FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION (See Section 10 and rule 13)
Title: AN INHALABLE PHARMACEUTICAL COMPOSITION COMPRISING
GLYCOPYRRONIUM
Applicant:
GLENMARK PHARMACEUTICALS LIMITED,
an Indian Company and having its office at
Glenmark House,
HDO – Corporate Bldg, Wing - A,
B.D. Sawant Marg, Chakala, Andheri (East),
Mumbai, India – 400 099.
The following specification particularly describes the invention and the manner in
which it is to be performed.

AN INHALABLE PHARMACEUTICAL COMPOSITION COMPRISING
GLYCOPYRRONIUM
PRIORITY DOCUMENT
This patent application claims priority to Indian Provisional Patent Application number 3493/MUM/2014 (filed on Nov 05, 2014), the contents of which are incorporated by reference herein.
TECHNICAL FIELD OF THE INVENTION The present invention relates to an inhalable pharmaceutical composition comprising glycopyrronium or its salt. Preferably, the present invention relates to an inhalable powder composition comprising an effective amount of glycopyrronium or its salt and lactose; a 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.
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 bromide (also known as Glycopyrrolate) is currently approved in the U.S. as Robinul® (as 0.2mg/ml injection and as tablets of 1mg 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 mcg of glycopyrronium bromide, equivalent to 50 mcg of glycopyrronium. The FDA has recently approved Seebri™ Neohaler® (glycopyrrolate) inhalation powder 15.6 mcg as a stand-alone monotherapy for the same COPD indication. Seebri™ Neohaler and Seebri Breezhaler® contains lactose and magnesium stearate as inactive ingredients.
International Publication No. WO 01/76575 describes a pharmaceutical composition for pulmonary delivery comprising glycopyrrolate in a controlled release formulation.

International Publication No. WO2005/107873 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.
There still exists a need for an effective therapeutic treatment for 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 salt and lactose.
In an embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose, wherein said composition is free from a hydrophobic excipient.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition consisting of an effective amount of glycopyrronium or its salt and lactose.
In an embodiment, the present invention relates to an inhalable pharmaceutical dry powder composition comprising (i) a co-micronized premix of glycopyrronium or its salt and one part of lactose in a weight ratio of about 1:5 to about 1:200 and having D90 particle size in the range of about 0.5 µm to about 10 µm, and (ii) another part of lactose having D90 particle size in the range of about 5 µm to about 200 µm; wherein said composition is free from a hydrophobic excipient.
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 salt and one part of lactose in a weight ratio of about 1:5 to about 1:200 and having D90 particle size in the range of about 0.5 µm to about 10 µm, and (ii) another part of lactose having D90 particle size in the range of about 5 µm to about 200 µm; wherein said composition is free from a hydrophobic excipient. In an aspect, the weight ratio of glycopyrronium or its salt to the one part of lactose in the co-micronized premix ranges from about 1:12 to about 1:75, or from about 1:14 to about 1:65.

In another embodiment, the present invention relates an inhalable pharmaceutical dry powder composition comprising (i) a co-micronized premix consisting of glycopyrronium or its salt and one part of lactose in a weight ratio of about 1:10 to about 1:100 and having D90 particle size in the range of about 1 µm to about 8 µm, and (ii) another part of lactose having D90 particle size in the range of about 8 µm to about 200 µm; wherein said composition is free from a hydrophobic excipient. In an aspect, the D90 particle size of the co-micronized premix is in the range of about 2 µm to about 7 µm, or about 3 µm to about 5 µm.
In the context of present invention, said inhalable pharmaceutical dry powder composition is free from a hydrophobic excipient.
In another embodiment, there is provided a process for preparing an inhalable pharmaceutical dry powder composition comprising glycopyrronium or its salt, wherein said process comprises:
(a) co-micronising glycopyrronium or its salt with one part of lactose to obtain a micronized premix having D90 particle size less than about 10 µm; and
(b) blending the co-micronized premix of step (a) with another part of lactose having D90 particle size in the range of about 5 µm to about 200 µm.
In another embodiment, there is provided a process for preparing an inhalable pharmaceutical dry powder composition comprising glycopyrronium or its salt, wherein said process comprises:
(a) co-micronising glycopyrronium or its salt with one part of lactose in a weight ratio of about 1:5 to about 1:200 to obtain a micronized premix having D90 particle size less than about 5 µm; and
(b) blending the co-micronized premix of step (a) with another part of lactose having D90 particle size in the range of about 8 µm to about 200 µm.
In another embodiment, there is provided a process for preparing an inhalable pharmaceutical dry powder composition comprising glycopyrronium or its salt, wherein said process comprises:

