GLYCOPYRRONIUM, INDACATEROL AND FLUTICASONE

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to Indian Provisional Patent Application No. 201921016035 filed on Apr 23, 2019, the entire contents of which are incorporated by reference herein.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to an inhalable pharmaceutical dry powder composition comprising two or more active ingredients that are useful for pulmonary administration. Preferably, the present invention relates to an inhalable pharmaceutical dry powder composition comprising effective amounts of glycopyrronium or its pharmaceutically acceptable salt, indacaterol or its pharmaceutically acceptable salt, fluticasone or its pharmaceutically acceptable ester and a diluent; and process of preparing such composition and its use in the treatment of respiratory disorders.

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.

The current therapy for asthma includes 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. Corticosteroid drugs are effective at reducing asthma symptoms by blocking the body's inflammatory response. The leukotriene antagonists have limited efficacy, with only small increases 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 inflammation of the bronchial airways. Emphysema is 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 the gravity.

Indacaterol is a long acting, beta-2 adrenergic agonist. Its chemical name is 5- {(lR)-2-((5,6-Diethyl-2, 3-dihydro- lH-inden-2-yl)amino)-l-hydroxyethyl} -8-hydroxy quinolin-2(lH)-one. It is structurally depicted as:

Indacaterol is currently available in U.S. as Arcapta Neohaler (Approved as indacaterol maleate equivalent to 75mcg of indacaterol as powder for inhalation). Indacaterol maleate is available in combination with glycopyrrolate under the brand name Utibron as powder for inhalation composition. Both the products are used as maintenance treatment of COPD.

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

(Glycopyrronium)

Glycopyrronium bromide (also known as Glycopyrrolate) is currently approved in the U.S. as Robinul ^® (as 0.2mg/ml injection and as tablets of lmg strength); which is indicated for treatment of peptic ulcer and as preoperative anti-muscarinic to reduce salivary, tracheobronchial, and pharyngeal secretions in anesthesia. Glycopyrronium bromide is also approved in Europe as dry powder inhaler Seebri Breezhaler ^® (Novartis) which is indicated for the treatment of 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 has recently approved Seebri™ Neohaler ^® (glycopyrrolate) inhalation powder 15.6 meg as a stand-alone monotherapy for the same COPD indication. Seebri™ Neohaler and Seebri Breezhaler ^® contains lactose and magnesium stearate as inactive ingredients.

Fluticasone propionate is a corticosteroid used to treat asthma and allergic rhinitis. The chemical name for fluticasone propionate is S-(fluoromethyl)-6a, 9- difluoro- 11 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 as FLOVENT ^® (USA and Canada) and FLIXOTIDE (EU) for asthma, and as FLONASE ^® (USA and Canada), FLIXONASE ^® and PIRINASE ^® for allergic rhinitis (hay fever), as well as a combination of fluticasone and salmeterol as ADVAIR ^® (USA and Canada) or SERETIDE ^® .

International Publication No. WO 2001/76575 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 treatment of childhood asthma.

International Publication No. WO 2005/105043 relates to dry powder compositions which exhibit improved stability over time comprising glycopyrronium, and methods for producing the same. International Publication No. WO 2005/110402A1 relates to medicament comprising glycopyrrolate and indacaterol for the treatment of an inflammatory or obstructive airway disease.

International Publication No. WO 2012/110770 relates to medicament comprising glycopyrrolate, indacaterol maleate and fluticasone furoate for the treatment of respiratory, inflammatory or obstructive airway disease.

There still exists a need to develop a therapeutically effective dry powder inhalation composition comprising glycopyrronium or its salt, indacaterol or its salt and fluticasone or its esters for the treatment of respiratory diseases like asthma and COPD.

SUMMARY OF THE INVENTION

The present invention relates to an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt, an effective amount of indacaterol or its pharmaceutically acceptable salt, fluticasone or its pharmaceutically acceptable ester and a diluent.

In an embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt; an effective amount of indacaterol or its pharmaceutically acceptable salt such as hydrochloride, maleate, acetate etc; fluticasone or its pharmaceutically acceptable ester such furoate, propionate etc and a diluent, wherein said composition is free from a hydrophobic excipient.

