WO2021033081A1 - Stable aerosol composition for inhalation comprising glycopyrronium, formoterol and corticosteroid - Google Patents

Abstract

The present invention relates to a stable aerosol composition for inhalation administration using metered dose inhaler (MDI) comprising glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt, a corticosteroid selected from fluticasone, budesonide, beclomethasone and its pharmaceutically acceptable salt or esters thereof, HFA propellant and one or more other pharmaceutically acceptable excipients. Particularly, the present invention relates to a suspension aerosol composition comprising glycopyrronium bromide, formoterol fumarate dihydrate and fluticasone propionate, co-solvent, optionally a stabilizer and HFA propellant wherein all the active ingredients are solely present in respirable suspended form in the composition. The present invention also relates to process for preparing such composition and its use for the treatment of respiratory disorders such as asthma and/or chronic obstructive pulmonary disease in a subject in need thereof.

Description

STABLE AEROSOL COMPOSITION FOR INHALATION COMPRISING GLYCOPYRRONIUM, FORMOTEROL AND CORTICOSTEROID

PRIORITY DOCUMENT

This patent application claims priority to Indian Provisional Patent Application number 201921033108 (filed on August 16, 2019), the contents of which are incorporated by reference herein.

TECHNICAL FIELD OF THE INVENTION The present invention relates to a stable aerosol composition for inhalation comprising glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt, a corticosteroid or its salt, and a pharmaceutically acceptable excipients. Particularly, the present invention relates to an inhalation aerosol composition comprising glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and corticosteroid selected from fluticasone, budesonide and beclomethasone and pharmaceutically acceptable salts and esters of any of the foregoing and pharmaceutically acceptable excipients. Preferably, the invention relates to an inhalation aerosol composition comprising glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and fluticasone and pharmaceutically acceptable salts and esters thereof. The present invention also relates to a process for preparing such composition and its use for the treatment of respiratory disorders such as asthma and/or chronic obstructive pulmonary disease in a subject in need thereof.

BACKGROUND OF THE INVENTION Respiratory disorders related to airway inflammation include a number of lung diseases including chronic obstructive pulmonary disease (COPD) and asthma.

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 an inflammation of the alveoli, or air sacs in the lungs. Emphysema has a number of causes, including smoking, exposure to environmental pollutants, alpha-one antitrypsin deficiency, and aging. COPD is a disease of the respiratory apparatus, characterized by an irreversible obstruction of the airways, of a degree that varies according to the severity.

There are very limited therapies currently available to arrest its progression and otherwise prevent its exacerbations, preserve lung function, and otherwise improve the quality of life of COPD patients. The arsenal of medications available to practitioners treating COPD patients have traditionally included: fast-acting P2-agonists, anticholinergic bronchodilators, long-acting bronchodilators, antibiotics, and expectorants. The currently available treatments for COPD exhibit short term benefits, however no long term effects were found on its progression, from administration of anti cholinergic drugs, adrenergic agonists, and oral steroids.

The current therapy for asthma includes bronchodilator drugs, corticosteroids and leukotriene antagonists. Bronchodilator drugs dilate the bronchi and bronchioles, decrease resistance in the respiratory airway and increase airflow to the lungs. Bronchodilators includes long acting b-2 agonists, short acting b-2 agonists and anti cholinergic agents. Corticosteroid drugs are effective at reducing asthma symptoms by blocking the body's inflammatory response. The leukotriene antagonists have limited efficacy, with only small increase in pulmonary function demonstrated in clinical trials.

Glycopyrronium bromide is approved in Europe as dry powder inhaler Seebri Breezhaler^® (Novartis) which is indicated as maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. Seebri Breezhaler is presented as an inhalation powder in hard capsules. Each capsule contains 63 meg of glycopyrronium bromide, equivalent to 50 meg of glycopyrronium; lactose and magnesium stearate as inactive ingredients.

Formoterol fumarate is commercially available in the U.S. as Symbicort^®, Dulera^® and Bevespi^® in a metered dose inhaler with budesonide, mometasone furoate and glycopyrrolate respectively for the treatment of asthma and/or COPD. Formoterol fumarate is also commercially available in the U.S. as an inhalation solution for nebulization (Perforomist) which is indicated for maintenance treatment of bronchoconstriction in patients with COPD and was previously approved as dry powder for inhalation (Foradil ) for maintenance treatment of asthma. Fluticasone propionate is an inhaled corticosteroid (ICS) used to treat asthma and allergic rhinitis. GlaxoSmithKline currently markets fluticasone propionate inhalation powder as FLO VENT^® Diskus (USA) for maintenance treatment of asthma. FLONASE^® (USA) is used for the temporary relief of symptoms of hay fever or other upper respiratory allergies. GlaxoSmithKline also currently markets ADVAIR^® DISKUS (a combination of fluticasone propionate and salmeterol xinafoate). Fluticasone propionate is also available in combination with formoterol fumarate as a metered dose suspension inhalation composition (FLUTIFORM^® in EU) for the treatment of asthma and as a dry powder inhalation capsule (AVESSA, MAXIFLO in India) for the treatment of asthma and COPD.

International Publication No. WO2001/76575 describes a pharmaceutical composition for pulmonary delivery comprising glycopyrrolate in a controlled release formulation.

International Publication No. W02018/051130 discloses inhalable compositions of glycopyrrolate in a propellant FIFA- 152a.

U.S. Patent No. 8,808,713 discloses metered dose inhalation composition comprising formoterol, glycopyrronium and dry particulate phospholipid material in a suspension medium. The suspension medium includes a propellant, a long-acting muscarinic antagonist, a long-acting beta-2 adrenergic receptor agonist and respirable suspending particles to form a co-suspension.

International Publication Nos. W02005/034911 and W02005/034927 disclose an aerosol inhalation composition comprising formoterol fumarate dihydrate in suspension form, HFA and ethanol wherein formoterol having a water content of about 4.8 to 4.28% by weight in the metered dose inhalation composition. The formulation may additionally comprised of steroids and stabilizer.

International Publication Nos. WO2011/045429 describes metered dose inhalation formulation comprising formoterol, fluticasone suspended in HFA propellant and additionally comprised of wetting agent and sodium cromoglycate.

International Publication No. WO2017/089404 describes the metered dose inhalation aerosol suspension formulation comprising of formoterol fumarate dihydrate, fluticasone propionate, glycopyrronium bromide, sodium cromoglycate, ethanol and HFA propellant.

International Publication Nos. WO2011/076841, WO2011/076842 and WO 2011/076843 discloses aerosol solution formulations comprising glycopyrronium as chloride and bromide salt respectively and also in combination with formoterol or a salt thereof dissolved in a mixture of HFA propellant and a co-solvent.

International Publication No. WO2018/033598 discloses aerosol solution formulations comprising glycopyrronium bromide, formoterol or its solvate and beclomethasone which are completely dissolved in a mixture of HFA propellant and co solvent. In addition the formulation may also comprised of inorganic acid as a stabilizing agent to reduce exacerbations associated with COPD.

International Publication No. W02008/025787 relates to medicaments or pharmaceutical compositions comprising a glycopyrronium salt, a beta-agonist selected from salmeterol or formoterol, and corticosteroids such as fluticasone propionate, budesonide, and mometasone furoate, for use in the treatment of inflammatory or obstructive airway disorders.

International Publication No. W02004/019985 discloses a triple combination pharmaceutical products and compositions comprising specific anti-cholinergic agents, beta-agonist and corticosteroids for use in the treatment of asthma and related disorder and COPD.

