NZ613915B2

NZ613915B2 - Combination of glycopyrrolate, fluticasone and indacaterol

Info

Publication number: NZ613915B2
Application number: NZ613915A
Authority: NZ
Inventors: Geena Malhotra; Shrinivas Madhukar Purandare
Original assignee: Cipla Limited
Priority date: 2011-02-17
Filing date: 2012-02-17
Publication date: 2015-12-01

Abstract

Provided are pharmaceutical compositions comprising glycopyrrolate, a beta2-adrenergic agonist, and optionally a corticosteroid. Exemplified beta2-adrenergic agonists include indacaterol, formoterol, vilanterol, carmoterol and olodaterol. Exemplified corticosteroids include fluticasone and mometasone. The compositions can be used in the treatment of respiratory, inflammatory or obstructive airway diseases. e. The compositions can be used in the treatment of respiratory, inflammatory or obstructive airway diseases.

Description

Combination of glycopyrrolate, ﬂuticasone and indacaterol Field of Invention The present invention relates to pharmaceutical compositions for inhalation which se one or more bronchodilators and optionally an inhaled corticosteroid. There is also provided a process for preparing such compositions and the use thereof in the treatment and/or prevention of respiratory, inﬂammatory or obstructive airway disease, particularly chronic obstructive pulmonary disease.

Background of ion Chronic obstructive pulmonary disease (COPD) is a severe respiratory condition that is increasing its prevalence worldwide. In India, the estimated prevalence is about 12.36 million. It is currently the fourth leading cause of death in the UK & US, and predicted to rank third in the global impact of disease by the year 2020.

COPD is a preventable and treatable disease state characterized by air flow tion that is not fully reversible. The airﬂow obstruction is usually progressive and associated with an abnormal inﬂammatory response of the lungs to noxious particles or gases, primarily caused by cigarette g. Although COPD affects the lungs it also produces cant systemic consequences. COPD is associated with mucus hyper secretion, emphysema, bronchiolitis.

The major goals of COPD therapy include smoking cessation, relief of ms, improvement in physiological functions and limiting complications, such as abnormal gas exchange and exacerbation of disease. However, an integrated approach to the treatment of COPD, involves a ation of healthcare maintenance such as smoking cessation, avoidance of , outdoor pollutants and allergens, and avoidance of occupational exposure to allergens, use of drugs and mental therapies in a ise fashion as the e progresses.

Currently, therapy for the treatment or prevention of COPD and asthma includes the use of one or more long acting bronchodilators and an inhaled osteroid (ICS).

Inhaled bronchodilators are the foundation in the therapy of COPD e of their ty to alleviate symptoms, decrease exacerbations of disease and improve quality of life. These drugs also improve airﬂow limitation and hyperinﬂation, thereby decreasing the work of breathing and improving exercise tolerance. In addition, bronchodilators may reduce respiratory muscle fatigue and improve mucociliary clearance.

More speciﬁcally, the choice of bronchodilators includes betag-agonists and anticholinergics. Further, betaz-agonists can be short acting for immediate relief, or long acting for long term prevention of asthma symptoms.

Long acting agonists (LABAs) improve lung function, reduce symptoms and protect against exercise-induced dyspnea in patients with asthma and COPD. LABAs induce bronchodilation by causing ged tion of airway smooth muscle. In addition to prolonged bronchodilation, LABAs exert other effects such as inhibition of airway smooth-muscle cell proliferation and inﬂammatory mediator release, as well as non smooth-muscle effects, such as stimulation of mucociliary transport, cytoprotection of the respiratory mucosa and attenuation of neutrophil recruitment and activation.

Also, use of a LABA reduces the ncy of drug administration. Commercially available LABAs include salmeterol and formoterol. olinergic agents also act as bronchodilators and are potential alternatives to beta agonists, particularly LABAs. r, anticholinergics can also be administered along with LABAs for the management of asthma. Anticholinergics act by competing with acetylcholine for the or sites at vagus nerve or nerve-muscle junctions. This prevents the transmission of reﬂexes that are induced by asthma stimuli.

Use of anticholinergics provides an advantage in elderly patients as the responsiveness of beta2~agonists declines with old age. Further it would be advantageous to use anticholinergics in patients who are intolerant to the use of betaz-agonists.

Even though it is know that betaz—agonists provide a symptomatic relief in bronchoconstriction, another ent of COPD, which is inﬂammation, requires a separate treatment such as with steroids. Most of the inhaled corticosteroids need to be administered in multiple dosage regimens.

Corticosteroids exhibit inhibitory effects on inﬂammatory cells and inﬂammatory ors involved in the pathogenesis of respiratory disorders such as COPD. ent with a corticosteroid/glueocorticoid is considered one of the most potent and effective therapies tly available for COPD.

However, the use of corticosteroids has been limited due to potential side effects associated with their use, including suppression of the Hypothalamic-Pituitary-Adrenal (HPA) axis, adverse effects on bone growth in children and on bone density in the elderly, ocular complications (cataract ion and glaucoma) and skin atrophy.

Commercially available corticosteroids include beclomethasone, budesonide, ﬂuticasone, mometasone, ciclesonide and triamcinolone. tly, there are l commercially available pharmaceutical compositions for inhalation comprising combinations of LABA and inhaled corticosteroid (ICS). es of such ations for the treatment of asthma and chronic obstructive pulmonary e (COPD) are salmeterol/ﬂuticasone propionate (Advair® diskus®, Advair® HFA), and erol fumarate dehydrate/budesonide (Symbicort®).

Thus combination therapy of a bronchodilator with an ICS improves pulmonary efﬁciency, reduces inﬂammatory response and provides symptomatic relief as compared to higher doses of ICS alone in patients affected by respiratory disorders such as COPD.

W0 2012/1 10770 PCT/G32012/000171 The selection of a speciﬁc bronchodilator and ICS plays a very important role in ation of ﬁxed dose combination therapies.

Further, combination therapy reduces the cost and also provides control of reSpiratory disorders. Reducing the dose frequency to the minimum is a main step in simplifying COPD management for improving patient adherence to the y.

USZOO9088408 discloses pharmaceutical compositions of anticholinergics, corticosteroids and betamimetics and their use in the ent of atory diseases.

The es of this application are inhalable powders or suspension aerosol compositions which contain tiotropium or opium bromide.

USZOOSO42174 discloses a combination of doses of a betaz-agonist, an anticholinergic agent and an anti-inﬂammatory steroid.

W02006105401 discloses anticholinergic in combination with a corticosteroid, and a long acting beta agonist, for simultaneous or tial administration in the prevention or treatment of a respiratory, atory or obstructive airway disease.

U82008279948 discloses a medicament sing a betaz-agonist, a glycopyrronium salt and mometasone furoate. The examples of this application contain the betaz-agonist indacaterol maleate.

U82008286363 discloses a medicament comprising a agonist (such as indacaterol maleate), a glycopyrronium salt and a corticosteroid. The examples of this application contain the corticosteroid 3-methyl—thiophene-2~carboxylic acid (6S,9R, 1 OS, 1 13,13 S, 16R, l7R)chloroﬂuoro- l l—hydroxy-l 7—methoxycarbonyl- ,13,l6-trimethyloxo-6,7,8,9,10,1 l ,12,13,l4,15, l6, l7-dodecahydro-3H~cyclopenta— [a]phenanthrenyl ester.

U82010166671 discloses a medicament comprising an antimuscarinic agent, a beta;- agonist and a corticosteroid. The examples of this application contain glycopyrronioum, formoterol fumarate and mometasone furoate.

US7439393 discloses n hanolamine tives for the treatment of respiratory diseases. The use of such compounds in combination therapy with other therapeutic agents is also disclosed.

U820080041369 discloses propellant-free aerosol formulations comprising inter alia olodaterol, a corticosteroid such as budesonide, beclomethasone or ﬂuticasone and an anticholinergic such as tiotropium, oxitropium or ipratropium.

U820050239778 discloses medicament combinations comprising inter alia olodaterol and at least one other active substance, such as a steroid.

USZOO80317862 ses medicaments comprising an antimuscarinic agent and a corticosteroid for the ent of inﬂammatory or obstructive airways diseases. In particular, this application discloses aerosol compositions comprising glycopyrronium and mometasone e.

U820060069073 discloses a combination of glycopyrronium and one or more steroids as a second active substance.

W02005110402 ses medicaments comprising glycopyrrolate in combination with betaz-agonist such as indacaterol maleate.

W020050749OO discloses a combination of an anticholinergic such as glycopyrronium and a long-acting beta-mimetic agent such as formoterol or salmeterol.

Thus, there is still a need to p suitable combinations comprising a beta t, an olinergic agent and/or an inhaled corticosteroid that alleviate COPD.

PCT/G32012/000171 Hence, there still exits a need to formulate ceutical compositions cemprising a beta agonist, an anticholinergic agent and an d corticosteroid exhibiting reduced side effects and which can be administered once a day.

Objects of the Invention The object of the present invention is to provide pharmaceutical compositions for inhalation comprising one or more bronchodilators and an inhaled corticosteroid for administration in the prevention or treatment of respiratory, inﬂammatory or obstructive airway disease.

Another object of the present invention is to e pharmaceutical compositions for inhalation comprising one or more bronchodilators and an inhaled corticosteroid for once daily administration for the prevention or treatment of respiratory, inﬂammatory or obstructive airway disease.

Yet another object of the present invention is to provide a process for preparing the pharmaceutical compositions comprising one or more odilators and an inhaled osteroid for administration in the prevention or ent of respiratory, atory or obstructive airway disease.

A further object of the present invention is to provide a method for prophylaxis or ent of COPD which comprises administering pharmaceutical compositions comprising one or more bronchodilators and an inhaled corticosteroid.

Summag of the Invention According to a ﬁrst aspect of the t invention, there is provided a pharmaceutical composition comprising glycopyrrolate and a betaz-agonist.

