization visit and the average FEV1 from the two measurements was considered as baseline FEV1. Spirometry was performed at +23h 15 min and +23h 45 min from the previous day’s morning dose at visits 3, 4, 5 and 6 (day 2) and the average FEV 1 from the two measurements was considered as trough FEV 1. At visit 6, day 1, spirometry was performed at -45 min and -15 min before dosing. Additionally spirometry was performed at 1 hour after dosing at visits 2 and visit 6, day 1. Spirometry was also performed at follow-up visit (visit 7) without any time condition.

STUDY FLOWCHART

The study was conducted according to the flowchart in Figure 1.

4. Subject Eligibility Criteria

Inclusion Criteria:

Subjects eligible for enrollment in the study must meet all of the following criteria:

1. Male or female, aged >40 to < 75 years at the time of informed consent.

2. Provide written informed consent and willing, able to comply with all aspects of the protocol. 3. Current or previous cigarette/beedi smokers with a history of cigarette/beedi smoking of at least 10 pack- years (number of pack years = [number of cigarettes/bidis per day/20] x number of years smoked [e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years]). Previous smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1.

4. Diagnosis of COPD (as defined by the GOLD Guidelines, 2017).

5. Post-bronchodilator FEV1/ FVC < 0.70 and post-bronchodilator FEV1 > 30% predicted and < 80% predicted, at screening visit. History of at least two exacerbations of COPD within 12 months before screening. A modified Medical Research Council dyspnea (mMRC) grade 2 or greater.

6. Patients using inhaled corticosteroid (ICS) with or without a long-acting b2 agonist (LABA) (as a free or fixed combination), or ICS with long-acting muscarinic antagonist (LAMA), or LABA with LAMA (as a free or fixed combination), or LAMA monotherapy as maintenance treatment for at least 1 month before screening.

7. No significant abnormality suggesting chest disease other than COPD, on chest x-ray or computed tomography (CT) scan taken within 6 months before screening. If there is no chest x- ray/CT scan taken less than or equal to 6 months before consent visit (Visit 0), a chest x-ray will be performed during screening to rule out any other significant abnormality.

8. Female subjects must have a negative pregnancy test at Visit 1, and agree to use an adequate forms of non-hormonal contraception during the study (i.e., women of child bearing potential must use a highly effective method of birth control, such as condom and spermicide, diaphragm or cervical cap and spermicide, condom and diaphragm or cervical cap, non-hormonal IUD), or females who are of non-child bearing potential i.e., who are surgically sterile (history of hysterectomy or bilateral tubal ligation or bilateral oophorectomy; partial hysterectomy is not sufficient or vasectomized partner) or postmenopausal (12 months of spontaneous amenorrhea) or who agree to remain abstinent.

Male subjects must agree to either remain abstinent or use a highly effective method of birth control as described above.

9. Ability to use dry powder inhaler independently & correctly in view of the investigator.

Exclusion Criteria A subject who meets any of the following criteria must not be entered into the lead-in phase/randomized/assigned to treatment in the study:

1. A current or historic diagnosis of asthma.

2. Treatment with long-acting muscarinic agonist (LAMA), long-acting beta-agonist (LABA) and inhaled corticosteroids (ICS) in one or multiple inhalers, within 1 month before screening.

3. Known respiratory disorders other than COPD including but not limited to alpha- 1 antitrypsin deficiency as the underlying cause of COPD, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, history of allergic rhinitis or atopy, pulmonary hypertension, and interstitial lung disease.

4. Inability to use the study drug and device satisfactorily in the opinion of the investigator, at visit 1.

5. Any previous lung resection surgery (e.g., lung volume reduction surgery or lobectomy).

6. Chest X-ray or CT scan, which reveals evidence of clinically significant abnormalities, not believed to be due to the presence of COPD (e.g., evidence of pneumonia, other infection, atelectasis, or pneumothorax).

7. Type I or uncontrolled Type II diabetes.

8. History of narrow-angle glaucoma, symptomatic prostatic hyperplasia or bladder-neck obstruction or moderate-to-severe renal impairment or urinary retention (Subjects with a transurethral resection of prostate, subjects who have undergone full re-section of the prostate and, subjects who are asymptomatic and stable on pharmacological treatment for the condition will be considered for the study). Patients with post- void residue of > 50 mL on ultrasonography at screening will be excluded from the study. Patients with an intra-ocular pressure of > 21 mm of Hg in any eye at screening will be excluded from the study.