(a) co-micronising glycopyrronium or its salt with one part of lactose in a weight
ratio of about 1:10 to about 1:100 to obtain a micronized premix having D90
particle size less than about 5 µm; and
(b) blending the co-micronized premix of step (a) with another part of lactose
having D90 particle size in the range of about 8 µm to about 200 µm.
Preferably, the weight ratio of glycopyrronium or its salt to lactose in the co-
micronized premix of the present invention ranges from about 1:5 to about 1:200, 1:10
to about 1:100, more preferably from about 1: 12 to about 1: 75 or from about 1:14 to
about 1:65.
In an embodiment of the present invention, the weight ratio of the co-micronized premix to lactose ranges from1:1 to 1:50, preferably, from 1:5 to 1:30.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising from about 0.01% to about 10% by weight, or preferably from about 0.1% to about 1% by weight of glycopyrronium or its salt, wherein the composition has fine particle mass in the range of 20 mcg to 30 mcg, and wherein said composition is prepared by a method comprising:
(a) co-micronising glycopyrronium or its salt with one part of lactose to obtain a micronized premix having D90 particle size less than about 5 µm; and
(b) blending the co-micronized premix of step (a) with another part of lactose having D90 particle size in the range of about 8 µm to about 200 µm.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising from about 0.01% to about 10% by weight, or preferably from about 0.1% to about 1% by weight of glycopyrronium or its salt, wherein the composition has fine particle mass in the range of 18 mcg to 30 mcg, and wherein said composition is prepared by a method comprising:
(a) co-micronising glycopyrronium or its salt with one part of lactose to obtain a micronized premix having D90 particle size less than about 5 µm; and
(b) blending the co-micronized premix of step (a) with another part of lactose having D90 particle size in the range of about 8 µm to about 200 µm.

In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising from about 0.1% to about 1% by weight of glycopyrronium or its salt, wherein the composition has fine particle mass in the range of 20 mcg to 30 mcg, and wherein said composition is prepared by a method comprising:
(a) co-micronising glycopyrronium or its salt with one part of lactose in a weight ratio of about 1:5 to about 1:200 to obtain a micronized premix having D90 particle size less than about 5 µm; and
(b) blending the co-micronized premix of step (a) with lactose having D90 particle size in the range of about 8 µm to about 200 µm.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising from about 0.1% to about 1% by weight of glycopyrronium or its salt, wherein the composition has fine particle mass in the range of 18 mcg to 30 mcg, and wherein said composition is prepared by a method comprising:
(a) co-micronising glycopyrronium or its salt with one part of lactose in a weight ratio of about 1:5 to about 1:200 to obtain a micronized premix having D90 particle size less than about 5 µm; and
(b) blending the co-micronized premix of step (a) with lactose having D90 particle size in the range of about 8 µm to about 200 µm.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising from about 0.1% to about 1% by weight of glycopyrronium or its salt, wherein the composition has fine particle mass in the range of 20 mcg to 30 mcg, and wherein said composition is prepared by a method comprising:
(a) co-micronising glycopyrronium or its salt with one part of lactose in a weight ratio of about 1:5 to about 1:200 to obtain a micronized premix having D90 particle size between 3 µm to 5 µm; and
(b) blending the co-micronized premix of step (a) with lactose having D90 particle size in the range of about 8 µm to about 200 µm.