Preferably the ition further comprises one or more inhaled corticosteroids.

PCT/GBZOlZ/000171 According to a second aspect of the present invention, there is provided a pharmaceutical composition comprising glycopyrrolate and vilanterol.

According to a third aspect of the present invention, there is provided a pharmaceutical composition comprising glycopyrrolate and olodaterol.

According to a fourth aspect of the present invention, there is provided a ceutical composition comprising yrrolate and cannoterol.

According to a ﬁfth aspect of the present invention, there is ed a ceutical composition comprising glycopyrrolate, olodaterol and ﬂuticasone, especially an ester of ﬂuticasone, in particular ﬂuticasone furoate.

According to a sixth aspect of the present invention, there is provided a pharmaceutical composition comprising glyc0pyrroiate, olodaterol and mometasone, eSpecially an ester of mometasone, in particular mometasone ﬁiroate.

According to a seventh aspect of the present invention, there is provided a pharmaceutical composition comprising glyc0pyrrolate, erol and asone, ally an ester of ﬂuticasone, in particular ﬂuticasone furoate.

According to a eighth aspect of the present invention, there is provided a pharmaceuticai composition comprising glycopyrrolate, fomoterol and ﬂuticasone, especially an ester of ﬂuticasone, in particular ﬂuticasone furoate.

According to a ninth aspect of the present invention, there is provided a pharmaceutical ition comprising glycopyrrolate, indacetrol and ﬂuticasone, eSpecially an ester of sone, in particular sone furoate.

According to a tenth aspect of the present invention, there is provided a process for preparing the pharmaceutical compositions described above.

W0 2012/1 10770 According to a eleventh aspect of the present invention, there is provided a method for prophylaxis or treatment of asthma, COPD or a related respiratory disorder which comprises administering a pharmaceutical itions described above.

According to a twelfth aspect of the present invention there is provided a use in treating disorders or conditions that respond to, or are prevented, ameliorated or eliminated by, the administration of pharmaceutical compositions described above.

Detailed ption of the Invention As discussed above, the selection of a c betag-agonist, anticholinergic agent and d corticosteroid (lCS) plays a very important role in formulation of ﬁxed dose combinations.

The present invention thus provides pharmaceutical compositiOns for inhalation comprising or consisting of glycopyrrolate, a betag-agonist, and an inhaled corticosteroid.

In one embodiment, there is provided a pharmaceutical composition for tion sing or consisting of: (a) yrrolate; (b) a betag—agonist ed from the group consisting of carmoterol, formoterol, indacaterol, olodaterol, vilanterol; and, optionally, when the LABA is selected from formoterol, indacaterol, olodaterol, vilanterol; (c) an inhaled corticosteroid (1C8) ed from the group consisting of ﬂuticasone, mometasone; preferably wherein (a), (b) and (c) are formulated for simultaneous, separate or sequential administration; and provided that the composition does not comprise glycopyrrolate, sone furoate and indacaterol maleate or formoterol fumarate.

A particularly preferred pharmaceutical composition of the present invention comprises, or consists of, (a) glycopyrrolate (b) indacaterol and (c) ﬂuticasone (especially fluticasone furoate).

A further ularly preferred pharmaceutical composition of the present invention comprises, or consists of, (a) glycopyrrolate, (b) formoterol and (c) ﬂuticasone (especially ﬂuticasone ﬁiroate).

A further particularly preferred pharmaceutical composition of the present invention comprises, or consists of, (a) yrrolate (b) vilanterol and (c) asone (especially ﬂuticasone ﬁiroare).

A further particularly preferred pharmaceutical ition of the present invention comprises, or consists of, (a) glycopyrrolate, (b) olodaterol and (c) sone (eSpecially ﬂuticasone furoate).

A still further particularly preferred pharmaceutical composition of the present ion comprises, or consists of, (a) yrrolate, (b) olodaterol and (c) mometasone.

In an alternative preferred embodiment of the invention, there is provided a ceutical composition comprising or consisting of glycopyrrolate and a beta;- agonist.

In a still further preferred embodiment of the invention, there is provided a pharmaceutical composition comprising or consisting of (a) yrrolate; and (b) a betaz-agonist selected from the group consisting of carmoterol, olodaterol, vilanterol; preferably wherein (a) and (b) are formulated for simultaneous, separate or sequential administration.

W0 2012,11 10770 ZO12/000171 A particularly preferred pharmaceutical composition of the present invention comprises, or consists of, (a) yrrolate and (b) vilanterol.

A further particularly preferred pharmaceutical composition of the present invention comprises, or ts of, (a) glycopyrrolatc and (b) olodaterol.

A still further particularly preferred pharmaceutical composition of the present invention comprises, or consists of, (a) glycopyrrolate and (b) carmoterol.

Our inventors have found that the above-mentioned ceutical compositions are effective for treating inﬂammatory and/or obstructive diseases of the respiratory tract, particularly asthma or chronic obstructive pulmonary disease (COPD).

Furthermore, the ceutical compositions of the present invention advantageously provide a rapid onset of action, longer duration of action and improved control of obstructive or inﬂammatory airway diseases, or reduction in the bations of the diseases.

Also, the pharmaceutical compositions of the present invention advantageously reduce the risk of undesirable side effects as compared to the repeated exposure of the steroid alone involved in the treatment of inﬂammatory or ctive airways diseases.

Another advantage of the pharmaceutical compositions of the present invention is that the invention facilitates the treatment of an obstructive and inﬂammatory airway e with a single medicament.

Further the pharmaceutical itions of the present invention provide for the administration of combination ies by use of a single inhaler for patients who currently have to make use of multiple inhalers. By way of example, patients may administer ceutical compositions of the present invention from a single inhaler instead of administering from three different inhalers, one for corticosteroid, one for WO 10770 anticholinergic and one for a long acting betaz—agonist. This is particularly important in case of elderly patients who may get conﬁised between the inhalers and who also suffer from several other medical conditions such as heart disease and arthritis, and are receiving multiple other tions.

In a preferred embodiment, the pharmaceutical compositions of the present invention are formulated for once daily administration.

The pharmaceutical compositions of the present invention comprise glycopyrrolate. The word “glycopyrrolate” can be interchangeably used with “glycopyrronium”.

Glycopyrrolate belongs to the class of quaternary ammonium anticholinergic drugs and antagonizes the neurotransmitter choline at its muscarinic receptors. This effect leads to a considerable smooth muscle tion ing in a prolonged bronchodilating effect. More speciﬁcally it inhibits acetylcholine binding to M3 muscarinic receptors thereby ting bronchoconstriction.

Glycopyrrolate is a quatemary ammonium salt. Suitable counter ions are ceutically acceptable counter ions including, for example, e, chloride, bromide, iodide, e, sulfate, phosphate, formate, acetate, triﬂuoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, te, p-chlorobenzoate, diphenyl-acetate or triphenylacetate, o-hydroxybenzoate, oxybenzoate, l- hydroxynaphthalene~2-carboxylate, 3-hydroxynaphthalenecarboxylate, methanesulfonate and benzenesulfonate. A particularly preferred salt of glycopyrrolate is the bromide salt thereof. The bromide salt of glycopyrrolate is chemically known as {3- [(Cyclopentyl-hydroxyphenylacetyl) oxy]—l, l-dimethylpynrolidinium bromide}.

Glycopyrrolate has two centers of asymmetry (chiral centers), and can exist in four stereoisometric forms namely (3R, 2'R)-, (38, 2'R)-, (3R, 2'S)- and (38, 2‘8), i. e. , two enantiomeric pairs of diastereomers. The two di- astereomer pairs have been ted from one another. Commercially available formulations of yrrolate contain both the (R, S)~glycopyrrolate and (S, R)-glycopyrrolate enantiomers.

W0 2012A 10770 Glycopyrrolate is currently available marketed in the form of oral tablets for adjunctive therapy in the treatment of peptic ulcer, as an injectable for therapy in the treatment of peptic ulcer and as a preoperative antimuscarinic to reduce secretions and as a capsule for reducing chronic severe drooling in patients aged between 3 to 16 years with neurologic conditions associated with problem drooling.

Glycopyrrolate also prevent the effects resulting from passage of es through the parasympathetic . This action results from their ability to inhibit the action of ransmitter acetylcholine by blocking its g to muscarinic cholinergic ors. Further, inhaled glycopyrrolate ts low systemic tion, and therefore is not associated with typical systemic antimuscarinic adverse effects.

According to the present invention, glycopyrrolate may be t in an amount of from about 50mcg to about ZOOmcg.

Bronchodilators used according to the present invention may be beta-agonists and/or anticholinergics. ing to the t invention, beta agonists may comprise, one or more, short acting beta agonist(s), long acting beta agonist(s) and/or ultra long acting beta agonist(s).

In addition to glycopyrrolate, the pharmaceutical compositions of the present invention further comprise a beta2~agonist, preferably selected from the group comprising erol, formoterol, indacaterol, olodaterol, vilanterol.

Carmoterol is chemically known as 8—hydroxy-5 - (l-hydroxy(N—(2-(4- methoxyzphenyl) -l-methyl:ethyl) amino)ethyl)-2 (lH)-quinolinone. erol is a long acting betaz-agonist characterized by having a rapid onset of action, prolonged duration of action and also having a high selectivity towards the beta; adrenoreceptor.

