DESC:TECHNICAL FIELD OF THE INVENTION
The present invention relates to a medicinal aerosol composition for inhalation to be delivered using pressurized metered dose inhaler (pMDIs) comprising glycopyrronium or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients. The present invention also relates to a process for preparing such composition and its use in the treatment and/or prevention of respiratory, inflammatory or obstructive airway disease, particularly chronic obstructive pulmonary disease.

BACKGROUND OF THE INVENTION
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 Europe as dry powder inhaler Seebri Breezhaler® (Novartis) which is indicated for the treatment of COPD. Seebri Breezhaler is presented as an inhalation powder in hard capsules. Each capsule contains 63 mcg of glycopyrronium bromide, equivalent to 50 mcg of glycopyrronium.
Asthma and chronic obstructive pulmonary disorder are the common respiratory conditions which are characterized by the airflow obstruction and inflammation of airways.
Asthma is a chronic inflammatory disorder characterized by hyper-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. This leads to recurrent episodes of breathlessness, chest tightening or wheezing. 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.
Chronic obstructive pulmonary disease (COPD) is a progressive airflow obstruction disorder that is not fully reversible. The term COPD is used to classify two major airflow obstruction disorders: chronic bronchitis and emphysema. Chronic bronchitis is 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.
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. 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.
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 ß2-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.
International Publication No. WO 2001/76575 describes a pharmaceutical composition for pulmonary delivery comprising glycopyrrolate in a controlled release formulation.
International Publication No. WO 2011/076842 discloses inhalable solution aerosol composition of glycopyrrolate present in dissolved form in the mixture comprising an inorganic acid, co-solvent and propellant.
International Publication No. WO2018/051130 discloses inhalable compositions of glycopyrrolate in a propellant HFA-152a.
Thus, there is a need to develop an improved aerosol composition for inhalation comprising glycopyrronium and its pharmaceutically acceptable salt which is free or essentially free of an inorganic acid. The inventors of the present inventions have developed such composition which is safe as well as stable at ambient conditions, exhibits good dose content uniformity, fine particle dose and fine particle fraction.

SUMMARY OF THE INVENTION
The present invention relates to a medicinal aerosol composition for inhalation suitable for pulmonary administration to be delivered by pressurized metered dose inhalers (MDIs) comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipient.
In an embodiment, the aerosol composition for inhalation comprises of a pharmaceutically acceptable excipient selected from stabilizer, lubricant, suspending agent, bulking agent, anti-adherent, a low volatility component and a propellant.
In an embodiment, the present invention relates to a pharmaceutical aerosol composition for inhalation comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt, a co-solvent and HFA propellant.
In another embodiment, the aerosol composition of the present invention may comprise a stabilizer.
In further embodiment, the aerosol composition of the present invention comprises an effective amount of glycopyrronium or its pharmaceutically acceptable salt, a co-solvent, optionally a stabilizer and HFA propellant.
The co-solvent may be present in the range of about 5% w/w to about 25% w/w of the total weight of the composition. In a preferred embodiment, the aerosol composition of present invention comprises not more than about 25% w/w or not more than about 20% w/w or not more than 15% w/w of co-solvent based on the total weight of the composition.
In an embodiment, the aerosol composition of the present invention is in a suspension or in a solution form, preferably in a solution form.
In another embodiment, the aerosol suspension composition of the present invention comprise solely drug in respirable suspended form.
In an embodiment, the present invention relates to an aerosol solution composition comprising (a) glycopyrronium or its pharmaceutically acceptable salt, (b) co-solvent, (c) optionally a stabilizer and (d) HFA propellant.
In an embodiment, the present invention relates to an aerosol suspension composition comprising (a) glycopyrronium or its pharmaceutically acceptable salt, (b) co-solvent, (c) optionally a stabilizer and (d) HFA propellant, wherein (a) is solely present in respirable suspended form in the composition.
Preferably, the aerosol composition of the present invention comprises all pharmaceutically acceptable excipients in dissolved form.
In further embodiment, the aerosol composition of the present invention is free or substantially free of an inorganic acid.