In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising from about 0.1% to about 1% by weight of glycopyrronium or its salt, wherein the composition has fine particle mass in the range of 18 mcg to 30 mcg, and wherein said composition is prepared by a method comprising:
(a) co-micronising glycopyrronium or its salt with one part of lactose in a weight ratio of about 1:5 to about 1:200 to obtain a micronized premix having D90 particle size between 3 µm to 5 µm; and
(b) blending the co-micronized premix of step (a) with lactose having D90 particle size in the range of about 8 µm to about 200 µm.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising a co-micronized premix consisting of glycopyrronium or its salt and lactose in a weight ratio of about 1:10 to about 1:200 and lactose wherein said premix has mean particle size of less than about 5 µm, and said composition is free from a hydrophobic excipient and wherein the composition has fine particle mass in the range of 20 mcg to 30 mcg.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising a co-micronized premix consisting of glycopyrronium or its salt and lactose in a weight ratio of about 1:10 to about 1:200 and lactose wherein said premix has mean particle size of less than about 5 µm, and said composition is free from a hydrophobic excipient and wherein the composition has fine particle mass in the range of 18 mcg to 30 mcg.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising a co-micronized premix of glycopyrronium or its salt and lactose in a weight ratio of about 1:10 to about 1:200, wherein said premix has mean particle size of less than about 5 µm, and said composition is free from a hydrophobic excipient and wherein the composition has fine particle mass in the range of 20 mcg to 30 mcg.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising a co-micronized premix of glycopyrronium or its salt and lactose in a weight ratio of about 1:10 to about 1:200, wherein said premix has

mean particle size of less than about 5 µm, and said composition is free from a hydrophobic excipient and wherein the composition has fine particle mass in the range of 18 mcg to 30 mcg.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising (a) glycopyrronium bromide in an amount of 5 mcg to 200 mcg, and (b) lactose, wherein said composition is free from magnesium stearate.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose wherein the said composition has Hausner ratio in the range of 1 to 2 or preferably Hausner ratio is in the range of 1.25 to 1.75 or more preferably Hausner ratio is in the range of 1.30 to 1.65.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose wherein said composition has Carr index in the range of 20% -45% or more preferably the Carr index is in the range of 22%-40%.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose wherein said composition has bulk density in the range of 0.45 g/mL – 0.65 g/mL or more preferably bulk density in the range of 0.5 g/mL – 0.6 g/mL.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose wherein said composition has tap density in the range of 0.65 g/mL – 0.95 g/mL or more preferably tap density in the range of 0.7 g/mL – 0.9 g/mL.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose wherein MMAD of glycopyrronium in said composition is in the range of 1 µm – 4 µm or more preferably MMAD of glycopyrronium in said composition is in the range of 1.5 µm – 3 µm.
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 and lactose, wherein said composition is free from magnesium stearate.
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.
In the context of present invention, the term “asthma” includes acute asthma, chronic asthma, intermittent asthma, mild persistent asthma, moderate persistent asthma, severe persistent asthma, chronic persistent asthma, mild to moderate asthma, mild to moderate persistent asthma, mild to moderate chronic persistent asthma, allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, nocturnal asthma, bronchial asthma, exercise induced asthma, occupational asthma, seasonal asthma, silent asthma, gastro-esophageal asthma, idiopathic asthma and cough variant asthma.
In an embodiment, the present invention relates to a method of treating asthma in a subject, said method comprising administering by inhalation route to the subject the dry powder composition comprising an effective amount of glycopyrronium bromide and lactose, wherein said composition is free from magnesium stearate.
In an embodiment, the present invention relates to a method of treating COPD in a subject, said method comprising administering by inhalation route to the subject the dry powder composition comprising an effective amount of glycopyrronium bromide and lactose, wherein said composition is free from magnesium stearate.
In a further embodiment, the present invention relates to use of an effective amount of glycopyrronium bromide in the inhalable pharmaceutical dry powder composition of the present invention for the treatment of respiratory disorders in a subject.