Furthermore, carmoterol is more potent than other LABAs such as formoterol and salmeterol. A particularly preferred pharmaceutically acceptable salt of carmoterol W0 2012/1 10770 PCT/GBZ012/000171 carmoterol hydrochloride. According to the present invention, carmoterol may be present in an amount of from about lmcg to about 4mcg. erol is chemically known as hydroxy[(1RS)-l-hydroxy[[(lRS)-2~(4— methoxyphenyl)-lmethylethyl]-amino] ethyl] formanilide. Formoterol is a selective LABA. Formoterol exhibits a quick onset of action (1-3 minutes) which helps to achieve an immediate therapeutic response. Furthermore formoterol exhibits a long duration of action of more than 12 hours. A particularly preferred pharmaceutically acceptable ester of formoterol is fonnoterol fumarate. A particularly preferred pharmaceutically acceptable ester of formoterol is formoterol fumarate dihydrate. According to the present ion, formoterol may be present in an amount of from about 12 to about 24mcg, preferably about 24mcg.

Indacaterol is chemically known as (R)-5—[2~[(5,6-Diethyl-2,3.dihydro-1H—inden-2— yl)amino]-l-hydroxyethyl]hydroxyquinolin-2(lilo-one is a uItra~Iong acting betaz- agonist. Indacaterol has a fast onset of action which is r to that of formoterol and faster than that of salmeterol. rmore, indacaterol exhibits a longer duration of action than salmeterol as well as has greater cardiovascular safety margin as compared to salmeterol and erol. A ularly preferred pharmaceutically acceptable salt of indacaterol is indacterol maleate. According to the present ion, indacaterol may be present in an amount of from about 25mcg to about 800mcg.

Olodaterol is chemically known as 6-hydroxy—8-K1R);l-hydroxy~2-{[2-(4~ methoxyphenyl)— l , l-dimethylethyl]amino]ethyl]~2H—1,4—benzoxazin—3(4H)- one. A particularly preferred ceutically acceptable salt of olodaterol is olodaterol hydrochloride monohydrate. According to the present invention, olodaterol may be present in an amount of from about 3mcg to about SOmcg.

Vilanterol is chemically known as 4-{(l R)[(6- {2-[(2,6— dichlorobenzyl)oxy]ethoxy}hexyl)amino]-l-hydroxyethyl}(hydroxymethyl)phenol is a long acting beta2-agonist. A particularly preferred pharmaceutically acceptable salt of W0 2012/1 10770 vilanterol is vilanterol trifenatate. According to the present invention, vilanterol may be present in an amount of from about 3mcg to about SOmcg.

In addition to glycopyrrolate and a betaz—agonist, the pharmaceutical compositions of the present invention may also comprise a corticosteroid; preferably selected from the group consisting of mometasone, ﬂuticasone.

Fluticasone is currently cially available as a furoate salt and a propionate salt.

Fluticasone furoate is a novel corticosteroid which ntially overcomes the potential side effects that are generally produced by the use of conventional corticosteroids.

Moreover ﬂuticasone furoate exhibits a 1.7 times higher binding afﬁnity for the human glucocorticoid receptor as compared to that of ﬂuticasone propionate and also provides prolonged protection up to 26 hours against airway hyperresponsiveness as compared to ﬂuticasone propionate. asone furuoate has a longer duration of action with an ation half life of 15.1 hrs.

Fluticasone e is a synthetic fluorinated corticosteroid that has been developed as an asal treatment for patients with symptoms of rhinitis and has an enhanced afﬁnity towards the glucocorticoid receptor. Further, ﬂuticasone furoate has greater potency than other ally used corticosteroids such as mometasone furoate, budesonide, fluticasone propionate, ciclesonide for the glucocorticoid receptor and against the proinflammatory transcription factors nuclear factor KB (NF-KB), tion protein-l, and tumor necrosis ~ induced interleukin-8 cytokine production. Chronic inﬂammation which is commonly ated with asthma is d by fluticasone furoate.

Particularly preferred phannaceutically acceptable esters of fluticasone are ﬂuticasone furoate and ﬂuticasone propionate, most preferably fluticasone e.

According to the present invention, ﬂuticasone furoate may be present in an amount of from about 25mcg to about 800mcg.

W0 2012/1 10770 PCT/G32012/000171 Mometasone furoate is chemically known as (11[B], l6[a])-9, 21-dichloro-l7-[(2- furanylcarbonyl) oxy]-1 1-hydroxy-l6-methylpregna-l,4-diene-3,20-dione. Mometasone furoate is a synthetic l7-heterocyclic corticosteroid and ts a long duration of action A particularly preferred pharrnaceutically able ester of mometasone is mometasone furoate. According to the present invention, mometasone e may be present in an amount of from about 400mcg to about 800mcg.

As used herein the terms “glycopyrronium”, “glycopyrrolate”, "ﬂuticasone e”, “mometasone furoare”, “carmoterol”, “olodaterol, “vilanterol’, terol” and “indacaterol” are used in broad sense to include not only “glycopyrronium”, “glycopyrrolate” “ﬂuticasone furoate” “mometasone furoare”, “carmoterol”, “clodaterol, “vilanterol’, ”formoterol” and “indacaterol” per se but also their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharrnaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, ceutically acceptable prodrugs, etc.

In on to active ceutical ingredients, the pharmaceutical compositions of the present ion typically comprise one or more pharmaceutically acceptable eXcipients.

The active ingredients may be used as separate formulations or as a single combined formulation. When combined in the same formulation, it will be appreciated that the active ingredients must be stable and compatible with each other and the other components of the formulation.

The pharmaceutical compositions of the present invention are formulated for inhalation and may therefore be administered by any suitable methods used for delivery of the drugs to the respiratory tract. For example, the ition of the present invention may be in the form of an aerosol composition, a nasal spray, nasal drops or an insufﬂation powder.

Such aerosol itions may be administered by any conventional means, for example using a metered dose inhaler (MDI), dry powder r (DPI) 0r nebulizer.

PCT/G32012/000171 The various dosage forms according to the present invention may comprise carriers/excipients suitable for formulating the same.

In one embodiment, the ceutical compositions of the present invention are in a form suitable for administration by a MDI, for example, in the form of an aerosol composition. Such compositions may comprise one or more pharmaceutically acceptable excipients, in particular selected from the group of HFC/HFA propellants, co—solvents, bulking agents, non-volatile ents, buffers/pH adjusting agents, surface active agents, preservatives, complexing agents, or combinations thereof.

Suitable pr0pellants are those which, when mixed with the cosolvent(s), form a homogeneous propellant system in which a eutically ive amount of the medicament can be dissolved. The I—IFC/HFA propellant must be toxicologically safe and must have a vapor pressure which is suitable to enable the ment to be administered via a pressurized MDI.

According to the present invention, the HFC/HFA propellants may comprise, one or more of l,l,1,2-tetraﬂuoroethane (HFA—134(a)) and 1,1,l,2,3,3,3,-heptaﬂuoropropane (HFA- 227), HFC-32 (diﬂuoromethane), HFC-l43(a) (l,l,l-triﬂuoroethane), HFC~134 (l,l,2,2— tetraﬂuoroethane), and HFC~152a (l,l-diﬂuoroethane) or combinations thereof and such other propellants which may be known to the person having a skill in the art.

In the context of the t invention, the term “co-solvent” means any t which is miscible in the ation in the amount desired and which, when added provides formulation in which the ment can be dissolved. The function of the co-solvent to increase the solubility of the medicament and the excipients in the formulation.

According to the present invention, the co-solvent may comprise one or more of, C2- C6 tic alcohols, such as, but not limited to, ethyl alcohol and isoprOpyl alcohol; glycols such as but not limited to propylene glycol, polyethylene glycols, opylene glycols, glycol ethers, and block copolymers of oxyethylene and oxypropylene; and other substances, such as, but not limited to, ol, polyoxyethylene alcohols, and polyoxyethylene fatty acid esters; hydrocarbons such as but not limited to n-propane, n~ , isobutane, n-pentane, iso-pentane, neo-pentane, and n-hexane; and others such as but not d to diethyl ether and combinations thereof. le surfactants which may be employed in an aerosol ition of the invention include those which may serve to stabilize the on formulation and improve the performance of valve systems of the metered dose inhaler. Preferred surfactants e one or more ionic and/or non~ ionic surfactants. Examples of suitbale surfactants include, but are not limited to, oleic acid, sorbitan trioleate, lecithin, isopropylmyristate, tyloxapol, nylpyrrolidone, polysorbates such as polysorbate 80, vitamin E-TPGS, and macrogol hydroxystearates such as macrogol~15~hydroxystearate and combinations thereof.

In the context of the present invention, the term “non~volatile component” refers to the suspended or ved constituents of the pharmaceutical composition that would remain after evaporation of the solvent(s) present.

According to the present invention, the n0n~volatile component may comprise one more of monosaccharides such as, but not limited to, glucose, ose; disaccharides such as lactose, maltose; oligosaccharides and polysaccharides such as, but not limited to, dextrans; polyalcohol such as, but not limited to, glycerol, ol, mannitol, xylitol; salts such as, but not limited to, potassium chloride, magnesium chloride, magnesium sulphate, sodium chloride, sodium citrate, sodium phosphate, sodium hydrogen phosphate, sodium hydrogen carbonate, potassium citrate, ium phosphate, potassium en phosphate, potassium hydrogen carbonate, calcium carbonate and calcium chloride and combinations thereof.

Suitable bulking agents may be employed in the pharmaceutical compositions of the invention, in particular aerosol compositions that are intended for administration using an MDI. The bulking agent may comprise one or more of saccharides, including PCT/G82012/000171 monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, se, ribose, mannose, e, terhalose, lactose, maltose, starches, dextran or mannitol and combinations f.

Suitable buffers or pH adjusting agents may be employed in the pharmaceutical compositions of the ion, in particular aerosol compositions that are intended for administration using an MDI. The buffer or the pH adjusting agent may comprise one or more of organic or inorganic acids such as, but not limited to, citric acid, ascorbic acid, hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid and combinations thereof.

