NEBULIZATION COMPOSITION COMPRISING GLYCOPYRROLATE AND

ARFORMOTEROL

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to Indian Provisional Patent Application No. 201921002099 filed on Jan 17, 2019, the entire contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to a nebulization composition comprising glycopyrrolate and arformoterol for the treatment of inflammatory or obstructive airway disease and a process for preparing the composition.

BACKGROUND OF THE INVENTION

Asthma and chronic obstructive pulmonary disease (COPD) are the common life threatening respiratory disorders.

There has been a persistently high growth in incidences of mortality in cases of COPD in US. It is believed to be the third leading cause of death in US and would be the fifth largest disease burden worldwide by 2020. Emphysema and chronic bronchitis are the two states of COPD. Emphysema is primarily characterized by irreversible enlargement of the air spaces distal to the terminal bronchioles leading to alveolar wall destruction. Chronic bronchitis on the other hand, is characterized by persistent productive cough in absence of any other cause of excessive sputum generation. All of these effects lead to clogging of the airways making it difficult for the patient to breathe.

Asthma is a chronic disease and is triggered by allergies, tobacco smoke and multiple such reasons. Asthma is characterized by tightening of the airway muscles, narrowing of the airway muscles, swollen or inflamed lining of the airways and excessive mucus production. Common symptoms of asthma include coughing, wheezing, and shortness of breath.

The commonly available dosage forms for the treatment of asthma and COPD include metered dose inhalation, dry powder inhalation and nebulization compositions. The user has to synchronize with the patient’s breathing pattern and the device characteristics in case of metered dose inhalation and dry powder inhalation. This often requires the patient to be trained with the device. The nebulization compositions on the other hand, do not require any specialized training or synchronization. This is of ultimate convenience to pediatric and geriatric patients. Nebulized drugs are deposited directly into the respiratory tract and thus higher drug concentrations can be achieved in the bronchial tree and pulmonary bed with fewer adverse effects.

Currently available treatment options include corticosteroids, beta agonists, anticholinergic agents, and expectorants. There are different dosage forms available such as nebulization, dry powder inhalers, and metered dose inhalers.

Glycopyrrolate is approved in the U.S. as nebulization dosage form under the brand name Lonhala Magnair Kit®.

Arformoterol is approved under the brand name Brovana® as a nebulization composition. US 6,667,344 covers a nebulization composition of arformoterol. US 7,473,710 and US 7,541,385 covers a method of treating bronchoconstriction by adding to a nebulizer an inhalation solution of arformoterol.

WO2010144628 relates to inhalation solutions for administration of beta 2-agonists or combinations of muscarinic antagonists and beta 2-agonists with a high efficiency nebulizer. The reference discloses high concentration inhalation solutions and require to be administered with a high efficiency nebulizer.

Combining two active drugs in a single nebulization formulation brings several challenges in terms of compatibility of the two actives and the stability of the formulation is highly unpredictable.

The inventors of the present invention has surprisingly found that a combination of glycopyrrolate and arformoterol provides a stable formulation suitable for administration as inhalation.

The present invention provides a nebulization composition of glycopyrrolate and arformoterol for the treatment of COPD or asthma. The present invention relates to a composition comprising a fixed dose combination of the two drugs in a single ampule or keeping the two drugs in separate ampules and mixing them together in the nebulizer before administration to a patient.

The term“combination of’ includes both fixed dose combination of the two drugs in a single ampule or keeping the two drugs in separate ampules and mixing them together in the nebulizer before administration to a patient.

SUMMARY OF THE INVENTION The present invention provides a nebulization composition comprising a combination of glycopyrrolate or a pharmaceutically acceptable salt thereof and arformoterol or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the nebulization composition comprises glycopyrronium bromide and arformoterol tartarate.

In one more preferred embodiment, the nebulization composition comprises a fixed dose composition of glycopyrronium bromide and arformoterol tartarate in a single ampule.

In another preferred embodiment, the nebulization composition comprises mixing of glycopyrronium bromide and arformoterol tartarate which are kept in separate ampules to be mixed together in a nebulizer prior to the administration to a patient.

In one embodiment, the glycopyrrolate and arformoterol are present in the nebulization composition in solubilized form.

One embodiment relates to a nebulization composition comprising a combination of glycopyrrolate or a pharmaceutically acceptable salt thereof and arformoterol or a pharmaceutically acceptable salt thereof for the treatment of an inflammatory or obstructive airway disease.

In an embodiment, the nebulization composition is a sterile, unit dose composition.

In a further embodiment, the nebulization composition comprises glycopyrrolate or a pharmaceutically acceptable salt thereof and arformoterol or a pharmaceutically acceptable salt thereof in a weight ratio of about 1 : 128 to about 400: 1.

In yet another embodiment, the nebulization composition comprises glycopyrronium bromide, arformoterol tartarate, buffering /pH adjusting agent, and an isotonicity agent. The nebulization composition may optionally further include a chelating agent, a pharmaceutically acceptable vehicle, or any combination thereof.