In a further embodiment, the present invention relates to an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium bromide 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" or "therapeutically effective amount" 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’). The particle size can be measured using various techniques like laser diffraction, photon correlation spectroscopy (PCS) and Coulter’s principle.
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.
The Carr index and Hausner ratio are frequently used in as an indication of the flowability of a powder. The Carr index and Hausner ratio can be determined using Tap Density Apparatus. The bulk density and tap density of the powder composition can be determined by Tap density apparatus.
The therapeutically effective amount of Glycopyrronium bromide to be administered per day ranges from about 5 mcg to about 400 mcg.
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. Examples of such excipients include but are not limited to diluents, solvents, and the like.
The pharmaceutically acceptable diluent suitable for use in the invention is selected from lactose, mannitol, sucrose, trehalose, cyclodextrin, or mixtures thereof. Preferably, the pharmaceutically acceptable diluent is lactose. Various grade of lactose are available for use in dry powder compositions are selected from Respitose® SV010, Respitose® SV003, Respitose® ML006, Lactose Monohydrate Inhalation 40M, Lactose Anhydrous 120M, Lactohale® 300, and the like.
Examples of solvents include water; propylene glycol; ether; petroleum ether; alcohols, e.g., methanol, ethanol, isopropyl alcohol and higher alcohols; alkanes, e.g.,

pentane, hexane and heptane; ketones, e.g., acetone and methyl ethyl ketone; and the like and mixtures thereof.
The process of preparing an inhalable pharmaceutical dry powder composition comprising glycopyrronium or its salts, wherein said process comprises:
(a) co-micronising glycopyrronium or its salts with one part of lactose to obtain a micronized premix having D90 particle size less than about 5 µm; and
(b) blending the co-micronized premix of step (a) with another part of lactose having D90 particle size in the range of about 8 µm to about 200 µm.
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.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose, wherein said composition is free from a hydrophobic excipient.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition consisting of an effective amount of glycopyrronium or its salt and lactose.
In an embodiment, the present invention relates to an inhalable pharmaceutical dry powder composition comprising (i) a co-micronized premix of glycopyrronium or its salt and one part of lactose in a weight ratio of about 1:5 to about 1:200 and having D90 particle size in the range of about 0.5 µm to about 10 µm, and (ii) another part of lactose having D90 particle size in the range of about 5 µm to about 200 µm; wherein said composition is free from a hydrophobic excipient.
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 salt and one part of lactose in a weight ratio of about 1:5 to about 1:200 and having D90 particle size in the range of about 0.5 µm to about 10 µm, and (ii) another part of lactose having D90 particle size in the range of about 5 µm to about 200

µm; wherein said composition is free from a hydrophobic excipient. In an aspect, the weight ratio of glycopyrronium or its salt to the one part of lactose in the co-micronized premix ranges from about 1:12 to about1:75, or from about1:14 to about1:65.
In another embodiment, the present invention relates an inhalable pharmaceutical dry powder composition comprising (i) a co-micronized premix consisting of glycopyrronium or its salt and one part of lactose in a weight ratio of about 1:10 to about 1:100 and having D90 particle size in the range of about 1 µm to about 8 µm, and (ii) another part of lactose having D90 particle size in the range of about 8 µm to about 200 µm; wherein said composition is free from a hydrophobic excipient. In an aspect, the D90 particle size of the co-micronized premix is in the range of about 2 µm to about 7 µm, or about 3 µm to about 5 µm.
In the context of present invention, said inhalable pharmaceutical dry powder composition is free from a hydrophobic excipient.
In another embodiment, there is provided a process for preparing an inhalable pharmaceutical dry powder composition comprising glycopyrronium or its salt, wherein said process comprises:
(a) co-micronising glycopyrronium or its salt with one part of lactose to obtain a micronized premix having D90 particle size less than about 10 µm; and
(b) blending the co-micronized premix of step (a) with another part of lactose having D90 particle size in the range of about 5 µm to about 200 µm.
In another embodiment, there is provided a process for preparing an inhalable pharmaceutical dry powder composition comprising glycopyrronium or its salt, wherein said process comprises:
(a) co-micronising glycopyrronium or its salt with one part of lactose in a weight ratio of about 1:5 to about 1:200 to obtain a micronized premix having D90 particle size less than about 5 µm; and
(b) blending the co-micronized premix of step (a) with another part of lactose having D90 particle size in the range of about 8 µm to about 200 µm.