In an embodiment, the aerosol composition of the present invention as described herein is free or substantially free of a low volatility component.
In an embodiment, the aerosol composition of the present invention is free or substantially free of lipids, phospholipids, amino acids, peptides, carbohydrates and moisture scavenging agent.
In an embodiment, the pharmaceutical aerosol composition for inhalation as described hereinbefore has a pH about 3 to about 8.0 or about 3.5 to about 6.0
In an embodiment, the pharmaceutical aerosol composition for inhalation as described herein may further comprise water as a solvent.
In another embodiment, the present invention relates to pharmaceutical aerosol composition for inhalation comprising glycopyrronium 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 about 1% w/w of the total weight of composition.
In an embodiment, the present invention relates to a pharmaceutical aerosol composition for inhalation wherein the composition delivers about 0.1 mcg to about 10 mg or about 0.1 mcg to about 1 mg or about 0.1 mcg to about 200 mcg or about 0.1 mcg to about 50 mcg of glycopyrronium or its pharmaceutically acceptable salt upon each actuation from a 50µl valve.
In an embodiment, the aerosol composition of the present invention optionally comprises a stabilizer, wherein the amount of stabilizer 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 0.001% to about 1% w/w or about 0.001% w/w to about 0.01% w/w of the total weight of the present composition.
In an embodiment, the glycopyrronium used hereinbefore is glycopyrronium bromide. Also referred to as “glycopyrrolate”.
In another embodiment, the present invention relates to pharmaceutical aerosol composition for inhalation comprising (a) glycopyrrolate in the range of about 0.01% w/w to 1% w/w (b) co-solvent in the range of about 5% w/w to about 25% w/w (c) optionally a stabilizer in the range of about 0.0001% 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 1% w/w or about 0.001% w/w to about 0.01% w/w and (d) an HFA propellant based upon the total weight of the composition.
In another embodiment, the present invention relates to pharmaceutical aerosol composition for inhalation comprising (a) glycopyrrolate in the range of about 0.01% w/w to about 1% w/w (b) ethanol in the range of about 5% w/w to about 25% w/w (c) optionally oleic acid in the range of about 0.0001% 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 1% w/w or about 0.001% w/w to about 0.01% w/w and (d) an HFA propellant based upon the total weight of the composition.
In another embodiment, the present invention relates to pharmaceutical aerosol composition for inhalation comprising (a) glycopyrrolate in the range of about 0.01% w/w to 1% w/w (b) co-solvent in the range of about 5% w/w to about 25% w/w (c) optionally a stabilizer in the range of about 0.0001% 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 1% w/w or about 0.001% w/w to about 0.01% w/w and (d) an HFA propellant based upon the total weight of the composition wherein the pH of the composition is about 3 to about 8.0 or about 3.5 to about 6.0.
In another embodiment, the present invention relates to pharmaceutical aerosol composition for inhalation comprising (a) glycopyrrolate in the range of about 0.01% w/w to 1% w/w (b) ethanol in the range of about 5% w/w to about 25% w/w (c) optionally a oleic acid in the range of about 0.0001% 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 1% w/w or about 0.001% w/w to about 0.01% w/w and (d) an HFA propellant based upon the total weight of the composition wherein the pH of the composition is about 3 to about 8.0 or about 3.5 to about 6.0.
In another embodiment, the present invention relates to pharmaceutical aerosol composition for inhalation comprising (a) glycopyrrolate in the range of about 0.01% w/w to about 1% w/w (b) ethanol in the range of about 5% w/w to about 25% w/w (c) optionally a oleic acid in the range of about 0.0001% 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 1% w/w or about 0.001% w/w to about 0.01% w/w and (d) an HFA propellant based upon the total weight of the composition, wherein MMAD of the composition is maintained from about 0.7 µm to about 4.5 µm to ensure the delivery of uniform dose upon each actuation of metered dose inhaler when actuated from a 50µl valve.