In one embodiment, the nebulization composition is free, or substantially free, of a preservative (such as a benzalkonium salt, e.g., benzalkonium chloride).

In another embodiment, the nebulization composition is free, or substantially free, of a complexing agent (such as ethylene diamine tetra-acetic acid (EDTA) or a salt thereof).

In a further embodiment, the nebulization composition is free, or substantially free, of (a) EDTA or a salt thereof and (b) a benzalkonium salt, such as benzalkonium chloride. In one embodiment, the nebulization composition comprises glycopyrronium bromide, arformoterol tartarate, buffer, isotonicity agent and sterile water.

In a further embodiment, the nebulization composition comprises glycopyrronium bromide, arformoterol tartarate, citric acid, sodium citrate, sodium chloride and sterile water.

In another embodiment, the nebulization composition comprises glycopyrronium bromide, arformoterol tartarate, citric acid, sodium citrate, sodium chloride, ethylene diamine tetra-acetic acid and sterile water

One more embodiment is a nebulization solution comprising glycopyrronium bromide, arformoterol tartarate, sodium chloride, sodium citrate and citric acid, hydrochloric acid, sodium hydroxide, water and optionally edetate disodium. The glycopyrronium bromide and arformoterol tartarate are in solubilized form. The nebulization solution is preferably free, or substantially free, of benzalkonium salts.

In another embodiment of any of the nebulization compositions described herein, the nebulization composition contains not more than about 0.5% of Impurity C of glycopyrrolate or pharmaceutically acceptable salt thereof.

In one embodiment, the nebulization composition contains not more than about 0.5% of total impurities of glycopyrrolate or pharmaceutically acceptable salt thereof.

In a further embodiment of any of the nebulization compositions described herein, the nebulization composition contains not more than about 0.4% of amine impurity of aformoterol or pharmaceutically acceptable salt thereof.

In an embodiment, the nebulization composition contains not more than about 4% of Impurity A (deshydroxy impurity) of aformoterol or pharmaceutically acceptable salt thereof.

In one more embodiment of any of the nebulization compositions described herein, the nebulization composition contains not more than about 0.3% of deshydroxy impurity of aformoterol or pharmaceutically acceptable salt thereof.

In a further embodiment, the nebulization composition contains not more than about 5% of total impurities of aformoterol or pharmaceutically acceptable salt thereof.

In one embodiment, the nebulization composition is administered once a day or twice a day to a subject in need thereof. A further embodiment is a kit comprising a nebulizer and a nebulization composition of the present invention. In one preferred embodiment, the nebulization composition comprises glycopyrronium bromide and arformoterol tartarate.

Yet another embodiment is a method of treating an inflammatory or obstructive airway disease by administering a nebulization composition of the present invention. In one preferred embodiment, the nebulization composition comprises glycopyrronium bromide and arformoterol tartarate.

Other objects, features and advantages of the present invention will be apparent to those of ordinary skill in the art in view of the following detailed description of the invention and accompanying drawings.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a nebulization composition comprising glycopyrrolate or a pharmaceutically acceptable salt thereof and arformoterol or a pharmaceutically acceptable salt thereof. The nebulization composition is useful for the treatment of an inflammatory or obstructive airway disease.

Glycopyrronium bromide, an anticholinergic is a quaternary ammonium salt with the following chemical name: (3RS)-3-[(2SR)-(2-cyclopentyl-2-hydroxy-2-phenylacetyl) oxy]-l,l- dimethylpyrrolidinium bromide. The quaternary ammonium compound inhibits acetyl choline binding to M3 muscarinic receptor is represented by structural formula.

Glycopyrrolate can be prepared using the procedures described in U.S. Pat. No.2956062. The present invention embraces using one or more of these isomeric forms, especially the 3S,2'R isomer, the 3R,2'R isomer or the 2S,3'R isomer, thus including single enantiomers, or racemates, especially the (3S,2'R/2S,3'R) racemate. As used herein, glycopyrrolate and glycopyrronium are used interchangeably. Arformoterol is a long-acting, beta 2-adrenergic receptor agonist. It is a (R,R) -enantiomer of formoterol. The tartarate salt of arformoterol is chemically described as formamide, N-[2- hydroxy-5-[(lR)-l-hydroxy-2-[[(lR)-2-(4-methoxyphenyl)-l-met hylethyl]amino]ethyl]phenyl]- ,(2R,3R)-2,3-dihydroxybutanedioate (1: 1 salt). Arformoterol tartarate has a molecular formula of C19H24N2C C4H6O6 and the following structure:

As used herein, the term“Arformoterol”, unless otherwise indicated, includes, but is not limited to, arformoterol in any physical form such as the amorphous form and crystalline forms (e.g., anhydrous, hydrate, and other solvate forms). The nebulization composition may contain Form A, Form B, Form C or mixtures thereof of arformoterol or its pharmaceutically acceptable salts thereof. Salts of arformoterol include, but are not limited to, acid addition salts and base salts thereof. Suitable salts of arformoterol include, but are not limited to, salts of mineral acids, such as hydrochlorides and sulfates, and salts of organic acids, such as acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates and tartarates. One preferred salt of arformoterol for the nebulization composition is arformoterol tartarate.