Suitable preservatives may be employed in in the pharmaceutical itions of the invention, in particular aerosol compositions that are intended for administration using MDI, to t the formulation from contamination with pathogenic bacteria. The preservative may comprise one or more of benzalkonium chloride, benzoic acid, benzoates such as sodium benzoate and such other preservatives which may be knowu to the person having a skill in the art and combinations thereof.

Suitable complexing agents may be empioyed in the pharmaceutical itions of the invention, in particular aerosol compositions that are intended for administration using MDI, capable of forming complex bonds. The complexing agent may comprise one or more of, but not d to, sodium EDTA or um EDTA and combinations thereof.

In one embodiment, the pharmaceutical compositions of the present invention are in a form suitable for administration by a dry powder inhaler (DPI).

The pharmaceutically acceptable excipients suitable for dry powder inhalation according to the present invention may be selected from suitable carriers which include, but are not limited to, sugars such as glucose, saccharose, lactose and se, es or starch derivatives, oligosaccharides such as dextrins, cyclodextrins and their derivatives, polyvinylpyrrolidone, alginic acid, tylose, silicic acid, cellulose, cellulose derivatives (for example cellulose , sugar ls such as mannitol or sorbitol, calcium carbonate, calcium phosphate, etc. lactose, lactitol, dextrates, , dextrose, maltodextrin, saccharides including monosaccharides, disaccharides, polysaccharides; sugar alcohols such as arabinose, , mannose, sucrose, trehalose, maltose, dextran and combinations thereof.

In an alternative embodiment, the pharmaceutical compositions of the t ion are in a form suitable for administration by nebulization.

Nebulization y has an advantage over other inhalation therapy, since it is easy to use and does not require co-ordination or much effort. It also works much more rapidly than medicines taken by mouth. Such compositions may comprise le ents such as one or more, but not limited to, ty agents, pH regulators, and chelating agents in a suitable vehicle.

Examples of suitable isotonicity-adjusting agents include sodium chloride, potassium chloride, zinc chloride, calcium chloride and mixtures thereof. Other isotonicity- adjusting agents may also include, but are not limited to, mannitol, ol, and se and mixtures thereof.

The pH of pharmaceutical compositions of the invention may be adjusted by the addition of one or more pH regulators such as pharmacologically acceptable acids.

Phannacologically acceptable inorganic acids or organic acids may be used for this purpose. Examples of preferred inorganic acids include one or more acids selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and phosphoric acid and combinations thereof. Examples of particularly suitable organic acids include one or more acids selected from the group consisting of ic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and propionic acid and ations thereof.

Examples of suitable chelating agents for use in a pharmaceutical compositions of the invention include editic acid (EDTA) or a salt thereof, e.g. sodium EDTA or disodium EDTA dihydrate (sodium edetate), and mixtures of such compounds.

PCT/G82012/000171 In addition to the excipients such as isotonicity-adjusting agents, pH regulators, chelating agents covered under nebulization therapy, the dosage forma as nasal spay and nasal drops may comprise thickening agents. es of suitable thickening agents may for use in a pharmaceutical itions of the invention include cellulose derivatives (for example cellulose ether) in which the cellulose-hydroxy groups are partially etherized with lower unsaturated aliphatic alcohols and/or lower unsaturated aliphatic oxyalcohols (for example methyl cellulose, ymethyl cellulose, hyd’roxypropylmethylcellulose), gelatin, polyvinylpyrrolidone, tragacanth, ethoxose (water soluble binding and thickening agents on the basis of ethyl cellulose), alginic acid, polyvinyl l, polyacrylic acid, pectin and equivalent agents.

Should these substances contain acid , the corresponding physiologically acceptable salts may also be used.

In addition to the entioned excipients, one or more anti-microbial preservative agents may also be added to the pharmaceutical compositions of the invention, in particular for dose es.

In an alternative embodiment, the composition according to the present invention may be included in one or more suitable containers provided with means enabling the application of the contained formulation to the respiratory tract.

Where the ceutical compositions of the invention are in the form of a powder for inhalation and are intended to be administered by a DPI, it may be encapsulated in capsules of gelatin or HPMC, or in blisters. In an alternative embodiment, the dry powder may be contained as a reservoir either in a single dose or multi-dose dry powder inhalation device. In a further alternative embodiment, the powder for tion may be suspended in a suitable liquid vehicle and packed in an aerosol container along with suitable propellants or mixtures thereof. In still a further alternative ment, the powder for inhalation may be dispersed in a suitable gas stream to form an aerosol composition.

Where the pharmaceutical compositions of the invention are in the form of an aerosol composition for administration using an MDI, it may be packed in plain aluminium cans or SS (stainless steel) cans or any such cans suitable for MDI delivery. Some aerosol drugs tend to adhere to the inner surfaces, i.e., walls of the cans and valves, of the MDI.

This can lead to the patient getting cantly less than the prescribed amount of the active agent upon each activation of the MDI. Such cans may be suitably d to avoid any adherence of the active on the walls thereof using techniques known in the art, for e coating the inner surface of the container with a suitable polymer can reduce this adhesion problem. Suitable coatings include ﬂuorocarbon c0polymers such as FEP~PES (ﬂuorinated ethylene propylene and polyethersulphone) and PFA-PES (perﬂuoroalkoxyalkane and polyethersulphone), epoxy and ethylene. Alternatively, the inner surfaces of the cans may be anodized, plasma treated or plasma coated.

Where the pharmaceutical. compositions of the invention are in the form of nasal sprays and nasal drops for administration into the nasal es it may be done by means of a dropper (or pipette) that includes a glass, plastic or metal dispensing tube. Fine droplets and Sprays can be provided by an intranasal pump dispenser or squeeze bottle as well knOWn in the art.

The pharmaceutical compositions of the present ion may further se, in addition to those ceutically active ingredients detailed above, one or more active(s) selected from the group comprising of , stamines, antiallergics or leukotriene antagonists, or their ceutically acceptable salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, gs or polymorphs thereof.

The pharmaceutical compositions of the t invention comprise glycopyrrolate, a betaz-agonist and, optionally, a corticosteroid. These active ingredients are formulated for simultaneous, separate or sequential administration. When the active ingredients are administered sequentially, either glycopyrrolate the long acting betaz-agonist, or where present, the corticosteroid, may be administered ﬁrst. When administration is simultaneous, the active ingredients may be administered either in the same or different PCT/GBZOIZ/000171 pharmaceutical compositions. Adjunctive therapy, ire. where one active ient is used as the y treatment and the other active ingredient(s) is/are used to assist that y ent is also an embodiment of the present invention.

According to a further embodiment of the invention, there is provided a product comprising (a) glycopyrrolate; (b) a betayagonist selected from the group comprising carmoterol, olodaterol, vilanterol; as a combined preparation for simultaneous, separate or sequential use for treatment and /or prevention of respiratory, inﬂammatory or obstructive airway disease According to a another embodiment of the invention, there is provided a product comprising (a) glycopyrrolate; (b) a betaz-agonist selected from the group comprising olodaterol, vilanterol, erol, indacaterol (c) a corticosteroid selected from the group consisting of ﬂuticasone, mometasone, as a combined preparation for simultaneous, separate or sequential use for treatment and /or prevention ofrespiratory, inﬂammatory or obstructive airway disease Compositions for use according to the present invention may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredients. These may for example, comprise metal or plastic foil, such as a blister pack. Where compositions are intended for administration as two separate compositions these may be presented in the form ofa twin pack. ceutical compositions may also be ibed in “patient packs” containing the whole course of treatment in a single package. The inclusion of a package insert has been shown to e patient compliance with the prescribing physician’s instructions.

According to a further embodiment of the t invention, there is provided a patient pack comprising at least one active ingredient of the combination according to the invention and an ation insert containing ions to use the combination of the ion. In one embodiment, the present invention provides a ﬁxed dose combination.

The pharmaceutical compositions of the present invention may be conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art. le s include the step of bringing into association the active ingredients with a carrier which constitutes one or more phannaceutically acceptable excipients. In general, compositions may be prepared by uniformly and intimately bringing into association the active ingredients with one or more liquid carriers or ﬁnely divided solid carriers, or both. It will be iated that when the active ingredients are administered independently, each may be administered by a different means.

The t invention also es a process to manufacture the itions according to the present invention.

In one embodiment, the present invention provides a process of preparing pharmaceutical compositions for administration by a metered dose r, which process comprises ng a phannaceutically acceptable carrier or excipient with one or more active pharmaceutical ingredients of the invention and a propellant, and thereafter transferring the composition to a suitable container, preferably a pre-crimped can.

In another embodiment, the invention provides a process of preparing a pharmaceutical compositions for administration by dry powder inhalation, which process comprises ng of a pharmaceutically acceptable r or excipient with one or more active pharmaceutical ients of the invention and providing the composition as a dry powder.

In a further embodiment, the invention provides a process of preparing pharmaceutical compositions for administration by nebulisation, which process comprises dissolving the drugs, optionally chelating agents, osmotic/isotonicity adjusting agents and any other suitable ingredients in the vehicle and adjusting the pH using a suitable pH adjusting agent W0 2012/1 10770 PCT/G32012/000171 In a further embodiment, the invention also es a method for the prevention and/or treatment of a respiratory, inﬂammatory or ctive airway disease, in particular chronic obstructive pulmonary disease, in a mammal, such as a human, which method comprises administration of a therapeutically ive amount of pharmaceutical compositions according to the present ion.

The present invention also provides pharmaceutical compositions according to the present invention for use in preventing and/or treating disorders or conditions that d to, or are prevented, ameliorated or eliminated by, the administration one or more bronchodilators and an inhaled corticosteroid (ICS), such as a atory, inﬂammatory or obstructive airway disease, in particular chronic obstructive pulmonary disease.

The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.

Ingredients Qty ISpray Process: 1) Fluticasone ﬁJroate, Glycopyrronium and Tiotropium were homogenized with part quantity ofHFA. 2) The suspension obtained in step 1 was transferred to the mixing vessel where remaining quantity ofHFA was added. 3) The resulting suspension was mixed, recirculated and ﬁlled in into imped aluminum cans.