In another embodiment, the present invention relates to pharmaceutical aerosol composition for inhalation comprising (a) about 0.05 µg to about 100 µg of glycopyrronium or its pharmaceutically acceptable salt, (b) not more than 25 mg of a co-solvent (c) optionally about 0.1 µg to about 5 mg of a stabilizer and (d) a HFA propellant upon each actuation.
In another embodiment, the present invention relates to pharmaceutical composition for inhalation comprising (a) about 0.05 µg to about 100 µg of glycopyrronium or its pharmaceutically acceptable salt, (b) not more than 25 mg of ethanol (c) optionally about 0.1 µg to about 5 mg of oleic acid and (e) a HFA propellant upon each actuation.
In an embodiment, the aerosol composition of present invention comprises an effective amount of glycopyrronium or its pharmaceutically acceptable salt, a co-solvent, optionally an additional active agent and HFA propellant wherein the final composition is to be delivered by pressurized metered dose inhalers (MDIs) suitable for pulmonary administration.
In an embodiment, the aerosol composition of present invention comprises an effective amount of glycopyrronium or its pharmaceutically acceptable salt and an effective amount of ß-agonist selected from albuterol, salmeterol, arformoterol, formoterol, indacaterol, olodaterol, and vilanterol.
In an embodiment, the present invention relates to a method of treating a respiratory disorder selected from but not limited to chronic obstructive pulmonary disease and asthma wherein the said method comprises of administering an aerosol composition for inhalation of the present invention to the subject in need thereof.
In further embodiment, the aerosol composition of present invention is prepared and filled using conventional process of mixing and filling in the appropriate canister. It comprises of the following steps:
1. Preparing a solution comprising co-solvent and optionally a stabilizer;
2. Adding glycopyrrolate into solution obtained in step 1;
3. Adding propellant into the manufacturing vessel through propellant addition valve followed by homogenization of mixture;
4. Stirring and re-circulation of solution obtained in step 3 followed by filling into crimped canisters.
In further embodiment, the invention relates to the use of the aerosol composition for inhalation for the treatment of a respiratory disorder selected from chronic obstructive pulmonary disease or asthma in a subject.
In yet another embodiment, a drug delivery device is provided comprising aerosol inhalation composition 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).

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.
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]-1,1-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]-1,1-dimethyl pyrrolidinium).
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" 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 and/or its pharmaceutically acceptable salts.
The term "pharmaceutical aerosol composition for inhalation" (used interchangeably with “aerosol 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).
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 ingredient 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.
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 medicinal aerosol composition for inhalation suitable for pulmonary administration to be delivered by pressurized metered dose inhalers (MDI’s) comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipient.
In an embodiment, the aerosol composition for inhalation comprises of a pharmaceutically acceptable excipient selected from stabilizer, lubricant, suspending agent, bulking agent, anti-adherent, a low volatility component and a propellant.
In an embodiment, the present invention relates to a pharmaceutical aerosol composition for inhalation comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt, a co-solvent and HFA propellant.
In another embodiment, the aerosol composition of the present invention may optionally comprise a stabilizer.
In further embodiment, the aerosol composition of the present invention comprises an effective amount of glycopyrronium or its pharmaceutically acceptable salt, a co-solvent, optionally a stabilizer and HFA propellant.
In an embodiment, the aerosol composition of the present invention is in a suspension or in a solution form, preferably in a solution form.
In an embodiment, the present invention relates to an aerosol solution composition comprising glycopyrronium or its pharmaceutically acceptable salt, wherein active ingredient is present in dissolved form. Particularly, the aerosol composition of the present invention comprises of (a) glycopyrronium or its pharmaceutically acceptable salt, (b) co-solvent, (c) optionally a stabilizer and (d) HFA propellant, wherein (a) is present in dissolved form in the composition.
In an embodiment, the present invention relates to an aerosol suspension composition comprising glycopyrronium or its pharmaceutically acceptable salt, wherein active ingredient is present in respirable suspended form. Particularly, the aerosol composition of the present invention comprises of (a) glycopyrronium or its pharmaceutically acceptable salt, (b) co-solvent, (c) optionally a stabilizer and (d) HFA propellant, wherein (a) is solely present in respirable suspended form in the composition.