The nebulization compositions may contain glycopyrronium bromide and arformoterol tartarate in solubilized form in a sterile unit dosage form.

The nebulization composition may contain glycopyrronium bromide in an amount of about 2.5 mcg/ml to about 1000 mcg/ml. Preferably, the composition contains glycopyrronium bromide in amounts of 2.5 mcg/ml, 5 mcg/ml, 10 mcg/ml, 20 mcg/ml, 40 mcg/ml, 80 mcg/ml, 160 mcg/ml, 320 mcg/ml, 500 mcg/ml, 750 mcg/ml and 1000 mcg/ml. Preferably, the nebulization composition may contain 12.5 mcg/ml, 25 mcg/ml, 50 mcg/ml of glycopyrronium bromide.

The nebulization composition may contain arformoterol tartarate in an amount of about 2.5 mcg/ml to about 320 mcg/ml. Preferably, the composition contains arformoterol tartarate in amounts of 2.5 mcg/ml, 5 mcg/ml, 10 mcg/ml, 20 mcg/ml, 40 mcg/ml, 80 mcg/ml, 160 mg/ml, and 320 mg/ml. Preferably, the nebulization composition may contain 5 mcg/ml, 10 mcg/ml, 15 mcg/ml, 20 mcg/ml of arformoterol tartarate. The ratio of glycopyrronium bromide and arformoterol tartarate in the nebulization composition may range from about 1 : 128 to about 400: 1.

The nebulization composition may additionally comprise one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients include, but are not limited to, pH adjusting agents, buffering agents, isotonicity agents, optionally chelating agents, surfactants, anti-oxidants, and pharmaceutically acceptable vehicles. In one embodiment, the composition includes a buffering/ pH adjusting agent, isotonicity agent, pharmaceutically acceptable vehicle, and optionally a chelating agent.

The nebulization composition is substantially free of preservative (such as benzalkonium and salts thereof), preferably substantially benzalkonium chloride free. A composition is “substantially benzalkonium chloride free” or“substantially free of benzalkonium chloride” when the amount of benzalkonium chloride is not an amount sufficient to materially act as a preservative for the nebulization composition. In one embodiment, benzalkonium chloride may be present in a concentration less than 0.008% w/w based on total weight of the composition. The term “substantially free of preservative” denotes that preservative is not an amount sufficient to materially act as a preservative for the nebulization composition. In one embodiment, the preservative may be present in a concentration less than 0.008% w/w based on total weight of the composition. Generally, nebulization compositions contain a preservative such as benzalkonium chloride. A common problem with benzalkonium chloride is that it may cause paradoxic bronchoconstriction if the solution is administered repeatedly over short intervals, and frequent exposure to benzalkonium chloride may lead to occupational asthma. Another problem is that, when inhaled by patients, the benzalkonium chloride can cause dose -dependent bronchoconstriction. The nebulization compositions of the present invention may be provided without benzalkonium chloride, thereby making them suitable for repeated administration over a short period of time. Also, administering a substantially benzalkonium chloride-free nebulization composition to a patient reduces the concomitant liability of adverse effects associated with benzalkonium chloride alone or in combination with other excipients and/or the active agents. It also negates the toxicity and other side effects associated with benzalkonium chloride.

The nebulization composition may be free, or substantially free, of complexing agents such as ethylene diamine tetra-acetic acid (EDTA) and salts thereof. The nebulization composition or solution may contain less than about 0.1% by weight of complexing agent such as EDTA. The absence of or reduction in the concentration of the additive EDTA and its salts helps to reduce the paradoxic effect associated with cough.

The nebulization composition may be formulated as a single composition comprising glycopyrrolate and arformoterol. Such a nebulization composition can be contained in a single chamber container. Such a single composition comprising both glycopyrronium and arformoterol (such as the combination glycopyrronium bromide and arformoterol tartarate) is stable under during long term storage. The pharmaceutical composition or solution may contain greater than about 80%, such as greater than about 85%, greater than about 90%, greater than about 95% or greater than about 98% of the initial amount of glycopyrronium /arformoterol or salts thereof in the nebulization composition after being stored for 3 or 6 months or 1, 2 or 3 years at 2-8° C and 25° C when stored in a suitable container.

The two active agents can also be separately formulated and contained in separate containers, which are then mixed prior to administration to a patient. In this instance, a composition comprising glycopyrronium bromide and one or more pharmaceutically acceptable excipients is contained in one chamber and another composition comprising arformoterol tartarate and one or more pharmaceutically acceptable excipients is contained in a separate chamber. This combination comprising separate compositions of glycopyrronium bromide and arformoterol tartarate can be contained in a dual chamber container. The two chambers of the dual chamber container may be separate or may be connected by a common septum. The dual chamber container with a common septum may contain a common top which when broken would provide simultaneous access to both compositions. The composition comprising glycopyrronium bromide may be mixed with the composition comprising arformoterol tartarate before being added to the reservoir of the nebulizer. In one instance, the composition comprising glycopyrronium bromide may be added to the reservoir of the nebulizer followed by addition of the composition comprising arformoterol tartarate and vice versa. In this instance, the two compositions would be mixed in the reservoir of the nebulizer device and then administered to the patient.