Thus, there is a need to develop a stable improved aerosol composition for inhalation comprising glycopyrronium, formoterol and corticosteroid which is stable for at least three months and used to combat problems and symptoms associated with respiratory diseases such as asthma/ or COPD by once daily administration.

SUMMARY OF THE INVENTION

The present invention relates to a stable aerosol composition for inhalation comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt, an effective amount of formoterol or its pharmaceutically acceptable salt, an effective amount of corticosteroid and other pharmaceutically acceptable excipients wherein the composition is to be delivered using pressurized MDI suitable for aerosol administration.

In an embodiment, the composition of present invention comprises an effective amount of glycopyrronium or its pharmaceutically acceptable salt, an effective amount of formoterol or its pharmaceutically acceptable salt, an effective amount of corticosteroid selected from fluticasone, budesonide, beclomethasone and pharmaceutically acceptable salts and esters of any of the foregoing, a co-solvent, optionally an additional pharmaceutically acceptable excipients and HFA propellant.

In an embodiment, the composition of present invention comprises an additional pharmaceutically acceptable excipients selected from stabilizer, lubricant, suspending agent, bulking agent, anti-adherent and a low volatility component.

In an embodiment, the composition of present invention comprises an effective amount of glycopyrronium or its pharmaceutically acceptable salt, an effective amount of formoterol or its pharmaceutically acceptable salt, an effective amount of corticosteroid selected from fluticasone, budesonide and beclomethasone, and pharmaceutically acceptable salts and esters of any of the foregoing, sugar or a sugar derivative and HFA propellant. Preferably, the sugar derivative is lactose.

In an embodiment, the present invention relates to a composition which is either in suspension form or in solution form.

In an embodiment, the present invention relates to an aerosol suspension composition comprising glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and corticosteroid selected from fluticasone, budesonide, beclomethasone and pharmaceutically acceptable salts and esters of any of the foregoing wherein one or more active ingredient is present in respirable suspended form. Particularly, the composition of the present invention comprises (a) an effective amount of a glycopyrronium or its pharmaceutically acceptable salt (b) an effective amount of formoterol or its pharmaceutically acceptable salt (c) an effective amount of corticosteroid selected from fluticasone, budesonide and beclomethasone and pharmaceutically acceptable salts and esters of any of the foregoing (d) a co-solvent, (e) optionally an additional pharmaceutically acceptable excipient and (f) an HFA propellant wherein (a), (b) and (c) are solely present in respirable suspended form. Preferably, the composition of the present invention comprises all pharmaceutically acceptable excipients in dissolved form.

In an embodiment, the composition of present invention as described herein is free or essentially free of lipids or phospholipids.

In an embodiment, the composition of present invention as described herein is free or essentially free of a moisture scavenging agent, like sodium cromolyn.

In an embodiment, the composition of present invention comprises (a) an effective amount of a glycopyrronium or its pharmaceutically acceptable salt (b) an effective amount of formoterol or its pharmaceutically acceptable salt (c) an effective amount of corticosteroid selected from fluticasone, budesonide, beclomethasone and pharmaceutically acceptable salts and esters of any of the foregoing (d) a co-solvent, (e) optionally a stabilizer and (f) an HFA propellant wherein the density of final composition is not more than 1.5 g/cm .

Further, the composition of present invention comprises (a) an effective amount of a glycopyrronium or its pharmaceutically acceptable salt (b) an effective amount of formoterol or its pharmaceutically acceptable salt, (c) an effective amount of corticosteroid selected from fluticasone, budesonide, beclomethasone and pharmaceutically acceptable salts and esters of any of the foregoing (d) polyethylene glycol, (e) povidone and (f) an HFA propellant wherein the density of final composition is not more than 1.5 g/cm .

In an embodiment, the composition of the present invention comprises (a) an effective amount of a glycopyrronium or its pharmaceutically acceptable salt (b) an effective amount of formoterol or its pharmaceutically acceptable salt, (c) an effective amount of corticosteroid selected from fluticasone, budesonide, beclomethasone and pharmaceutically acceptable salts and esters of any of the foregoing (d) ethanol, (e) optionally oleic acid and (f) an HFA propellant wherein the density of final composition not more than 1.5 g/cm .

In an embodiment, the composition of present invention comprises (a) an effective amount of a glycopyrronium or its pharmaceutically acceptable salt (b) an effective amount of formoterol or its pharmaceutically acceptable salt, (c) an effective amount of corticosteroid selected from fluticasone, budesonide, beclomethasone and pharmaceutically acceptable salts and esters of any of the foregoing (d) lactose (e) an HFA propellant wherein the density of final composition is not more than 1.5 g/cm .

In an embodiment, the composition of the present invention comprises a corticosteroid selected from fluticasone, budesonide, beclomethasone and pharmaceutically acceptable salts and esters of any of the foregoing.

Particularly, the composition of the present invention comprises (a) an effective amount of a glycopyrronium or its pharmaceutically acceptable salt (b) an effective amount of formoterol or its pharmaceutically acceptable salt (c) an effective amount of fluticasone and its pharmaceutically acceptable salts and esters thereof (d) a co-solvent, (e) optionally an additional pharmaceutically acceptable excipient and (f) an HFA propellant wherein no pharmaceutically acceptable excipient is present in respirable suspended form.

In particular, the composition of the present invention to be delivered by pressurized metered dose inhalers (MDIs) suitable for aerosol administration comprises (a) an effective amount of a glycopyrronium or its pharmaceutically acceptable salt (b) an effective amount of formoterol or its pharmaceutically acceptable salt (c) an effective amount of fluticasone and its pharmaceutically acceptable salts and esters thereof (d) a co-solvent, (e) optionally an additional pharmaceutically acceptable excipient and (f) an HFA propellant.

In particular, the composition of the present invention comprises (a) an effective amount of a glycopyrronium or its pharmaceutically acceptable salt (b) an effective amount of formoterol or its pharmaceutically acceptable salt (c) an effective amount of fluticasone and its pharmaceutically acceptable salts and esters thereof (d) a co-solvent, (e) optionally a stabilizer and (f) an HFA propellant to be delivered by pressurized metered dose inhalers (MDIs) suitable for aerosol administration.

In an embodiment, the composition of present invention as described herein may additionally comprise glycerol.

In an embodiment, the composition of present invention comprises (a) an effective amount of a glycopyrronium or its pharmaceutically acceptable salt (b) an effective amount of formoterol or its pharmaceutically acceptable salt, (c) an effective amount of fluticasone and its pharmaceutically acceptable salts and esters thereof (d) ethanol (e) glycerol (f) an HFA propellant wherein the density of final composition is not more than 1.5 g/cm .

In another embodiment, the composition of the present invention comprises (a) about 0.001% w/w to about 5% w/w or about 0.005% w/w to about 3% w/w or 0.01% w/w to about 1% w/w of glycopyrronium or its pharmaceutically acceptable salt, (b) about 0.0005% w/w to about 5% w/w or about 0.001% w/w to about 3% w/w or about 0.001% w/w to about 0.1% w/w of formoterol or its pharmaceutically acceptable salt (c) about 0.001% w/w to about 5% w/w or about 0.01% w/w to about 2% w/w or about 0.1% w/w to about 1% w/w of fluticasone and its pharmaceutically acceptable salts and esters thereof (d) not more than 20% w/w or not more than 10% w/w or not more than 5% w/w or not more than 2.5% w/w of ethanol (e) optionally about 0.0001% w/w to about 1% w/w or about 0.001% w/w to about 0.1% w/w or about 0.005% w/w to about 0.01% w/w of oleic acid and (f) HFA propellant, based upon the total weight of the composition.