In another embodiment, there is provided a process for preparing an inhalable pharmaceutical dry powder composition comprising glycopyrronium or its salt, wherein said process comprises:
(a) co-micronising glycopyrronium or its salt with one part of lactose in a weight
ratio of about 1:10 to about 1:100 to obtain a micronized premix having D90
particle size less than about 5 µm; and
(b) blending the co-micronized premix of step (a) with another part of lactose
having D90 particle size in the range of about 8 µm to about 200 µm.
Preferably, the weight ratio of glycopyrronium or its salt to lactose in the co-
micronized premix of the present invention ranges from about 1:5 to about 1:200, 1:10
to about 1:100, more preferably from about 1: 12 to about 1: 75 or from about 1:14 to
about 1:65.
In an embodiment of the present invention, the weight ratio of the co-micronized premix to lactose ranges from1:1 to 1:50, preferably, from 1:5 to 1:30.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising from about 0.01% to about 10% by weight, or preferably from about 0.1% to about 1% by weight of glycopyrronium or its salt, wherein the composition has fine particle mass in the range of 20 mcg to 30 mcg, and wherein said composition is prepared by a method comprising:
(a) co-micronising glycopyrronium or its salt with one part of lactose to obtain a micronized premix having D90 particle size less than about 5 µm; and
(b) blending the co-micronized premix of step (a) with another part of lactose having D90 particle size in the range of about 8 µm to about 200 µm.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising from about 0.1% to about 1% by weight of glycopyrronium or its salt, wherein the composition has fine particle mass in the range of 20 mcg to 30 mcg, and wherein said composition is prepared by a method comprising:

(a) co-micronising glycopyrronium or its salt with one part of lactose in a weight ratio of about 1:5 to about 1:200 to obtain a micronized premix having D90 particle size less than about 5 µm; and
(b) blending the co-micronized premix of step (a) with lactose having D90 particle size in the range of about 8 µm to about 200 µm.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising from about 0.1% to about 1% by weight of glycopyrronium or its salt, wherein the composition has fine particle mass in the range of 20 mcg to 30 mcg, and wherein said composition is prepared by a method comprising:
(a) co-micronising glycopyrronium or its salt with one part of lactose in a weight ratio of about 1:5 to about 1:200 to obtain a micronized premix having D90 particle size between 3 µm to 5 µm; and
(b) blending the co-micronized premix of step (a) with lactose having D90 particle size in the range of about 8 µm to about 200 µm.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising a co-micronized premix consisting of glycopyrronium or its salt and lactose in a weight ratio of about 1:10 to about 1:200 and lactose wherein said premix has mean particle size of less than about 5 µm, and said composition is free from a hydrophobic excipient and wherein the composition has fine particle mass in the range of 20 mcg to 30 mcg.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising a co-micronized premix of glycopyrronium or its salt and lactose in a weight ratio of about 1:10 to about 1:200, wherein said premix has mean particle size of less than about 5 µm, and said composition is free from a hydrophobic excipient and wherein the composition has fine particle mass in the range of 20 mcg to 30 mcg.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising (a) glycopyrronium bromide in an amount of 5 mcg to 200 mcg, and (b) lactose, wherein said composition is free from magnesium stearate.