The pH of the nebulization composition may vary from about 1 to about 7. The pH of the glycopyrrolate nebulization composition is preferably between about 3 to about 6, preferably about 4.5. The pH of the arformoterol nebulization composition is between about 3 to about 6, preferably about 5.5. The pH of the nebulization composition containing both glycopyrrolate and arformoterol is about 3 to about 6, preferably about 5.5. The pH may be adjusted by the addition of one or more pharmaceutically acceptable acids. Non-limiting examples of suitable pharmaceutically acceptable acids include inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid, and any combination of any of the foregoing. Non-limiting examples of other suitable pharmacologically acceptable acids include organic acids, such as ascorbic acid, citric acid, malic acid, maleic acid, tartaric acid, succinic acid, fumaric acid, acetic acid, formic acid, propionic acid, and any combination of any of the foregoing. The pH adjusting agents may be selected from one or more organic acids selected from ascorbic acid, fumaric acid and citric acid. A preferred organic acid is citric acid. Mixtures of the abovementioned acids may also be used, particularly in the case of acids which have other properties in addition to their acidifying properties, e.g., those which act as flavorings or antioxidants, such as citric acid or ascorbic acid.

The nebulization composition may contain sodium citrate, for example, at a concentration of about 0.0001% w/v to about 2.20% w/v, and citric acid, for example, at a concentration of about 0.0001% w/v to about 0.53% w/v, to control pH.

The pharmaceutically acceptable vehicle in the nebulization composition includes water and optionally a cosolvent. Any cosolvent that is suitable for inhalation and capable of dissolving or solubilizing the glycopyrronium or arformoterol in the mixture of cosolvent and water can be used. Examples of suitable cosolvents include, for example, alcohols, ethers, hydrocarbons, and perfluorocarbons. Preferably, the cosolvent is a short chain polar alcohol. More preferably, the cosolvent is an aliphatic alcohol having from one to six carbon atoms, such as ethanol or isopropanol. A preferred cosolvent is ethanol. Non-limiting examples of suitable hydrocarbons include n-butane, isobutane, pentane, neopentane and isopentanes. Non-limiting examples of suitable ethers include dimethyl ether and diethyl ether. Non-limiting examples of suitable perfluorocarbons include perfluoropropane, perfluorobutane, perfluorocyclobutane, and perfluoropentane.

Suitable surfactants include, but are not limited to, C _5-20 -fatty alcohols, Cs- ₂₀ -fatty acids, C _5-20 -fatty acid esters, lecithin, glycerides, propylene glycol esters, polyoxyethylenes, polysorbates, sorbitan esters, carbohydrates, and any combination of any of the foregoing. C _5-20 - fatty acids, propylene glycol diesters of the Cv ₂₀ -fatty acids, triglycerides of the Cs- ₂₀ -fatty acids, and sorbitans of the Cs- ₂₀ -fatty acids are preferred. In one preferred embodiment, the surfactant is selected from oleic acid, sorbitan mono-, di- or trioleates, and any combination of any of the foregoing.

Any of the nebulization compositions described herein may optionally include a buffer. Suitable general and biological buffers that may be used, such as those in the pH range of about 2 to about 8 include, but are not limited to, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, Mcllvaine, phosphate, Prideaux-Ward, phosphate, citrate, borate, succinate, citrate -phosphate -borate (Teorell-Stanhagen), veronal acetate, 2-(N- morpholino)ethanesulfonic acid (MES), BIS-TRIS, N-(2-Acetamido)iminodiacetic acid, N-(2- Acetamido)-2-aminoethanesulfonic acid (ADA), piperazine-N,N'-bis(2-ethanesulfonic acid) (PIPES), P-Hydroxy-4-morpholinepropanesulfonic acid (MOPSO), 1,3- bis(tris(hydroxymethyl)methylamino)propane (BIS TRIS Propane), N,N-Bis(2-hydroxyethyl)-2- aminoethanesulfonic acid (BES), (3-(N-morpholino)propanesulfonic acid) (MOPS), N- [Tris(hydroxymethyl)methyl]-2-aminoethanesulfonic acid (TES), (4-(2-hydroxyethyl)-l- piperazineethanesulfonic acid) (HEPES), N,N-Bis(2-hydroxyethyl)-3-amino-2- hydroxypropanesulfonic acid (DIPSO) , (3-(N-morpholino)propanesulfonic acid) (MOBS), 2- Hydroxy-3 - [tris(hydroxymethyl)methylamino] - 1 -propanesulfonic acid (TAPS O),