In another embodiment, the composition of present invention comprises (a) about 0.001% w/w to about 5% w/w or about 0.005% w/w to about 3% w/w or 0.01% w/w to about 1% w/w of glycopyrronium or its pharmaceutically acceptable salt, (b) about 0.0005% w/w to about 5% w/w or about 0.001% w/w to about 3% w/w or about 0.001% w/w to about 0.1% w/w of formoterol or its pharmaceutically acceptable salt (c) about 0.001% w/w to about 5% w/w or about 0.01% w/w to about 2% w/w or about 0.1% w/w to about 1 % w/w of budesonide or beclomethasone and its pharmaceutically acceptable salts and esters thereof (d) not more than 20% w/w or not more than 10% w/w or not more than 5% w/w or not more than 2.5% w/w of ethanol (e) optionally about 0.0001% w/w to about 1% w/w or about 0.001% w/w to about 0.1% w/w or about 0.005% w/w to about 0.01% w/w of oleic acid and (f) HFA propellant, based upon the total weight of the composition.

In another embodiment, the composition of present invention comprises (a) about 0.001% w/w to about 5% w/w or about 0.005% w/w to about 3% w/w or 0.01% w/w to about 1% w/w of glycopyrronium or its pharmaceutically acceptable salt, (b) about 0.0005% w/w to about 5% w/w or about 0.001% w/w to about 3% w/w or about 0.001% w/w to about 0.1% w/w of formoterol or its pharmaceutically acceptable salt (c) about 0.001% w/w to about 5% w/w or about 0.01% w/w to about 2% w/w or about 0.1% w/w to about 1% w/w of fluticasone and its pharmaceutically acceptable salts and esters thereof (d) about 0.001% w/w to about 2.5% w/w of polyethylene glycol (e) about 0.0001% w/w to about 0.1% w/w or about 0.001% w/w to about 0.1% w/w or about 0.005% w/w to about 0.01% w/w of povidone and (f) HFA propellant, based upon the total weight of the composition.

In another embodiment, the composition of the present invention comprises (a) about 0.001% w/w to about 5% w/w or about 0.005% w/w to about 3% w/w or 0.01% w/w to about 1% w/w of glycopyrronium or its pharmaceutically acceptable salt, (b) about 0.0005% w/w to about 5% w/w or about 0.001% w/w to about 3% w/w or about 0.001% w/w to about 0.1% w/w of formoterol or its pharmaceutically acceptable salt (c) about 0.001% w/w to about 5% w/w or about 0.01% w/w to about 2% w/w or about 0.1% w/w to about 1% w/w of fluticasone and its pharmaceutically acceptable salts and esters thereof (d) not more than 20% w/w or not more than 10% w/w or not more than 5% w/w or not more than 2.5% w/w of ethanol (e) about 0.01% w/w to about 2% w/w or about 0.1% w/w to about 1.5% w/w or about 0.1% w/w to about 1% w/w of glycerol and (f) HFA propellant, based upon the total weight of the composition.

In an embodiment, the present invention relates to an aerosol composition for inhalation which delivers (a) about 0.1 meg to about 10 mg or about 1 meg to about 1 mg or about 1 meg to 25 meg of glycopyrronium or its pharmaceutically acceptable salt per actuation, (b) about 0.01 meg to about 10 mg or about 0.1 meg to about 1 mg or about 1 meg to 25 meg of formoterol or its pharmaceutically acceptable salt per actuation and (c) about 20 meg to about lg or about 20 meg to about 100 mg or about 50 meg to 1000 meg of fluticasone and its pharmaceutically acceptable salts and esters thereof per actuation.

In an embodiment, the present invention relates to an aerosol composition for inhalation which delivers (a) about 0.1 meg to about 10 mg or about 1 meg to about 1 mg or about 1 meg to 25 meg of glycopyrronium or its pharmaceutically acceptable salt per actuation, (b) about 0.01 meg to about 10 mg or about 0.1 meg to about 1 mg or about 1 meg to 25 meg of formoterol or its pharmaceutically acceptable salt per actuation and (c) about 20 meg to about lg or about 20 meg to about 100 mg or about 50 meg to 1000 meg of budesonide or beclomethasone and its pharmaceutically acceptable salts and esters thereof per actuation.

In another embodiment, the present invention relates to an aerosol composition for inhalation comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt, an effective amount of formoterol or its pharmaceutically acceptable salt and an effective amount of fluticasone and its pharmaceutically acceptable salts and esters thereof in a weight ratio ranging from about 1:0.1:10 to about 1:2:200, or from about 1:0.5:10 to about 1:2:50 or from 1.5: 1:2 to about 1:1.5:25.

In another embodiment, the present invention relates to an aerosol composition for inhalation comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt, an effective amount of formoterol or its pharmaceutically acceptable salt and an effective amount of budesonide or beclomethasone and its pharmaceutically acceptable salts and esters thereof in a weight ratio ranging from about 1:0.1:10 to about 1:2:200, or from about 1:0.5:10 to about 1:2:50 or from 1.5:1:2 to about 1:1.5:25.

In an embodiment, the present invention relates to a method of treating a respiratory disorder in a subject, wherein the said method comprises administering an aerosol composition as described herein.

In further embodiment, the aerosol composition of the present invention is prepared and filled using conventional process of mixing and filling in the appropriate canister. It comprises of the following steps:

1. Disperse glycopyrrolate, formoterol fumarate dihydrate and corticosteroid selected from fluticasone, budesonide and beclomethasone and its pharmaceutically acceptable salts and esters thereof in a part quantity of HFA followed by homogenizing the mixture to form a suspension.

2. Disperse the suspension of step ( 1 ) in a premix made up of co-solvent and part quantity of HFA or optionally in combination with glycerol and/or stabilizer;

3. Add remaining quantity of HFA and co-solvent each in the mixture of step (2) in the manufacturing vessel followed by mixing and re-circulation of the mixture.

4. Fill the suspension obtained in step (3) into crimped canisters provided with a suitable valve. DETAILED DESCRIPTION OF THE INVENTION

Before describing the present invention in detail, it is to be understood that this invention is not limited to particular propellants, drug delivery devices and the like, as such may vary. It is also to be understood that the terminology used herein is for describing particular embodiments only, and is not intended to be limiting.

The term singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes a single excipient as well as two or more different excipients, and the like.

The terms “fluticasone” or “budesonide” or “beclomethasone” or “formoterol” as used herein includes the base form and pharmaceutically acceptable salts, solvates, hydrates, enantiomers, esters, polymorphs, complex, co-crystals thereof.

Unless otherwise specified, the term “glycopyrronium” refers to a pharmaceutical acceptable salt of glycopyrronium in any stereochemistry ( e.g ., S,S-, S,R-, R,S- or Re forms) or a mixture of such stereoisomers, e.g. A racemic mixture (S,S-, S,R-, R,S- and R,R-forms) or an enantiomerically enriched S,S-, S,R-, R,S- and R,R-forms of the pharmaceutical acceptable salt of glycopyrronium (i.e. pharmaceutically acceptable salt of (3S,2'S)-3-[(cyclopentylhydroxyphenylacetyl)oxy]-l,l-dimethylpyrrolidinium, pharmaceutically acceptable salt of (3S,2'R)-3-[(cyclopentylhydroxyphenylacetyl)oxy]- 1,1-dimethylpyrrolidinium, pharmaceutically acceptable salt of (3R,2'S)-3- [(cyclopentylhydroxyphenylacetyl)oxy] -1,1 -dimethylpyrrolidinium and pharmaceutically acceptable salt of (3R,2'R)-3-[(cyclopentylhydroxyphenylacetyl)oxy]-l,l- dimethylpyrrolidinium) .