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 and lactose, wherein said composition is free from magnesium stearate.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose wherein the said composition has Hausner ratio in the range of 1 to 2 or preferably Hausner ratio is in the range of 1.25 to 1.75 or more preferably Hausner ratio is in the range of 1.30 to 1.65.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose wherein said composition has Carr index in the range of 20% -45% or more preferably the compressibility index is in the range of 22%-40%.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose wherein said composition has bulk density in the range of 0.45 g/mL – 0.65 g/mL or more preferably bulk density in the range of 0.5 g/mL – 0.6 g/mL.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose wherein said composition has tap density in the range of 0.65 g/mL – 0.95 g/mL or more preferably tap density in the range of 0.7 g/mL – 0.9 g/mL.
In another embodiment, there is provided an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose wherein MMAD of glycopyrronium in said composition is in the range of 1 µm – 4 µm or more preferably MMAD of glycopyrronium in said composition is in the range of 1.5 µm – 3 µm.
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.
In the context of present invention, the term “asthma” includes acute asthma, chronic asthma, intermittent asthma, mild persistent asthma, moderate persistent asthma, severe persistent asthma, chronic persistent asthma, mild to moderate asthma, mild to moderate persistent asthma, mild to moderate chronic persistent asthma, allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, nocturnal asthma, bronchial asthma, exercise induced asthma, occupational asthma, seasonal asthma, silent asthma, gastro-esophageal asthma, idiopathic asthma and cough variant asthma.
In an embodiment, the present invention relates to a method of treating asthma in a subject, said method comprising administering by inhalation route to the subject the dry powder composition comprising an effective amount of glycopyrronium bromide and lactose, wherein said composition is free from magnesium stearate.
In an embodiment, the present invention relates to a method of treating COPD in a subject, said method comprising administering by inhalation route to the subject the dry powder composition comprising an effective amount of glycopyrronium bromide and lactose, wherein said composition is free from magnesium stearate.
In a further embodiment, the present invention relates to use of an effective amount of glycopyrronium bromide in the inhalable pharmaceutical dry powder composition of the present invention for the treatment of respiratory disorders in a subject.
In a further embodiment, the present invention relates to an inhalable dry powder composition comprising an effective amount of glycopyrronium bromide for the treatment of respiratory disorders in a subject.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.
EXAMPLES

EXAMPLE 1: Premix Preparation:

# Ingredients D90 Particle size Quantity (mg)
1. Glycopyrrolate below 5 µm 0.063
2. Lactose monohydrate (Respitose® SV010) 160 to 190 µm 1.937
Premix Total in mg 2.000
Manufacturing process:
1. Glycopyrrolate and Lactose were mixed thoroughly.
2. The blend from Step1 was micronised in Air jet mill till the D90 particle size is in the range of about 3 µm to about 5 µm.
EXAMPLES 2-4: DPI Compositions comprising Glycopyrronium bromide

# Ingredients D90 Particle size Example 2 Example 3 Example 4
1. Glycopyrrolate co-micronised Premix from Example 1 3 to 5 µm 2.000 2.000 2.000
2. Lactose monohydrate
(Lactohale® 300) < 10 µm - 1.000 2.000
3. Lactose monohydrate
(Respitose® ML006) < 45 µm 8.000 7.000 6.000
4. Lactose monohydrate
(Respitose® SV010) 160 to 190 m 15.000 15.000 15.000
Total blend weight in mg 25.000 25.000 25.000
Fine Particle Mass (mcg) 24.09 28.53 24.24
Manufacturing process:
1. Glycopyrrolate micronised Premix from Example 1 and fine grade Lactose were
sifted and then mixed in a suitable blender.

2. The blend of step 1 was sifted with a part of coarse grade lactose monohydrate and then mixed in a suitable blender.
3. The blend of step 2 was sifted with remaining part of lactose and then mixed in a suitable blender.
4. The blend of step 3 was filled in a capsule or dose packet or blister.
Fine Particle Mass Determination:
The Fine Particle Mass was determined using Andersen Cascade Impactor. The Cascade Impactor was connected to the flow system. The mouth piece of inhaler device having capsule or dose packet or blister containing pharmaceutical composition was attached to mouthpiece adaptor of Cascade Impactor. The inhaler device was actuated and the powder was discharged into the Cascade Impactor by opening of the valves for specific time. The content from each stage of Cascade Impactor was collected and analysed for Fine Particle Mass content.
EXAMPLE 5: Premix Preparation:

# Ingredients D90 Particle size Quantity (mg)
1. Glycopyrrolate below 5 µm 0.063
2. Lactose monohydrate (Respitose® SV010) 160 to 190 µm 0.937
Premix Total in mg 1.000
Manufacturing process:
1. Glycopyrrolate and Lactose were mixed thoroughly.
2. The blend from Step1 was micronised in Air jet mill till the D90 particle size is in the range of about 3 µm to about 5 µm.
EXAMPLES 6 -7: DPI Compositions comprising Glycopyrronium bromide