[Tris(hydroxymethyl)aminomethane] (TRIZMA), (2-Hydroxyethyl)-piperazine-N-2- hydroxypropanesulfonic acid) (HEPPSO), Piperazine- 1 ,4-bis(2-hydroxypropanesulfonic acid) dihydrate (POPSO), Triethanolamine (TEA), 4-(2-Hydroxyethyl)-l-piperazinepropanesulfonic acid (EPPS), (N-Tris(Hydroxymethyl) Methylglycine) (TRICINE), Diglycine (GLY-GLY), N,N- Bis(2-hydroxyethyl)glycine (BICINE), N-(2-Hydroxyethyl)piperazine-N'-(4-butanesulfonic acid) (HEPBS), N-[Tris(hydroxymethyl)methyl]-3-aminopropanesulfonic acid (TAPS), and 2-Amino- 2-methyl- 1,3 -propanediol (AMPD) buffers. In certain embodiments, the buffer is sodium hydrogen phosphate dihydrate, anhydrous disodium hydrogen phosphate buffer, citric acid monohydrate, trisodium citrate dihydrate, or any combination thereof.

The osmolality of the nebulization composition may be from about 200-500 mOsm/kg. The nebulization composition may comprise a tonicity adjusting agent, such as an ionic salt (e.g., about 0.0001% w/v to about 264% w/v ionic salt). Suitable tonicity adjusting agents include, but are not limited to, ammonium carbonate, ammonium chloride, ammonium lactate, ammonium nitrate, ammonium phosphate, amonium sulfate, ascorbic acid, bismuth sodium tartrate, boric acid, calcium chloride, calcium disodium edetate, calcium gluconate, calcium lactate, citric acid, dextrose, diethanolamine, dimethyl sulfoxide, edetate disodium, edetate trisodium monohydrate, fluorescein sodium, fmctose, galactose, glycerin, lactic acid, lactose, magnesium chloride, magnesium sulfate, mannitol, polyethylene glycol, potassium acetate, potassium chlorate, potassium chloride, potassium iodide, potassium nitrate, potassium phosphate, potassium sulfate, propylene glycol, silver nitrate, sodium acetate, sodium bicarbonate, sodium biphosphate, sodium bisulfite, sodium borate, sodium bromide, sodium cacodylate, sodium carbonate, sodium chloride, sodium citrate, sodium iodide, sodium lactate, sodium metabisulfite, sodium nitrate, sodium nitrite, sodium phosphate, sodium propionate, sodium succinate, sodium sulfate, sodium sulfite, sodium tartrate, sodium thiosulfate, sorbitol, sucrose, tartaric acid, triethanolamine, urea, urethan, uridine, zinc sulfate, and any combination of any of the foregoing. Suitable osmotic adjusting agents include, but are not limited to, sodium chloride, potassium chloride, zinc chloride, calcium chloride and any combination of any of the foregoing. Other osmotic adjusting agents include, but are not limited to, mannitol, glycerol, dextrose and any combination of any of the foregoing.

The nebulization compositions may contain osmolality adjusting agents such as sodium chloride in amount of about 0.375% to about 1.125%, preferably about 0.9%.

Suitable antioxidants include, but are not limited to, ascorbic acid, vitamin A, vitamin E, tocopherols, and any combination of any of the foregoing.

A nebulization composition of the present invention may have a fill volume of from about 0.5 ml to about 5 ml. Preferably, the nebulization composition has a fill volume of 2 ml.

The nebulization composition may be contained in a prefilled, unit-dose, low-density polyethylene (LDPE) container. Each unit-dose container may be disposed in a foil pouch, and each foil pouch may contain one or more unit-dose containers. Each foil pouch containing the unit dose container may be disposed in a shelf carton. The container may have a TWIST-FLEX ^™ top, such top comprising an easy-to-grip tab-like handle such that the container may be opened, for example, by twisting off the tab by hand. The TWIST-FLEX ^™ top is advantageous in that it allows for easy dispensing of the solution, prevents spillage and eliminates the need to open the container by cutting or tearing off the top, thereby reducing cross-contamination. One or more of the single unit dose containers may be prepackaged in an aluminum foil pouch, such that the foil provides a protective barrier against environmental contaminants and light as it helps to improve the shelf- life and stability of the nebulization composition. Dispensing vials may include, but are not limited to, any container comprising glass, low density polyethylene, or any other material capable of preventing the solution from leaking out of the container. The vial may be enclosed by any conventional means including, but not limited to, screw cap, heat seal, snap-on top, flip-top, twist- off stopper, and peel away top.

In another embodiment, the nebulization composition of the present invention may be contained in a multi-dose container, optionally provided with a dropper and a measuring cup. Such nebulization compositions may further contain a preservative.

The nebulization composition may comprise of one or more prefilled containers containing a nebulization composition of the present invention. Each container comprises a single unit dose of a nebulization composition of the present invention.

One embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide and 10 meg arformoterol tartarate. The nebulization composition may additionally contain a buffer, an isotonicity agent and optionally a complexing agent.

Another embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide, about 10 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid as buffer and sodium chloride as isotonicity agent.

One more embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide and 10 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid and sodium citrate as buffer and sodium chloride as isotonicity agent.