Preferably, the aerosol composition of the present invention comprises all pharmaceutically acceptable excipients in dissolved form.
In another embodiment, the aerosol suspension composition of the present invention comprise solely drug in respirable suspended form.
In further embodiment, the aerosol composition of the present invention is free or substantially free of an inorganic acid. The inorganic acid is selected from hydrochloric acid, nitric acid, sulphuric acid, phosphoric acid and mixture thereof.
In another embodiment, the aerosol composition of the present invention as described herein is free or substantially free of a low volatility component. A low component may be those selected from glycerol, glycols like propylene glycol, polyethylene glycol etc.
In an embodiment, the aerosol composition of the present invention is free or substantially free of lipids, phospholipids, amino acids, peptides, carbohydrates andmoisture scavenging agent (such as sodium cromolyn or sodium cromoglycate).
In an embodiment, the pharmaceutical aerosol composition for inhalation as described hereinbefore has a pH about 3 to about 8.0 or about 3.5 to about 6.0.
In an embodiment, the pharmaceutical aerosol composition for inhalation as described herein may further comprise water as a solvent.
In another embodiment, the present invention relates to the use of low amount of co-solvent in the present composition 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.
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-227(a), HFA-32, HFC-143(a), HFC-134, HFC-152(a) and mixture thereof, preferably, HFA-134(a) and HFA-227(a). More preferably, the HFA propellant is HFA-134(a).
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 in insoluble form 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.
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.
The co-solvent may be present in the range of about 5% w/w to about 25% w/w of the total weight of the composition. In a preferred embodiment, the aerosol composition of the present invention comprises not more than 25% w/w or not more than 20% w/w or not more than 15% w/w of co-solvent based on the total weight of the composition.
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, 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 mixtures thereof. Preferably, an organic acid is citric acid, oleic acid or ascorbic acid. More preferably, an organic acid is oleic acid.
In an embodiment, the amount of stabilizer in the present aerosol composition for inhalation may vary from about 0.0001% w/w to about 5% w/w or 0.001% w/w to 3% w/w or 0.001% w/w to about 1% w/w or about 0.001% w/w to about 0.01% w/w of the total weight of the present composition.
In another embodiment, the present invention relates to a pharmaceutical aerosol composition for inhalation comprising glycopyrronium or its pharmaceutically acceptable salt 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 about 1% w/w of the total weight of composition.
In an embodiment, glycopyrronium provided here is glycopyrronium bromide. Also referred to as “glycopyrolate”.
In another embodiment, the present invention relates to pharmaceutical aerosol composition for inhalation comprising (a) glycopyrrolate in the range of about 0.01% w/w to 1% w/w (b) co-solvent in the range of about 5% w/w to about 25% w/w (c) optionally, a stabilizer in the range of about 0.0001% 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 1% w/w or about 0.001% w/w to about 0.01% w/w and (d) an HFA propellant based upon the total weight of the composition.
In another embodiment, the present invention relates to pharmaceutical aerosol composition for inhalation comprising (a) glycopyrrolate in the range of about 0.01% w/w to 1% w/w (b) co-solvent in the range of about 5% w/w to about 25% w/w (c) optionally, a stabilizer in the range of about 0.0001% 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 1% w/w or about 0.001% w/w to about 0.01% w/w and (d) an HFA propellant based upon the total weight of the composition wherein the density of the composition is not more than 1.5 g/cm3.
In another embodiment, the present invention relates to pharmaceutical aerosol composition for inhalation comprising (a) glycopyrrolate in the range of about 0.01% w/w to 1% w/w (b) ethanol in the range of about 5% w/w to about 25% w/w (c) optionally a oleic acid in the range of about 0.0001% 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 1% w/w or about 0.001% w/w to about 0.01% w/w and (d) an HFA propellant based upon the total weight of the composition wherein the density of the composition is not more than 1.5 g/cm3.