In an embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrrolate, an effective amount of indacaterol hydrochloride, an effective amount of fluticasone propionate and a diluent, wherein said composition is free from a hydrophobic excipient.

The pharmaceutically acceptable diluent suitable for use in the present invention is selected from lactose, mannitol, sucrose, trehalose, cyclodextrin, or mixtures thereof. Preferably, the pharmaceutically acceptable diluent is lactose monohydrate.

In an embodiment, the present invention relates to an inhalable pharmaceutical dry powder composition comprising (i) a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and lactose; (ii) indacaterol hydrochloride and fluticasone or its pharmaceutically acceptable ester and (iii) lactose; wherein said composition is free from a hydrophobic excipient.

In an embodiment, the present invention relates to an inhalable pharmaceutical dry powder composition comprising (a) glycopyrronium bromide in an amount of 5 meg to 100 meg, (b) indacaterol hydrochloride in an amount of 5 meg to 500 meg (c) fluticasone propionate in an amount of 25 meg to 1000 meg and (d) lactose wherein said composition is free from a hydrophobic excipient.

In another embodiment, the present invention relates to an inhalable pharmaceutical dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt from about 0.01% w/w to about 5% w/w or from about 0.05% w/w to about 2.5% w/w or from about 0.1% w/w to about 1% w/w, indacaterol hydrochloride from about 0.01% w/w to about 5% w/w or from about 0.05% w/w to about 3% w/w or from about 0.075% w/w to about 2.5% w/w and fluticasone or its pharmaceutically acceptable ester from about 0.01% w/w to about 5% w/w or from about 0.05% w/w to about 3% w/w or from about 0.075% w/w to about 2.5% w/w by total weight of inhalable composition.

In another embodiment, there is provided an inhalable pharmaceutical dry powder composition, wherein the composition has fine particle mass in the range of about 0.03 mg to about 10 mg having average particle size less than 80 pm or less than 60 pm or less than 50 pm

In further embodiment coarse particle mass in the range of about 5 mg to about 50 mg having average particle size more than 80 pm but less than 350 pm, preferably more than 90 pm or more than 100 pm, of the total inhalable composition

In another embodiment, there is provided an inhalable pharmaceutical dry powder composition, wherein the composition has fine lactose particles in the range of about 0.5 mg to about 15 mg having average particle size less than 80 pm or less than 60 pm or less than 50 pm and coarse lactose particles in the range of about 10 mg to about 30mg having average particle size more than 80 pm but less than 350 pm, preferably more than 90 pm or more than 100 pm, of total weight of inhalable composition.

In another embodiment, there is provided an inhalable pharmaceutical dry powder composition, wherein the composition has fine lactose particle mass in the range of about 0.1% w/w to about 40% w/w having average particle size less than 80 pm and coarse lactose particles in the range of about 50% w/w to about 99.9% w/w by having average particle size more than 80 pm but less than 350 pm, preferably more than 90 pm or more than 100 pm of total weight of inhalable composition.

In an embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in the weight ratio of about 1:1 to about 1:100 wherein D90 particle size of lactose is in the range of 140 pm to about 210 pm prior to co-micronization process.

In an embodiment of the present invention, the diluent is a admixture of lactose particles consisting of: (i) about to 0 to 10% w/w of fine particles of lactose having particle size D90 less than about 50 pm; and (ii) about 90 to 99.9 % w/w of coarse lactose having particle size D90 in the range of about 30 pm to about 350 pm.

In an embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising (i) a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in the weight ratio of about 1:1 to about 1:100 wherein D90 particle size of co-micronized premix is in the range of about 0.5 pm to about 10 pm; (ii) indacaterol or its pharmaceutically acceptable salt and fluticasone or its pharmaceutically acceptable ester; and (iii) another part of lactose having D90 particle size in the range of about 5 pm to about 400 pm; wherein said composition is free from a hydrophobic excipient.