9. Use of oral/depot corticosteroids or antibiotics for COPD exacerbation within 6 weeks prior to Visit 1 or subject has had a change in dose or type of any medications for COPD within 1 month before Visit 1.

10. Hospitalization for COPD exacerbation or pneumonia within 3 months prior to Visit 1.

11. Has a clinically significant laboratory abnormality or a clinically significant condition, in the judgment of the investigator, such as (but not limited to):

12. Unstable ischemic heart disease, left ventricular failure (New York Heart Association Class III and IV), history of myocardial infarction, arrhythmia (excluding chronic stable atrial fibrillation). Subjects with such events not considered clinically significant by the investigator will be considered for inclusion in the study.

13. An abnormal and clinically significant 12-lead electrocardiogram (ECG) as per investigator’s judgement. For the purposes of this study, an abnormal ECG will be defined as a 12-lead tracing which is interpreted with (but not limited to) any of the following:

14. Clinically significant conduction abnormalities (e.g., left bundle branch block, Wolff- Parkinson-White syndrome).

15. Myocardial ischemia.

16. Clinically significant arrhythmias (e.g., atrial fibrillation, ventricular tachycardia).

17. A mean QTcB value at screening >450 msec (for males) / >470 msec (for females) and, the

QTc(B) of all 3 screening ECGs are not within 10% of the mean, or an ECG that is not suitable for QT measurements (e.g. poorly defined termination of the T wave).

18. A known case of positive Hepatitis B surface antigen or positive hepatitis C antibody at Visit

1.

19. Known to be human immunodeficiency virus (HIV) positive.

20. A current malignancy or previous history of cancer in remission for < 5 years prior to Visit 1 (localized basal cell or squamous cell carcinoma of the skin that has been resected is not exclusionary). Subjects with a history of cancer that is considered surgically cured and without a recurrence within the past 5 years may participate in the study. History of hematologic/lymphatic malignancy treated with chemotherapy or radiation is not allowed, under any condition.

21. History of allergy or hypersensitivity to the study medications or any of the excipients.

22. Additional Medications: Unable to stop the following medications at the defined times prior to screening spirometry:

23. Currently enrolled in another interventional clinical study or have used any IPs, study drug, or device within 30 days or 5 times the half-life, whichever is longer preceding informed consent or scheduled to participate in another clinical study involving an IP.

24. Use of long-term oxygen therapy (LTOT) or supplemental oxygen require for greater than 12 hours a day. Oxygen prn use is not prohibited.

25. Subjects with clinically significant sleep apnea that requires continuous positive airway pressure (CPAP).

26. Use of nocturnal positive pressure or non-invasive positive pressure ventilation (NIPPV).

27. Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. Subjects who are in the maintenance phase of a pulmonary rehabilitation program were not excluded.

28. Study investigators, sub-investigators, study coordinators, employees of a participating investigator or study site, or an immediate family member of the aforementioned were excluded from participation in this study.

29. History of psychiatric disease, intellectual deficiency, poor motivation, substance abuse in the 2 years prior to Visit 1 (including drug and alcohol), or other conditions as per Investigator’s discretion.

30. Pregnant or lactating women.

5. Assessment of Efficacy

Spirometry

Spirometry was performed as per the standards laid down by the American Thoracic Society (ATS)/European Respiratory Society (ERS) Statement on Standardization of Spirometry, 2005 (Miller et al. 2005). Spirometer satisfying the criteria laid down by the ATS/ERS was used for conducting spirometry. Calibration check with the help of calibration syringe was performed as required by the ATS/ERS. A minimum of 3 acceptable and 2 repeatable graphs was saved for each test. Individual spirograms was considered as acceptable, if they (i) are free from these artefacts: cough during first second of exhalation, glottis closure that influences the measurement, early termination or cut-off, effort that is not maximal throughout, leak, obstructed mouthpiece, (ii) have good starts (extrapolated volume < 5% of FVC or 150 mL, whichever is greater), and (iii) show satisfactory exhalation: duration of exhalation > 6 seconds or a plateau in the volume-time curve. For achieving repeatability, the highest to FVCs within the 3 acceptable tests should be within 150 mL of each other and the highest two FEV 1 should be within 150 mL of each other. At screening, spirometry was performed pre-bronchodilator and between 15 and 30 minutes after administration of 4 puffs of salbutamol 100 pg using MDI with spacer.