In another embodiment, the present invention relates to pharmaceutical aerosol composition for inhalation comprising (a) glycopyrrolate in the range of about 0.01% w/w to 1% w/w (b) co-solvent in the range of about 5% w/w to about 25% w/w (c) optionally a stabilizer in the range of about 0.0001% 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 1% or about 0.001% w/w to about 0.01% w/w and (d) an HFA propellant based upon the total weight of the composition wherein the composition is free or substantially free of an inorganic acid, a low volatility component, lipids, phospholipids, amino acids, peptides, carbohydrates and moisture scavenging agent.
In another embodiment, the present invention relates to pharmaceutical aerosol composition for inhalation comprising (a) glycopyrrolate in the range of about 0.01% w/w to 1% w/w (b) ethanol in the range of about 5% w/w to about 25% w/w (c) optionally a oleic acid in the range of about 0.0001% 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 1% w/w or about 0.001% w/w to about 0.01% w/w and (d) an HFA propellant based upon the total weight of the composition wherein the composition is free or substantially free of an inorganic acid, a low volatility component, lipids, phospholipids, amino acids, peptides, carbohydrates and moisture scavenging agent.
In another embodiment, the present invention relates to pharmaceutical aerosol composition for inhalation comprising (a) glycopyrrolate in the range of about 0.01% w/w to 1% w/w (b) co-solvent in the range of about 5% w/w to about 25% w/w (c) optionally a stabilizer in the range of about 0.0001% 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 1% w/w or about 0.001% w/w to about 0.01% w/w and (d) an HFA propellant based upon the total weight of the composition wherein the pH of the composition is about 3 to about 8.0 or about 3.5 to about 6.0.
In another embodiment, the present invention relates to pharmaceutical aerosol composition for inhalation comprising (a) glycopyrrolate in the range of about 0.01% w/w to 1% w/w (b) ethanol in the range of about 5% w/w to about 25% w/w (c) optionally a oleic acid in the range of about 0.0001% 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 1% w/w or about 0.001% w/w to about 0.01% w/w and (d) an HFA propellant based upon the total weight of the composition wherein the pH of the composition is about 3 to about 8.0 or about 3.5 to about 6.0.
In another embodiment, the present invention relates to pharmaceutical aerosol composition for inhalation comprising (a) glycopyrrolate in the range of about 0.01% w/w to 1% w/w (b) ethanol in the range of about 5% w/w to about 25% w/w (c) optionally a oleic acid in the range of about 0.0001% 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 1% w/w or about 0.001% w/w to about 0.01% w/w and (d) an HFA propellant based upon the total weight of the composition, wherein MMAD of the composition is maintained from about 0.7 µm to about 4.5 µm to ensure the delivery of uniform dose upon each actuation of metered dose inhaler when actuated from a 50µl valve.
In further embodiment, the pharmaceutical aerosol composition of the present invention comprises (a) glycopyrrolate in the range of about 0.01% w/w to about 1% w/w (b) ethanol in the range of about 5% w/w to about 25% w/w (c) optionally a oleic acid in the range of about 0.0001% 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 1% w/w or about 0.001% w/w to about 0.01% w/w and (d) an HFA propellant based upon the total weight of the composition wherein at least 50% or at least 70% or at least 90% of the particles have a Mass Median Aerodynamic Diameter (MMAD) of not more than about 10 µm, or from about 0.5 µm to about 5 µm and the fine particle fraction (FPF) is from about 20% to about 80%, or preferably from about 40 % to about 70 %.
In an embodiment, the present invention relates to a pharmaceutical aerosol composition for inhalation wherein the composition delivers about 0.1 mcg to about 10 mg or about 0.1 mcg to about 1 mg or about 0.1 mcg to about 200 mcg or about 0.1 mcg to about 50 mcg of glycopyrronium or its pharmaceutically acceptable salt upon each actuation from a 50µl valve.
In a preferred embodiment, the present aerosol composition for inhalation when administered using suitable pressurized metered dose inhaler delivers about 5 mcg to about 50 mcg of glycopyrronium base upon each actuation.
In an another preferred embodiment, the present aerosol composition for inhalation is to be administered as 1-2 actuations atleast once daily or atleast twice daily.