Process: 1) Fluticasone furoate, Indacaterol and GlyCOpyrronium were homogenized with lactose and pan quantity ofHFA. 2) The suspension obtained in step I was transferred to the mixing vessel where remaining ty of HFA was added. 3) The resulting suspension was mixed, recirculated and ﬁlled in into pre-crimped aluminum cans.

Fluticasone Furoate 50 meg Glycopyrronium 50 meg 4. PEG400/1000 0.3% of total fonnulation . PVP K 25 0.001% oftotal formulation HFA134A OR HFA227 _ Process: 1) PVP was dissolved in PEG and part quantity of HFA] 34A or HFA227.

W0 2012/1 10770 2) The solution obtained in Step 1 was erred to a mixing vessel. 3) Fluticasone furoate, Indacaterol and Glycopyrronium were homogenized with a part quantity of HFA. 4) The suspension obtained in step 3 was transferred to the mixing vessel where remaining quantity ofHFA was added.

) The resulting total su3pension was mixed, recirculated and ﬁlled in into imped aluminum cans.

Example 4 -20% of total formulation 1% of total formulation Process: 1) Glycerol was dissolved in ethanol and required quantity ofHCl was added. 2) Fluticasone furoate, Indacaterol and Glycopyrronium were dissolved in the solution obtained in step 1. 3) The resulting solution was erred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, recirculated and ﬁlled in into imped aluminum cans.

PCT/G32012/00017l Example 5 4. Ethanol 15-20% of total formulation HCL ( 0.08N) pH 2.5-3.5 Process: 1) Required quantity ofHCl was added to ethanol. 2) Fluticasone furoate, Indacaterol and Glycopyrronium were ved in the on obtained in step 1. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, recirculated and filled in into imped aluminum cans.

Example 6 Sr. No. Ingredients Qty ISpray 1. Fluticasone Furoate 50 mcg 2. Glycopyrronium 50 meg -lndacaterol3. 50 meg -4. Ethanol 15-20% of total formulation -5. Glycerol 1% of total formulation Citric acid anhydrous 7. HFA134a q.s.

Process: 1) Citric acid anhydrous and glycerol were dissolved in ethanol. 2) Fluticasone furoate, Indacaterol and Glycopyrronium were dissolved in the solution obtained in step (1). 3) The solution obtained in step (2) was transferred to the main mixing vessel where it was mixed with entire quantity ofHFAl34a. 4) The resulting suspension was mixed, recirculated and filled in into pre~crimped aluminum cans.

Example 7 Qty/sway 4. Ethanol 15-20% of total formulation Citric acid anhydrous ~ . .

HFA134a Process: 1) Citric acid ous was ved in ethanol. 2) Fluticasone furoate, Indacaterol and Glycopyrronium were dissolved in the on obtained in step (1). 3) The solution ed in step (2) was transferred to the main mixing'vessel where it was mixed with entire quantity of HFAl34a. 4) The resulting sion was mixed, recirculated and ﬁlled in into pre-crimped aluminum cans.

PCT/G32012/000171 Example 8 Sr. No. Ingredients Qty ISpray Fluticasone Furoate Glycopyrronium 50 meg 4. Ethanol 1-2% of total formulation 4a or HFA227 q.s.

Process: 1) Lecithin was dissolved in ethanol. 2) Glycopyrronium and Indacaterol were homogenized with part quantity of HFA and transferred to the mixing vessel. 3) Fluticasone e was homogenized with lecithin and ethanol. 4) The sion ed instep (3) was transferred to the main mixing vessel where the remaining quantity of HFA was added.

) The resulting suspension was mixed, recirculated and ﬁlled in into pre-crimped aluminum cans.

Example 9 . Ingredients Qty /Spray Fluticasone Furoate 50 mcg Glycopyrronium 50 meg 3 . lndacaterol 50 mcg 4. Ethanol 1-2% of total formulation . Oleic acid 0.02 — 5% of the W0 2012/1 10770 Process: 1) Oleic acid was dissolved in ethanol. 2) Glycopyrronium and Indacaterol were homogenized with part quantity of HFA and transferred to the mixing vessel. 3) Fluticasone furoate was nized with oleic acid and ethanol. 4) The suspension obtained instep (3) was transferred to the main mixing vessel where the remaining quantity of HFA was added; ) The resulting suspension was mixed, recirculated and filled in into pre~crimped aluminum cans.

Example 10 Qty/mama _Glycopyrronium bromide 0.050 Indacaterol Maleate 0.194 Lactose monohydrate IP/Ph.Eur/NF 24.656 1) Glycopyrronium, Indacaterol and asone furoate were sifted with a part quantity of lactose. 2) The co-siﬁ of step I was then sifted with the remaining quantity of lactose and blended. 3) The blend of step 2 was then ﬁlled in capsules.

WO 10770 Example 11 Ingredients Qty / unit (mg) Glycopyrronium bromide 0.100 Indacaterol Maleate 0.194 Fluticasone Furoate 0.200 Lactose monohydrate lP/Ph.Eur/NF 24.506 .000 Process: 1) GlyCOpyrronium, lndacaterol and Fluticasone furoate were sifted with a part quantity of lactose. 2) The co-siﬁ of step 1 was then sifted with the remaining quantity of e and blended. 3) The blend of step 2 was then ﬁlled in capsules.

Example 12 -Glycopyrronium e 0.200 2. Indacaterol Maleate 0.388 Fluticasone Furoate Process: l) Glycopyrronium, Indacaterol and Fluticasone furoate were sifted with a part quantity of lactose. 2) The co-sift of step I was then sifted with the ing quantity of lactose and blended. 3) The blend of step 2 was then ﬁlled in capsules.

Example 13 Glycopyrronium 50 mcg Formoterol 4A OR HFA227 Process: 1) Fluticasone furoate, Glycopyrronium and Formoterol were homogenized with part quantity of HFA. 2) The suspension obtained in step 1 was transferred to the mixing vessel where remaining quantity ofHFA was added. 3) The resulting suspension was mixed, recirculated and ﬁlled in into pre-crimped aluminum cans.

Example 14 1) Fluticasone e, Formoterol and Glycopyrronium were homogenized with lactose and part quantity of HFA. 2) The suspension obtained in step I was transferred to the mixing vessel where remaining quantity of HFA was added.

W0 2012/1 10770 3) The resulting suspension was mixed, recirculated and ﬁlled in into pre-crimped aluminum cans.

Example 15 O.3% of total formulation 0.001% l formulation Process: 1) PVP was ved in PEG and part quantity of HFA134A or HFA227. 2) The solution obtained in Step 1 was transferred to a mixing vessel. 3) Fluticasone furoate, Formoterol and Glycopyrronium were homogenized with a part quantity of HFA. 4) The suspension obtained in step 3 was transferred to the mixing vessel where remaining quantity ofHFA was added.

) The resulting total suspension was mixed, recirculated and ﬁlled in into pre~crimped aluminum cans.

Example 16 Formoterol 24 meg PCT/G32012/000171 . Glycerol 1% of total formulation uHCL ( 0.08N) pH 2.5 — 3.5 Process: 1) Glycerol was dissolved in ethanol- and required quantity of HCl was added. 2) Fluticasone furoate, Formoterol and Glycopyn'onium were dissolved in the solution obtained in step 1. 3) The ing solution was transferred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, ulated and ﬁlled in into pre-crimped aluminum cans.

Example 17 4. l 15—20% of total formulation HCL ( 0.08N) pH 2.5-3.5 Process: 1) Required ty of HCl was added to ethanol. 2) Fluticasone ﬁiroate, Formoterol and Glycopyrronium were dissolved in the solution obtained in step 1. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, recirculated and ﬁlled in into pre-crimped aluminum cans.

Example 18 Ingredients Fluticasone Furoate 1-2% of total formulation Lecithin 0.02 of the API HFA134a or HFA227 Process: 1) Lecithin was ved in l. 2) Glycopyrronium and Formoterol were homogenized with part quantity of HFA and transferred to the mixing vessel. 3) Fluticasoen furoate was nized with lecithin and ethanol. 4) The su5pension obtained instep (3) was transferred to the main mixing vessel where the remaining quantity ofHFA was added.

Example 19 _Fluticasone Furoate 50 mcg Glycopyrronium 50 mcg 4. l 1-2% of total formulation S.‘ Oleic acid 0.02 — 5% of the W0 2012/1 10770 2012/000171 Process: 1) Oleic acid was dissolved in ethanol. 2) Glycopyrronium and Formoterol were homogenized with part quantity of HFA and transferred to the mixing vessel. 3) asone furoate was nized with oleic acid and ethanol. 4) The suspension obtained instep (3) was transferred to the main mixing vessel where the remaining quantity ofHFA was added.

Example 20 Qty/unit (mg) 2. Formeterol Fumarate dihydrate Lactose monohydrate lP/Ph.Eur/NF Process: 1) Glycopyrronium, Fonnoterol and asone furoate were sifted with a part quantity of lactose. 2) The co-siﬁ of step 1 was then sifted with the remaining quantity of lactose and blended. 3) The blend of step 2 was then ﬁlled in capsules.

Example 21 Qty/unit mg) -Glycopyrronium bromide 0.010 Formeterol Fumarate dihydrate 0.006 3. Fluticasone Furoate 0.200 =4. Lactose drate IP/Ph.Eur/NF 24.694 Process: 1) Glycopyrronium, Formoterol and Fluticasone furoate were sifted with a part quantity of lactose. 2) The co-sift of step 1 was then sifted with the remaining quantity of lactose and blended. 3) The blend of step 2 was then ﬁlled in capsules.

Example 22 Qty I unlit (mg) Glycopyrronium e -Formeterol Fumarate ate2.