Spirometry was performed at -45 min and -15 min before dosing at randomization visit and the average FEV1 from the two measurements was considered as baseline FEV1. Spirometry was performed at +23h 15 min and +23h 45 min from the previous day’s morning dose at visits 3, 4, 5 and 6 (day 2) and the average FEV1 from the two measurements was considered as trough FEV1. At visit 6, day 1, spirometry was performed at -45 min and -15 min before dosing. Additionally spirometry was performed at 1 hour after dosing at visits 2 and visit 6, day 1. Spirometry was also performed at follow-up visit (visit 7) without any time condition.

The time points for spirometry at each treatment visit (visits 2, 3, 4, 5 and 6) represent the time of start of the test. A window of ±5 minutes was permitted for each pre-dose spirometry time point and a window of ±1 hour was permitted for each trough FEV1 time point at these visits. The time difference between the start of the two trough FEV 1 (23 h 15 min & 23 h 45 min) tests should not be less than 15 minutes and should not be more than 45 minutes. Although there was no time limit for end of the test, undue prolongation of time for completing spirometry should be avoided.

Trough FEV1 is defined as the mean of FEV1 obtained at 23 hours 15 min and 23 hours 45 min after the morning dose of the study medication on the previous day.

Baseline FEV 1 Baseline FEV1 is defined as the mean of the pre-dose FEV1 measured at -45 min and -15 min from administration of the study drug at the randomization visit, visit 2.

Baseline FVC

Baseline FVC is defined as the average of the pre-dose FVC measured at -45 min and -15 min from administration of the study drug at the randomization visit, Visit 2.

Trough FVC is defined as the mean of FVC obtained at 23 hours 15 min and 23 hours 45 min after the morning dose of the study medication on the previous day.

Symptom and Quality of Fife measurement

Modified Medical Research Council Questionnaire (mMRC) mMRC was administered at each clinic visit. The questionnaire was translated into local languages as required. The patient would answer the questionnaire at each visit.

6. Assessment of Safety

Safety assessments consisted of monitoring and recording all adverse events (AEs) and serious adverse events (SAEs), vital signs, physical examination, ECG, USG e amination for urinary retention, and ophthalmic assessment for intra-ocular pressure.

7. Summary of Data Analysis Plan

• Change from baseline in trough FEV1 at the end of 12 weeks of treatment.

• Change from baseline in post-dose FEV1 at week 12 of treatment.

• Rescue medication use averaged over week 11 and 12 of treatment.

• Change from baseline in trough forced vital capacity (FVC) at week 12 of treatment.

• Change from baseline in modified Medical Research Council (mMRC) score at week 12.

• Compliance with the study medication.

• Frequency of exacerbations during Week 0 to 12 week of treatment in both the arm.

• Frequency of hospitalization during Week 0 to 12 week of treatment in both the arm.

• Number and percentage of patients with treatment emergent adverse events (TEAE). Safety End Points:

Safety assessments consist of monitoring and recording all adverse events (AEs) and serious adverse events (SAEs), vital signs, physical examination, ECG and blood and urine investigations.

Not applicable .

Analysis of Primary Efficacy Endpoint(s)

FEV1 is the amount of air that can be forcibly exhaled from the lungs in the first second of a forced exhalation. The primary endpoint is defined as the change from baseline in trough FEV 1 at Day 85 (Week 12). Study baseline FEV1 is defined as the mean of the available pre-dose FEV1 values at the baseline visit. Average of FEV 1 values at -45 min and -15 min before dosing at randomization visit will be considered as baseline FEV 1. Average of FEV 1 values at +23h 15 min and +23h 45 min from the previous day’s morning dose at visits 3, 4, 5 and 6 (day 2) will be considered as trough FEV1. Change from baseline in trough FEV1 will be analyzed using Mixed-Effect Model Repeated Measure (MMRM) with fixed categorical terms for treatment, visit, treatment by visit interaction, center and continuous fixed covariates of baseline trough FEV 1 and baseline trough FEV 1 by visit.

