Nebulization composition comprising glycopyrrolate, formoterol and budesonide

Abstract

The present application relates to an inhalable liquid composition suitable for nebulization comprising a fixed dose combination comprising glycopyrronium, formoterol and budesonide for treating a pulmonary disorder(s). The present application also relates to a process for preparing such a composition comprising a fixed dose combination comprising glycopyrronium, formoterol and budesonide.

Description

[0001] NEBULIZATION COMPOSITION COMPRISING GLYCOPYRROLATE, FORMOTEROL AND BUDESONIDE

[0002] RELATED APPLICATION

[0003] This application claims the benefit of Indian Provisional Application No. 202421070954 filed on September 19, 2024; which is hereby incorporated by reference in its entirety.

[0004] FIELD OF THE INVENTION

[0005] The present application relates to an inhalable liquid composition suitable for nebulization comprising a fixed dose combination comprising glycopyrronium, formoterol and budesonide for treating a pulmonary disorder(s). The present application also relates to a process for preparing such a composition comprising a fixed dose combination comprising glycopyrronium, formoterol and budesonide.

[0006] BACKGROUND OF THE INVENTION

[0007] Chronic obstructive airway disease and asthma are the most common life threatening conditions among respiratory disorders.

[0008] There has been persistent increase in prevalence, disease burden and mortality cases in US because of chronic obstructive pulmonary disease (COPD). COPD currently ranks as the third leading cause of death in the United States (U.S.). It is projected that, by 2020, COPD would be the fifth leading burden of disease worldwide. The mortality rates due to COPD continue to rise worldwide. COPD can be broadly defined into two states, emphysema and chronic bronchitis. Emphysema is characterized by irreversible enlargement of the air spaces distal to the terminal bronchioles leading to alveolar wall destruction. There is no evidence of fibrosis in emphysema. 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 subject to breath.

[0009] Asthma is a chronic disease. Demographic data suggests that asthma affects almost 22 million Americans of which about 6 million of these are children under age 18. Allergies or exposure to tobacco smoke is the most common reason of developing asthma. Asthma is characterized by three major changes which leads to this condition. One of the three changes includes bronchospasm which is characterized by tightening of the muscles which surround the airways, thus, making them narrow. Second change comprises swollen or inflamed lining of the airways. Excessive mucus production above normal levels by the cells which line the airways constitutes the third change in this chronic condition. Common symptoms of asthma include coughing, wheezing, and shortness of breath.

[0010] Glycopyrronium is approved in the U.S. under the brand name Lonhala Magnair ® as a solution for inhalation. Formoterol is approved under the brand name Perforomist® as a solution for inhalation and Budesonide nebulization is approved in US under the brand name Pulmicort Respules®.

[0011] US Patent Application 2008 / 300226 discloses topically inhaled medicinal formulations comprising a combination of inhaled anticholinergic and glucocorticoid and its use in the symptomatic and prophylactic treatment of diseases of the respiratory tract. US Patent Application 2007 / 207091 discloses a nebulization composition of formoterol and budesonide. US Patent No. 8,518,918 discloses a combination of R,R-glycopyrronium with formoterol and budesonide. The patent cites R-enantiomer of glycopyrronium and not the racemic form of glycopyrronium and no specific nebulization composition is disclosed in the patent.

[0012] The present application describes a nebulization composition comprising the combination of glycopyrronium or a pharmaceutically acceptable salt thereof, formoterol or a pharmaceutically acceptable salt thereof and budesonide suitable for treatment ofa pulmonary disease.

[0013] SUMMARY OF THE INVENTION

[0014] The present application relates to an inhalable liquid composition suitable for nebulization comprising a combination of glycopyrronium or a pharmaceutically acceptable salt thereof, formoterol or a pharmaceutically acceptable salt thereof and budesonide.

[0015] In an embodiment, the inhalable liquid composition suitable for nebulization comprising a fixed dose combination of glycopyrronium or a pharmaceutically acceptable salt thereof, formoterol or a pharmaceutically acceptable salt thereof and budesonide.

[0016] In an embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising: a fixed dose combination of glycopyrronium or a pharmaceutically acceptable salt thereof, formoterol or a pharmaceutically acceptable salt thereof and budesonide is administered to a subject using a nebulizer.

[0017] In an embodiment, the glycopyrronium, formoterol and budesonide are present in the nebulization composition in a single unit dose package. In another embodiment, the glycopyrronium and formoterol are present in the nebulization composition in solubilized form and budesonide is present in a suspended form.

[0018] One embodiment relates to an inhalable liquid composition suitable for nebulization comprising a combination of glycopyrronium or a pharmaceutically acceptable salt thereof, formoterol or a pharmaceutically acceptable salt thereof and budesonide for the treatment of a pulmonary disease in a subject in need thereof.

[0019] In a preferred embodiment, the nebulization composition comprises about 0.1 mcg to about 500 mcg of glycopyrronium, about 0.1 mcg to about 500 mcg of formoterol fumarate and about 0.1 mcg to about 1000 mcg of budesonide.

[0020] In a preferred embodiment, the nebulization composition comprises about 1 mcg to about 100 mcg of glycopyrronium, about 1 mcg to about 100 mcg of formoterol fumarate and about 200 mcg to about 800 mcg of budesonide.

[0021] In a preferred embodiment, the nebulization composition comprises about 20 mcg to about 30 mcg of glycopyrronium, about 10 mcg to about 30 mcg of formoterol fumarate and about 400 mcg to about 600 mcg of budesonide.

[0022] In a preferred embodiment, the nebulization composition comprises about 20 mcg of glycopyrronium, about 10 mcg of formoterol fumarate and about 400 mcg of budesonide.

[0023] In a preferred embodiment, the nebulization composition comprises about 22 mcg of glycopyrronium, about 15 mcg of formoterol fumarate and about 450 mcg of budesonide.

[0024] In a preferred embodiment, the nebulization composition comprises about 25 mcg of glycopyrronium, about 20 mcg of formoterol fumarate and about 500 mcg of budesonide.

[0025] In a preferred embodiment, the nebulization composition comprises about 30 mcg of glycopyrronium, about 25 mcg of formoterol fumarate and about 550 mcg of budesonide.

[0026] In an embodiment, the nebulization composition is a sterile, unit dose composition.

[0027] In one more embodiment, the nebulization composition is in a single chamber container for administration to a subject.

[0028] In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization is contained in a triple chamber container, wherein glycopyrronium bromide, formoterol fumarate and budesonide are contained separately in three different chambers and the contents of the three chambers are combined together before, or at the time of, administration to a subject.