In an embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising (i) a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in the weight ratio of about 1:1 to about 1:100 wherein D90 particle size of co-micronized premix is in the range of about 1 pm to about 8 pm; (ii) indacaterol or its pharmaceutically acceptable salt and fluticasone or its pharmaceutically acceptable ester; and (iii) another part of lactose having D90 particle size in the range of about 30 pm to about 350 pm; wherein said composition is free from a hydrophobic excipient.

In further embodiment, the weight ratio of fine particle mass to coarse particle mass in the present inhalable composition ranges from about 1:1 to about 1:100. In another embodiment, there is provided a process for preparing an inhalable pharmaceutical dry powder composition, wherein said process comprises:

(a) Co-micronizing glycopyrronium or its pharmaceutically acceptable salt with lactose to obtain a micronized premix having D90 particle size is less than about 20 pm; and

(b) Blending the co-micronized premix of step (a) with an effective amount of indacaterol hydrochloride, fluticasone or its pharmaceutically acceptable ester and one part of lactose

(c) Blending the mixture obtained in step (b) with another part of lactose, wherein said composition is free from a hydrophobic excipient and wherein said composition has fine particle mass in the range of 0.2 mg to 20 mg and coarse particle mass in the range of about 5 mg to about 50 mg, of the total inhalable composition.

In another embodiment, there is provided a process for preparing an inhalable pharmaceutical dry powder composition, wherein said process comprises:

(a) Co-micronizing glycopyrronium or its pharmaceutically acceptable salt with coarser particles of lactose to obtain a micronized premix having D90 particle size is less than about 20 pm; and

(b) Blending the co-micronized premix of step (a) with an effective amount of indacaterol hydrochloride, fluticasone or its pharmaceutically acceptable ester and fine particle of lactose having average particle size less than 80 pm or less than 60 pm or less than 50 pm

(c) Blending the mixture obtained in step (b) with coarse particles of lactose having average particle size more than 80 pm or more than 90 pm or more than 100 pm.

wherein said composition is free from a hydrophobic excipient and wherein said composition has fine particle mass in the range of 0.2 mg to 20 mg and coarse particle mass in the range of about 5 mg to about 50 mg, of the total inhalable composition.

In an embodiment, the present invention relates to a method of treating respiratory disorders in a subject, said method comprising administering by inhalation route to the subject the dry powder composition comprising an effective amount of glycopyrronium bromide, indacaterol hydrochloride and fluticasone propionate, wherein said composition is free from hydrophobic agent. In a further embodiment, the present invention relates to use of an effective amount of glycopyrronium bromide and indacaterol hydrochloride in the inhalable pharmaceutical dry powder composition of the present invention for the treatment of respiratory disorders in a subject.

DETAILED 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.

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, 1- 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 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 "effective amount" and "therapeutically effective amount" are interchangeable and denotes an amount of an active ingredient that, when administered to a subject for treating respiratory disorders, produces an intended therapeutic benefit in a subject. The term“active ingredient” (used interchangeably with“active” or“active substance” or“drug”) as used herein includes Glycopyrronium or a pharmaceutically acceptable salt thereof.

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

The term "subject" includes mammals like human 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.

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’) and Dio value refers to about 10 volume percent of all the particles measured have size less than a defined particle size value (also referred to as Dio particle size). The particle size can be measured using various techniques like laser diffraction, photon correlation spectroscopy (PCS) and Coulter’s principle. For the purpose of the present invention term“fine particles” refer to the particles with D10 value of about 0.1 pm to about 20 pm, D50 value of about 1 pm to about 45 pm and D90 value less than 65 pm and term“coarse particles” refer to the particles with D10 value of about 60 mih to about 200 mih, Dso value of about 80 mih to about 300 mih and D90 value less than 320 mhi.

The therapeutically effective amount of fluticasone or its pharmaceutically acceptable ester to be administered per day ranges from about 1 pg to about 1000 pg, and preferably from about 10pg to about 800 pg and more preferably from about 20 pg to about 500 pg.

The therapeutically effective amount of indacaterol or its pharmaceutically acceptable salt to be administered per day ranges from about 1 meg to about 1000 meg, and preferably from about 10 meg to about 800 meg, and more preferably from about 20 meg to about 600.