International guidance on non-inferiority margins recommends 95% -95% approach for deciding the non-inferiority (NI) margin (U.-F. Guidance 2016, EMEA 2005, Gupta SK 2011). According to this approach, the first 95% refers to the confidence interval of the estimated effect of the control based on the historical studies demonstrating the effect (Ml), and the second 95% refers to the confidence interval used to test the null hypothesis in the NI study (M2).

Meta-analysis of already published studies was performed using the“random effects” model because of high heterogeneity observed in the included studies (12=85%, P<0.00001). The pooled effect size in the LAMA+LABA group for change in trough FEV1 from baseline in comparison with placebo was 195.44 mL with 95% Cl: 164.75 - 226.14 mL.

Non-inferiority margin: 50% of lower bound of this 95% Cl (i.e. 164 mL) is 164/2=82. Hence, 80 mL difference in trough FEV1 is an appropriate and adequately conservative non-inferiority margin. A non inferiority margin of 100 mL was used by Novartis for comparison between FDC inhaler of Indacaterol + Glycopyrronium versus the two mono-components administered together in separate inhalers (Dahl R et al. Efficacy and safety of QVA149 compared to the concurrent administration of its monocomponents indacaterol and glycopyrronium: the BEACON study. Int J Chron Obstruct Pul m on Dis. 2013;8:501-508).

Analysis of Secondary Efficacy Endpoint(s)

• Change from baseline in post-dose FEV1 at week 12 of treatment.

• Rescue medication use averaged over week 11 and 12 of treatment.

• Compliance with the study medication.

• Number and percentage of patients with treatment emergent adverse events (TEAE).

Safety Analysis:

Incidence of AEs, and Vital signs (pulse rate and systolic and diastolic blood pressure). Descriptive analyses of USG examination for urinary retention, ophthalmic assessment for IOP, ECG and physical examination would be provided.

CLINICAL TRIAL RESULTS

TABLE 3: Summary of Subject Disposition Randomized Population

FAS: Full analysis set; PPS: Per protocol set; SAF: Safety analysis set

Primary Efficacy Endpoints:

Both the treatment groups demonstrated statistically significant (P <0.01) change from baseline in trough FEV1 at week 12. In the G/FF/FP group, there was statistically significant improvement in trough FEV1 at week 2, which remain sustained and statistically significant at all the visits. (P <0.01 at all the visits). The FS mean (SE) change from baseline in trough FEV1 at week 12 in the FAS population, using MMRM, was 0.062 F [±0.0184]) in the G/FF/FP group. The mean change from baseline in trough FEV1 at week 12 in the FDC of glycopyrronium 12.5 pg / formoterol fumaratel2 pg / fluticasone propionate 250 pg (G/FF/FP) group was non-inferior compared to glycopyrronium 50 pg with FDC of formoterol fumarate 12 pg/ fluticasone propionate 250 pg (G+FF/FP) in FAS population using MMRM. The p-value of test for non inferiority was statistically significant (P <0.05) with FS mean difference (90% Cl) between the 2 groups of -0.038 F (-0.078,0.003). In the G/FF/FP group, there was increase in trough FEV1

(SE) of 0.062 (±0.02) F compared to baseline, using ANCOVA with FOCF in the FAS population which was statistically significant (P<0.05). The mean change from baseline in trough FEV1 at week 12 in the G/FF/FP group was non-inferior compared to G±FF/FP group (non inferiority test was statistically significant withP <0.05). See Figure 2.

Table 4: Analysis of Lung Function Trough FEV1 (L) and Change from baseline in FAS Population using MMRM

p-valuel is calculated for the one-sided non-inferior test with NI margin -80 mL (T-R) and p-value2 for two-sided superiority test.