In another embodiment, the present invention relates to pharmaceutical aerosol composition for inhalation comprising (a) about 0.05 µg to about 100 µg of glycopyrronium or its pharmaceutically acceptable salt, (b) not more than 25 mg of a co-solvent (c) optionally about 0.1 µg to about 5 mg of a stabilizer and (d) a HFA propellant upon each actuation.
In another embodiment, the present invention relates to pharmaceutical aerosol composition for inhalation comprising (a) about 0.05 µg to about 100 µg of glycopyrronium or its pharmaceutically acceptable salt, (b) not more than 25 mg of ethanol (c) optionally about 0.1 µg to about 5 mg of oleic acid and (d) a HFA propellant upon each actuation.
In another embodiment, the present invention relates to pharmaceutical aerosol composition for inhalation comprising (a) about 0.05 µg to about 100 µg of glycopyrronium or its pharmaceutically acceptable salt, (b) not more than 25 mg of ethanol (c) about 0.1 µg to about 5 mg of oleic acid and (d) a HFA propellant upon each actuation wherein the composition is free or substantially free of an inorganic acid, a low volatility component, phospholipids, lipids, peptides, carbohydrates, amino acids and moisture scavenging agent.
In an embodiment, the aerosol composition of present invention comprises an effective amount of glycopyrronium or its pharmaceutically acceptable salt, a co-solvent, optionally an additional active agent and HFA propellant wherein the final composition is to be delivered by pressurized metered dose inhalers (MDIs) suitable for pulmonary administration.
In an embodiment, the aerosol composition of present invention comprises an effective amount of glycopyrronium or its pharmaceutically acceptable salt and an effective amount of ß-agonist selected from albuterol, salmeterol, arformoterol, formoterol, indacaterol, olodaterol, and vilanterol.
In an embodiment, the present invention relates to a method of treating a respiratory disorder selected from but not limited to chronic obstructive pulmonary disease and asthma wherein the said method comprises of administering an aerosol inhalation composition of the present invention to the subject in need thereof.
In further embodiment, the aerosol composition of present invention is prepared and filled using conventional process of mixing and filling in the appropriate canister. It comprises of the following steps:
1. Preparing a solution comprising co-solvent and optionally a stabilizer;
2. Adding glycopyrrolate into solution obtained in step 1;
3. Adding propellant into the manufacturing vessel through propellant addition valve followed by homogenization of mixture;
4. Stirring and re-circulation of solution obtained in step 3 followed by filling into crimped canisters.
In further embodiment, the invention relates to the use of the aerosol composition for inhalation for the treatment of a respiratory disorder selected from chronic obstructive pulmonary disease or asthma in a subject.
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 another embodiment, the aerosol composition for inhalation provides a mean median aerodynamic diameter (MMAD) of drug particle in the range of about 0.1 to 10 µm, about 0.5 to 8 µm; about 1 to 5 µm; about 1 to 3 µm; about 1 to 2 µm.
In another embodiment, the aerosol composition for inhalation provides a fine particle fraction (FPF) of drug particle 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 yet another embodiment, a drug delivery device is provided comprising a pharmaceutical aerosol composition 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 aerosol 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 pharmaceutical aerosol 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 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 composition for inhalation 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 and 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.
The valve employed in the device may vary as per the requirement and any person skilled in the art may use a suitable valve ranging from 10µl to 100µl based on the ex-valve dose of the drug.
In another embodiment, the present invention relates to an aerosol composition for inhalation 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. In further embodiment, these pharmaceutical composition of present invention exhibits good dose content uniformity (DCU), fine particle dose (FPD), and fine particle fraction (FPF). Preferably, such stable compositions provide acceptable dose content uniformity for a period of at least 1 month or at least 2 months, or at least 3 months or at least 6 months.
The respiratory disorder, in the context of present invention, includes but is not limited to asthma, emphysema, bronchitis, COPD, sinusitis, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), irritant induced asthma, occupational asthma, sensory hyper-reactivity, airway (or pulmonary) inflammation, multiple chemical sensitivity, and aid in smoking cessation therapy.
