WO2020229966A1

WO2020229966A1 - Stable aerosol composition for inhalation comprising glycopyrronium

Info

Publication number: WO2020229966A1
Application number: PCT/IB2020/054345
Authority: WO
Inventors: Raveendra Pai; Ashok KATKURWAR; Ramakant CHANAGARE; Kautik SHIROLE; Gaurav VAIDYA; Sushrut Kulkarni
Original assignee: Glenmark Pharmaceutical Limited
Priority date: 2019-05-10
Filing date: 2020-05-07
Publication date: 2020-11-19

Abstract

The present invention relates to a stable suspension aerosol composition for inhalation comprising glycopyrronium or its pharmaceutical acceptable salt, HFA propellant and one or more pharmaceutically acceptable excipients, to be delivered by pressurized metered dose inhalers (MDIs) for pulmonary administration. The present aerosol composition for inhalation may further optionally comprises of one or more additional active agents like β-agonist. The present invention provides a suspension aerosol composition wherein active ingredients selected from glycopyrronium or its pharmaceutical acceptable salt and/or formoterol or its pharmaceutically acceptable salt are solely present in respirable suspended form. The aerosol composition of present invention is free of respirable suspended particles of phospholipid, lipids, carbohydrate, amino acid, organic and inorganic salts. Further, the present invention also relates to process of preparing the suspension aerosol composition and use of such composition 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

PRIORITY DOCUMENT

This patent application claims priority to Indian Provisional Patent Application number 201921018715 (filed on May 10, 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 salt to be delivered using pressurized metered dose inhaler (pMDIs). Particularly, the present invention relates to a stable aerosol composition for inhalation composition comprising glycopyrronium or its salt, optionally additional active agent and pharmaceutically acceptable excipients. 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.

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

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

COPD is a term used to classify two major airflow obstruction disorders: chronic bronchitis and emphysema. Chronic bronchitis is an inflammation of the bronchial airways. Emphysema is an over inflation 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.

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.

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

(Glycopyrronium)

Glycopyrronium bromide (hereinafter Glycopyrrolate) is currently approved in the U.S. as Robinul^® (as 0.2mg/ml injection and as tablets of lmg strength); which is indicated for treatment of peptic ulcer and as preoperative anti-muscarinic agent to reduce salivary, tracheobronchial, and pharyngeal secretions in anesthesia. Glycopyrronium bromide is also approved in Europe as dry powder inhaler Seebri Breezhaler^® (Novartis) as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. Seebri Breezhaler is presented as an inhalation powder in hard capsules. Each capsule contains 63 meg of glycopyrronium bromide, equivalent to 50 meg of glycopyrronium. The FDA has recently approved Seebri™ Neohaler^® (glycopyrrolate) inhalation powder 15.6 meg as a stand-alone monotherapy for the maintenance treatment of COPD. Seebri™ Neohaler and Seebri Breezhaler^® contains lactose and magnesium stearate as inactive ingredients.

International Publication No. WO2001/76575 describes a dry powder inhaler (DPI) formulation for pulmonary delivery comprising glycopyrrolate in a controlled release formulation.

International publication No. WO2018/051130 discloses inhalable compositions of glycopyrrolate in a propellant HFA- 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.

Thus, there is a need to develop an aerosol composition for inhalation comprising glycopyrronium, which is stable at ambient conditions (e.g., about 25 °C and a relative humidity (RH) of about 60 %) for at least 3 months. The inventors of the present invention have also found that these compositions exhibited good dose content uniformity (DCU), fine particle dose (FPD), and fine particle fraction (FPF) and/or do not show particle agglomeration after shaking (e.g., for 1 minute) and having a total impurity less than 1 % w/w of active ingredients for a period of at least 15 days, or at least 1 months or at least 3 months.

SUMMARY OF THE INVENTION

The present invention relates to a stable aerosol composition for inhalation comprising an effective amount of glycopyrronium or its salt and a pharmaceutically acceptable excipient, to be delivered by pressurized metered dose inhalers (MDIs) for pulmonary administration.