# Ingredients D90 Particle size Example 6 Example 7
1. Glycopyrrolate co- 3 to 5 µm 1.000 1.000

# Ingredients D90 Particle size Example 6 Example 7
micronised Premix from Example 5
2. Lactose monohydrate
(Lactohale® 300) < 10 µm - 3.000
3. Lactose monohydrate
(Respitose® ML006) < 45 µm 9.000 6.000
4. Lactose monohydrate
(Respitose® SV010) 160 to 190 m 15.000 15.000
Total blend weight in mg 25.000 25.000
Fine Particle Mass (mcg) 21.54 23.36
Manufacturing process:
1. Glycopyrrolate micronised Premix from Example 7 and fine grade Lactose were
sifted and then mixed in a suitable blender.
2. The blend of step 1 was sifted with a part of coarse grade lactose monohydrate and then mixed in a suitable blender.
3. The blend of step 2 was sifted with remaining part of lactose and then mixed in a suitable blender.
4. The blend of step 3 was filled in a capsule or dose packet or blister.
EXAMPLE 8: Premix Preparation:

# Ingredients D90 Particle size Quantity (mg)
1. Glycopyrrolate below 5 µm 0.063
2. Lactose monohydrate (Respitose® SV010) 160 to 190 µm 3.937
Premix Total in mg 4.000
Manufacturing process:
1. Glycopyrrolate and Lactose were mixed thoroughly.

2. The blend from Step1 was micronised in Air jet mill till the D90 particle size is in the range of about 3 µm to about 5 µm.
EXAMPLES 9 -11: DPI Compositions comprising Glycopyrronium bromide

# Ingredients D90 Particle size Example 9 Example 10 Example 11
1. Glycopyrrolate co-micronised Premix from Example 8 3 to 5 µm 4.000 4.000 4.000
2. Lactose monohydrate
(Lactohale® 300) < 10 µm - - 1.000
3. Lactose monohydrate
(Respitose® ML006) < 45 µm 6.000 3.500 5.000
4. Lactose monohydrate
(Respitose® SV010) 160 to 190 15.000 17.500 15.000
Total blend weight in mg 25.000 25.000 25.000
Fine Particle Mass (mcg) 26.90 21.37 28.52
Manufacturing process:
1. Glycopyrrolate micronised Premix from Example 8 and fine grade Lactose were sifted and then mixed in a suitable blender.
2. The blend of step 1 was sifted with a part of coarse grade lactose monohydrate and then mixed in a suitable blender.
3. The blend of step 2 was sifted with remaining part of lactose and then mixed in a suitable blender.
4. The blend of step 3 was filled in a capsule or dose packet or blister.
EXAMPLE 12: Premix Preparation:

# Ingredients D90 Particle size Quantity (mg)
1. Glycopyrrolate below 5 µm 0.063
2. Lactose monohydrate (Respitose® SV010) 160 to 190 µm 1.937
Premix Total in mg 2.000
Premix Manufacturing process:
1. Glycopyrrolate and Lactose were mixed thoroughly.
2. The blend from Step1 was micronised in Air jet mill till the D90 particle size is in the range of about 3 µm to about 5 µm.
Final Blending:

# Ingredients D90 Particle size Qty. in mg
1. Glycopyrrolate co-micronised Premix 3 to 5 µm 2.000
2. Lactose monohydrate
(Respitose® ML006) < 45 µm 8.000
3. Lactose monohydrate
(Respitose® SV010) 160 to 190 m 15.000
Total blend weight i n mg 25.000
Final Blending process:
1. Glycopyrrolate co-micronised Premix and fine grade Lactose were sifted and then mixed in a suitable blender.
2. The blend of step 1 was sifted with a part of coarse grade lactose monohydrate and then mixed in a suitable blender.
3. The blend of step 2 was sifted with remaining part of lactose and then mixed in a suitable blender.
4. The blend of step 3 was filled in a HPMC capsule.

Stability study of Example 12

Test Parameters for Glycopyrronium

Initial 1 Month (40°C-75%RH) 2 Month (40°C-75%RH) 3 Month (40°C-75%RH)
FPM (mcg) 28.80 20.08 19.77 24.94
MMAD (µm) 19.97 2.12 2.19 2.68
GSD 2.81 2.48 2.53 2.37
Assay (%) By HPLC 99.6 99.5 99.8 103.2
COMPARATIVE EXAMPLES
Comparative Examples A1-A8: DPI compositions of Glycopyrronium bromide prepared
by conventional mixing process.