Yet another embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide and 10 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid as buffer and ethylene diamine tetra-acetic acid (EDTA) as a complexing agent and sodium chloride as isotonicity agent.

An embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide and 10 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid and sodium citrate as buffer and ethylene diamine tetra-acetic acid (EDTA) as a complexing agent and sodium chloride as isotonicity agent. One embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide and 15 meg arformoterol tartarate. The nebulization composition may additionally contain a buffer, an isotonicity agent and optionally a complexing agent.

Another embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide, about 15 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid as buffer and sodium chloride as isotonicity agent.

One more embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide and 15 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid and sodium citrate as buffer and sodium chloride as isotonicity agent.

Yet another embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide and 15 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid as buffer and ethylene diamine tetra-acetic acid (EDTA) as a complexing agent and sodium chloride as isotonicity agent.

An embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide and 15 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid and sodium citrate as buffer and ethylene diamine tetra-acetic acid (EDTA) as a complexing agent and sodium chloride as isotonicity agent.

One embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide and 20 meg arformoterol tartarate. The nebulization composition may additionally contain a buffer, an isotonicity agent and optionally a complexing agent.

Another embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide, about 20 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid as buffer and sodium chloride as isotonicity agent.

One more embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide and 20 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid and sodium citrate as buffer and sodium chloride as isotonicity agent.

Yet another embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide and 20 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid as buffer and ethylene diamine tetra-acetic acid (EDTA) as a complexing agent and sodium chloride as isotonicity agent.

An embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide and 20 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid and sodium citrate as buffer and ethylene diamine tetra-acetic acid (EDTA) as a complexing agent and sodium chloride as isotonicity agent.

One embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 10 meg arformoterol tartarate. The nebulization composition may additionally contain a buffer, an isotonicity agent and optionally a complexing agent.

Another embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide, about 10 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid as buffer and sodium chloride as isotonicity agent.

One more embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 10 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid and sodium citrate as buffer and sodium chloride as isotonicity agent.

Yet another embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 10 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid as buffer and ethylene diamine tetra-acetic acid (EDTA) as a complexing agent and sodium chloride as isotonicity agent.

An embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 10 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid and sodium citrate as buffer and ethylene diamine tetra-acetic acid (EDTA) as a complexing agent. One embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 15 meg arformoterol tartarate. The nebulization composition may additionally contain a buffer, an isotonicity agent and optionally a complexing agent.

Another embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide, about 15 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid as buffer and sodium chloride as isotonicity agent.

One more embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 15 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid and sodium citrate as buffer and sodium chloride as isotonicity agent.

Yet another embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 15 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid as buffer and ethylene diamine tetra-acetic acid (EDTA) as a complexing agent and sodium chloride as isotonicity agent.

An embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 15 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid and sodium citrate as buffer and ethylene diamine tetra-acetic acid (EDTA) as a complexing agent and sodium chloride as isotonicity agent.

One embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 20 meg arformoterol tartarate. The nebulization composition may additionally contain a buffer, an isotonicity agent and optionally a complexing agent.

Another embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide, about 20 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid as buffer and sodium chloride as isotonicity agent.

One more embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 20 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid and sodium citrate as buffer and sodium chloride as isotonicity agent.

Yet another embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 20 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid as buffer and ethylene diamine tetra-acetic acid (EDTA) as a complexing agent and sodium chloride as isotonicity agent.

An embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 20 meg arformoterol tartarate. The nebulization composition may additionally contain citric acid and sodium citrate as buffer and ethylene diamine tetra-acetic acid (EDTA) as a complexing agent and sodium chloride as isotonicity agent.

In another embodiment of any of the nebulization compositions described herein, the nebulization composition contains not more than about 0.5% of Impurity C of glycopyrrolate or pharmaceutically acceptable salt thereof.

In one embodiment, the nebulization composition contains not more than about 0.5% of total impurities of glycopyrrolate or pharmaceutically acceptable salt thereof.

In a further embodiment of any of the nebulization compositions described herein, the nebulization composition contains not more than about 0.4% of amine impurity of aformoterol or pharmaceutically acceptable salt thereof.

In an embodiment, the nebulization composition contains not more than about 4% of Impurity A (deshydroxy impurity) of aformoterol or pharmaceutically acceptable salt thereof.

In one more embodiment of any of the nebulization compositions described herein, the nebulization composition contains not more than about 0.3% of deshydroxy impurity of aformoterol or pharmaceutically acceptable salt thereof.

In a further embodiment, the nebulization composition contains not more than about 5% of total impurities of aformoterol or pharmaceutically acceptable salt thereof.

The nebulization compositions described herein can also comprise a prefilled container containing a nebulization composition comprising glycopyrronium bromide and arformoterol tartarate, and optionally one or more pharmaceutically acceptable excipients, wherein the nebulization composition is in a solid dosage form, e.g. powder form which can be reconstituted prior to nebulization, with an appropriate diluent supplied in another prefilled container. The solid dosage form can be prepared by various methods, such as dry mixing, spray drying, lyophilization and the like.