The present invention relates to a stable aerosol composition for inhalation comprising an effective amount of glycopyrronium or its salt, a co-solvent and HFA propellant.

In a particular embodiment, the present composition comprises a therapeutically effective amount of glycopyrronium or its salt, a co-solvent, optionally an additional active agent and HFA propellant to be delivered by pressurized metered dose inhalers (MDIs) for pulmonary administration.

The additional active agent may be selected from but not limited to b-agonists or corticosteroids. In a particular embodiment, the b-agonist may be selected from albuterol, salmeterol, arformoterol, formoterol, indacaterol, olodaterol and vilanterol.

In a further additional embodiment, the composition comprises an effective amount of glycopyrronium or its salt, an effective amount of formoterol or its salt, a co-solvent and HFA propellant.

In yet another embodiment, the present composition may additionally comprise a stabilizer.

In further embodiment, the present composition comprises an effective amount of glycopyrronium or its salt, an effective amount of formoterol or its salt, a co-solvent, a stabilizer and HFA propellant.

The composition of present invention may be in a suspension or a solution form, preferably in a suspension form.

In further embodiment, the present composition is in a suspension form wherein either or both active pharmaceutical agent/s (API) selected from glycopyrronium or its salt and formoterol or its salt is present in respirable suspended form in the composition. In preferred embodiment, the suspension composition wherein both glycopyrronium or its salt and formoterol or its salt are solely in respirable suspended form.

Preferably, the present invention relates to a stable aerosol suspension composition for inhalation comprising (a) an effective amount of a glycopyrronium or its salt (b) an effective amount of formoterol or its salt (c) a co-solvent, (d) a stabilizer and (e) an HFA propellant, to be delivered by pressurized metered dose inhalers (MDIs) for pulmonary administration.

More preferably, the composition is- (i) substantially free or (ii) free of any respirable suspended lipid and/or phospholipid particles.

The amount of glycopyrronium in the composition is comprised between 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 composition.

The amount of formoterol in the composition may be in the range of about 0.0001% w/w to about 5% w/w or about 0.0005% w/w to about 1% w/w or about 0.001% w/w to about 0.1% w/w of the total weight of composition. In particular, the present invention uses low amount of co-solvent to enhance the amount of fine particle fraction of the composition and/or to maintain desired density not more than 1.8 g/cm³ of the present composition, preferably not more than 1.5 g/cm³.

The co-solvent may present in the range of not more than 8% w/w or not more than 5% w/w or not more than 2% w/w of the total weight of the present composition.

The amount of stabilizer in the present aerosol composition may vary from about 0.0001% w/w to about 5% w/w or about 0.001% w/w to about 3% w/w or about 0.0015% w/w to about 1% w/w of the total weight of the present composition.

Preferably, the present aerosol composition comprises (a) glycopyrrolate in the range of about 0.01 % w/w to about 1 % w/w (b) formoterol in the range of about 0.001 % w/w to about 0.1% w/w (c) co-solvent not more than 8% w/w or not more than 5% w/w or not more than 2% w/w (d) a stabilizer in the range of about 0.0001% w/w to about 5% w/w and (e) an HFA propellant based upon the total weight of the composition.

In an embodiment, the present aerosol composition for inhalation delivers (a) about 0.1 meg to about 10 mg of glycopyrronium or its salt, and (b) about 0.01 meg to about 10 mg of formoterol or its salt upon each actuation.

Preferably, the ratio of an effective amount of glycopyrronium or its salt and an effective amount of formoterol or its salt is in a weight ratio ranging from about 0.01: 1 to about 20: 1, or from about 0.01: 1 to about 10: 1, or from about 0.05: 1 to about 5: 1.

The present aerosol composition for inhalation comprising (a) about 0.1 pg to about 100 pg of glycopyrronium or its salt, (b) about 0.1 pg to about 50 pg of formoterol or its salt, (c) not more than 15 mg or not more than 10 mg of a co-solvent (d) about 0.1 pg to about 5 mg of a stabilizer and (e) a HFA propellant.