[0029] In a further embodiment, the present application relates to an inhalable liquid composition suitable for nebulization is contained in a dual chamber container, wherein one chamber comprises glycopyrronium bromide and formoterol fumarate together and the other chamber comprises budesonide, and the contents of the two chambers are mixed together before, or at the time of, administration to a subject.

[0030] In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization is contained in a dual chamber container, wherein one chamber comprises budesonide and formoterol fumarate together and the other chamber comprises glycopyrronium bromide, and the contents of the two chambers are mixed together before, or at the time of, administration to a subject.

[0031] In one more embodiment, the present application relates to an inhalable liquid composition suitable for nebulization is contained in a dual chamber container, wherein one chamber comprises glycopyrronium bromide and budesonide together and the other chamber comprises formoterol fumarate, and the contents of the two chambers are mixed together before, or at the time of administration to a subject.

[0032] In yet another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprises glycopyrronium bromide, formoterol fumarate, budesonide, 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.

[0033] In a further embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprises glycopyrronium bromide, formoterol fumarate, budesonide, citric acid, sodium citrate, sodium chloride and sterile water.

[0034] In one embodiment, the nebulization composition is free, or substantially free, of a preservative (such as a benzalkonium salt, e.g., benzalkonium chloride).

[0035] In another embodiment, the nebulization composition is free, or substantially free, of a complexing agent (such as ethylene diamine tetra-acetic acid (EDTA)).

[0036] In a further embodiment, the nebulization composition is free, or substantially free, of (a) EDTA and (b) a benzalkonium salt, such as benzalkonium chloride.

[0037] In one embodiment, the nebulization composition of the present application comprises glycopyrronium, formoterol, budesonide, a buffer, an isotonicity agent and water.

[0038] In an embodiment, the nebulization composition of the present application comprises glycopyrronium, formoterol, budesonide, a citric acid, sodium citrate, sodium chloride and water.

[0039] In another embodiment, the nebulization composition of the present application comprises glycopyrronium, formoterol, budesonide, a buffer, a surfactant, a complexing agent, an isotonicity agent and water. In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising i) a combination of about 0.1 mcg to about 500 mcg of glycopyrronium, about 0.1 mcg to about 500 mcg of formoterol, and about 0.1 mcg to about 1000 mcg of budesonide; ii) one or more pharmaceutically acceptable excipient(s) selected from a buffer, a surfactant, a complexing agent, and an isotonicity agent; and iii) water.

[0040] In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 0.1 mcg to about 500 mcg of glycopyrronium, about 0.1 mcg to about 500 mcg of formoterol, about 0.1 mcg to about 1000 mcg of budesonide, a buffer, a surfactant, a complexing agent, an isotonicity agent and water.

[0041] In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 1 mcg to about 100 mcg of glycopyrronium, about 1 mcg to about 100 mcg of formoterol, about 200 mcg to about 800 mcg of budesonide, a buffer, a surfactant, a complexing agent, an isotonicity agent and water.

[0042] In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 20 mcg to about 30 mcg of glycopyrronium, about 10 mcg to about 30 mcg of formoterol fumarate and about 400 mcg to about 600 mcg of budesonide, a buffer, a surfactant, a complexing agent, an isotonicity agent and water.

[0043] In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising i) a combination of about 20 mcg of glycopyrronium, about 10 mcg of formoterol, and about 400 mcg of budesonide, ii) one or more pharmaceutically acceptable excipient(s) selected from a buffer, a surfactant, a complexing agent, an isotonicity agent and water.

[0044] In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising i) a fixed dose combination of about 22 mcg of glycopyrronium, about 15 mcg of formoterol, and about 450 mcg of budesonide, ii) one or more pharmaceutically acceptable excipient(s) selected from a buffer, a surfactant, a complexing agent, an isotonicity agent and water.

[0045] In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising i) a fixed dose combination of about 25 mcg of glycopyrronium, about 20 mcg of formoterol, and about 500 mcg of budesonide, ii) one or more pharmaceutically acceptable excipient(s) selected from a buffer, a surfactant, a complexing agent, an isotonicity agent and water. In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 30 mcg of glycopyrronium, about 25 mcg of formoterol, about 550 mcg of budesonide, a buffer, a surfactant, a complexing agent, an isotonicity agent and water.

[0046] In an embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising glycopyrronium, formoterol, budesonide, a citric acid, sodium citrate, polysorbate 80, disodium edetate, sodium chloride and water.

[0047] In an embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising i) about 0.1 mcg to about 500 mcg of glycopyrronium, about 0.1 mcg to about 500 mcg of formoterol, and about 0.1 mcg to about 1000 mcg of budesonide, and ii) one or more pharmaceutically acceptable excipient(s) selected from a citric acid, sodium citrate, polysorbate 80, disodium edetate, sodium chloride and water.

[0048] In an embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 0.1 mcg to about 500 mcg of glycopyrronium, about 0.1 mcg to about 500 mcg of formoterol, about 0.1 mcg to about 1000 mcg of budesonide, a citric acid, sodium citrate, polysorbate 80, disodium edetate, sodium chloride and water.

[0049] In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization composition of the present application comprising about 1 mcg to about 100 mcg of glycopyrronium, about 1 mcg to about 100 mcg of formoterol, about 200 mcg to about 800 mcg of budesonide, a citric acid, sodium citrate, polysorbate 80, disodium edetate, sodium chloride and water.

[0050] In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 20 mcg to about 30 mcg of glycopyrronium, about 10 mcg to about 30 mcg of formoterol fumarate and about 400 mcg to about 600 mcg of budesonide, a citric acid, sodium citrate, polysorbate 80, disodium edetate, sodium chloride and water.

[0051] In an embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 20 mcg of glycopyrronium, about 10 mcg of formoterol, about 400 mcg of budesonide, a citric acid, sodium citrate, polysorbate 80, disodium edetate, sodium chloride and water.

[0052] In an embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 22 mcg of glycopyrronium, about 15 mcg of formoterol, about 450 mcg of budesonide, a citric acid, sodium citrate, polysorbate 80, disodium edetate, sodium chloride and water. In an embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 25 mcg of glycopyrronium, about 20 mcg of formoterol, about 500 mcg of budesonide, a citric acid, sodium citrate, polysorbate 80, disodium edetate, sodium chloride and water.

[0053] In an embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 30 mcg of glycopyrronium, about 25 mcg of formoterol, about 550 mcg of budesonide, a citric acid, sodium citrate, polysorbate 80, disodium edetate, sodium chloride and water.