The therapeutically effective amount of fluticasone or its pharmaceutically acceptable ester to be administered per day ranges from about 1 pg to about 1000 pg, and preferably from about 10pg to about 800 pg and more preferably from about 20 pg to about 500 pg.

The therapeutically effective amount of glycopyrronium or its pharmaceutically acceptable salt to be administered per day ranges from about 1 meg to about 500 meg, and preferably from about 5 meg to about 250 meg, and more preferably from about 10 meg to about 100 meg.

The term“co-micronisation” refers to milling or micronisation of the active ingredient and lactose together in suitable mill to obtain micronised mixture of active ingredient and lactose. The mixture of active ingredient and lactose after co- micronisation process can be called as co-micronised premix of active ingredient and lactose. Jet mill, Air jet mill, Ball mill and the like can be used for the milling purpose. Preferably Air Jet Mill may be used for co-micronisation.

The fine particle mass test is normally conducted using a validated multistage impactor or impinger method, or a suitably validated alternative. It is normally 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 should be 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 determined by suitable multistage impactor or impinger method

The pharmaceutical composition in the above embodiments may optionally comprise one or more pharmaceutically acceptable excipients.

The inhalable pharmaceutical dry powder composition of the present invention may contain one or more pharmaceutically acceptable excipients.

The powder composition may be further be 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. Alternately, the composition can be filled, either as discrete dosage units, in a blister or a sachet or in a reservoir for multiple use.

The present invention relates to an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt, an effective amount of indacaterol or its pharmaceutically acceptable salt, fluticasone or its pharmaceutically acceptable ester and a diluent.

In an embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt, an effective amount of indacaterol or its pharmaceutically acceptable salt, fluticasone or its pharmaceutically acceptable ester and a diluent, wherein said composition is free from a hydrophobic excipient.

In an embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrrolate, an effective amount of indacaterol hydrochloride, an effective amount of fluticasone propionate and a diluent, wherein said composition is free from a hydrophobic excipient.

The pharmaceutically acceptable diluent suitable for use in the present invention is selected from lactose, mannitol, sucrose, trehalose, cyclodextrin, or mixtures thereof. Preferably, the pharmaceutically acceptable diluent is lactose, preferably lactose monohydrate. Various grade of lactose are available for use in dry powder compositions and are selected from Respitose ^® SV010, Respitose ^® SV003, Respitose ^® ML006, Lactose Monohydrate Inhalation 40M, Lactose Anhydrous 120M, Lactohale ^® 200, Lactohale ^® 300, Lactohale ^® 70, Inhalac 500 and the like. In an embodiment, the present invention relates to an inhalable pharmaceutical dry powder composition comprising (i) a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and lactose; (ii) indacaterol hydrochloride and fluticasone or its pharmaceutically acceptable ester and (iii) lactose; wherein said composition is free from a hydrophobic excipient.

In an embodiment, the present invention relates to an inhalable pharmaceutical dry powder composition comprising dry mix comprising (i) glycopyrronium or its pharmaceutically acceptable salt (ii) indacaterol hydrochloride (iii) fluticasone or its pharmaceutically acceptable ester and (iv) lactose; wherein said composition is free from a hydrophobic excipient.

In an embodiment, the present invention relates to an inhalable pharmaceutical dry powder composition comprising (a) glycopyrronium bromide in an amount of 5 meg to 100 meg, (b) indacaterol hydrochloride in an amount of 5 meg to 500 meg (c) fluticasone propionate in an amount of 25 meg to 1000 meg and (d) lactose wherein said composition is free from a hydrophobic excipient.

In another embodiment, the present invention relates to an inhalable pharmaceutical dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt from about 0.01% w/w to about 5% w/w or from about 0.05% w/w to about 2.5% w/w or from about 0.1% w/w to about 1% w/w, indacaterol hydrochloride from about 0.01% w/w to about 5% w/w or from about 0.05% w/w to about 3% w/w or from about 0.075% w/w to about 2.5% w/w and fluticasone or its pharmaceutically acceptable ester from about 0.01% w/w to about 5% w/w or from about 0.05% w/w to about 3% w/w or from about 0.075% w/w to about 2.5% w/w by total weight of inhalable composition.