Table 5: Analysis of Lung Function Trough FEV1 (L) and Change from baseline in the FAS Population, using ANCOVA with LOCF

ANCOYA: Analysis of Covariance; LOCF: Last observation carried forward

In the PPS population, both the treatment groups demonstrated statistically significant (P <0.01) change from baseline in trough FEV1 at week 12. In the G/FF/FP group, there was statistically significant improvement in trough FEV 1 at week 2, which remained sustained and statistically significant at all the visits (p<0.05 at all the visits). The FS mean (SE) change from baseline in trough FEV1 at week 12 in the PPS population, using MMRM was 0.067 F [±0.02]) in the

G/FF/FP group. For the mean change from baseline in trough FEV1 at week 12 in the FDC of glycopyrronium 12.5 pg / formoterol fumaratel2 pg / fluticasone propionate 250 pg (G/FF/FP) compared to glycopyrronium 50 pg with FDC of formoterol fumarate 12 pg/fluticasone propionate 250 pg (G+FF/FP) p-value for NI was 0.13 and not non-inferior. In the G/FF/FP group there was statistically significant increase in trough FEV1 (SE) of 0.063 (±0.02) F compared to baseline, using ANCOVA with FOCF in the PPS population (p <0.05). See Figure 3. Table 6: Analysis of Lung Function Trough FEV1 (L) and Change from baseline in the

PPS Population using MMRM

With post-hoc statistical treatment of outliers (as per US-FDA guidance 1998), the p-value for non-inferiority was significant in FAS and PPS using both MMRM and ANCOVA-LOCF, thus demonstrating non-inferiority of G/FF/FP vs. G+FF/FP.

Table 7: Post-hoc after outlier treatment. Analysis of Lung Function Trough FEV1 (L) and Change from baseline in the PPS Population, using MMRM

Table 8: Post-hoc Analysis of Lung Function Trough FEV1 (L) and Change from baseline in the PPS Population, using ANCOVA and LOCF

Secondary Efficacy Endpoints:

All the secondary efficacy endpoints were achieved, demonstrating comparability between the test and reference group and supporting the non-inferiority results of the primary endpoint.

Change from Baseline in Post-dose FEVl at Week 12 of Treatment

The change from baseline in post-dose FEVl at week 12 was statistically significant in the G/FF/FP group (P <0.01). There was a statistically significant increase in FEVl 1 h post dose, after the first dose in the G/FF/FP group at Day 0 (p<0.01) which was sustained until week 12. The change from baseline in post-dose FEVl at week 12 was comparable between the 2 groups with a FS mean difference (95% Cl) of -0.022 (-0.073, 0.028) F and P =0.3801. See Figure 4.

Table 9: Analysis of Lung Function Post-Dose FEVl (L) and Change from baseline by Visits

Change from baseline in trough forced vital capacity (FVC) at week 12 of treatment

At baseline, the mean (SD) trough FVC values in the FAS were comparable between the treatment groups. There was a statistically significant increase in trough FVC compared to baseline in both treatment groups at all visits (both P <0.05). In the GB/FF/FP group, there was statistically significant improvement in trough FVC at week 2, which remained sustained and statistically significant at all the visits (P <0.05 at all the visits). The within group mean (SD) change from baseline in trough FVC at week 12 was statistically significant: GB/FF/FP group and was 0.0813 (±0.29557) F, (P =0.0003). The FS mean change in trough FVC at week 12 of treatment in the GB/FF/FP group was 0.087 (±0.0232) F and in the GB±FF/FP group was 0.109 (±0.0240) F using a MMRM model in the FAS. The difference in change from baseline in trough FVC at week 12 between GB/FF/FP group and GB±FF/FP group was -0.022 (±0.0310) F (95% Cl: -0.083, 0.039) and was not statistically significant (P =0.4816), thus demonstrating comparability between the two treatments. There was no difference in change from baseline in trough FVC at week 12 between the test and reference groups. See Figure 5.

Change from baseline in modified Medical Research Council (mMRC) score

In the G/FF/FP group, there was statistically significant improvement in the mMRC score at week 2, which remained sustained and statistically significant at all the visits (p<0.01 at all the visits). In the FAS, the FS mean (SD) change from baseline in mMRC score at week 12 was comparable across the two groups (-0.0 [95% Cl: -0.1, 0.1], P =0.96). Both groups were comparable with regard to change from baseline in breathlessness measured by mMRC score at Visit 3, Visit 4, Visit 5 and Visit 6 between the test and reference groups supporting noninferiority of the two groups. See Figure 6.