The nebulization composition can be prepared as follows.

A. Composition comprising Glycopyrronium and Arformoterol together

1. Add approximately 75-90% quantity of purified water to an appropriately sized stainless steel mixing vessel.

2. Add sodium chloride to mixing vessel and mix until dissolved (e.g., no visible solid particles observed).

3. Add citric acid to mixing vessel and mix until dissolved (e.g., no visible solid particles observed).

4. Add sodium citrate to mixing vessel and mix until dissolved (e.g., no visible solid particles observed).

5. Add EDTA to mixing vessel and mix until dissolved (e.g., no visible solid particles observed).

6. Add glycopyrrolate to mixing vessel and mix until dissolved (e.g., no visible solid particles observed).

7. Add arformoterol to mixing vessel and mix until dissolved (e.g., no visible solid particles observed).

8. Make up volume with remainder of purified water and continue mixing for a minimum of 15 minutes.

9. Measure pH and adjust with HCL/NaOH if required to achieve target pH.

10. Sterilize solution by filtration.

11. Fill 2 mL of solution into appropriately sized vial for nebulization.

B. Composition comprising Glycopyrronium and Arformoterol in separate containers B.l. Composition of Glycopyrronium

A nebulization composition of glycopyrronium can be prepared in a similar manner as illustrated above.

B.2. Composition of Arformoterol

A nebulization composition of arformoterol can be prepared in a similar manner as illustrated above. B.3 Mixing of the compositions B.l and B.2

(i) Mix the nebulization compositions B.l and B.2 to obtain a nebulization composition B.3

(ii) Add the B.3 nebulization composition to the reservoir of the nebulizer device.

(iii) Nebulization compositions B.l and B.2 can be separately added to the reservoir of the nebulizer device and mixed to form a nebulization composition B.3

The nebulization composition provided herein has a long shelf life, i.e., it is stable during long term storage. The composition may contain greater than about 80%, such as greater than about 85%, greater than about 90%, greater than about 95% or greater than about 98% of the initial amount of glycopyrronium (or its salt) and arformoterol (or its salt) in the composition after being stored for 3 or 6 months or 1, 2 or 3 years at 2-8 ⁰ C and 25° C when stored in a suitable container (such as a LDPE container in an aluminium pouch). The stability may be determined using Arrhenius kinetics.

The nebulization composition may be administered by nebulizer. Suitable nebulizers include, but are not limited to, a jet nebulizer, an ultrasonic nebulizer, vibrating mesh nebulizer and a breath actuated nebulizer. The nebulization composition may be administered by nebulizers manufactured, designed or sold by Omron, such as the Omron MICRO AIR ^™ Ultrasonic Nebulizer or those manufactured, designed, or sold by Aerogen, or with the Nebu-Tec device, M-Neb ^® or with the Zephair ^® device from Aerosonix, or with the Fox inhaler ^® from Vectura, or with the Alphazer ^® device from Omega or with the e-flow device from Pari. Additionally, the nebulization compositions described herein can also be nebulized using inhalers other than those described above.

In one embodiment, any of the nebulization compositions described herein, when administered by a nebulizer provides a mass median aerodynamic diameter (MMAD) of below about 10 microns, such as between about 3 and about 6 microns.

In another embodiment, any of the nebulization compositions described herein, when administered by a nebulizer provides a geometric standard deviation (GSD) of below about 5, such as between about 1 and about 3.

In another embodiment, any of the nebulization compositions described herein, when administered by a nebulizer device provides a fine particle dose which is not less than about 10%. In another embodiment of any of the nebulization compositions described herein, the fine particle fraction (FPF) obtained following administration of the nebulizable composition in a nebulizer is about 30% to about 70%.

In another embodiment of any of the nebulization compositions described herein, the time taken to nebulize the nebulizable composition from the nebulizer device is about 1 to about 10 minutes.

In another embodiment of any of the nebulization compositions described herein, the nebulization composition exhibits a delivered dose between about 40% to about 99%.

The nebulization compositions also may be provided as a kit wherein the kit comprises a nebulizer and the nebulization composition comprising glycopyrronium bromide and arformoterol tartar ate.

The nebulization compositions of the present invention may be administered once a day or twice a day to a subject in need thereof.

The present invention includes methods of treating an inflammatory or obstructive airway disease such as asthma and COPD by administering to a patient a nebulization composition comprising glycopyrronium (or its salt) and arformoterol (or its salt) via a nebulizer.

The nebulization compositions of the present invention comprising the combination of glycopyrrolate and arformoterol may be useful in cases where monotherapy i.e. glycopyrrolate or arformoterol alone have been ineffective in the treatment of inflammatory or obstructive airway disease such as asthma or COPD.

The nebulization composition of the present invention comprising glycopyrrolate and arformoterol provide a synergistic effect. Accordingly, it may be possible to reduce the effective daily dose of these agents, thus, reducing the adverse effects posed by these agents. The nebulization composition provides a rapid onset of action and the effect may be extended for a long duration. A significant improvement in lung function leading to effective control of inflammatory or obstructive disease may be observed. The methods of treating inflammatory or obstructive airway disease such as asthma or COPD by the nebulization compositions as per the present invention may eliminate the need for other concurrent treatment modalities.