[0054] In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising glycopyrronium, formoterol, budesonide, a buffer, a complexing agent, an isotonicity agent and water.

[0055] In an embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising glycopyrronium, formoterol, budesonide, a citric acid, sodium citrate, disodium edetate, sodium chloride and water.

[0056] In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising glycopyrronium, formoterol, budesonide, a buffer, a surfactant, an isotonicity agent and water.

[0057] In an embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising glycopyrronium, formoterol, budesonide, a citric acid, sodium citrate, polysorbate 80, sodium chloride and water.

[0058] In yet another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization is remain stable at least for 3 months at room temperature that is in accelerated condition.

[0059] In yet another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization is remain stable at least for 6 months at 2°C to 8°C.

[0060] In a specific embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising glycopyrronium bromide, formoterol fumarate, budesonide, sodium chloride, sodium citrate and citric acid, hydrochloric acid, sodium hydroxide, water and optionally edetate disodium. The glycopyrronium bromide and formoterol fumarate are in solubilized form in the solution while budesonide is in suspension form. The nebulization composition is preferably free, or substantially free, of benzalkonium salts. Another embodiment is a kit comprising a nebulizer and a nebulization composition of the present application. In one preferred embodiment, the nebulization composition comprises glycopyrronium bromide, formoterol fumarate and budesonide.

[0061] Yet another embodiment is a method of treating a pulmonary disease in a subject in need thereto, wherein the method comprises administering a nebulization composition of the present application using a nebulizer. In one preferred embodiment, the nebulization composition comprises glycopyrronium bromide, formoterol fumarate and budesonide.

[0062] DETAILED DESCRIPTION OF THE INVENTION

[0063] 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. In particular, a nebulization composition may comprise one or more dose unit such as single dose unit or dual chamber comprising two dose units and the like. Similarly, a composition may be referred herein to mean a composition of solution composition, suspension composition; or a mixture of solution and suspension.

[0064] The term “about” as used herein refers to dose or weight in a composition or other numeral amounts means plus or minus up to 20% (alternatively, up to 10% or 5%) of the reported value.

[0065] The term “mcg” as used herein refers to commonly used to express the amount of an active pharmaceutical ingredient (API) present per unit dose of inhalable composition.

[0066] The term “Substantially free” as used herein refers to a specified component present in the inhalable composition of present application less than about 1% by weight of the specified component. “Free” of a specified component refers to a composition where the specified component is absent. The term substantially free herein also referred as presence of substance inseparable amount.

[0067] The term “nebulization” as used herein refers to a process of nebulization using nebulizer.

[0068] The term “nebulization composition” or “inhalable composition” or “inhalation composition” as used herein refers collectively to any liquid inhalable composition suitable for nebulization and / or nebulized from the nebulizer. This nebulization composition can be defined as follows (i) a nebulizable composition that is suitable for administration by nebulization using a nebulizer device and / or (ii) a nebulized composition that results of nebulization process from nebulizer that is generated from such composition. The term encompasses liquid, suspension, or solution composition intended to be administered using a nebulizer device to produce a fine mist or a cloud for inhalation by a subject. In some embodiment, the term nebulization composition refers to either nebulizable composition or nebulized composition, however, it shall be understood in context of the describing embodiment in specification. In a specific embodiment, the inhalable composition suitable for nebulization is an inhalable suspension composition.

[0069] The term “pulmonary disease” or “pulmonary disorder” as used herein refers to any disorder, condition, or dysfunction affecting the lungs, airways, or respiratory system, including, but not limited to diseases characterized by airflow limitation, airway inflammation, bronchoconstriction, mucus hypersecretion, or impaired gas exchange. The term Pulmonary disease according to the present application comprises both acute and chronic conditions, and specifically includes, without limitation, asthma, chronic obstructive pulmonary disease (including chronic bronchitis and emphysema), as well as related obstructive, restrictive, or mixed respiratory disorders.

[0070] The term “stable” as used herein refers to a nebulizable pharmaceutical composition that maintains its physical, chemical, and functional integrity under specified storage conditions. In the context of the present application, a composition is considered stable when: (i) Chemical stability: total impurity does not increase more than 5% at least for 3 months when stored at 25 °C ± 2 °C / 60 % RH ± 5 % RH or (ii) physical stability: no substantial change in one or more critical physical parameters of nebulization composition such as osmolality, pH at least for 3 months when stored at 25 °C ± 2 °C / 60 % RH ± 5 % RH.

[0071] The term “impurity” as used herein refers to chemical substance that degradants from the active that is glycopyrronium, formoterol and budesonide. The term impurity as used herein refers to total impurity or total related substance in the composition.

[0072] The present application relates to a nebulization composition comprising glycopyrronium, formoterol and budesonide for a pulmonary disease in a subject in need thereof. The present application also relates to a process for preparing the nebulization composition comprising glycopyrronium, formoterol and budesonide.

[0073] Chronic obstructive pulmonary disease (COPD) and asthma are the most prevalent of the respiratory disorders and the number of subjects is increasing. Dosage forms currently available include metered dose inhalers, dry powder inhalers and nebulization dosage forms. All the three dosage forms require a device which enable a subject to administer the appropriate dose. The first two dosage forms namely metered dose inhalers and dry powder inhalers require specific devices which need synchronization with the breathing capacity and the breathing pattern of the subject so as to ensure that the effective dose reaches its target sites. It is often observed that subjects need to undergo training to get the drug delivered from the devices in these two dosage forms. There is a significant risk of under-dosing if the subject fails to achieve the co-ordination while inhaling the dose from the device. The latter dosage form, the nebulization dosage form does not require the subject to undergo such a cumbersome and tedious training. It is not required for the subject to synchronize breathing pattern with the device and the dose delivery is reasonably independent of the breathing capacity or the breathing pattern of the subject. This is especially convenient for pediatric and geriatric subjects. 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.

[0074] The term “glycopyrronium” or “glycopyrrolate” as used herein refers to glycopyrronium or a pharmaceutically acceptable salt(s), a synthetic quaternary ammonium antimuscarinic (anticholinergic) compound, specifically refers to glycopyrronium bromide. Glycopyrronium acts as a competitive antagonist of muscarinic acetylcholine receptors (MIMS) and is used as a bronchodilator for the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD) and asthma. The term encompasses all pharmaceutically acceptable salts, solvates, hydrates, crystalline and amorphous forms, polymorphs, stereoisomers, enantiomers, and mixtures thereof, unless otherwise specified. Glycopyrronium bromideis chemically known as (3RS)-3-[(2SR)-(2-cyclopentyl-2 -hydroxy-2 - phenylacetyl) oxy]-l,l-dimethylpyrrolidinium bromide (Formula I)

[0075] Formula I

[0076] Glycopyrronium can be prepared using the procedures described in U.S. Pat. No.2956062. The present application 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, glycopyrronium and glycopyrronium are used interchangeably.