By “salt” or “pharmaceutically acceptable salt”, it is meant those salts 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 salts include chloride, furoate, bromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, propionate, tartrate, ascorbate, glucoheptonate, lactobionate, lauryl sulphate, sodium, calcium, potassium and magnesium.

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

The term “active ingredient” (used interchangeably with “active” or “active agent” or “drug”) as used herein includes glycopyrronium, formoterol and fluticasone or budesonide or beclomethasone and/or its pharmaceutically acceptable salts and esters. The active ingredients are solely present in respirable suspended form in the composition.

The term "stable aerosol composition for inhalation" or “composition” means a pharmaceutical composition which exhibits substantial chemical stability over a period of time comprising a medicament suitable for aerosol inhalation delivered using pressurized meter dose inhalers for delivery of the drug to the respiratory tract.

The term “soluble” (used interchangeably with dissolved) means that a composition is either totally soluble in a particular solvent or it is sparingly soluble in that particular solvent, for example, a particular solute having a solubility of from 10 to 30 parts per solvent. The term soluble includes the definition of “very soluble” (less than 1 part of solvent per parts of solute), freely soluble (from 1 to 10 parts of solvent per part of solute), sparingly soluble (from 30 to 100 parts of solvent per part of solute).

The term "substantially insoluble" means that a composition is either totally insoluble in a particular solvent or it is poorly soluble in that particular solvent. The term "substantially insoluble" means that a particular solute has a solubility of less than one part per 100 parts solvent. The term "substantially insoluble" includes the definitions of "slightly soluble" (from 100 to 1000 parts solvent per 1 part solute), "very slightly soluble" (from 1000 to 10,000 parts solvent per 1 part solute) and "practically insoluble" (more than 10,000 parts solvent per 1 part solute).

By “pharmaceutically acceptable excipients”, it is meant any of the components of a pharmaceutical composition other than the active ingredients and which are approved by regulatory authorities or are generally regarded as safe for human or animal use. The term “respirable suspended” refers to particles present in suspended form comprising of only active ingredients and sized such that they can be inhaled or deliver to the airways of the lungs.

In the context of the compositions described herein, the term "fine particle dose" or "FPD" refers to the dose, either in total mass or fraction of the metered dose that is within a respirable range. The dose that is within the respirable range is the dose that deposits beyond the throat stage of a cascade impactor in vitro.

In the context of the compositions described herein, the term "fine particle fraction" or "FPF" refers to the proportion of the delivered material relative to the delivered dose (i.e., the amount that exits the actuator of a delivery device, such as an MDI) that is within a respirable range. The amount of delivered material within the respirable range is measured as the amount of material that deposits beyond the throat stage of a cascade impactor in vitro.

When used to refer to an aerosol composition described herein, the terms "stability" and "stable" refer to a composition that is resistant to one or more of aggregation, flocculation, and particle size changes due to solution mediated transformations and is capable of substantially maintaining the MMAD of suspending particles and the fine particle dose.

The term “treating” or “treatment” as used herein includes the prophylaxis, mitigation, prevention, amelioration, or suppression of a disease, condition or disorder in a mammal.

The term "subject" includes mammals such as 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.

The term “respiratory disorder” means a pulmonary disease involving any obstructive or destructive conditions of respiratory tract, vascular diseases and infectious diseases which may or may not be acute or chronic and communicable or non- communicable. The respiratory disorder selected from chronic obstructive pulmonary disease, asthma, 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 in a subject.

Compositions

The present invention relates to a stable aerosol composition for inhalation comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt, an effective amount of formoterol or its pharmaceutically acceptable salt, an effective amount of corticosteroid and other pharmaceutically acceptable excipients wherein the composition is to be delivered using pressurized MDI suitable for aerosol administration.

The composition of present invention comprises an effective amount of glycopyrronium or its pharmaceutically acceptable salt, an effective amount of formoterol or its pharmaceutically acceptable salt, an effective amount of corticosteroid selected from fluticasone, budesonide, beclomethasone and pharmaceutically acceptable salts and esters of any of the foregoing, a co-solvent, optionally an additional pharmaceutically acceptable excipients and HFA propellant.

The additional pharmaceutically acceptable excipients is selected from stabilizer, lubricant, suspending agent, bulking agent, anti-adherent, a low volatility component and HFA propellant.

The composition of the present invention is preferably in suspension form.

In an embodiment, the glycopyrronium is provided as glycopyrronium bromide.

In an embodiment, the formoterol is provided as formoterol fumarate dihydrate.

In the above compositions, the fluticasone is provided as an ester of fluticasone, such as fluticasone furoate or fluticasone propionate, preferably fluticasone propionate.

In an embodiment, the budesonide is provided as an budesonide free base and beclomethasone is available as an beclomethasone propionate.

A suitable HFA propellant as used in the composition is toxicologically safe and must have a vapor pressure in order to enable the medicament to be administered via a pressurized MDI. An HFA propellant can be selected from HFA- 134a, HFA-227a, HFA- 32, HFC-143a, HFC-134, HFC-152a and mixture thereof. Suitable bulking agent may be employed in the aerosol composition, including those intended for administration through metered dose inhalers, which may serve to provide stability to the suspension based metered aerosol composition. Bulking agent can be selected from group consisting of ascorbic acid, saccharides, polysaccharides, amino acids, organic or inorganic salts, urea and propyliodone. Preferably, saccharides, more preferably lactose anhydrous.

A co-solvent is any solvent which is miscible in the composition in the amount desired and which, when added, provides a composition in which the drug(s) can be dissolved or remain substantially insoluble or in suspended form. The function of the co solvent is to increase the solubility of the drug(s) and the excipients in the composition or to improve the valve function and thereby increasing the fine particle mass of active ingredients in the composition as desired for good deposition into lungs to produce desired therapeutic action.

The concentration of suitable co-solvent and/or stabilizer as used in the composition play an important role in providing synergistic effect, maintaining the stability of the present aerosol composition and desired fine particle mass.

The present invention comprises a small amount of co-solvent in the inhalation composition. It was found that co-solvent in lower amount such as not more than 20% w/w, or not more than 10% w/w or not more than 5% w/w or not more than 2.5% w/w of the total weight of composition can improve the stability of the composition by reducing the electrostatic charges between the active ingredients with HFA. This increases the uniformity of dose and enhances efficacy by producing a higher amount of fine particle fraction that would be able to reach deeper into the lungs upon delivery. Further, adding lower amount of co-solvent also reduced rate of aggregation or flocculation, rate of separation, density of cream or sediment layer, adhesion to container walls, adhesion to valve components, and rate and level of dispersion upon agitation thus maintaining the accuracy of dosing throughout the life of the inhaler. Use of higher amount of co-solvent leads to reduced delivery efficiency by following mechanism. Firstly, larger size of atomized droplet due to higher concentration of co-solvent. Secondly, the atomized droplets that contain a greater proportion of co-solvent evaporate more slowly than droplets containing less co-solvent or only the propellant. As a result of stated mechanism, the atomized droplets from formulation with higher concentration of co solvent remain for a longer duration at sizes that are likely to deposit in the turbulent region of the airways (i.e., oropharynx and upper airways).