Further, the aerosol suspension composition of the present invention comprises (a) an effective amount of a glycopyrronium or its salt (b) an effective amount of formoterol or its salt (c) a co-solvent not more than 5% w/w, (d) a stabilizer in the range of about 0.001% w/w to 0.01% w/w and (e) an HFA propellant, wherein the density of the composition not more than 1.8 g/cm³.

Further, preferably, the present invention relates to a stable aerosol suspension composition for inhalation comprising (a) an effective amount of a glycopyrronium or its salt (b) ethanol not more than 2% w/w, (c) optionally stabilizer in the range of about 0.001% w/w to 0.01% w/w and (d) an HFA propellant, wherein the density of the composition is not more than 1.8 g/cm³. More preferably, the present invention relates to a stable aerosol suspension composition for inhalation comprising (a) an effective amount of a glycopyrronium or its salt (b) an effective amount of formoterol or its salt, (c) ethanol not more than 2% w/w, (d) oleic acid in the range of about 0.001% w/w to 0.01% w/w and (e) an HFA propellant, wherein the density of the composition not more than 1.5 g/cm³.

In the composition of the present invention, the total impurity of active ingredients upon storage at 25°C / 60% RH for atleast 1 month, preferably atleast 3 months, more preferably atleast 6 months is less than 1 % w/w.

Further, preferably, the stable aerosol suspension composition for inhalation, is provided in an aerosol canister with a metering valve having at least a butyl rubber or ethylene propylene diene monomer (EPDM) or a cyclic olefin co-polymer gasket and/or at least one pre-ring.

The present invention also provides a method of treating a respiratory disorder by administering the aerosol composition of the present invention.

The aerosol composition of the present invention may be prepared and filled using conventional process of mixing and filling in the appropriate canister. It comprises of the following steps:

(a) Disperse glycopyrrolate and optionally an additional active agent in a part quantity of HFA followed by homogenizing the mixture to form a suspension.

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

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

(d) Fill the suspension obtained in step (c) 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“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 R,R-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, 1-dimethylpyrrolidinium, pharmaceutically acceptable salt of (3S,2'R)-3-[(cyclopentylhydroxyphenylacetyl)oxy]-l, 1-dimethylpyrrolidinium, pharmaceutically acceptable salt of (3R,2'S)-3-[(cyclopentylhydroxyphenylacetyl)oxy]-l,l- dimethylpyrrolidinium and pharmaceutically acceptable salt of (3R,2'R)-3- [(cyclopentylhydroxyphenylacetyl)oxy]-l, 1-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, tartrate, ascorbate, glucoheptonate, lactobionate, lauryl sulphate, sodium, calcium, potassium and magnesium.

The term "effective amount" or“therapeutically effective amount” used interchangeably, 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” or“active pharmaceutical ingredients” (APIs)) as used herein includes glycopyrronium and formoterol and/or its salts. 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 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) as given in Table 16-1 of Remington: The Science and Practice of Pharmacy, 20^thed. Lippincott, Williams & Wilkins, 2001, p. 209, which is hereby incorporated by reference.

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) as given in Table 16-1 of Remington: The Science and Practice of Pharmacy, 21st ed. Lippincott, Williams & Wilkins, 2001, p. 209, which is hereby incorporated by reference.

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.

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. In the context of the compositions described herein, the term“respirable suspended particles” refers to a material or combination of materials in the form of particles, aggregates, drops, etc. sized such that they can be inhaled and reach the airways of the lung for respiratory delivery. Here in the present invention, active agent is present solely in respirable suspended form in the composition.

When used to refer to a suspension compositions 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 humans and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife). Preferably, the subject is a human.

The term“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 additional active agent may be selected from but not limited to b-agonists or corticosteroids.