[0077] In the context of present application, glycopyrronium may refer to any pharmaceutically acceptable salts of glycopyrronium, but not limited to, glycopyrronium bromide, glycopyrronium chloride, or glycopyrronium iodide, as well as all individual stereoisomers and any mixtures thereof. Suitable counter ions are pharmaceutically acceptable counter ions including, for example, fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartarate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl-acetate or triphenylacetate, ohydroxybenzoate, p-hydroxybenzoate, 1- hydroxynaphthalene-2-carboxylate, 3- hydroxynaphthalene-2-carboxylate, methanesulfonate and benzenesulfonate.

[0078] One preferred salt of glycopyrronium for the nebulization composition is glycopyrronium bromide.

[0079] The term “Formoterol” as used herein refers to formoterol or one or more pharmaceutically acceptable salt(s) of formoterol. Formoterol is a long-acting, beta 2- adrenergic receptor agonist and chemically known as (±)-2-hydroxy-5-[(l RS)- 1 -hydroxy-2 - [[(lRS)-2-(4-m ethoxyphenyl) -1 -methyl ethyl] -amino]ethyl] formanilide. Formoterol has a molecular formula of C19H24N2O4 and the following structure (Formula II):

[0080] Formula II

[0081] In the context of the present application, the term “formoterol”, unless otherwise indicated, includes, but is not limited to, formoterol in any physical form such as the amorphous form and crystalline forms (e.g., anhydrous, hydrate, and other solvate forms). Salts of formoterol include, but are not limited to, acid addition salts and base salts thereof. Suitable salts of formoterol 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 fumarates. One preferred salt of formoterol for the nebulization composition is formoterol fumarate, such as in the form of its dihydrate salt (formoterol fumarate dihydrate).

[0082] The term “Budesonide” as used herein refers to budesonide or any pharmaceutically acceptable salt(s), ester(s) of budenoside. Budesonide is a corticosteroid having antiinflammatory properties and is chemically known as (RS)-l ip, 16a, 17, 21- tetrahydroxypregna-1, 4-diene-3, 20-dione cyclic 16, 17-acetal. Budesonide has a chemical formula of C25H34O6 and the following structure:

[0083] Formula III

[0084] As used herein, the term budesonide refers to the racemic, optically pure, or optically enriched forms thereof. The budesonide can be present in amorphous or crystalline form or a mixture thereof. Budesonide used in the nebulization compositions herein can be sterile or non- sterile. In one instance, where budesonide is used in a non-sterile form, the compositions can be sterilized by autoclaving. Alternatively, if budesonide is used in a pre-sterilized form, the compositions can be processed by an aseptic process.

[0085] Sterilization of budesonide can be effected by either dry heat sterilization, moist heat sterilization or by bulk sterilization of final bulk suspension. Budesonide used in the nebulization compositions herein can be in micronized form or alternatively micronization can be effected during preparation of the nebulization composition. Micronization may be carried out till a desired particle size is achieved which may be maintained throughout the shelf life of the product.

[0086] The term “combination” as used herein refers to a therapeutic regimen comprising three active agents, specifically glycopyrronium, formoterol, and budesonide. In the context of the present application, the combination may be provided as: (i) Fixed-dose combination (FDC): a single inhalable composition comprising glycopyrronium, formoterol, and budesonide in fixed, pre-determined amounts; (ii) Dual + single combination: two of the active agents co-formulated in a single container and the third active agent provided in a separate container, for concurrent use or co-administration; or (iii) Triple single combination: each of glycopyrronium, formoterol, and budesonide provided in separate containers, for simultaneous or sequential administration within a defined treatment regimen. The present application relates to an inhalable composition suitable for nebulization comprising glycopyrronium, formoterol and budesonide.

[0087] In an embodiment, the present application relates to an inhalable composition suitable for nebulization comprising a fixed dose combination comprising: glycopyrronium, formoterol and budesonide. In an embodiment, the present application relates to an inhalable composition suitable for nebulization comprising a fixed dose combination comprising: glycopyrronium, formoterol and budesonide; and one or more pharmaceutically acceptable excipient(s) thereof.

[0088] A single nebulization composition containing the three active agents glycopyrronium, formoterol and budesonide would combine the benefits offered by the three active agents. In addition, the combination offers a synergistic effect with a possible reduction in the dose of the three active agents, thereby, reducing adverse effects.

[0089] In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 0.1 mcg to about 500 mcg of glycopyrronium, about 0.1 mcg to about 500 mcg of formoterol, about 0.1 mcg to about 1000 mcg of budesonide, a buffer, a surfactant, a complexing agent, an isotonicity agent and water.

[0090] In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising: a fixed dose combination comprising: (i) about 0.1 mcg to about 500 mcg of glycopyrronium, (ii) about 0.1 mcg to about 500 mcg of formoterol, and (iii) about 0.1 mcg to about 1000 mcg of budesonide; a buffer, a surfactant, a complexing agent, an isotonicity agent and water.

[0091] In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 1 mcg to about 100 mcg of glycopyrronium, about 1 mcg to about 100 mcg of formoterol, about 200 mcg to about 800 mcg of budesonide, a buffer, a surfactant, a complexing agent, an isotonicity agent and water.

[0092] In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 20 mcg to about 30 mcg of glycopyrronium, about 10 mcg to about 30 mcg of formoterol fumarate and about 400 mcg to about 600 mcg of budesonide, a buffer, a surfactant, a complexing agent, an isotonicity agent and water.

[0093] In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 20 mcg of glycopyrronium, about 10 mcg of formoterol, about 400 mcg of budesonide, a buffer, a surfactant, a complexing agent, an isotonicity agent and water.

[0094] In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 22 mcg of glycopyrronium, about 15 mcg of formoterol, about 450 mcg of budesonide, a buffer, a surfactant, a complexing agent, an isotonicity agent and water. In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 25 mcg of glycopyrronium, about 20 mcg of formoterol, about 500 mcg of budesonide, a buffer, a surfactant, a complexing agent, an isotonicity agent and water.

[0095] In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 30 mcg of glycopyrronium, about 25 mcg of formoterol, about 550 mcg of budesonide, a buffer, a surfactant, a complexing agent, an isotonicity agent and water.