In another embodiment, there is provided an inhalable pharmaceutical dry powder composition, wherein the composition has fine particle mass in the range of about 0.03 mg to about 10 mg having average particle size less than 80 pm or less than 60 pm or less than 50 pm

In further embodiment coarse particle mass in the range of about 5 mg to about 50 mg having average particle size more than 80 pm but less than 350 pm, preferably more than 90 pm or more than 100 pm, of the total inhalable composition In another embodiment, there is provided an inhalable pharmaceutical dry powder composition, wherein the composition has fine lactose particles in the range of about 0.5 mg to about 15 mg having average particle size less than 80 pm or less than 60 pm or less than 50 pm and coarse lactose particles in the range of about 10 mg to about 30mg having average particle size more than 80 pm but less than 350 pm, preferably more than 90 pm or more than 100 pm, of total weight of inhalable composition.

In another embodiment, there is provided an inhalable pharmaceutical dry powder composition, wherein the composition has fine lactose particle mass in the range of about 0.1% w/w to about 40% w/w having average particle size less than 80 pm and coarse lactose particles in the range of about 50% w/w to about 99.9% w/w by having average particle size more than 80 pm but less than 350 pm, preferably more than 90 pm or more than 100 pm of total weight of inhalable composition.

In an embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in the weight ratio of about 1:1 to about 1:100 wherein D90 particle size of lactose is in the range of 140 pm to about 210 pm prior to co-micronization process.

In an embodiment of the present invention, the diluent is a admixture of lactose particles consisting of: (i) about to 0 to 10% w/w of fine particles of lactose having particle size D90 less than about 50 pm; and (ii) about 90 to 99.9 % w/w of coarse lactose having particle size D90 in the range of about 30 pm to about 350 pm.

In an embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising (i) a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in the weight ratio of about 1:1 to about 1:100 wherein D90 particle size of co-micronized premix is in the range of about 0.5 pm to about 10 pm; (ii) indacaterol or its pharmaceutically acceptable salt and fluticasone or its pharmaceutically acceptable ester; and (iii) another part of lactose having D90 particle size in the range of about 5 pm to about 400 pm; wherein said composition is free from a hydrophobic excipient.

In an embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising (i) a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in the weight ratio of about 1:1 to about 1:100 wherein D90 particle size of co-micronized premix is in the range of about 1 pm to about 8 pm; (ii) indacaterol or its pharmaceutically acceptable salt and fluticasone or its pharmaceutically acceptable ester; and (iii) another part of lactose having D90 particle size in the range of about 30 pm to about 350 pm; wherein said composition is free from a hydrophobic excipient.

In further embodiment, the weight ratio of fine particle mass to coarse particle mass in the present inhalable composition ranges from about 1:1 to about 1:100.

In another embodiment, there is provided a process for preparing an inhalable pharmaceutical dry powder composition, wherein said process comprises:

(a) Co-micronizing glycopyrronium or its pharmaceutically acceptable salt with lactose to obtain a micronized premix having D90 particle size is less than about 20 pm; and

(b) Blending the co-micronized premix of step (a) with an effective amount of indacaterol hydrochloride, fluticasone or its pharmaceutically acceptable ester and one part of lactose

(c) Blending the mixture obtained in step (b) with another part of lactose, wherein said composition is free from a hydrophobic excipient and wherein said composition has fine particle mass in the range of 0.2 mg to 20 mg and coarse particle mass in the range of about 5 mg to about 50 mg, of the total inhalable composition.

In another embodiment, there is provided a process for preparing an inhalable pharmaceutical dry powder composition, wherein said process comprises:

(a) Co-micronizing glycopyrronium or its pharmaceutically acceptable salt with coarser particles of lactose to obtain a micronized premix having D90 particle size is less than about 20 pm; and

(b) Blending the co-micronized premix of step (a) with an effective amount of indacaterol hydrochloride, fluticasone or its pharmaceutically acceptable ester and fine particle of lactose having average particle size less than 80 pm or less than 60 pm or less than 50 pm

(c) Blending the mixture obtained in step (b) with coarse particles of lactose having average particle size more than 80 pm or more than 90 pm or more than 100 pm. wherein said composition is free from a hydrophobic excipient and wherein said composition has fine particle mass in the range of 0.2 mg to 20 mg and coarse particle mass in the range of about 5 mg to about 50 mg, of the total inhalable composition.