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: Glycopyrronium Bromide MDI composition with oleic acid as stabilizer

Ingredient Composition (% w/w)
1 2 3 4 5 6 7 8 9
Glycopyrrolate IP 0.015 0.015 0.015 0.03 0.03 0.03 0.05 0.05 0.05
Ethanol IP 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 15.0
Oleic acid IP 0.0050 0.0050 0.0050 0.0050 0.0050 0.0050 0.0050 0.0050 0.0050
Propellant HFA 134a q.s to 100 q.s to 100 q.s to 100 q.s to 100 q.s to 100 q.s to 100 q.s to 100 q.s to 100 q.s to 100

Manufacturing Process:
1. Preparing a solution comprising ethanol and oleic acid.
2. Adding glycopyrrolate into solution obtained in step 1.
3. Adding propellant HFA-134a into the manufacturing vessel through propellant addition valve followed by homogenization of mixture.
4. Stirring and re-circulation of solution obtained in step 3 followed by filling into crimped canisters.

EXAMPLE 10-18: Glycopyrronium Bromide MDI composition without oleic acid as stabilizer

Ingredient Composition (% w/w)
10 11 12 13 14 15 16 17 18
Glycopyrrolate IP 0.015 0.015 0.015 0.03 0.03 0.03 0.05 0.05 0.05
Ethanol IP 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 15.0
Propellant HFA 134a q.s to 100 q.s to 100 q.s to 100 q.s to 100 q.s to 100 q.s to 100 q.s to 100 q.s to 100 q.s to 100

Manufacturing Process
1. Preparing a solution comprising ethanol and glycopyrrolate.
2. Adding propellant HFA 134a into the manufacturing vessel through propellant addition valve followed by homogenization of mixture.
3. Stirring and re-circulation of solution obtained in step 2 followed by filling into crimped canisters.

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.
All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.
,CLAIMS:We claim:
1. A medicinal aerosol composition for inhalation comprising:
(a) glycopyrronium or its pharmaceutically acceptable salt;
(b) co-solvent;
(c) HFA propellant;
(d) optionally a stabilizer.
2. An aerosol composition as claimed in claim 1, wherein the said composition is free or substantially free of inorganic acid selected from hydrochloric acid, nitric acid, sulphuric acid, phosphoric acid; a low volatility component such as glycerol, glycols; phospholipids, lipids, peptides, carbohydrates, amino acids and moisture scavenging agent such as sodium cromolyn.
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 about 1% w/w of the total weight of the composition.
4. An aerosol composition as claimed in claim 1, wherein a co-solvent is ethanol, present in the range of about not more than about 25% w/w or not more than about 20% w/w or not more than 15% w/w of the total weight of the composition.
5. An aerosol composition as claimed in claim 1, wherein a stabilizer is an organic acid present in the range of about 0.0001% 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 1% w/w or about 0.001% w/w to about 0.01% w/w of the total weight of the composition.
6. An aerosol composition as claimed in claim 5, the organic acid is selected from citric acid, tartaric acid, oleic acid, lactic acid, acetic acid, ascorbic acid, maleic acid or succinic acid and mixture thereof.
7. An aerosol composition as claimed in claim 1, when administered by a pressurized metered dose inhaler delivers about 5 mcg to about 50 mcg of glycopyrronium base upon each actuation.
8. A process for preparing an aerosol composition as claimed in any of the preceding claim wherein the said process comprises steps of:
(a) Preparing a solution comprising co-solvent and optionally a stabilizer;
(b) Adding glycopyrrolate into solution obtained in step (a);
(c) Adding propellant into the manufacturing vessel through propellant addition valve followed by homogenization of mixture;
(d) Stirring and re-circulation of solution obtained in step (c) followed by filling into crimped canisters.
9. 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 .
10. An aerosol composition as claimed in any of the preceding claims, wherein the composition is administered as one to two actuations for atleast once daily or atleast twice daily for the treatment or prevention of respiratory disease selected from chronic obstructive pulmonary disease or asthma.