Rescue medication use averaged over week 11 and 12 of treatment There was a statistically significant reduction in the use of rescue medication in the G/FF/FP group (p<0.01). In the FAS population the mean rescue medication use decreased from 0.26 puffs/day at baseline to 0.13 puffs/day at end of treatment (week 11 and 12 of treatment period) in the G/FF/FP group. There was a no difference between the two treatment groups for rescue medication use using MMRM (P =0.3387) with a LSM change from baseline in rescue medication use averaged over week 11 and 12 of treatment being reported as -0.122 puffs/day in the G/FF/FPgroup demonstrating comparability of the two groups.

Table 10: Summary of Rescue medication use averaged over week 11 and 12 of treatment

Frequency of exacerbations during week 0 to 12 weeks of treatment in both the groups

In the FAS, 8/197 (4.1%) of the subjects in G/FF/FP group reported at least one exacerbation of

COPD during the 12 week treatment period compared to 10/190 (5.3%) in the G+FF/FP group. The difference in the proportion of subjects with exacerbations between the 2 groups was comparable supporting non-inferiority of the two groups. In the FAS, the proportion of subjects with one exacerbation, two exacerbations, > three exacerbations during week 0 to week 12 was comparable between the 2 groups.

Frequency of hospitalization during week 0 to 12 weeks of treatment in both the groups In the FAS, total number of hospitalizations were 3 in the G/FF/FP group (Hospitalization rate = 0.015 or 1.5%) compared to 5 in the G+ FF/FP group (Hospitalization rate = 0.026 or 2.6%). 3/197 (1.5%) of the subjects in G/FF/FP group were hospitalized during the 12 week treatment period compared to 1/190 (0.5%) in the G+FF/FP group. The proportion of subjects with hospitalization between the 2 groups was comparable.

Safety Results:

Overall, the safety profile of FDC of glycopyrronium 12.5 pg / formoterol fumarate 12 pg / fluticasone propionate 250 pg (G/FF/FP) was comparable to that of glycopyrronium 50 pg with FDC of formoterol fumarate 12 pg/fluticasone propionate 250 pg (G+FF/FP) group over 12 weeks of treatment in subjects with COPD. G/FF/FP was found to be safe and well tolerated.

The incidence of treatment emergent adverse events (TEAEs) was comparable across the 2 treatment groups; the incidence of TEAEs was 25.3% in the G/FF/FP group and 24.9% in the G+FF/FP group. Most of the TEAEs were mild-to-moderate and were resolved.

Table 11: Summary of Subjects with TEAEs Safety Population

From the above stated results, it can be concluded that overall FDC DPI (fixed dose combination dry powder inhaler) comprising gycopyrronium, formoterol and fluticasone propionate was found to be efficacious and safe in patients with COPD. FDC of glycopyrronium 12.5 pg / formoterol fumarate 12 pg/fluticasone propionate 250 pg (G12.5/FF12/FP250) was associated with significant improvements from baseline in trough FEV 1 , post-dose FEV 1 , trough FVC, mMRC score and rescue medication use. Overall, this study demonstrated that FDC of glycopyrronium 12.5 pg/ formoterol fumarate 12 pg/ fluticasone propionate 250 pg increased trough FEV1 at 12 weeks and demonstrated comparability with glycopyrronium 50 pg with FDC of formoterol fumarate 12 pg/fluticasone propionate 250 pg. FDC of glycopyrronium 12.5 pg/ formoterol fumaratel2 pg/fluticasone propionate 250 pg was found to be non-inferior to glycopyrronium 50 pg with FDC of formoterol fumarate 12 pg/fluticasone propionate 250 pg with statistical significance in subjects with COPD.

The secondary endpoints were met consistently across post-dose FEV1, Trough FVC, mMRC score, rescue medication usage, hospitalization rates and exacerbation rates. The treatment emergent adverse events were found to be similar across arms. Most of the AEs were mild to moderate. Overall, The FDC of glycopyrronium 12.5 pg/ formoterol fumaratel2 pg/fluticasone propionate 250 pg as a DPI was safe and well tolerated for use in subjects with COPD. Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.

All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

1. An inhalable fixed dose dry powder composition comprising:

(a) an effective amount of glycopyrronium bromide,

(b) an effective amount of formoterol fumarate dihydrate,

(c) an effective amount of fluticasone propionate, and

(d) a pharmaceutically acceptable carrier.