In one embodiment, the co-solvent comprises one or more of C2- C6 aliphatic alcohols (such as, but not limited to, ethyl alcohol and isopropyl alcohol), glycerol, polyoxyethylene alcohols, polyoxyethylene fatty acid esters, hydrocarbons (such as, but not limited to, n-propane, n-butane, isobutane, n-pentane, iso-pentane, neo-pentane, and n-hexane), ethers (such as but not limited to diethyl ether) and mixture thereof. The alcoholic co-solvent in the present invention comprises one or more of C2- C6 aliphatic alcohols, glycerol, polyoxyethylene alcohols and mixture thereof, wherein co-solvent may further comprise water. Preferably, the co-solvent is anhydrous ethanol.

Suitable stabilizer may be employed in the aerosol composition, including those intended for administration through metered dose inhalers, which may serve to stabilize the aerosol composition and improve the performance of valve systems of the metered dose inhaler. The stabilizer may comprise one or more ionic and/or non-ionic surfactants including, but not limited to, salts of stearic acids such as magnesium stearate, esters such as ascorbyl palmitate, isopropyl myristate and tocopherol esters, lecithin, tyloxapol, polysorbates such as polysorbate 80, polysorbate 20, and polysorbate 40, vitamin E- TPGS, macrogol hydroxystearates such as macrogol- 15 -hydroxys tear ate, acetylated monoglycerides such as Myvacet 9-45 and Myvacet 9-08, polyoxyethylene ethers, ethyloleate, glyceryl trioleate, glyceryl monolaurate, glyceryl monooleate, glyceryl monosterate, glyceryl monoricinoleate, cetylalcohol, sterylalcohol, cetylpyridinium chloride, block polymers, natural oils, polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbitantrioleate, polyethoxylatedsorbitan fatty acid esters (for example polyethoxylatedsorbitantrioleate), sorbimacrogololeate, synthetic amphotensides (tritons), ethylene oxide ethers of octylphenolformaldehyde condensation products.

The organic acid is used as a stabilizer and is selected from a group consisting of citric acid, tartaric acid, lactic acid, oleic acid, formic acid, acetic acid, oxalic acid, ascorbic acid, malic acid and succinic acid or mixtures thereof. Preferably, an organic acid is citric acid, oleic acid or ascorbic acid. More preferably, an organic acid is oleic acid.

Suitable low volatility component may be employed in the aerosol composition, including those intended for administration through metered dose inhalers, which may be capable of affecting the size or density of the aerosol particles thereby affecting the MMAD and fine particle mass. A low volatility component has low saturated vapour pressure which helps in achieving desired MMAD and fine particle mass, hence improving the performance of aerosol composition. A low volatility component may be selected from glycerol, glycols (eg. propylene glycol) etc. Preferably glycerol is used as low volatility component.

In a preferred embodiment of the present invention, the composition may additionally comprised of glycerol as a low volatility component.

In a preferred embodiment of the present invention, the composition comprised of active ingredients in respirable suspended form.

The composition of the present invention to be delivered by pressurized metered dose inhalers (MDIs) suitable for aerosol administration comprises (a) an effective amount of a glycopyrronium or its pharmaceutically acceptable salt (b) an effective amount of formoterol or its pharmaceutically acceptable salt (c) an effective amount of corticosteroid selected from fluticasone, budesonide, beclomethasone and pharmaceutically acceptable salts and esters of any of the foregoing (d) a co-solvent (e) optionally an additional pharmaceutically acceptable excipient and (f) an HFA propellant wherein (a), (b) and (c) are solely present in respirable suspended form.

Preferably, the composition of the present invention comprises all the excipients other than active agents are present in dissolved form.

The composition of present invention as described herein is free or essentially free of lipids or phospholipids.

In further embodiment, the present invention relates to a composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt, an effective amount of formoterol or its pharmaceutically acceptable salt, an effective amount of corticosteroid and pharmaceutically acceptable salts and esters of any of the foregoing, a co-solvent, optionally a stabilizer and HFA propellant wherein said inhalation composition is free of any phospholipid selected from phosphoglycerides such as dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, diarachidoylphosphatidylcholine, dibehenoylphosphatidylcholine, diphosphatidyl glycerol, short-chain phosphatidylcholines, long-chain saturated phosphatidylethanolamines, long-chain saturated phosphatidylserines, long-chain saturated phosphatidylglycerols, and long-chain saturated phosphatidylinositols.

Furthermore, the composition of present invention as described herein is free or essentially free of a moisture scavenging agent, like sodium cromolyn.

In an embodiment, the composition of present invention comprises (a) an effective amount of a glycopyrronium or its pharmaceutically acceptable salt (b) an effective amount of formoterol or its pharmaceutically acceptable salt (c) an effective amount of corticosteroid selected from fluticasone, budesonide, beclomethasone and pharmaceutically acceptable salts and esters of any of the foregoing (d) a co-solvent, (e) optionally a stabilizer and (f) an HFA propellant wherein the density of final composition is not more than 1.5 g/cm .

In an embodiment, the composition of the present invention comprises (a) an effective amount of a glycopyrronium or its pharmaceutically acceptable salt (b) an effective amount of formoterol or its pharmaceutically acceptable salt, (c) an effective amount of fluticasone and its pharmaceutically acceptable salts and esters thereof (d) ethanol, (e) optionally oleic acid and (f) an HFA propellant wherein the density of final composition not more than 1.5 g/cm .

In an embodiment, the composition of the present invention comprises (a) an effective amount of a glycopyrronium or its pharmaceutically acceptable salt (b) an effective amount of formoterol or its pharmaceutically acceptable salt, (c) an effective amount of fluticasone and its pharmaceutically acceptable salts and esters thereof (d) ethanol, (e) glycerol and (f) an HFA propellant wherein the density of final composition not more than 1.5 g/cm

In another embodiment, the composition of the present invention comprises (a) about 0.001% w/w to about 5% w/w or about 0.005% w/w to about 3% w/w or 0.01% w/w to about 1% w/w of glycopyrronium or its pharmaceutically acceptable salt, (b) about 0.0005% w/w to about 5% w/w or about 0.001% w/w to about 3% w/w or about 0.001% w/w to about 0.1% w/w of formoterol or its pharmaceutically acceptable salt (c) about 0.001% w/w to about 5% w/w or about 0.01% w/w to about 2% w/w or about 0.1% w/w to about 1% w/w of fluticasone and its pharmaceutically acceptable salts and ester thereof (d) not more than 20% w/w, not more than 10% w/w, not more than 5% w/w or not more than 2.5% w/w of ethanol (e) optionally about 0.0001% w/w to about 1% w/w or about 0.001% w/w to about 0.1% w/w or about 0.005% w/w to about 0.01% w/w of a oleic acid and (f) HFA propellant, based upon the total weight of the composition.

In another embodiment, the composition of the present invention comprises (a) about 0.001% w/w to about 5% w/w or about 0.005% w/w to about 3% w/w or 0.01% w/w to about 1% w/w of glycopyrronium or its pharmaceutically acceptable salt, (b) about 0.0005% w/w to about 5% w/w or about 0.001% w/w to about 3% w/w or about 0.001% w/w to about 0.1% w/w of formoterol or its pharmaceutically acceptable salt (c) about 0.001% w/w to about 5% w/w or about 0.01% w/w to about 2% w/w or about 0.1% w/w to about 1% w/w of fluticasone and its pharmaceutically acceptable salts and esters thereof (d) not more than 20% w/w or not more than 10% w/w or not more than 5% w/w or not more than 2.5% w/w of ethanol (e) about 0.01% w/w to about 2% w/w or about 0.1% w/w to about 1.5% w/w or about 0.1% w/w to about 1% w/w of glycerol and (f) HFA propellant, based upon the total weight of the composition.