Preferably, the weight ratio of glycopyrronium or its pharmaceutically acceptable salt to lactose in the co-micronized premix of the present invention ranges from about 1:1 to about 1:300, from about 1:5 to about 1:200 or from about 1:10 to about 1:100.

In further embodiment, the weight ratio of the co-micronized premix to lactose ranges from about 1: 1 to about 1:50, preferably from about 1:5 to about 1:30.

In another embodiment of the present inhalable composition the weight ratio of fine lactose to coarse lactose ranges from about 1:1 to about 1:80.

In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising (a) glycopyrronium bromide (b) indacaterol hydrochloride (c) fluticasone propionate and (d) lactose, wherein said composition is free from hydrophobic agents selected from amino acids, fatty acids, peptides, talc, stearic acid and its derivatives such as calcium stearate, magnesium stearate.

In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt, indacaterol hydrochloride and lactose wherein Median mass aerodynamic diameter (MMAD) of said composition is in the range of 1 pm - 6 pm or more preferably in the range of 2.5 pm - 4.5 pm.

In an embodiment, the present invention relates to a method of treating respiratory disorders in a subject, said method comprising administering by inhalation route to the subject the dry powder composition comprising an effective amount of glycopyrronium bromide, indacaterol hydrochloride and fluticasone propionate, wherein said composition is free from hydrophobic agent.

In a further embodiment, the present invention relates to use of an effective amount of glycopyrronium bromide and indacaterol hydrochloride in the inhalable pharmaceutical dry powder composition of the present invention for the treatment of respiratory disorders in a subject. The respiratory disorder, in the context of present invention, 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. EXAMPLES

EXAMPLE 1: Preparation of Co-Micronization Premix:

Manufacturing process:

1. Glycopyrrolate and Lactose were mixed thoroughly.

2. The blend from Stepl was micronised in Air jet mill till the D90 particle size is about

< 10 pm.

EXAMPLES 2 - 7 : DPI Compositions comprising Glycopyrronium bromide,

Indacaterol hydrochloride and Fluticasone propionate using co-micronization process

EXAMPLES 8 - 13: DPI Compositions comprising Glycopyrronium bromide,

Indacaterol hydrochloride and Fluticasone propionate using co-micronization process

EXAMPLES 14 - 19: DPI Compositions comprising Glycopyrronium bromide,

Indacaterol hydrochloride and Fluticasone propionate using co-micronization process

EXAMPLES 20 - 25: DPI Compositions comprising Glycopyrronium bromide,

Indacaterol hydrochloride and Fluticasone propionate using co-micronization process

Manufacturing Process: 1. Glycopyrrolate micronized premix from example 1 is mixed with Indacaterol hydrochloride, fluticasone propionate and fine grade or micronized Lactose particles in a suitable blender and sifted. If fine lactose not used then mix with half part coarse lactose particles.

2. Blend in Step 1 is mixed with a part of coarse grade lactose monohydrate and then mixed in a suitable blender and sifted.

3. The blend of step 2 is filled in a capsule or dose packet or blister.

EXAMPLE 26 - 31: DPI Compositions comprising Glycopyrronium bromide,

Indacaterol hydrochloride and Fluticasone propionate using dry mixing:

EXAMPLE 32 - 37: DPI Compositions comprising Glycopyrronium bromide,

Indacaterol hydrochloride and Fluticasone propionate using dry mixing:

EXAMPLE 38 - 43: DPI Compositions comprising Glycopyrronium bromide,

Indacaterol hydrochloride and Fluticasone propionate using dry mixing:

Manufacturing Process:

1. Glycopyrrolate, Indacaterol hydrochloride and fluticasone propionate are mixed with fine grade or micronized Lactose particles, sifted and then mixed in a suitable blender.

2. Coarse grade lactose monohydrate is added to the mixture of Step 1, sifted and then mixed in a suitable blender.

3. The blend of step 2 is filled in a capsule or dose packet or blister. 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.