2. The dry powder composition according to claim 1, wherein the composition is free from a hydrophobic excipient.

3. The dry powder composition according to claim 1 or claim 2, wherein the composition is free from a hydrophobic excipient selected from magnesium stearate, calcium stearate, amino acids, fatty acid, peptides and phospholipids.

4. The dry powder composition according to any one of claims 1-3, wherein the pharmaceutically acceptable carrier is selected from lactose, mannitol, trehalose, sucrose and any mixture thereof.

5. The dry powder composition according to any one of claims 1-4, wherein the pharmaceutically acceptable carrier is lactose monohydrate.

6. The dry powder composition according to any one of claims 1-5, wherein the pharmaceutically acceptable carrier is a admixture of lactose particles comprising: i) about 0.1 to about 10 % w/w of particles of lactose having a particle size D90 less than about 50pm; and (ii) about 90 to 99.9 % w/w of particles of lactose having a particle size D90 more than about 150 pm.

7. The dry powder composition according to any one of claims 1-6, wherein the pharmaceutically acceptable carrier is a admixture of (i) lactose particles having a particle size D50 less than about 30pm and (ii) lactose particles having a particle size D50 more than 80 pm.

8. The dry powder composition according to any one of claims 1-7, where the composition is filled into a capsule or into a blister for use in a dry powder inhaler.

9. The dry powder composition according to claim 8, wherein the dry powder inhaler is selected from a single dose capsule inhaler device and a multiple dose capsule inhaler device.

10. The dry powder composition according to claim 9, wherein the composition is filled into a capsule for use in the single dose capsule inhaler device.

11. An inhalable fixed dose dry powder composition comprising:

(a) about 5 pg to about 50 pg of glycopyrronium or its pharmaceutically acceptable salt,

(b) about 5 pg to about 25 pg of formoterol or its pharmaceutically acceptable salt, and

(c) about 50 pg to about 500 pg of fluticasone propionate, and a lactose admixture comprising (i) about 0.1 to about 10 % w/w of particles of lactose having particle size D50 less than about 30 pm; and (ii) about 90 to about 99.9 % w/w of particles of lactose having particle size D50 more than about 80pm;

wherein the composition is free from hydrophobic excipients.

12. A process for preparing an inhalable fixed dose dry powder composition, the process comprising:

(i) mixing glycopyrronium bromide, formoterol fumarate dihydrate and fluticasone propionate with particles of lactose having an average particle size less than about 30 pm;

(ii) blending the mixture obtained in step (i) with lactose having average particle size of about more than 80 pm and;

(iii) filling the blend of step (ii) in a capsule or a blister.

13. The process according to claim 12, wherein about 1% w/w to about 10% w/w of the lactose particles have a D90 particle size less than about 50 pm and about 90% to about 99% w/w of the lactose particles have a D90 particle size more than about 150 pm.

14. The process according to any one of claims 12-13, wherein the process does not include any step of co-micronization.

15. The process according to any one of claims 12-14, where the glycopyrronium bromide, formoterol fumarate dihydrate and fluticasone propionate are in micronized form having D50 value of each drug not more than 5 pm, preferably not more than 4 pm and/or D90 of each drug not more than 10 pm, preferably not more than 6 pm.

16. The dry powder composition according to any one of claims 1-11, wherein the composition has D50 values as less than 120 pm or less than 100 pm.

17. The dry powder composition according to any one of claims 1-11, wherein the composition has D90 values as about 120 pm to about 200 or about 150 pm to about 180 pm.

18. The dry powder composition to any one of claims 1-11, wherein the composition has fine particle mass having particle size less than about 50pm is in the range of about 5% to about 30% and/or coarse particle mass having particle size more than 80 pm is in the range of about 20% to about 90%w/w.

19. The dry powder composition according to claim 10, wherein the capsule comprises gelatin or HPMC having a reduced moisture content less than 15% w/w, such as less than 10% w/w.

20. The dry powder composition according to any one of claims 1-11, wherein the composition has a bulk density in the range of about 0.3 g/ml to about 1 g/ml and/or a tapped density in the range of about 0.5 g/ml to about 1.25 g/ml.