In another embodiment, the composition of present invention comprises (a) about 0.001% w/w to about 5% w/w or about 0.005% w/w to about 3% w/w or about 0.001% w/w to about 0.1% w/w of glycopyrronium or its pharmaceutically acceptable salt, (b) about 0.0005% to about 5% or about 0.001% to about 3% or about 0.001% w/w to about 0.1% w/w of formoterol or its pharmaceutically acceptable salt (c) about 0.001% w/w to about 5% w/w or about 0.01% w/w to about 2% w/w or about 0.1% w/w to about 1% w/w of fluticasone and its pharmaceutically acceptable salts and esters thereof (d) about 0.001 w/w to about 2.5% w/w of polyethylene glycol (e) about 0.0001% w/w to about 0.1% w/w or about 0.001% w/w to about 0.1% w/w or about 0.005% w/w to about 0.01% w/w of povidone and (f) HFA propellant, based upon the total weight of the composition.

In another embodiment, the present invention relates to use of not more than 20% w/w or not more than 10% w/w or not more than 5% w/w or not more than 2.5% w/w of ethanol in aerosol composition comprising (a) an effective amount of a glycopyrronium or its pharmaceutically acceptable salt (b) an effective amount of formoterol or its pharmaceutically acceptable salt (c) a corticosteroid selected from an effective amount of fluticasone, an effective amount of budesonide or an effective amount of beclomethasone and pharmaceutically acceptable salts and esters thereof wherein the said composition is to be delivered using pressurized metered dose inhalers (MDIs) suitable for aerosol administration to enhance efficacy of the composition by producing higher amount of fine particle fraction.

In an embodiment, the present invention relates to an aerosol composition for inhalation which delivers (a) about 0.1 meg to about 10 mg or about 1 meg to about 1 mg or about 1 meg to 25 meg of glycopyrronium or its pharmaceutically acceptable salt per actuation, (b) about 0.01 meg to about 10 mg or about 0.1 meg to about 1 mg or about 1 meg to 25 meg of formoterol or its pharmaceutically acceptable salt per actuation and (c) about 20 meg to about lg or about 20 meg to about 100 mg or about 50 meg to 1000 meg of fluticasone and its pharmaceutically acceptable salts and esters thereof per actuation.

In an embodiment, the present invention relates to an aerosol composition for inhalation which delivers (a) about 0.1 meg to about 10 mg or about 1 meg to about 1 mg or about 1 meg to 25 meg of glycopyrronium or its pharmaceutically acceptable salt per actuation, (b) about 0.01 meg to about 10 mg or about 0.1 meg to about 1 mg or about 1 meg to 25 meg of formoterol or its pharmaceutically acceptable salt per actuation and (c) about 20 meg to about lg or about 20 meg to about 100 mg or about 50 meg to 1000 meg of budesonide or beclomethasone and its pharmaceutically acceptable salts and esters thereof per actuation.

The weight ratio of glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and corticosteroid selected from group of an effective amount of fluticasone, an effective amount of budesonide or an effective amount of beclomethasone and pharmaceutically acceptable salts and esters thereof is ranges from of about 1:0.1:10 to about 1:2:200, or from about 1:0.5:10 to about 1:2:50 or from 1.5:1:2 to about 1:1.5:25.

Any of the compositions described herein is to be used for the treatment of respiratory disease by inhalation administration as 1 or 2 actuation or spray in a subject in need thereof for atleast once daily or atleast twice daily. There are a number of routinely applied analytical tests for aerosol composition for inhalation administration, including mass median aerodynamic diameter (MMAD), fine particle dose or fraction (FPD or FPF), and geometric standard deviation (GSD). Out of these, MMAD, the particle size below which 50% of the particle population lies on the basis of mass, is probably the most widespread, although acceptance criteria are typically based on fine particle dose (FPD) applicable to the active. The content uniformity in inhalers may be evaluated by tests such as uniformity of delivered dose (UODD) and assay at initial, middle and end points of the aerosol from a metered dose inhaler.

In the context of the present invention, various analytical tests including, but not limited to, MMAD, FPD, FPF and GSD can be measured by various instruments such as Anderson Cascade Impactor, a device that uses a series of impaction stages with decreasing particle cut size so that particles can be separated into relatively narrow intervals of aerodynamic diameter.

In another embodiment, the aerosol inhalation composition provides a mean median aerodynamic diameter (MMAD) of drug particles in the range of about 0.1 to 10 pm, about 0.5 to 8 pm; about 1 to 5 pm; about 1 to 3 pm; about 1 to 2 pm.

In another embodiment, the aerosol inhalation composition provides a fine particle fraction (FPF) of drug particles in the range of about 20% to about 75%, about 25% to about 60%, about 25% to about 50%, about 30% to about 40%.

In an embodiment, composition of present invention comprises an effective amount of glycopyrronium or its pharmaceutically acceptable salt, an effective amount of formoterol or its pharmaceutically acceptable salt, an effective amount of fluticasone or salt and ester thereof, a co-solvent, optionally a stabilizer and a HFA propellant wherein at least 50% or at least 70% or at least 90% of the particles having a Mass Median Aerodynamic Diameter (MMAD) of no more than about 10 pm, or from about 1 pm to about 5 pm and the fine particle fraction (FPF) is from about 30% to about 80%, or preferably from about 30 % to about 70 %.

In an preferred embodiment of the present invention, the aerosol composition, when tested for Aerodynamic particle size distribution (APSD) (e.g., using an Andersen Cascade Impactor apparatus), results in a fine particle mass for (a) glycopyrronium bromide from about 1 pg to about 4 pg or about 1 pg to about 3.5 pg or about 1 pg to about 3 mg, (b) formoterol fumarate dihydrate from about 1 mg to about 4 mg or about 1 mg to about 3.5 mg or about 1 mg to about 3 mg, and (c) fluticasone propionate from about 25 pg to about 70 pg or about 30 pg to about 60 pg or about 30 pg to about 50 pg per actuation of inhalation composition using suitable metered dose inhaler.

In a most preferred embodiment, the present inhalation aerosol composition contained in a suitable metered dose inhaler device as described hereinbefore when tested for their APSD values using Anderson cascade impactor apparatus results in one or more of the following in-vitro performance attributes as:

(a) the fine particle mass (FPM) of the active ingredients (i) glycopyrronium bromide is in the range of about 1 pg to about 4 pg or about 1 pg to about 3.5 pg or about 1 pg to about 3 pg per actuation; (ii) formoterol fumarate dihydrate is in the range of about 1 pg to about 4 pg or about 1 pg to about 3.5 pg or about 1 pg to about 3 pg per actuation; (iii) fluticasone propionate is in the range of about 25 pg to about 70 pg or about 30 pg to about 60 pg or about 30 pg to about 50 pg per actuation;

(b) the fine particle fraction (FPF) of the active ingredients (i) glycopyrronium bromide is not less than about 20% to about 25%; (ii) formoterol fumarate dihydrate is not less than about 35% to about 40% (iii) fluticasone propionate is not less than about 30% or about 35%;

(c) the mass median aerodynamic diameter (MMAD) of the active ingredients (i) glycopyrronium bromide (ii) formoterol fumarate dihydrate and (iii) fluticasone propionate is in the range of 1 to 5 pm; wherein the said composition is free of respirable suspending particles of lipids, phospholipids, carbohydrate, amino acid, organic salt, inorganic salts, peptide, protein and alditols.