[0096] In an embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 0.1 mcg to about 500 mcg of glycopyrronium, about 0.1 mcg to about 500 mcg of formoterol, about 0.1 mcg to about 1000 mcg of budesonide, a citric acid, sodium citrate, polysorbate 80, disodium edetate, sodium chloride and water.

[0097] In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 1 mcg to about 100 mcg of glycopyrronium, about 1 mcg to about 100 mcg of formoterol, about 200 mcg to about 800 mcg of budesonide, a citric acid, sodium citrate, polysorbate 80, disodium edetate, sodium chloride and water.

[0098] In another embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 20 mcg to about 30 mcg of glycopyrronium, about 10 mcg to about 30 mcg of formoterol fumarate and about 400 mcg to about 600 mcg of budesonide, a citric acid, sodium citrate, polysorbate 80, disodium edetate, sodium chloride and water.

[0099] In an embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 20 mcg of glycopyrronium, about 10 mcg of formoterol, about 400 mcg of budesonide, a citric acid, sodium citrate, polysorbate 80, disodium edetate, sodium chloride and water.

[0100] In an embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 22 mcg of glycopyrronium, about 15 mcg of formoterol, about 450 mcg of budesonide, a citric acid, sodium citrate, polysorbate 80, disodium edetate, sodium chloride and water.

[0101] In an embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 25 mcg of glycopyrronium, about 20 mcg of formoterol, about 500 mcg of budesonide, a citric acid, sodium citrate, polysorbate 80, disodium edetate, sodium chloride and water. In an embodiment, the present application relates to an inhalable liquid composition suitable for nebulization comprising about 30 mcg of glycopyrronium, about 25 mcg of formoterol, about 550 mcg of budesonide, a citric acid, sodium citrate, polysorbate 80, disodium edetate, sodium chloride and water.

[0102] The inventors have surprisingly and unexpectedly formulated a inhalable composition suitable for nebulization comprising a fixed dose combination of glycopyrronium, formoterol, and budesonide and the said composition is stable physically and chemically during storage at room temperature at least for 3 months and / or at least 6 months 2-8°C.

[0103] A development of neubulization composition involves optimization of various formulation parameter such as uniformity in suspension, compatibility of excipients with container, pH and ionic strength of the solution that can affect the solubility of the actives, irritancy profile of each excipient and their concentration. The composition of the present application comprises three active agents in which two active agents (glycopyrronium, and formoterol) are solubilized in the composition and budesonide is suspended in the composition, hence, the pH and ionic strength of the composition plays crucial role.

[0104] In some embodiment, the nebulization composition of the present application has osmolality of from about from about 200 mOsmol / kg to about 400 mOsmol / kg when stored at 2-8°C.

[0105] In some embodiment, the nebulization composition of the present application has osmolality of from about from about 250 mOsmol / kg to about 350 mOsmol / kg when stored at 2-8°C.

[0106] In some embodiment, the nebulization composition of the present application has pH of from about 4 to about 5.

[0107] In some embodiments, the nebulization composition of the present application is diluted before administering to subject.

[0108] In some embodiments, the nebulization composition of the present application is administered using delivery cup size from about 2 ml to about 10 ml.

[0109] Single unit dosage form

[0110] The nebulization composition comprises glycopyrronium bromide and formoterol fumarate, where both are in solubilized form and budesonide is present in a suspension form. The nebulization compositions of the present application comprise a single unit dosage form comprising glycopyrronium bromide, formoterol fumarate and budesonide. The nebulization composition may include other pharmaceutically acceptable excipients. Such a composition can be contained in a single chamber container. Such a single composition comprising glycopyrronium, formoterol and budesonide (such as the combination glycopyrronium bromide, formoterol fumarate and budesonide) is stable during long term storage. The pharmaceutical 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 each of the glycopyrronium, formoterol, and budesonide (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, 25° C and at 40° C when stored in a suitable container.

[0111] Dual chamber container

[0112] In a first instance, glycopyrronium and formoterol can be formulated together as a solution in a single composition along with one or more pharmaceutically acceptable excipients. Budesonide can be separately formulated as a suspension along with one or more pharmaceutically acceptable excipients. Such a composition can be filled into a dual chamber container. In this instance, the composition comprising glycopyrronium and formoterol along with one or more pharmaceutically acceptable excipients can be contained in one chamber, whereas the composition comprising budesonide can be contained in another chamber.

[0113] Alternatively, in a second instance, budesonide and formoterol can be formulated together in a single composition along with one or more pharmaceutically acceptable excipients. Glycopyrronium can be separately formulated as a solution along with one or more pharmaceutically acceptable excipients. Such a composition can be filled into a dual chamber container. In this instance, the composition comprising budesonide and formoterol along with one or more pharmaceutically acceptable excipients can be contained in one chamber, whereas the composition comprising glycopyrronium can be contained in another chamber.

[0114] In a third instance, budesonide and glycopyrronium can be formulated together in a single composition along with one or more pharmaceutically acceptable excipients. Formoterol can be separately formulated as a solution along with one or more pharmaceutically acceptable excipients. Such a composition can be filled into a dual chamber container. In this instance, the composition comprising budesonide and glycopyrronium along with one or more pharmaceutically acceptable excipients can be contained in one chamber, whereas the composition comprising formoterol can be contained in another chamber.

[0115] 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 the compositions. For example, as in the first instance, the compositions comprising glycopyrronium bromide and formoterol fumarate may be mixed with the composition comprising budesonide before being added to the reservoir of the nebulizer. Alternatively, the composition comprising glycopyrronium bromide and formoterol fumarate and the composition comprising budesonide may be sequentially added to the reservoir of the nebulizer and hence would be mixed in the reservoir of the nebulizer device and then administered to the subject.

[0116] Triple chamber container

[0117] The three active agents can be formulated separately and contained in separate containers, which are then mixed prior to administration to a subject. In this instance, a composition comprising glycopyrronium bromide and one or more pharmaceutically acceptable excipients is contained in one chamber, another composition comprising formoterol fumarate and one or more pharmaceutically acceptable excipients is contained in a separate chamber and one more composition comprising budesonide and one or more pharmaceutically acceptable excipients is contained in a separate chamber. This combination comprising separate compositions of glycopyrronium bromide, formoterol fumarate and budesonide can be contained in a triple chamber container. The three chambers of the triple chamber container may be separate or may be connected by a common septum. The triple chamber container with a common septum may contain a common top which when broken would provide simultaneous access to three compositions. The compositions comprising glycopyrronium bromide, formoterol fumarate and budesonide may be mixed before being added to the reservoir of the nebulizer. In one instance, the compositions comprising glycopyrronium bromide, formoterol fumarate and budesonide may be sequentially added to the reservoir of the nebulizer. In this instance, the three compositions would be mixed in the reservoir of the nebulizer device and then administered to the subject.