Lactose drate IP/Ph.Eur/NF 24.388 Process: 1) Glycopyrronium, Formoterol and Fluticasone furoate were sifted with a part quantity of lactose. 2) The co-siﬁ of step I was then sifted with the remaining quantity of lactose and blended. 3) The blend of step 2 was then ﬁlled in capsules.

Example 23 . . Ingredients Process: 1) Fluticasone furoate, Glycopyrronium and Vilanterol were homogenized with part quantity of HFA. 2) The suspension ed in step I was transferred to the mixing vessel where remaining quantity of HFA was added. 3) The resulting suspension was mixed, recirculated and ﬁlled in into pre-crimped aluminum cans. e 24 Sr. No. ients Process: 1) Fluticasone furoate, Vilanterol and Glycopyrronium were homogenized with lactose and pan quantity of HFA.

PCT/G32012/000171 2) The suspension obtained in step I was erred to the mixing vessel where remaining quantity ofHFA was added. 3) The ing suspension was mixed, recirculated and ﬁlled in into pre-crimped aluminum cans.

Example 25 Ingredients Fluticasone Furoate yrronium PEG400/1000 0.3% of total formulation 0.001% oftotal formulation HFA134A OR HFA227 q.s.

Process: 1) PVP was dissolved in PEG and part quantity ofHFA134A or HFA227. 2) The solution obtained in Step 1 was transferred to a mixing . 3) Fluticasone furoate, Vilanterol and Glycopyrronium were homogenized with a part quantity of HFA. 4) The suspension obtained in step 3 was transferred to the mixing vessel where remaining quantity of HFA was added.

) The resulting total suspension was mixed, recirculated and ﬁlled in into pre-crimped aluminum cans.

Example 26 Sr. No. 1 Ingredients Qty /Spray W0 2012/1 10770 PCT/G32012/000171 4. Ethanol 15-20% of total formulation ol 1% of total formulation -W__ Process: 1) Glycerol was dissolved in l and ed quantity of HCl was added. 2) Fluticasone furoate, Vilanterol and Glycopyrronium were dissolved in the on obtained in step 1. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, recirculated and ﬁlled in into pre-crimped aluminum cans.

Example 27 Fluticasone Furoate 50 meg 4. Ethanel 154.0% of total formulation HCL ( 0.03m pH 2.5-3.5 Process: 1) Required quantity of HCl was added to ethanol. 2) Fluticasone furoate, Vilanterol and Glycopyrronium were dissolved in the solution obtained in step I. 3) The resulting solution was transferred to the mixing vessel where HFA was added.

W0 2012/1 10770 4) The resulting suspension was mixed, recirculated and ﬁlled in into pre-crimped aluminum cans.

Example 28 Ingredients Qty lSpray _Fluticasone Furoate 50 mcg GlyCOpyrronium 50 mcg -M12.5 meg Ethanol 1-2% of total formulation 0.02 of the API HFA134a or HFA227 q.s.

Process: 1) Lecithin was dissolved in ethanol. 2) Glycopyrronium and Vilanterol were homogenized with part quantity of HFA and erred to the mixing . 3) Fluticasoen ﬁiroate was homogenized with lecithin and ethanol. 4) The suspension obtained instep (3) was transferred to the main mixing vessel where the remaining quantity ofHFA was added.

) The resulting suSpension was mixed, recirculated and ﬁlled in into pre-crimped um cans.

Example 29 ESr. No. Qty /Spray Glycopyrronium 50 meg Vi [anterol 12.5 mcg 4. l 1-2% of total formulation Oleic acid 0.02 - 5% of the HFA134a or HFA227 _ Process: 1) Oleic acid was dissolved in ethanol. 2) Glycopyrronium and erol were homogenized with part quantity of HFA and transferred to the mixing vessel. 3) Fluticasoen furoate was homogenized with oleic acid and ethanol. 4) The sion obtained instep (3) was transferred to the main mixing vessel where the remaining ty of HFA was added.

) The resulting suspension was mixed, recirculated and ﬁlled in into imped aluminum cans.

Example 30 Process: 1) Glycopyrronium, Vilanterol Trifenatate and Fluticasone furoate were siﬁed with a part quantity of lactose. 2) The co-siﬁ of step 1 was then sifted with the remaining quantity of lactose and blended. 3) The blend ofstep 2 was then ﬁlled in capsules.

W0 2012/1 10770 PCT/G32012/000171 e 31 . Ingredients Qty / unit (mg) Glycopyrronium bromide 0.010 2. Vilanterol atate 0.025 Lactose monohydrate lP/Ph.Eur/NF 24.675 Process: 1) Glycopyrronium, Vilanterol Trifenatate and Fluticasone furoate were sifted with a part quantity of lactose. 2) The co—sift of step 1 was then sifted with the remaining quantity of lactose and blended. 3) The blend of step 2 was then ﬁlled in capsules.

Example 32 Sr. No. Ingredients Qty / unit (mg) -Glycopyrronium bromide 0.200 Vilanterol Trifenatate 0.050 asone Furoate 0.400 _Lactose monohydrate IP/Ph.Eur/NF 24.350 -Total 25.000 Process: i) Glycopyrronium, Vilanterol atate and Fluticasone furoate were sifted with a part quantity of lactose.

WO 10770 PCT/G32012/000171 2) The co-siﬁ of step 1 was then sifted with the remaining ty of lactose and blended. 3) The blend of step 2 was then ﬁlled in capsules.

Example 33 Process: 1) Fluticasone furoate, Glycopyrronium and Olodaterol were homogenized with part quantity ofHFA. 2) The suspension obtained in step 1 was transferred to the mixing vessel where remaining quantity of HFA was added. 3) The resulting suspension was mixed, recirculated and ﬁlled in into preocrimped aluminum cans.

Example 34 W0 2012/1 10770 PCT/GBZOlZ/00017l Process: 1) asone ﬁJroate, Olodaterol and Glycopyrronium were homogenized with lactose and part quantity of HFA. 2) The suspension obtained in step 1 was transferred to the mixing vessel where remaining ty ofHFA was added. 3) The resulting suspension was mixed, recirculated and filled in into imped aluminum cans.

Example 35 Ingredients Qty ISpray Fluticasone Furoate “ 50 mcg 2. yrronium 50 meg Olodaterol 5 mcg 4. PEG400/1000 0.3% of total formulation . PVP K 25 0.001% oftotal formulation _HFA134A OR HFA227 q.s.

Process: 1) PVP was dissolved in PEG and part quantity of HFA134A or HFA227. 2) The solution obtained in Step 1 was transferred to a mixing vessel. 3) Fluticasone furoate, Olodaterol and Glycopyrronium were homogenized with a part quantity of HFA. 4) The suspension obtained in step 3 was transferred to the mixing vessel where remaining quantity ofHFA was added.

) The resulting total SUSpension was mixed, recirculated and ﬁlled in into imped aluminum cans.

Example 36 Qty /Spray -20% of total formulation Glycerol 1% of total formulation nHCL(0.08N) ' pH 2.5 - 3.5 -ﬁ_q.s_ Process: l) Glycerol was dissolved in ethanol and required ty of HCl was added. 2) Fluticasone furoate, Olodaterol and yrronium were dissolved in the solution obtained in step 1. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, recirculated and ﬁlled in into pre—crimped aluminum cans.

Example 37 Sr. No. ients Qty ISpray Fluticasone Furoate 50 mcg iGlycopyrronium 50 mcg Olodaterol 5 meg . Ethanol 15-20% of total formulation . HCL ( 0.08N) pH 2.5-3.5 HFA 134a q.s.

PCT/G32012/000171 Process: 1) Required quantity of HCI was added to ethanol. 2) Fluticasone e, Olodaterol and Glycopyrronium were dissolved in the solution obtained in step 1. 3) The resulting solution was transferred to the mixing vesse l where HFA was added. 4) The resulting suspension was mixed, recirculated and ﬁlled in into pre—crimped aluminum cans.

Example 38 Ingredients l. asone Furoate Glycopyrronium -3. Olodaterol 1-2% of total formulation 0.02 of the API _HFA 1 34a or HFA227 Process: 1) in was dissolved in ethanol. 2) Glycopyrronium and Olodaterol were homogenized with part quantity of HFA and transferred to the mixing vessel. 3) Fluticasone ﬁiroate was homogenized with lecithin and ethanol. 4) The suspension ed instep (3) was erred to the main mixing vessel where the remaining quantity ofHFA was added.

Example 39 Sr. N0. ients Qty /Spray 1. Fluticasone Furoate 2. Glycopyrronium 50 mcg 3. Olodaterol 5 mcg 1—2% of total formulation . Oleic acid 0.02 —— 5% of the 6. HFAl34a or HFA227 q.s.

]) Oleic acid was dissolved in ethanol. 2) Glycopyrronium and Olodaterol were homogenized with part quantity of HFA and transferred to the mixing vessel. 3) Fluticasone furoate was homogenized with oleic acid and ethanol. 4) The suspension obtained instep (3) was transferred to the main mixing vessel where the remaining quantity ofHFA was added.

Example 40 Sr. N0. Ingredients Qty/ unit (mg) -Glycopyrronium bromide 0.050 Olodaterol ‘ 0.005 Lactose monohydrate IP/Ph.Eur/NF 24.845 WO 10770 PCT/G32012/000171 Process: 1) Glycopyrronium, Olodaterol and Fluticasone furoate were sifted with a part quantity of lactose. 2) The co—siﬁ of step 1 was then sifted with the ing quantity of lactose and blended. 3) The blend of step 2 was then ﬁlled in capsules.

Example 41 Qty / unit (mg) 1. Glycopyrronium bromide N Olodaterol - Process: 1) GlyCOpyrronium, Olodaterol and Fluticasone furoate were sifted with a part quantity of lactose. 2) The co—siﬁ of step 1 was then sifted with the remaining quantity of lactose and 3) The blend of step 2 was then ﬁlled in capsules.