In another preferred embodiment, the present inhalation aerosol composition when administered using suitable metered dose inhaler delivers about 5 meg to about 25 meg of glycopyrronium bromide, about 3 meg to about 25 meg formoterol fumarate dihydrate and about 50 meg to about 400 meg of fluticasone propionate per actuation.

In another preferred embodiment, the present inhalation aerosol composition when administered using suitable metered dose inhaler delivers about 5 meg to about 7.5 meg of glycopyrronium base, about 4 meg to about 5 meg formoterol fumarate dihydrate and about 80 meg to about 100 meg of fluticasone propionate per actuation.

In a most preferred embodiment, the present inhalation aerosol composition is to be administered as 1-2 actuations atleast once daily or atleast twice daily.

In another preferred embodiment, there is provided an inhalable metered dose aerosol composition comprising (a) glycopyrronium bromide in an amount of about 5 meg to about 25 meg, (b) formoterol fumarate dihydrate in an amount of about 3 meg to about 25 meg (c) fluticasone propionate in an amount of about 50 meg to about 400 meg and (d) HFA propellant (e) co-solvent as ethanol (f) optionally a stabilizer as oleic acid, wherein said composition is free from respirable suspending particles of lipids, phospholipids, carbohydrate, amino acid, organic salt, inorganic salts peptide, protein and alditols.

In another preferred embodiment, there is provided an inhalable metered dose aerosol composition comprising (a) glycopyrronium bromide in an amount of about 5 meg to about 25 meg, (b) formoterol fumarate dihydrate in an amount of about 3 meg to about 25 meg (c) fluticasone propionate in an amount of about 50 to about 400 meg and (d) HFA propellant (e) co-solvent (f) optionally a stabilizer, wherein said composition is prepared by process which comprises:

(1) Dispersing glycopyrrolate, formoterol fumarate dihydrate and fluticasone propionate in a part quantity of HFA followed by homogenizing the mixture to form a suspension;

(2) Dispersing suspension of step (1) in a premix made up of co-solvent, part quantity of HFA and optionally in combination with glycerol and/or stabilizer;

(3) Adding remaining quantity of HFA and co-solvent each in the mixture of step (2) in the manufacturing vessel followed by mixing and re-circulation of the mixture.

(4) Filling the suspension obtained in step (3) into crimped canisters provided with a suitable valve.

In an embodiment, an aerosol composition as described hereinbefore, when administered using a pressurized metered dose inhaler is bioequivalent to the commercially available AIRZ-FF (a dry powder inhalation capsules comprising combination of 12.5 meg glycopyrronium, 12 meg formoterol fumarate dihydrate and 250 meg of fluticasone propionate).

In yet another embodiment, a drug delivery device is provided comprising a composition of the present invention as described herein. The drug delivery device may be any conventional device designed to administer a pressurized aerosol composition to the lungs. A particularly preferred drug delivery device is a metered-dose inhaler. The compositions of the present invention may be delivered using a metered dose inhaler (MDI).

The composition of the present invention can be delivered using conventional metered-dose inhalers. The drug delivery device comprises a suitable aerosol canister with a metering valve containing a composition of the present invention and actuator housing adapted to hold the canister and allow for drug delivery. The canister in the drug delivery device has a head space representing greater than about 15% of the total volume of the canister. The amount of one or more of active ingredients delivered from the valve may vary from about 20m1 to about 100m1 upon each actuation.

The canister may be made of any suitable material such as aluminium, aluminium alloys, stainless steel, tin, plastic or glass which may be coated or uncoated. Some drugs tend to adhere to the inner surfaces, i.e., walls of the canister and may clog metering valves of the device components. This can lead to the patient getting significantly less than the prescribed amount of the active agent upon each actuation of the MDI. Coating the inner surface of the container with a suitable polymer can reduce this adhesion problem. Suitable coatings include fluorocarbon copolymers such as FEP-PES (fluorinated ethylene propylene and polyethersulphone) and PFA-PES (perfluoroalkoxyalkane and polyethersulphone), epoxy and ethylene. Alternatively, the inner surfaces of the canister may be anodized, plasma treated or plasma coated. In preferred embodiment, the aerosol inhalation composition of the present invention is filled into aluminum canister whose inner surface is coated with fluorocarbon polymer. The canister is fitted with a valve, preferably a metering valve. Metering valves suitable to deliver a specific amount of the composition each time the device is actuated. Once a valve is crimped into place, the canisters must be able to adequately seal the propellant without leaking. A gasket may also be used between the valve and the canister to prevent leakage of the composition. Preferably, the gasket used is rubber or polymer gasket, more preferably, the gasket used is ethylene propylene diene monomer (EPDM) or cyclic olefin co-polymer with and/or atleast one pre-ring made up of polyamide, polystyrene or polyethylene polymer which prevent degradation and leakage of composition during storage or transportation.

In an embodiment, the stable aerosol inhalation composition of the present invention is provided in an aerosol canister with a metering valve having at least a butyl rubber or EPDM or a cyclic olefin co-polymer gasket and/or at least one pre-ring to prevent degradation of the product and/or to prevent the leakage of product contained in the canister during storage or transportation. A suitable gasket and presence of at least one pre-ring helps in reducing the moisture absorption and leachable volume of the composition. The pre-ring is made up of material selected from polyamide, polystyrene & polyethylene polymer.

The aerosol composition of the present invention may be placed in the canister using conventional methods such as cold filling or back filling leaving a sufficient “head space”. The filled canisters are then placed in a suitable housing to complete the drug delivery device. In operation, when the canister is moved relative to the housing such that the metering valve is depressed, a fixed amount of composition is released initially through the metering valve and then though the cylindrical passage of the housing. As the propellant vaporizes, the drug is suspended in air. Patients then inhale the suspended drug, thereby effecting pulmonary drug administration.

In another embodiment, the present invention relates to an aerosol inhalation composition which are found to be stable when stored at ambient (e.g., about 25 °C and a relative humidity (RH) of about 60 %) or at accelerated conditions (e.g., at about 40°C and about 75% RH) for at least 1 month. These compositions also exhibited good dose content uniformity (DCU), fine particle dose (FPD), and fine particle fraction (FPF). Preferably, such stable compositions provide acceptable dose content uniformity and/or do not show particle agglomeration after shaking (e.g., for 1 minute) for a period of at least 2 months, or at least 3 months or at least 6 months. In further embodiment, the aerosol composition of the present invention is prepared and filled using conventional process of mixing and filling in the appropriate canister. It comprises of the following steps:

1. Disperse glycopyrrolate, formoterol fumarate dihydrate and corticosteroid selected from fluticasone, budesonide, beclomethasone and pharmaceutically acceptable salts and esters in a part quantity of HFA followed by homogenizing the mixture to form a suspension.

2. Disperse the suspension of step ( 1 ) in a premix made up of co-solvent and part quantity of HFA or optionally in combination with glycerol and/or stabilizer;

3. Add remaining quantity of HFA and co-solvent each in the mixture of step (2) in the manufacturing vessel followed by mixing and re-circulation of the mixture.

4. Fill the suspension obtained in step (3) into crimped canisters provided with a suitable valve. 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 (1-9) MDI composition comprising Glycopyrronium Bromide, Formoterol Fumarate Dihydrate and Fluticasone Propionate

Manufacturing process:

1. Dispersed glycopyrrolate, formoterol fumarate dihydrate and fluticasone propionate in a part quantity of HFA followed by homogenizing the mixture to form a suspension.

2. Dispersed the suspension of step (1) in a premix made up of co-solvent and part quantity of HFA or optionally in combination with glycerol and/or stabilizer;

3. Added remaining quantity of HFA and co-solvent each in the mixture of step (2) in the manufacturing vessel followed by mixing and re-circulation of the mixture.