Throughout this specification it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.

The following examples further illustrate the invention, but are not limiting.

A. Examples of Nebulization composition comprising Glycopyrronium bromide and Arformoterol tartarate in a single composition

Manufacturing process:

1. Dissolve batch quantity of sodium chloride, Citric acid, Sodium Citrate & edetate disodium, in water for injection under stirring. Check clarity of the solution. Check the pH of solution.

2. Weigh accurately batch quantity of Glycopyrrolate & Arformoterol. Add it to the bulk of step 1 under stirring. Continue the stirring till the clear solution is obtained.

3. Make up volume with water for injection. Filter the solution through 0.22micron PES/PVDF filter.

4. Fill the filtered bulk in LDPE ampules.

Composition 28

Manufacturing process:

1. Dissolve batch quantity of sodium chloride, Citric acid, Sodium Citrate & edetate disodium, in water for injection under stirring. Check clarity of the solution. Check the pH of solution.

2. Weigh accurately batch quantity of Glycopyrrolate & Arformoterol. Add it to the bulk of step 1 under stirring. Continue the stirring till the clear solution is obtained.

3. Make up volume with water for injection. Filter the solution through 0.22micron PES/PVDF filter.

4. Fill the filtered bulk in FDPE ampules. Three replicate batches of Example 28 were tested for stability and device performance by a vibrating mesh nebulizer.

The below table represents a stability data for the three replicate batches for Example 28.

The data shown below is a representation of the in-vitro aerodynamic particle size distribution (APSD) data by NGI and the Breath simulator (BRS) data for the three replicate batches of Examples 28. FPM refers to fine particle mass. MB refers to mass balance. MOC refers to micro-orifice collector. IP refers to induction port. S 1 to S7 refers to stages 1 through stage 7 respectively. DD refers to drug delivery.

BRS Data

B. Examples of Nebulization composition comprising Glycopyrronium bromide and Arformoterol tartarate prepared separately and to be mixed prior to administration

The following examples illustrate the compositions of glycopyrronium and arformoterol which are formulated separately and are mixed prior to administration to a patient.

B.l Nebulization compositions comprising Glycopyrronium bromide

Manufacturing process

1. Dissolve batch quantity of sodium chloride in water for injection under stirring. Check clarity of the solution. Adjust the pH of solution using dilute hydrochloric acid.

2. Weigh accurately batch quantity of Glycopyrrolate. Add it to the bulk of step 1 under stirring. Continue the stirring till the clear solution is obtained.

3. Make up volume with water for injection. Filter the solution through 0.22micron PES/PVDF filter.

4. Fill the filtered bulk in LDPE ampules. B.2 Nebulization compositions comprising Arformoterol tartarate

Manufacturing process

1. Dissolve batch quantity of sodium chloride, Citric acid, Sodium Citrate & edetate disodium, in water for injection under stirring. Check clarity of the solution. Check the pH of solution.

2. Weigh accurately batch quantity of Arformoterol Tartarate. Add it to the bulk of step 1 under stirring. Continue the stirring till the clear solution is obtained.

3. Make up volume with water for injection. Filter the solution through 0.22micron PES/PVDF filter.

4. Fill the filtered bulk in LDPE ampules.

C. Examples of Nebulization composition comprising Glycopyrronium bromide and Arformoterol tartarate prepared separately and to be mixed prior to administration

The following examples illustrate the compositions of glycopyrronium and arformoterol which are formulated separately and are mixed prior to administration to a patient.

C.l Nebulization compositions comprising Glycopyrronium bromide

Manufacturing process

1. Dissolve batch quantity of sodium chloride in water for injection under stirring. Check clarity of the solution. Adjust the pH of solution using dilute hydrochloric acid.

2. Weigh accurately batch quantity of Glycopyrrolate. Add it to the bulk of step 1 under stirring.

Continue the stirring till the clear solution is obtained.

3. Make up volume with water for injection. Filter the solution through 0.22micron PES/PVDF filter.

4. Fill the filtered bulk in LDPE ampules.

C.2 Nebulization compositions comprising Arformoterol tartarate

Manufacturing process

1. Dissolve batch quantity of sodium chloride, Citric acid, Sodium Citrate & edetate disodium, in water for injection under stirring. Check clarity of the solution. Check the pH of solution.

2. Weigh accurately batch quantity of Arformoterol Tartarate. Add it to the bulk of step 1 under stirring. Continue the stirring till the clear solution is obtained.

3. Make up volume with water for injection. Filter the solution through 0.22micron PES/PVDF filter.

4. Fill the filtered bulk in LDPE ampules.

The ampules C 1 and C2 are packaged together in a foil pouch.

Three replicate batches C (i), C (ii) and C (iii) containing the above compositions Cl +C2 together were tested for stability and the data is as given below:

Throughout this specification it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.