In a particular embodiment, the b-agonist may be selected from albuterol, salmeterol, arformoterol, formoterol, indacaterol, olodaterol and vilanterol.

More preferably, the composition is- (i) free or (ii) substantially free of any respirable suspended lipid and/or phospholipid particles.

In further embodiment, the present composition may be (i) free or (ii) substantially free of any respirable suspended particles other than APIs such as glycopyrronium and formoterol. In further embodiment, the present composition is- (i) free or (ii) substantially free of any respirable suspended particles of the lipid, phospholipid, carbohydrate, amino acid, organic salt, peptide, protein, alditols.

The composition of present invention 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.

The amount of glycopyrronium in the composition is comprised between 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 of the total weight of the composition.

The amount of formoterol in the composition may be in the range of about 0.0001% w/w to about 5% w/w or about 0.0005% w/w to about 1% w/w or about 0.001% w/w to about 0.1% w/w of the total weight of the composition.

In particular, the present invention uses of low amount of co-solvent to enhance the amount of fine particle fraction of the composition and/or to maintain desired density not more than 1.8g/cm³ of the present composition preferably not more than 1.5 g/cm³.

A suitable HFA propellant 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- 134(a), HFA-227A, HFA-32 HFC- 143(a), HFC-134, HFC-152a and mixture thereof, preferably, HFA- 134(a) and HFA-227. More preferably, the HFA propellant is HFA- 134(a).

A co-solvent may be 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 suspended. The function of the co-solvent is to increase the solubility of the drug(s) and the excipients in the composition or to enhance valve function. Co-solvent can influence the delivery characteristics of MDIs in three ways: (1) by changing the formulation density and thus changing the total mass of formulation atomized during actuation of the device, (2) by changing atomization of the formulation and the size of the atomized droplets, and (3) by changing the evaporation rate of these droplets towards their residual particle sizes. The present invention comprises only a small amount of co-solvent in the inhalation composition. It was found that co-solvent in lower amount such as less than 10% w/w, preferably less than 5% w/w or more preferably less than 2% w/w 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 and maintains desired density of the composition. Further, adding lower amount of co-solvent also reduces 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.

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), and ethers (such as but not limited to diethyl ether). The alcoholic co-solvent in the present invention comprises one or more of C2- C6 aliphatic alcohols, glycerol, polyoxyethylene alcohols, wherein co-solvent may further comprise water. More preferably, the co-solvent is anhydrous ethanol and free of water

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-hydroxystearate, 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 (PVP), sorbitan fatty acid esters such as sorbitan trioleate, polyethoxylated sorbitan fatty acid esters (for example polyethoxylated sorbitan trioleate), sorbimacrogol oleate, 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 any mixtures thereof. Preferably, an organic acid is citric acid, oleic acid or ascorbic acid. More preferably, an organic acid is oleic acid.

The amount of stabilizer in the present aerosol composition may vary from about 0.0001%w/w to about 5%w/w or about 0.001% w/w to about 3% w/w or about 0.0015 % w/w to about 1 % w/w of the total weight of the present composition.

The use of ethanol to aid surfactant solubilization can affect the vapor pressure of the mixture and the respirable fraction. It can also affect the undesirable crystal growth of the drug particles.

Preferably, the present aerosol composition comprises (a) glycopyrrolate in the range of about 0.01% w/w to 1% w/w (b) formoterol in the range of about 0.001% w/w to about 0.1% w/w (c) co-solvent not more than 8% w/w or not more than 5% w/w or not more than 2% w/w (d) a stabilizer in the range of about 0.0001% w/w to about 5% w/w and (e) an HFA propellant based upon the total weight of the composition.

In an embodiment, the present aerosol composition for inhalation delivers (a) about 0.1 meg to about 10 mg an of glycopyrronium or its salt, and (b) about 0.01 meg to about 10 mg of formoterol or its salt upon each actuation.