[0118] The nebulization compositions of the present application may contain about 0.001% w / v to about 0.01% w / v of glycopyrronium bromide.

[0119] The nebulization compositions of the present application contain about 0.0005% w / v to about 0.002% w / v of formoterol fumarate.

[0120] The nebulization compositions of the present application contain about 0.01% w / v to about 0.1 % w / v of budesonide.

[0121] The nebulization compositions of the present application may contain from about 0.00125% w / v to about 0.005% w / v of glycopyrronium bromide.

[0122] The nebulization compositions of the present application contain about from about 0.001% w / v to about 0.004% w / v of formoterol fumarate.

[0123] The nebulization compositions of the present application may contain from about 0.025% w / v to about 0.1% w / v budesonide. The nebulization composition may comprise glycopyrronium bromide, formoterol fumarate, budesonide and one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients include, but are not limited to, pH adjusting agents, isotonicity agents, optionally chelating agents, surfactants, anti-oxidants, and pharmaceutically acceptable vehicles. In one embodiment, the composition includes a pH adjusting agent, isotonicity agent, pharmaceutically acceptable vehicle, and optionally a chelating agent.

[0124] The nebulization composition may be 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. For example, the nebulization composition may contain less than about 0.1% by weight of preservative (or quaternary ammonium preservative) (such as less than about 0.05%, less than about 0.02%, or less than about 0.008%), based on 100% total weight of 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 subjects, the benzalkonium chloride can cause dose-dependent bronchoconstriction. The nebulization compositions of the present application 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 subject 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. In one embodiment, the nebulization compositions contain EDTA in an amount of 0.05% or less. In a preferred embodiment, the nebulization compositions contain EDTA in an amount of 0.02% or less. The absence of or reduction in the concentration of the additive EDTA and its salts helps to reduce the paradoxic effect associated with cough.

[0125] In one embodiment, the nebulization composition of the present application comprises glycopyrronium , formoterol, budesonide, a buffer, an isotonicity agent and water.

[0126] In an embodiment, the nebulization composition of the present application comprises glycopyrronium, formoterol, budesonide, a citric acid, sodium citrate, sodium chloride and water.

[0127] In another embodiment, the nebulization composition of the present application comprises glycopyrronium, formoterol, budesonide, a buffer, a surfactant, a complexing agent, an isotonicity agent and water.

[0128] In an embodiment, the nebulization composition of the present application comprises glycopyrronium, formoterol, budesonide, a citric acid, sodium citrate, polysorbate 80, disodium edetate, sodium chloride and water.

[0129] In another embodiment, the nebulization composition of the present application comprises glycopyrronium, formoterol, budesonide, a buffer, a complexing agent, an isotonicity agent and water.

[0130] In an embodiment, the nebulization composition of the present application comprises glycopyrronium, formoterol, budesonide, a citric acid, sodium citrate, disodium edetate, sodium chloride and water.

[0131] In an embodiment, the nebulization composition of the present application comprises glycopyrronium, formoterol, budesonide, a citric acid, sodium citrate, polysorbate 80, sodium chloride and water.

[0132] In some embodiments, the nebulization composition of the present application comprises sterile budesonide and having 90% particles of budesonide is less than about 10 microns.

[0133] In some embodiments, the nebulization composition of the present application comprises suspended sterile budesonide and having 90% particles of budesonide is less than about 9 microns or less than about 8 microns or less than 7 microns, or less than about 6 microns or less than about 5 microns or less than about 4 microns, or less than about 3 microns.

[0134] In some embodiments, the nebulization composition of the present application comprises suspended sterile budesonide and having 90% particles of budesonide is from about 5 microns to about 1 micron. In some embodiments, he nebulization composition of the present application comprises suspended sterile budesonide and having 50% particles of budesonide is less than about 5 microns.

[0135] In some embodiments, he nebulization composition of the present application comprises suspended sterile budesonide and having 50% particles of budesonide is less than about 4 microns.

[0136] In some embodiments, he nebulization composition of the present application comprises suspended sterile budesonide and having 50% particles of budesonide is less than about 3 microns.

[0137] In some embodiments, he nebulization composition of the present application comprises suspended sterile budesonide and having 50% particles of budesonide is less than about 2.5 microns.

[0138] The pH of the nebulization composition may vary from about 1 to about 8. 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. The pH of the nebulization composition is in the range of about 4 to about 5.

[0139] 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, about 0.001 to about 0.1% w / v to control pH.

[0140] The nebulization composition may optionally include a buffer. Buffers in the pH range of about 2.0 to about 8.0 include, but are not limited to, acetate, barbital, borate, Britton- Robinson, cacodylate, citrate, collidine, formate, maleate, Mcllvaine, phosphate, Prideaux- Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen), veronal acetate, MES, BISTRIS, ADA, ACES, PIPES, MOPSO, BIS-TRIS PROPANE, BES, MOPS, TES, HEPES, DIPSO, MOBS, TAPSO, TRIZMA, HEPPSO, POPSO, TEA, EPPS, TRICINE, GLY-GLY, BICINE, HEPBS, TAPS, and AMPD buffers. The nebulization composition described herein contain Tartaric acid and monosodium citrate as buffering agent. Alternatively, the nebulization composition described herein may contain tartaric acid and sodium tartarate dihydrate as buffering agent. The nebulization composition described herein may also contain phosphoric acid, citric acid monohydrate, trisodium citrate dihydrate, sodium dihydrogen phosphate dihydrate as buffering agent. Additionally, the nebulization composition described herein may not contain a buffering agent.

[0141] 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, fructose, 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. In a preferred embodiment, the tonicity agent is sodium chloride and is present in the range of form about 0.001% w / v to about 10% w / v, or 0.001% w / v to about 2% w / v.

[0142] 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.

[0143] The pharmaceutically acceptable vehicle in the nebulization composition may include water and optionally a cosolvent. Any cosolvent that is suitable for inhalation and capable of dissolving or solubilizing the glycopyrronium 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.

[0144] Suitable surfactants include, but are not limited to, C5-20-fatty alcohols, C5-20-fatty acids, C5-20-fatty acid esters, lecithin, glycerides, propylene glycol esters, polyoxyethylenes, polysorbates, sorbitan esters, carbohydrates, and any combination of any of the foregoing. C5- 20-fatty acids, propylene glycol diesters of the C5-20-fatty acids, triglycerides of the C5-20- fatty acids, and sorbitans of the C5-20-fatty acids are preferred. The nebulization compositions may contain about 0.0006% w / v to about 9% w / v, about 0.001 to about 1% w / v, about 0.001 to about 0.5 % w / v, about 0.001 to about 0.1% w / v of surfactant or co-surfactant. In a preferred embodiment, the surfactant present in the composition is in the range of about 0.001 % w / v to about 0.1% w / v.