Example 42 Qty/mm Glycopyrronium bromide 0.200 Olodaterol 0.010 Lactose monohydrate IP/Ph.Eur/NF 24.390 Process: 1) Glycopyrronium, Olodaterol and Fluticasone furoate were siﬁed with a part quantity of lactose. 2) The co—siﬁ of step 1 was then sifted with the ing ty of lactose and blended. 3) The blend of step 2 was then ﬁlled in capsules.

Example 43 Process: 1) sone furoate, Glycopyrronium and Olodaterol were homogenized with part quantity of HFA. 2) The suspension obtained in step 1 was transferred to the mixing vessel where remaining duantity of HFA was added. 3) The resulting suspension was mixed, recirculated and ﬁlled in into pre—crimped aluminum cans.

Example 44 PCT/G32012/000171 Process: 1) Mometasone furoate, erol and Glycopyrronium were homogenized with lactose and part quantity ofHFA. 2) The suspension obtained in step 1 was transferred to the mixing vessel where remaining quantity ofHFA was added. 3) The resulting suspension was mixed, recirculated and ﬁlled in into pre-crimped aluminum cans.

Example 45 Qty ISpray l. Mometasone furoate 2. Glycopyrronium 0.3% of total formulation 0.001% of total formulation Process: 1) PVP was dissolved in PEG and part ty of HFA 134A or . 2) The solution obtained in Step 1 was transferred to a mixing vessel. 3) Mometasone furoate, erol and Glycopyrronium were homogenized with a part quantity of HFA. 4) The suspension obtained in step 3 was transferred to the mixing vessel where ing quantity of HFA was added.

) The resulting total suspension was mixed, recirculated and ﬁlled in into pre—crimped aluminum cans.

W0 2012/1 10770 2012/000171 Example 46 Ingredients oJ' \U} "U 1a:"< Mometasone furoate 400 mcg Glycopyrronium 50 mcg Olodaterol 5 meg -Ethanol4. 15-20% oftotal formulation - . 1% of total formulation EHCL ( 0.08N) pH 2.5 — 3.5 Process: 1) Glycerol was dissolved in ethanol and required quantity of HCl was added. 2) Mometasone furoate, Olodaterol and Glycopyrronium were dissolved in the solution obtained in step 1. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, recirculated and filled in into pre-crimped um cans. e 47 Sr. No. Ingredients Glycopyrronium 50 meg Olodaterol 5 meg ‘4. Ethanol 15-20% of total formulation HCL ( 0.08N) pH 2.5—3.5 Process: 1) ed quantity of HCl was added to ethanol. 2) sone furoate, Olodaterol and Glycopyrronium were dissolved in the solution obtained in step 1. 3) The resulting solution was transferred to the mixing vessel Where HFA was added. 4) The resulting suspension was mixed, recirculated and ﬁlled in into pre-crimped um cans.

Example 48 Sr. No. Ingredients O‘3a"U3<4 -Mometasone furoate 400 mcg Glycopyrronium 50 mcg Olodaterol 5 meg 4. Ethanol 1—2% of total formulation _HFAl34a or HFA227 q.s Process: 1) Lecithin was dissolved in l. 2) yrronium and Olodaterol were homogenized with part quantity of HFA and transferred to the mixing vessel. 3) Mometasone furoate was homogenized with lecithin and ethanol. 4) The suspension obtained instep (3) was transferred to the main mixing vessel where the remaining quantity ofHFA was added.

Example 49 Sr. No. Ingredients Qty /Spray Oiodaterol 5 meg 4. 1-2% of total formulation . Oleic acid 0.02 —- 5% ofthe _HFA134a or HFA227 Process: 1) Oleic acid was dissolved in ethanol. 2) yrronium and Olodaterol were homogenized with part quantity of HFA and transferred to the mixing vessel. 3) Mometasone furoate was homogenized with oleic acid and ethanol. 4) The suspension obtained instep (3) was erred to the main mixing vessel where the remaining quantity ofHFA was added.

Example 50 Lactose monohydrate IP/Ph.Eur/NF 24.390 2012/000171 Process: ]) Glycopyrronium, Olodaterol and Mometasone furoate were siﬁed with a part quantity of lactose. 2) The co—sift of step 1 was then sifted with the remaining quantity of lactose and blended. 3) The blend of step 2 was then ﬁlled in capsules.

Example 51 Qty / unit (mg) 1) Glycopyrronium and Vilanterol Trifenatate were sifted with a part quantity of lactose. 2) The co—siﬁ of step I was then siﬁed with the remaining quantity of lactose and blended. 3) The blend of step 2 was then ﬁlled in capsules.

Example 52 . Ingredients Process: 1) Glycopyrronium and Vilanterol Trifenatate were sifted with a part quantity of lactose. 2) The co-sift of step I was then sifted with the remaining ty of lactose and blended. 3) The blend of step 2 was then ﬁlled in capsules.

Example 53 Qty / unit (mg) Glycopyrronium bromide 0.200 Vilanterol Trifenatate 0.050 Lactose monohydrate IP/Ph.Eur/NF 24.750 Process: 1) Glycopyrronium and Vilanterol Trifenatate were siﬁed with a part quantity of lactose. 2) The co-sift of step 1 was then siﬁed with the remaining quantity of lactose and blended. 3) The blend of step 2 was then ﬁlled in capsules.

Example 54 Process: 1) yrronium and Vilanterol were homogenized with part quantity of HFA. 2) The sion obtained in step 1 was transferred to the mixing vessel where remaining quantity ofHFA was added. 3) The resulting suspension was mixed, recirculated and ﬁlled in into pre-crimped aluminum cans.

Example 55 Qty /Spray 50 meg 12.5 mcg 100% ofthe drug q.s.

Process: 1) Vilanterol and Glycopyrronium were homogenized with lactose and part quantity of HFA. 2) The suspension obtained in step 1 was transferred to the mixing vessel where remaining ty of HFA was added. 3) The resulting suspension was mixed, recirculated and ﬁlled in into pre-crimped aluminum cans. e 56 Sr. No. i Ingredients Oq E'53Nt< l. Glyc0pyrronium 50 mcg iVilanterol 12.5 mcg i.PEG400/1000 0.3% of total formulation 4. PVP K 25 0.001% of total formulation Process: 1) PVP was dissolved in PEG and part quantity of A or HFA227. 2012/000171 2) The solution obtained in Step 1 was transferred to a mixing vessel. 3) Vilanterol and Glycopyrronium were homogenized with a part quantity of HFA. 4) The suspension obtained in step 3 was transferred to the mixing vessel where remaining quantity ofHFA was added.

Example 57 3. l 15-20% of total formulation 4. Glycerol 1% of total formulation HCL ( 0.08N) pH 2.5 — 3.5 CEM— Process: 1) Glycerol was dissolved in ethanol and required quantity of HCl was added. 2) Vilanterol and yrronium were dissolved in the solution obtained in step 1. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, ulated and ﬁlled in into pre'crimped aluminum cans.

Example 58 -Glycopyrronium 50 mcg Ethanol 15-20% of total HCL ( 0.08N) pH 2.5—3.5 Process: 1) Required quantity of HCl was added to ethanol. 2) Vilanterol and Glycopyrronium were dissolved in the on obtained in step I. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, recirculated and ﬁlled in into pre-crimped aluminum cans. e 59 Qty/Spray Glycopyrronium 50 meg 3. l 1-2% of total formulation HFAl34a or HFA227 Process: 1) Lecithin was dissolved in ethanol. 2) Glycopyrronium and erol were homogenized with part quantity of HFA and transferred to the mixing . 3) The solution obtained in step (1) was homogenized with part quantity ofHFA 4) The mixture obtained in step (3) was transferred to the main mixing vessel where the remaining quantity ofHFA was added.

) The resulting suspension was mixed: recirculated and ﬁlled in into pre—erimped aluminum cans.

Example 60 Qtv /Spray l2 5 mcg 1-2°/o of total formulation Oleic acid 0.02 — 5% ofthe HFA134a or HFAZZ’I q.s.

Process: 1) Oleic acid was dissolved in ethanol. 2) Glycopyrronium and Vilanterol were nized with part quantity of HFA and transferred to the mixing vessel. 3) The on obtained in step (1) was homogenized with part quantity ofHFA 4) The mixture obtained in step (3) was transferred to the main mixing vessel where the remaining quantity of HFA was added.

Example 61 Ingredients Qty / unit (mg) Glycopyrronium bromide Olodaterol ’ 0.005 Lactose monohydrate Eur/NF 24.944 Process: 1) yrronium and Olodaterol were siﬁed with a part quantity of lactose.

PCT/GBZOlZ/000171 2) The co-siﬁ of step 1 was then sifted with the remaining ty of lactose and blended. 3) The blend of step 2 was then ﬁlled in capsules. e 62 Process: 1) Glycopyrronium and Olodaterol were sifted with a part quantity of lactose. 2) The co-siﬁ of step 1 was then sifted with the remaining quantity of lactose and blended. 3) The blend of step 2 was then filled in capsules.

Example 63 HFA134A OR HFA227 Process: 1) Glycopyrronium and Olodaterol were homogenized with part quantity ofHFA. 2) The suspension obtained in step liwas transferred to the mixing vessel where remaining quantity ofHFA was added. 3) The resulting suspension was mixed, recirculated and ﬁlled in into pre-crimped aluminum cans.

Example 64 Glycopyrronium 100 mcg 100% ofthe drug Process: 1) erol and Glycopyrionium were homogenized with lactose and part quantity of EPA. 2) The suspension obtained in step 1 was transferred to the mixing vessel where remaining quantity ofHFA was added. 3) The resulting suspension was mixed, recirculated and ﬁlled in into pre-crimped aluminum cans.