Further, preferably, the present invention relates to a stable aerosol suspension composition for inhalation comprising (a) an effective amount of a glycopyrronium or its salt (b) ethanol not more than 2% w/w, (c) optionally stabilizer in the range of about 0.001% w/w to 0.01% w/w and (d) an HFA propellant, wherein the density of the composition is not more than 1.8 g/cm³.

More preferably, the present invention relates to a stable aerosol suspension composition for inhalation comprising (a) an effective amount of a glycopyrronium or its salt (b) an effective amount of formoterol or its salt, (c) ethanol not more than 2% w/w, (d) oleic acid in the range of about 0.001% w/w to 0.01% w/w and (e) an HFA propellant, wherein the density of the composition not more than 1.5 g/cm³.

Suspension for inhalation comprises an effective amount of glycopyrronium or its salt, an effective amount of formoterol or its salt, a co-solvent, 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 40 % to about 70 %.

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:

(a) Disperse glycopyrrolate and optionally an additional active agent in a part quantity of HFA followed by homogenizing the mixture to form a suspension

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

In the present invention, the active agent and co-solvent are not directly mixed with each other. They are first separately treated along with HFA followed by addition into manufacturing vessel. The direct mixing of active agent and co-solvent leads to partial solubilization of active agent which further results into crystal formation in aerosol composition and hence affecting the uniformity of dose delivery of the composition using MDI.

There are a number of routinely applied analytical tests for aerosol dosage forms 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 yet another embodiment, a drug delivery device is provided comprising a suspension for inhalation 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 drug delivery device comprises a suitable aerosol canister with a metering valve containing a suspension for inhalation 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 suspension for inhalation of the present invention can be delivered using conventional metered-dose inhalers. Furthermore, the compositions do not clog any part of the drug delivery device, e.g., valve. 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 through 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 15 days or atleast 1 months or at least 3 months or at least 6 months. In the composition of the present invention, the total impurity of active ingredients upon storage at 25°C / 60%RH for atleast 1 month, preferably atleast 3 months, more preferably atleast 6 months is less than 1 % w/w.

The present invention provides to a method of treating a respiratory disorder in a subject, wherein the said method comprises administering a suspension for inhalation comprising (a) an effective amount of glycopyrronium or its salt, (b) an effective amount of formoterol or its salt (c) a co-solvent (d) a stabilizer and (e) a HFA propellant.

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

Using higher concentration of ethanol, there is reduction in assay and fine particle dose at initial time point as well as during stability. The aforementioned problem may be due to partial solubility of both actives in higher ethanol concentration which further leads to the increasing level of impurities. As the concentration of ethanol increases, the atomization force of the formulation decreases which leads to a larger residual particles being present after evaporation of the droplets in the aerosol spray. Additionally, the larger droplets cause increased deposition in the mouth and throat. Thus, increased ethanol concentration leads to a decrease in FPF and fine particle mass, thereby decreasing the overall dosing efficiency. On the other hand, using a lower concentration of ethanol may results in increase in formulation variability about 10-15% in assay and uniformity of delivered dose. Hence, the composition of present invention comprising suitably optimum amount of ethanol and suitable stabilizer provides a stable aerosol having good fine particle dose thereby providing excellent therapeutic effect.

The inventors of the present invention have found that optimum amount of ethanol together with stabilizer (like oleic acid, PVP, polysorbate, citric acid) has a subtle influence on the particles that are present in the suspension; it permits homogenous distribution of the particles by controlling the in-flight tendency of the particles within the suspension and as a result when the formulation is used for inhalation, there is no loss of particles in the final spray and entire dose is faithfully and fully delivered to the patient. These effects are due to the specific combination of ingredients chosen and the synergistic effect achieved by such combination.