[0145] Suitable antioxidants include, but are not limited to, ascorbic acid, vitamin A, vitamin E, tocopherols, and any combination of any of the foregoing.

[0146] A nebulization composition of the present application may have a fill volume of from about 0.5 ml to about 5 ml. In some embodiments, the fill volume is from about 0.5 ml to 4 ml; or 1 ml to 3 ml. In a preferred embodiment, the fill volume is about 2 ml.

[0147] 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), formoterol (or its salt), and budesonide in the composition after being stored for 3 or 6 months or 1, 2 or 3 years at 2-8° C, 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.

[0148] The nebulization composition may be contained in a 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 TWISTFLEX™ 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.

[0149] 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. Additionally, the nebulization compositions described herein can also be nebulized using inhalers other than those described above.

[0150] In some embodiments, the nebulization composition of the present application is dispensed in a multidose bottle with preservative.

[0151] In some embodiments, the nebulization composition of the present application is substantially free of surfactant.

[0152] In some embodiments, the nebulization composition of the present application is substantially free of complexing agent.

[0153] In some embodiments, the nebulization composition of the present application is substantially free of a buffering agent.

[0154] In some embodiments, the nebulization composition of the present application is substantially free of a preservative.

[0155] In some embodiments, the one or more excipient(s) discloses in the present specification may perform multifunction in the composition. For example, a complexing agent may perform antioxidant function and the like.

[0156] The nebulization compositions also may be provided as a kit wherein the kit comprises a nebulizer and the nebulization composition comprising glycopyrronium bromide, formoterol fumarate and budesonide. In some embodiments, the nebulization composition of the present application is stable for at least about 6 months at room temperature.

[0157] In a preferred embodiment, the nebulization composition of the present application comprises i) a combination of about 0.1 mcg to about 500 mcg of glycopyrronium, about 0.1 mcg to about 500 mcg of formoterol, and about 0.1 mcg to about 1000 mcg of budesonide; ii) one or more pharmaceutically acceptable excipient(s) selected from a buffer, a surfactant, a complexing agent, and an isotonicity agent; and iii) water.

[0158] In a preferred embodiment, the nebulization composition of the present application comprises i) a combination of about 0.1 mcg to about 500 mcg of glycopyrronium, about 0.1 mcg to about 500 mcg of formoterol, and about 0.1 mcg to about 1000 mcg of budesonide; ii) one or more pharmaceutically acceptable excipient(s) selected from a buffer, a surfactant, a complexing agent, and an isotonicity agent; and iii) water; wherein the composition is stable and the impurity concentration does not exceed more than 2% of the total active agent concentration when stored at room temperature for about 6 months.

[0159] In a preferred embodiment, the present application relates to a nebulization composition comprising: i) a combination of about 0.1 mcg to about 500 mcg of glycopyrronium, about 0.1 mcg to about 500 mcg of formoterol, and about 0.1 mcg to about 1000 mcg of budesonide; ii) a buffering agent selected from citric acid or its salts and trisodium citrate or its salts; iii) a tonicity agent is selected from sodium chloride; iv) water for injection and optionally, one or more pharmaceutically acceptable excipient(s) thereof.

[0160] In a preferred embodiment, the present application relates to a nebulization composition comprising: i) a combination of about 0.1 mcg to about 500 mcg of glycopyrronium, about 0.1 mcg to about 500 mcg of formoterol, and about 0.1 mcg to about 1000 mcg of budesonide; ii) a buffering agent selected from citric acid or its salts and trisodium citrate or its salts; iii) a surfactant is selected from polysorbate; iv) a tonicity agent is selected from sodium chloride; v) a complexing agent is selected from ethylene diamine tetra-acetic acid (EDTA) and its salts thereof and vi) water for injection.

[0161] In a preferred embodiment, the present application relates to an inhalable composition suitable for nebulization comprising: i) a combination of about 0.0001 to about 0.05% w / v of glycopyrronium, about 0.0001 to about 0.01 % w / v of formoterol and about O.OOlto about 0.5% w / v of budesonide; ii) from about 0.001 to about 0.1% w / v of a buffering agent which is selected from citric acid or its salts, hydrates and trisodium citrate or its salts, hydrates thereof; iii) from about 0.001 % w / v to about 0.1% w / v of polysorbate 80; iv) from about 0.001% w / v to about 0.1% w / v of ethylene diamine tetraacetic acid; v) from about 0.1% w / v to about 2% w / v of sodium chloride; and vi) water for injection.

[0162] In a preferred embodiment, the present application relates to an inhalable composition suitable for nebulization comprising: i) a combination of about 0.0001 to about 0.05% w / v of glycopyrronium, about 0.0001 to about 0.01 % w / v of formoterol and about O.OOlto about 0.5% w / v of budesonide; ii) from about 0.001 to about 0.1% w / v of a buffering agent which is selected from citric acid or its salts, hydrates and trisodium citrate or its salts, hydrates thereof; iii) from about 0.001 % w / v to about 0.1% w / v of polysorbate 80; iv) from about 0.001% w / v to about 0.1% w / v of ethylene diamine tetraacetic acid; v) from about 0.1% w / v to about 2% w / v of sodium chloride; vi) preservative and vii) water for injection; wherein the inhalable composition is present in multidose container.

[0163] In a preferred embodiment, the present application relates to an inhalable composition suitable for nebulization comprising: i) a fixed dose combination of about 20 mcg to about 30 mcg of glycopyrronium, about 10 mcg to about 30 mcg of formoterol fumarate and about 400 mcg to about 600 mcg of budesonide; ii) from about 5 mg to about 15 mg citric acid and trisodium citrate or its salts, hydrates thereof; iii) from about 0.1 mg to about 5 mg of polysorbate 80; iv) from about 0.05 mg to about 1 mg ethylene diamine tetraacetic acid; v) from about 5 mg to about 25mg of sodium chloride; and vi) water for injection.