4. Filled the suspension obtained in step (3) into crimped canisters provided with a suitable valve.

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.

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

Claims

1. An aerosol composition for inhalation comprising:

(a) an effective amount of glycopyrronium or its pharmaceutically acceptable salt;

(b) an effective amount of formoterol or its pharmaceutically acceptable salts;

(c) an effective amount of corticosteroid selected from fluticasone, budesonide, beclomethasone and its pharmaceutically acceptable salts and esters thereof;

(d) a co-solvent selected from ethanol, glycerol, polyoxyethylene alcohols, polyethylene glycol, propylene glycol and mixtures thereof;

(e) HFA propellant selected from HFA 134a, HFA 227a, HFA 152a and mixtures thereof;

(f) optionally a stabilizer selected from polysorbates, organic acids, sorbitans fatty acid esters, polyvinylpyrrolidone and mixtures thereof; wherein the active agents (a), (b), (c) are solely present in respirable suspended form in the composition.

2. An aerosol composition as claimed in claim 1, wherein the said composition is substantially free of respirable suspended particles selected from phospholipid, lipids, carbohydrate, amino acid, peptide, protein, alditols, organic salt, inorganic salts and moisture scavenging agent.

3. An aerosol composition as claimed in claim 1, wherein the glycopyrronium is glycopyrronium bromide present in the range of about 0.001% w/w to about 5% w/w, or about 0.005% w/w to about 3% w/w, or about 0.01% w/w to 1% w/w of the total weight of the said composition.

4. An aerosol composition as claimed in claim 1 , wherein the formoterol is formoterol fumarate dihydrate present in the range of about 0.0005% w/w to about 5% w/w, or about 0.001% w/w to about 3% w/w or about 0.001% w/w to about 0.1% w/w of the total weight of the said composition.

5. An aerosol composition as claimed in claim 1, wherein the corticosteroid is fluticasone propionate present in the range of about 0.001% w/w to about 5% w/w, or about 0.01% w/w to about 2% w/w, or about 0.1% w/w to about 1% w/w of the total weight of the said composition.

6. An aerosol composition as claimed in claim 1, wherein a co-solvent is ethanol, present in an amount of not more than 10% w/w, or not more than 5% w/w or not more than 2.5% w/w of the total weight of the said composition.

7. An aerosol composition as claimed in claim 1, wherein the stabilizer is an organic acid selected from citric acid, tartaric acid, oleic acid, lactic acid, acetic acid, ascorbic acid, maleic acid and succinic acid.

8. An aerosol composition as claimed in claim 7, wherein the stabilizer is oleic acid present in the range from about 0.0001% w/w to about 1% w/w, or about 0.001% w/w to about 0.1% w/w or about 0.005 % w/w to about 0.01 % w/w of the total weight of the said composition.

9. An aerosol composition for use in pressurized metered dose inhaler (pMDI) comprising:

(a) Glycopyrronium bromide in an amount of about 0.001% w/w to about 5% w/w or about 0.005% w/w to about 3% w/w or about 0.01% w/w to about 1% w/w;

(b) Formoterol fumarate dihydrate in an amount of about 0.0005% w/w to about 5% w/w, or about 0.001% w/w to about 3% w/w or about 0.001% w/w to about 0.1% w/w

(c) Fluticasone propionate in an amount of about 0.001% w/w to about 5% w/w or about 0.01% w/w to about 2% w/w or about 0.1% w/w to about 1% w/w;

(d) Ethanol in an amount not more than 10% w/w or not more than 5% w/w, or not more than 2.5% w/w;

(e) HFA-134a;

(f) optionally oleic acid in an amount of about 0.0001% w/w to about 1% w/w or about 0.001% w/w to about 0.1% w/w or about 0.005% w/w to about 0.01% w/w ; wherein (a), (b) and (c) are present in respirable suspended form in the composition.

10. An aerosol composition as claimed in any of preceding claim, wherein the composition may additionally comprises glycerol in an amount of about 0.01% w/w to about 2% w/w.

11. An aerosol composition as claimed in any of the preceding claim for use in pressurized metered dose inhaler (pMDI) when tested for ASPD using Andersen cascade impactor apparatus results in one or more of the following in-vitro performance attributes:

(a) the fine particle mass (FPM) of the active ingredients (i) glycopyrronium bromide is in the range of about 1 pg to about 4 pg or about 1 pg to about 3.5 pg or about 1 pg to 3 pg per actuation; (ii) formoterol fumarate dihydrate is in the range of about 1 pg to 4 pg or about 1 pg to 3.5 pg or about 1 pg to about 3 pg per actuation; (iii) fluticasone propionate is in the range of about 25 pg to about 70 pg or about 30 pg to about 60 pg or about 30 pg to about 50 pg per actuation;

(b) the fine particle fraction (FPF) of the active ingredients (i) glycopyrronium bromide is not less than about 20% to about 25%; (ii) formoterol fumarate dihydrate is not less than about 35% to about 40% (iii) fluticasone propionate is not less than about 30% to about 35%;

(c) the mass median aerodynamic diameter (MMAD) of the active ingredients (i) glycopyrronium bromide (ii) formoterol fumarate dihydrate and (iii) fluticasone propionate is in the range of 1 to 5 pm;

12. An aerosol composition as claimed in any of the preceding claim, wherein the composition is administered as one to two actuations for atleast once daily or atleast twice daily.

13. An aerosol composition as claimed in claim 9, for use in pressurized metered dose inhaler for delivering about 5 to about 25 meg of glycopyrronium or its salt, about 3 meg to about 25 meg of formoterol fumarate dihydrate and about 50 meg to about 400 meg of fluticasone propionate upon each actuation.

14. An aerosol composition as claimed in claim 13, for use in pressurized metered dose inhaler for delivering about 5 meg to about 7.5 meg of glycopyrronium base, about 4 meg to about 5 meg of formoterol fumarate dihydrate and about 80 meg to about 100 meg of fluticasone propionate upon each actuation.

15. An aerosol composition as claimed in claim 13-14, wherein the said composition is bioequivalent to a dry powder inhalation capsules comprising combination of 12.5 meg glycopyrronium, 12 meg formoterol fumarate dihydrate and 250 meg of fluticasone propionate.

16. An aerosol composition as claimed in any of the preceding claim, wherein the said composition is provided in a crimped aerosol canister with a metering valve having atleast ethylene propylene diene monomer or a cyclic olefin co-polymer gasket and/or at least one pre-ring to prevent degradation and leakage of the composition .

17. An aerosol composition as claimed in claim 16, wherein the pre-ring is made up of material selected from group of polyamide, polystyrene and polyethylene polymer.

18. A process for preparing an aerosol composition as claimed in any of the preceding claim wherein the said process comprises steps of: (a) Dispersing glycopyrrolate, formoterol fumarate dihydrate and corticosteroid in a part quantity of HFA followed by homogenizing the mixture to form a suspension;

(b) Dispersing suspension of step (a) in a premix made up of co-solvent, part quantity of HFA and optionally in combination with glycerol and/or stabilizer;

(c) Adding remaining quantity of HFA and ethanol each in the mixture of step (b) in the manufacturing vessel followed by mixing and re-circulation of the mixture.

(d) Filling the suspension obtained in step (c) into crimped canisters provided with a suitable valve.

19. An aerosol composition as claimed in any of the preceding claim, wherein the composition is used for the treatment or prevention of respiratory disease selected from chronic obstructive pulmonary disease or asthma.