Impact of co-solvent and/or stabilizer: The influence of co-solvent and/or stabilizer employed in the formulation was evaluated in order to produce a stable aerosol composition of glycopyrrolate and formoterol which can provide desired FPF (fine particles fraction), thereby provide uniform dosing efficiency. It was observed that the absence of stabilizer increases the rate of settling of drug particles (Reference example I). It has also been observed by the inventors that higher amount of co-solvent like ethanol causes re crystallization of drug particles in the formulation which may be due to partial solubilization of drugs in the co-solvent like ethanol. (Reference Example II to IV). The inventors also tried formulation using bulking agent like lactose which remain in respirable suspended form along with drug particles, there was sticking of drug particles to the surface of container due to high electrostatic charge between the drugs and HFA. (Reference Example V)

Reference Examples (I-V):

Therefore, the inventors of the present invention had optimized the concentration of co solvent like ethanol and/or appropriate selection of stabilizer to circumvent the aforementioned problems. The formulator of the present invention shows a synergistic effect between co-solvent and stabilizer, in the pMDI composition comprising glycopyrronium and formoterol, which aid in maintaining the stability of the suspension by preventing irreversible drug particle aggregation and also prevent adhesion of drug particles towards the walls of the container and valve component.

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 1-4- MDI composition comprising Glycopyrronium bromide and Formoterol fumarate dihydrate

Manufacturing process:

1) Disperse glycopyrrolate and formoterol fumarate dihydrate in a part quantity of HFA followed by homogenizing the mixture to form a suspension; 2) Disperse suspension of step (1) in a premix made-up of ethanol, part quantity of HFA and stabilizer selected from polysorbate, polyvinylpyrrolidone (PVP) oleic acid and citric acid; preferably oleic acid;

3) Add remaining quantity of HFA and ethanol 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 metering valve.

The metering valve employed in this invention has cyclic olefin co-polymer gasket and one pre-ring made up of polyethylene polymer (HDPE).

The stability results (Initial, 1 month, 2 months, 3 months and/or 6 months at 40^°C/75%RH) when stored at accelerated conditions for glycopyrronium bromide (GP) and formoterol fumarate dihydrate (FFD) are provided below. Table 1 and Table 2 reports the amount of glycopyrronium bromide and formoterol fumarate dihydrate observed, the fine particle dose (FPD) and fine particle fraction (FPF), mass medium aerodynamic diameter (MMAD), and geometric standard deviation (GSD) for each active ingredient as measured using an Anderson Cascade Impactor for example 1 and example 4 respectively.

Table 1: Stability Data at accelerated conditions for Example 1

GP: Glycopyrrolate; FFD: Formoterol Fumarate Dihydrate; FPD: Fine Particle Dose; FPF: Fine Particle Fraction; MMAD: Mass Median Aerodynamic Diameter; GSD: Geometric Standard Deviation

Table 2: Stability Data at accelerated conditions for Example 4

The stability results (Initial, 3 months and/or 6 months at 25^°C/60% RH and 30^°C/75% RH) when stored at ambient conditions for glycopyrronium bromide (GP) and formoterol fumarate dihydrate (FFD) are provided below. Table 3 and Table 4 reports the amount of glycopyrronium bromide and formoterol fumarate dihydrate observed, the fine particle dose (FPD) and fine particle fraction (FPF), mass medium aerodynamic diameter (MMAD), and geometric standard deviation (GSD) for each active ingredient as measured using an Anderson Cascade Impactor for example 1 and example 4 respectively.

Table 3: Stability Data at ambient conditions for Example 1

Table 4: Stability Data at ambient conditions for Example 4

Table 5 and Table 6 reports the results of a delivered dose uniformity value measuring the percentage of each active ingredient in the initial, middle, and end dose of the aerosol from its container when stored at accelerated conditions (e.g., at about 40°C and about 75% RH) using High Performance Liquid Chromatography (HPLC) for example 1 and example 4 respectively.

Table 5: Uniformity of delivered dose at different stages (Initial, Middle, End Dose) at accelerated conditions for Example 1

Table 6: Uniformity of delivered dose at different stages (Initial, Middle, End Dose) at accelerated conditions for Example 4

Table 7 and Table 8 reports the results of a delivered dose uniformity value measuring the percentage of each active ingredient in the initial, middle, and end dose of the aerosol from its container when stored at ambient condition (e.g., about 25 °C or 30°C and a relative humidity (RH) of about 60 % to about 75 %) using HPLC for example 1 and example 4 respectively.