21. An inhalable fixed dose dry powder composition comprising:

(a) glycopyrronium bromide,

(b) formoterol fumarate,

(c) fluticasone propionate, and

(d) an admixture of fine lactose monohydrate particles and coarse lactose monohydrate, wherein

(ii) the fine lactose particles have a D50 of from about 2pm to about 20 pm and/or a D90 from about 4 pm to about 50 pm,

(iii) the coarse lactose particles have a D50 of from about 80 pm to about 130 pm and/or a D90 from about 150 to about 200 pm, and

(iv) the composition is free or substantially free of hydrophobic excipients and/or propellants.

22. The composition of claim 21, wherein the composition is encapsulated in a capsule, wherein (i) the capsule comprises hydroxypropyl methylcellulose and (ii) the composition, when tested for aerodynamic particle size distribution, results in a fine particle mass for (a) glycopyrronium bromide of from about 2 pg to about 5 pg, (b) formoterol fumarate of from about 2 pg to about 5 pg, and (c) fluticasone propionate of from about 45 pg to about 70 hg·

23. The composition of claim 21 or 22, wherein the fine lactose particles have a D50 of from about 2 pm to about 10 pm and/or a D90 of from about 5 pm to about 20 pm.

24. The composition of any one of claims 21-23, wherein the fine lactose particles have a D50 of no more than 5 pm and/or a D90 of no more than 10 pm.

25. The composition of any one of claims 21-24, wherein the coarse lactose particles have a D50 of from about 95 pm to about 125 pm and/or a D90 from about 160 pm to about 190 pm.

26. The composition of any one of claims 21-25, wherein the weight ratio of fine lactose particles to coarse lactose particles ranges from about 1: 100 to about 1:7.

27. The composition of claim 26, wherein the weight ratio of fine lactose particles to coarse lactose particles ranges from about 1: 15 to about 1 :40.

28. A method of treating a respiratory disease in a subject in need thereof comprising inhalation administration of a pharmaceutical composition comprising:

(a) an effective amount of glycopyrronium bromide,

(b) an effective amount of formoterol fumarate dihydrate,

(c) an effective amount of fluticasone propionate, and

(d) optionally, a pharmaceutically acceptable carrier.

29. The method according to claim 28, where the composition is free of a hydrophobic excipient.

30. The method according to claim 28 or 29, where the composition is free of a hydrophobic excipient selected from magnesium stearate, calcium stearate, amino acids, fatty acid, peptides or phospholipids.

31. The method according to any one of claims 28-30, wherein the amount of glycopyrronium or its salt is from about 5 meg to about 50 meg, the amount of formoterol or its salt is from about 5 meg to about 50 meg and the amount of fluticasone propionate is from about 50 meg to about 500 meg.

32. The method according to any one of claims 28-31, wherein the composition comprises glycopyrronium or its salt, formoterol or its salt, and fluticasone or its salt in the weight ratio from about 1:0.1: 10 to about 1:2:200 or from about 1:0.5: 100 to about 1 : 1 :50 or from about 0.8: 1: 15 to about 2.5: 1:25.

33. The method according to any one of claims 28-32, wherein the composition is administered to a subject in need at least once or at least twice daily.

34. The method according to any one of claims 28-33, wherein the composition is administered to a subject in need thereof by inhalation using a suitable dry powder inhaler.

35. The method according to claim 34, wherein the dry powder inhaler is selected from a single dose capsule inhaler device and a multiple dose capsule inhaler device.

36. The method according to claim 34 or 35, wherein the inhaler is capable of delivering 12.5 meg or 25 meg of glycopyrronium, 12 meg of formoterol fumarate dihydrate and 250 meg of fluticasone propionate upon each actuation.

37. The method according to any one of claims 28-36, wherein the respiratory disease is COPD and /or asthma.

38. The method according to any one of claims 28-37, wherein the composition provides an improvement in lung function in a subject having a respiratory disease in the span of at least about 4 weeks, at least about 8 weeks or at least about 12 weeks.

39. The dry powder composition according to claim 10, wherein the inhaler device comprises a single medicament chamber for holding the capsule, a rotatable mouthpiece and a piercing means for perforating the said capsule, contained in said capsule.

40. A dry powder inhaler device for administration of a fixed dose inhalable composition, the composition comprising glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt, fluticasone propionate and lactose monohydrate, wherein the inhaler device comprises a medicament chamber for holding a capsule comprising the composition, a rotatable mouthpiece and a piercing means for perforating the capsule.