Example 65 Sr. No.

Glycopyrronium 100 mcg Olodaterol 5 mcg ‘ 3. PEG400/1000 0.3% of total formulation 4. PVP K 25 0.001% oftotal formulation Process: 1) PVP was dissolved in PEG and part quantity of HFAl34A or HFA227. 2) The on obtained in Step 1 was transferred to a mixing vessel. 3) erol and Glycopyrronium were nized with a part quantity of HF‘A. 4) The suspension obtained in step 3 was transferred to the mixing vessel where remaining quantity of HFA was added.

) The resulting total suspension was mixed, ulated and ﬁlled in into pre-crimped aluminum cans.

Example 66 Sr. No. ients Qty ISpray _Glycopyrronium 100 mcg 3. Ethanol 15—20% of total formulation 4. Glycerol 1%. oftotal formulation HCL ( 0.08N) pH 2.5 — 3.5 Process: 1) ol was dissolved in ethanol and required quantity of HCl was added. 2) Olodaterol and Glycopyrronium were dissolved in the solution obtained in step 1. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The ing suspension was mixed, recirculated and ﬁlled in into pre—crimped aluminum cans.

Example 67 Qty /Spray _Glycopyrronium 100 mcg Olodaterol 5 mcg 3. Ethanol 15-20% of total formulation . HCL ( 0.08N) pH 2.5~3.5 W0 2012/1 10770 PCT/G32012/000171 -EM_ Process: 1) Required quantity of HCl was added to ethanol. 2) Olodaterol and Glycopyrronium were dissolved in the solution obtained in step 1. 3) The resulting solution was transferred to the mixingvessel where HFA was added. 4) The resulting suspension was mixed, recirculated and ﬁlled in into pre-crimped um cans. e 68 Ingredients Qty /Spray 1-2% of total formulation 1) Lecithin was dissolved in ethanol. 2) Glycopyrronium and erol were homogenized with part quantity of HFA and transferred to the mixing vessel. 3) The solution obtained in step (I) was homogenized with part quantity ofHFA 4) The mixture obtained in step (3) was transferred to the main mixing vessel where the remaining quantity ofHFA was added.

) The resulting suspension was mixed, recirculated and ﬁlled in into pre-crimped aluminum cans. 2012/000171 Example 69 ients Qty ISpray Glycopyrroniurn 100 mcg 3. Ethanol l~2% of total formulation 4. Oleic acid 0.02 - 5% of the Process: 1) Oleic acid was dissolved in ethanol. 2) Glycopyrronium and Olodaterol were homogenized with part quantity of HFA and transferred to the mixing vessel. 3) The solution obtained in step (1) was homogenized with part quantity ofHFA 4) The mixture obtained-in step (3) was transferred to the main mixing vessel where the remaining quantity of HFA was added.

) The resulting suspension was mixed, recirculated and ﬁlled in into pre—crimped aluminum cans.

Example 70 Ingredients Qty / unit (mg) 1. ‘ yrronium bromide 2. l Cannoterol Hydrochloride e monohydrate IP/Ph.Eur/NF Process: 1) Glycopyrronium and Cannoterol were sifted with a part quantity of lactose.

W0 2012/1 10770 PCT/G32012/000171 2) The co-sift of step 1 was then sifted with the remaining quantity of e blended. 3) The blend of step 2 was then ﬁlled in capsules.

Example 71 Sr. No. Ingredients Qty / unit (mg) Process: 1) Giycopyrronium and Carmoterol were sifted with a part quantity of lactose. 2) The co-siﬁ of step 1 was then siﬁed with the ing quantity of lactose blended. 3) The blend of step 2 was then ﬁlled in capsules.

Example 72 -Glycopyrronium 100 mcg HFA134A OR HFA227 Process: 1) Glycopyrronium and Carmoterol were homogenized with part quantity ofHFA. 2) The suspension obtained in Step 1 was transferred to the mixing vessel where remaining ty ofHFA was added. 3) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.

PCT/G32012/000171 Example ‘73 Ingredients Qty ISpray _Glycopyrronium 100 mcg 100% ofthe drug 4. HFA134A OR HFA227 Process: 1) erol and Glycopyrronium were nized with lactose and part quantity of HFA. 2) The suspension obtained in step 1 was erred to the mixing vessel where remaining quantity ofHFA was added. 3) The resulting sion was mixed, recirculated and ﬁlled in into pre-crimped aluminum cans.

Example 74 Sr. No. Ingredients Qty /Spray Glycopyrronium 100 mcg 3. PEG400/1000 0.3% of total formulation 4. PVP K 25 0.001% of total formulation HFA134A OR HFA227 q.s.

Process: 1) PVP was dissolved in PEG and part quantity of HFA134A or HFA227. 2) The solution obtained in Step 1 was transferred to a mixing vessel. 3) Cannoterol and Glycopyrronium were homogenized with a part quantity of HFA. 4) The suspension obtained in step 3 was transferred to the mixing vessel where remaining quantity of HFA was added.

) The resulting total suspension was mixed, ulated and ﬁlled in into pre~crimped aluminum cans.

Example 75 Ingredients Qty ISpray -Glycopyrronium 100 mcg 3. Ethanol 15-20% of total formulation 4. Glycerol 1% of total ' HCL ( 0.08N) pH 2.5 — 3.5 Process: 1) Glycerol was dissolved in ethanol and required quantity of HG] was added. 2) Carmoterol and Glyeopyrronium were dissolved in the solution obtained in step I. 3) The resulting solution was erred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, recirculated and ﬁlled in into pre—erimped aluminum cans.

Example 76 D 100 mcg I- iOs»S5-?9... 2 mcg 3. l 15-20% of total formulation * .o533 pH 2.5-3.5 WO 10770 Process: 1) Required quantity of HCl was added to ethanol. 2) Carmoterol and Glycopyrronium were dissolved in the solution obtained in step I. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, recirculated and ﬁlled in into prevcrimped aluminum cans.

Example 77 Sr. No. Ingredients Qty lSpray 1. Glycopyrronium 100 mcg I. Ethanol 1-2% of total formulation 0.02 of the API . HFA134a or HFA227 Process: 1) Lecithin was dissolved in ethanol. 2) yrronium and Cannoterol were homogenized with part quantity of HFA and transferred to the mixing vessel. 3) The solution obtained in step (1) was homogenized with part quantity ofHFA 4) The mixture obtained in step (3) was transferred to the main mixing vessel where the remaining quantity ofHFA was added.

) The resulting suspensiorr was mixed, recirculated and ﬁlled in into precrimped aluminum cans.

Example 78 Glycopyrronium 100 mcg 3. Ethanol 1-2% of total formulation 4. Oleic acid 0.02 — 5% of the Process: ]) Oleic acid was dissolved in ethanol. 2) Glycopyrronium and Carmoterol were homogenized with part quantity of HFA and transferred to the mixing vessel. 3) The solution obtained in step (1) was homogenized with part quantity ofHFA 4) The mixture obtained in step (3) was transferred to the main mixing vessel where the remaining ty of HFA was added.

It will be readily apparent to one skilled in the art that varying substitutions and modiﬁcations may be made to the invention sed herein without departing from the spirit of the invention. Thus, it should be understood that although the t invention has been speciﬁcally disclosed by the preferred ments and optional features, ation and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modiﬁcations and variations are ered to be falling within the scope of the invention.

It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” ising,” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

It must be noted that, as used in this speciﬁcation and the appended claims, the 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 ent as well as two or more different excipients, and the like.

Claims

1. A pharmaceutical composition comprising glycopyrrolate in combination with indacaterol and ﬂuticasone, ally with one or more pharmaceutically acceptable excipients.

2. A pharmaceutical composition according to claim 1, wherein glycopyrrolate, indacaterol and/or ﬂuticasone are in the form of a pharmaceutically acceptable salt, ester, solvate, e, enantiomer or polymorph.

3. A pharmaceutical composition according to claim 1 or 2, n indacaterol is present in an amount ranging from 25-800 mcg.

4. A pharmaceutical composition according to claim 1, 2 or 3, wherein the ﬂuticasone is in the form of an ester.

5. A pharmaceutical composition according to any ing claim, wherein the ﬂuticasone is present in an amount ranging from 25 ~800 mcg.

6. A pharmaceutical composition according to any preceding claim, wherein the ﬂuticasone is in the form of ﬂuticasone furoate.

7. A ceutical composition according to any preceding claim, wherein the glycopyrrolate is present in an amount ranging from 50-200 mcg.

8. A pharmaceutical composition according to any preceding claim, compiising glycopyrrolate, indacaterol maleate and fluticasone furoate.

9. A pharmaceutical composition according to any ing claim, in the form of te formulations or a single combined formulation.

10. A pharmaceutical composition ing to any preceding claim, formulated as a composition for inhalation.

11. A pharmaceutical composition according to claim 10, formulated as a composition for inhalation in the form of a metered dose inhaler (MDI), dry powder inhaler (DPI), zer, nasal spray, nasal drops or an insufﬂation powder.

12. A pharmaceutical composition according to any ing claim for once daily administration.

13. A process for manufacturing a pharmaceutical composition ing to any one of claims 1 to 12, sing combining glycopyrrolate with indacaterol and sone, optionally with one or more ceutically acceptable excipients.

14. Use of glycopyrrolate in combination with indacaterol and ﬂuticasone, in the manufacture of a medicament for the prophylaxis or treatment of a respiratory, inﬂammatory or obstructive airway disease.

15. The use according to claim 14 wherein the disease is COPD or asthma.

16. A pharmaceutical composition according to claim 1, substantially as herein described with reference to the examples.

17. A process according to claim 13, substantially as herein described with reference to the examples.

18. The use according to claim 14, substantially as herein described with reference to any one of the Examples thereof.