Table 7: Uniformity of delivered dose at different stages (Initial, Middle, End Dose) at ambient conditions for Example 1

Table 8: Uniformity of delivered dose at different stages (Initial, Middle, End Dose) at ambient conditions for Example 4

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) a therapeutically effective amount of active agent selected from glycopyrronium or its pharmaceutically acceptable salt and/or optionally b-agonist;

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

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

(d) optionally a stabilizer selected from polysorbates, organic acids, sorbitans fatty acid esters, polyvinylpyrrolidone and mixtures thereof; wherein the active agent is present solely in respirable suspended form in the composition.

2. An aerosol composition as claimed in claim 1, wherein the composition is in suspension form.

3. An aerosol composition as claimed in claim 1, wherein b-agonist is selected from albuterol, salmeterol, aformoterol, formoterol, indacaterol, olodaterol and vilanterol.

4. An aerosol composition as claimed in claim 1-3, wherein the said composition is substantially free of respirable suspended particles selected from phospholipid, lipids, carbohydrate, amino acid, organic and inorganic salts.

5. An aerosol composition as claimed in claim 1, wherein the glycopyrronium is glycopyrronium bromide.

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

7. An aerosol composition as claimed in claim 3, wherein b-agonist is formoterol fumarate dihydrate, present in the range of about 0.0001% w/w to about 5% w/w, preferably about 0.0005% w/w to about 1% w/w, more preferably about 0.001% w/w to about 0.1% w/w of the total weight of the said composition.

8. An aerosol composition as claimed in claim 1, wherein a co-solvent is ethanol, present in an amount of not more than 8% w/w, preferably not more than 5% w/w, more preferably not more than 2% w/w of the total weight of the said composition.

9. 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.

10. An aerosol composition as claimed in claim 9, wherein the stabilizer is oleic acid.

11. An aerosol composition as claimed in claim 10, wherein the oleic acid is present in the range from about 0.0001% w/w to about 5% w/w, preferably about 0.001% w/w to about 3% w/w, more preferably about 0.0015 % w/w to about 1% w/w of the total weight of the said composition.

12. An aerosol composition as claimed in claim 1, where in the said composition is used for the treatment of respiratory disorders, selected from asthma and COPD.

13. An aerosol composition as claimed in claim 1-12, 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, preferably about 0.005% w/w to about 3% w/w, more preferably about 0.01% w/w to 1% w/w;

(b) optionally formoterol fumarate dihydrate in an amount of about 0.0001% w/w to about 5% w/w, preferably about 0.0005% w/w to about 1% w/w, more preferably about 0.001% w/w to about 0.1% w/w;

(c) Ethanol in an amount not more than 8% w/w, preferably not more than 5% w/w, more preferably not more than 2% w/w;

(d) HFA-134a;

(e) oleic acid in an amount of about 0.0001% w/w to about 5% w/w, preferably about 0.001% w/w to about 3% w/w, more preferably about 0.0015% w/w to about 1% w/w;

wherein (a) and (b) are present in respirable suspended form in the composition.

14. 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 (EPDM) or a cyclic olefin co-polymer gasket and/or at least one pre-ring to prevent degradation and leakage of the composition .

15. An aerosol composition as claimed in claim 14, wherein the pre-ring is made up of material selected from group of polyamide, polystyrene and polyethylene polymer.

16. An aerosol composition as claimed in any of the preceding claim, wherein the said composition contains less than 1 % w/w of the total impurity of active ingredients upon storage at 25°C / 60%RH, for atleast 1 month, preferably atleast 3 months, more preferably atleast 6 months.

17. A process for preparing an aerosol composition as claimed in claim 1 and 13, wherein the said process comprises steps of:

(a) Dispersing glycopyrrolate and formoterol fumarate dihydrate 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 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.