# Ingredients A1 A2 A3 A4 A5 A6 A7 A8
1. Glycopyrrolate 0.0630 0.0630 0.0630 0.0630 0.0630 0.0630 0.0630 0.0630
2. Lactose (Lactohale LH 300) 3.7500 3.7500 2.5000 1.2500 - 4.0000 2.2500 2.2500
3. Lactose
(Respitose®
ML006) - - - - - 6.0000 - -
4. Lactose
(Respitose®
SV010) 21.186 3 21.1870 22.4370 23.6870 - 14.9370 12.6870 12.6866
5. Lactose Anhydrous 40M - - - - 10.0000 - - -
6. Lactose
Anhydrous
120M - - - - 14.9370 - - -
7. Magnesium Stearate 0.0007 - - - - - - 0.0004
Weight in mg 25.000 0 25.0000 25.0000 25.0000 25.0000 25.0000 15.0000 15.0000
Fine Particle Mass (mcg) 11.03 12.00 11.30 7.16 10.85 16.91 12.68 12.64
Manufacturing process:
1. Micronized Glycopyrrolate, fine grade Lactose and Magnesium stearate (A1 or A8) were sifted and then mixed in a suitable blender.
2. The blend of step 1 was sifted with a part of coarse grade lactose monohydrate and then mixed in a suitable blender.

3. The blend of step 2 was sifted with remaining part of lactose and then mixed in a suitable blender.
4. The blend of step3 was filled in in 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.

CLAIMS
We Claim,
1. An inhalable pharmaceutical dry powder composition comprising (i) a co-micronized premix of glycopyrronium or its salt and one part of lactose in a weight ratio of about 1:5 to about 1:200 and having D90 particle size in the range of about 0.5 µm to about 10 µm, and (ii) another part of lactose having D90 particle size in the range of about 5 µm to about 200 µm; wherein said composition is free from a hydrophobic excipient.
2. The pharmaceutical dry powder composition of claim 1, wherein the said composition is free from magnesium stearate.
3. The pharmaceutical dry powder composition of claim 1, wherein weight ratio of glycopyrronium or its salt to the one part of lactose in the co-micronized premix ranges from about 1:12 to about 1:75, or from about 1:14 to about 1:65.
4. The pharmaceutical dry powder composition of claim 1, wherein the D90 particle size of the co-micronized premix is in the range of about 2 µm to about 7 µm, or about 3 µm to about 5 µm.
5. The pharmaceutical dry powder composition of claim 1, wherein the composition comprises of about 0.01% to about 10% by weight of glycopyrronium or its salt.
6. The pharmaceutical dry powder composition of claim 1, wherein the composition has fine particle mass in the range of 18 mcg to 30 mcg.
7. The pharmaceutical dry powder composition of claim 1, wherein said composition has Hausner ratio in the range of 1 to 2 or preferably Hausner ratio is in the range of 1.25 to 1.75.
8. The pharmaceutical dry powder composition of claim 1, wherin the said composition has Carr index in the range of 20% -45% or more preferably the Carr index is in the range of 22%-40%.

9. The pharmaceutical dry powder composition of claim 1, wherin the said composition has bulk density in the range of 0.45 g/mL - 0.65 g/mL or more preferably bulk density in the range of 0.5 g/mL - 0.6 g/mL.
10. The pharmaceutical dry powder composition of claim 1, wherin the said composition has tap density in the range of 0.65 g/mL - 0.95 g/mL or more preferably tap density in the range of 0.7 g/mL - 0.9 g/mL.
11. A process for preparing an inhalable pharmaceutical dry powder composition comprising glycopyrronium or its salt, wherein said process comprises:

(a) co-micronising glycopyrronium or its salt with one part of lactose in a weight ratio of about 1:10 to about 1:100 to obtain a micronized premix having D90 particle size less than about 5 um; and
(b) blending the co-micronized premix of step (a) with another part of lactose having D90 particle size in the range of about 8 um to about 200 um;
wherein said composition is free from a hydrophobic excipient.
12. 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 and lactose, wherein
said composition is free from magnesium stearate.