[0164] In a preferred embodiment, the present application relates to an inhalable composition suitable for nebulization comprising: i) a fixed dose combination of (a) glycopyrronium, (b) formoterol, (b) budesonide; and ii) a pharmaceutically acceptable excipient(s) thereof; wherein the composition comprises glycopyrronium and formoterol in solubilized form and budesonide in suspended form; 90% of the total budesonide particles are less than about 10 microns; and wherein the composition has one or more characteristics selected from (i) osmolality of the composition from about 200 mOsm / kg to about 400 mOsm / kg; (ii) pH from about 3 to about 6; (iii) impurity(ies) present in the composition less than about 5% and (iv) the composition is not aerosol composition. In some embodiment, the nebulization composition of the present application has pH of from about 4 to about 5.

[0165] In a preferred embodiment, the present application relates to an inhalable composition suitable for nebulization comprising: i) a fixed dose combination of (a) glycopyrronium, (b) formoterol, (b) budesonide; and ii) a pharmaceutically acceptable excipient(s) thereof; wherein the composition comprises glycopyrronium and formoterol in solubilized form and budesonide in suspended form; 50% of the total budesonide particles are less than about 5 microns; and wherein the composition has one or more characteristics selected from (i) osmolality of the composition from about 200 mOsm / kg to about 400 mOsm / kg; (ii) pH from about 3 to about 6; (iii) impurity(ies) present in the composition less than about 5% and (iv) the composition is not aerosol composition. In some embodiment, the nebulization composition of the present application has pH of from about 4 to about 5.

[0166] In a preferred embodiment, the present application relates to an inhalable composition suitable for nebulization comprising: i) a fixed dose combination of (a) glycopyrronium, (b) formoterol, (b) budesonide; and ii) a pharmaceutically acceptable excipient(s) thereof; wherein the composition comprises glycopyrronium and formoterol in solubilized form and sterile particles of budesonide in suspended form; 90% of the total budesonide particles are less than about 5 microns; and wherein the composition has one or more characteristics selected from (i) osmolality of the composition from about 200 mOsm / kg to about 400 mOsm / kg; (ii) pH from about 3 to about 6; (iii) impurity(ies) present in the composition less than about 5% and (iv) the composition is not aerosol composition.

[0167] In a preferred embodiment, the present application relates to an inhalable composition suitable for nebulization comprising: i) a fixed dose combination of (a) glycopyrronium, (b) formoterol, (b) budesonide; and ii) a pharmaceutically acceptable excipient(s) thereof; wherein the composition comprises glycopyrronium and formoterol in solubilized form and sterile particles of budesonide in suspended form; 90% of the total budesonide particles are less than about 5 microns; and wherein the composition has one or more characteristics selected from (i) osmolality of the composition from about 250 mOsm / kg to about 350 mOsm / kg; (ii) pH from about 3 to about 4; (iii) impurity(ies) present in the composition less than about 3% and (iv) the composition is not aerosol composition.

[0168] In a preferred embodiment, the present application relates to an inhalable composition suitable for nebulization comprising: i) a fixed dose combination of about 0.0001 to about 0.05% w / v of glycopyrronium or its salts, about 0.0001 to about 0.01 % w / v of formoterol or its salts and about O.OOlto about 0.5% w / v of budesonide; and ii) a pharmaceutically acceptable excipient(s) thereof; wherein the composition comprises glycopyrronium and formoterol in solubilized form and sterile particles of budesonide in suspended form; 90% of the total budesonide particles are less than about 5 microns; and wherein the composition has one or more characteristics selected from (i) osmolality of the composition from about 250 mOsm / kg to about 350 mOsm / kg; (ii) pH from about 3 to about 4; (iii) impurity(ies) present in the composition less than about 3% and (iv) the composition is not aerosol composition.

[0169] In a preferred embodiment, the present application relates to a process for preparing a nebulization composition comprising steps of: i) preparing a solution comprising glycopyrronium and formeterol in a part of water for injection; ii) sterile filtering the solution of step i) in aseptic processing; iii) preparing suspension containing sterile budesonide in part of water for injection with high shear mixing to form uniform suspension; and iv) final inhalation composition is prepared by mixing suspension of budesonide and solution of glycopyrronium and formoterol and optionally comprises: adjusting pH, osmolality, volume adjustment and the like.

[0170] A respirable dose delivery rate of about 0.25 pg / min to about 20 pg / min may be achieved by the nebulizable composition when administered by a nebulizer device.

[0171] The nebulizable composition administered by a standard jet nebulizer may provide an aerosol having a Geometric Standard Deviation of emitted droplet size distribution of the nebulizable composition of about 1 to about 3.

[0172] In an embodiment, the present application relates to a nebulized composition comprising: a fixed dose combination of glycopyrronium, formoterol, and budesonide; and a pharmaceutically acceptable excipient(s); wherein the composition exhibits effective amount of lung deposition to a subject in a need thereof using standard jet nebulizer.

[0173] The nebulizable composition administered by a standard jet nebulizer may provide an aerosol having a Mass Median Aerodynamic Diameter of droplet size of the nebulizable composition of about 2.5 microns to about 10.5 microns.

[0174] A method of administering an inhalation composition comprising a fixed dose combination of glycopyrronium, formoterol, and budesonide by a standard jet nebulizer, wherein said nebulization composition when administered by the said standard jet nebulizer provides an aerosol having a mass median aerodynamic diameter of about 2.5 microns to about 10.5 microns and a geometric standard deviation of emitted droplet distribution of about 1 to about 3.

[0175] The nebulizable composition administered by a standard jet nebulizer may provide a fine particle dose which is not less than about 10%. The fine particle fraction obtained by administering the nebulizable composition in a standard jet nebulizer may be about 5% to about 60%.

[0176] The fine particle fraction obtained by administering the nebulizable composition in a standard jet nebulizer may be about 5% to about 40%.

[0177] The fine particle dose obtained by administering the nebulizable composition in a standard jet nebulizer may be about 5% to about 30%.

[0178] The present application includes methods of treating a pulmonary disease in a subject by administering to the subject a nebulization composition comprising a fixed dose combination of glycopyrronium, formoterol and budesonide via a nebulizer.

[0179] In a preferred embodiment, the present application relates to a method of treating a pulmonary disease in a subject by administering to the subject a nebulization composition comprising a fixed dose combination of glycopyrronium, formoterol and budesonide via a nebulizer; wherein the composition provides an increase in trough FEV1 of at least 10% or at least 100 mL, above placebo.

[0180] In a preferred embodiment, the present application relates to a inhalable liquid composition suitable for administering via nebulizer for treating a pulmonary disease in a subject by administering to the subject a nebulization composition comprising a fixed dose combination of glycopyrronium, formoterol and budesonide via a nebulizer; wherein the composition provides an increase in trough FEV1 of at least 10% or at least 100 mL, above placebo.

[0181] In a preferred embodiment, the present application relates to an inhalable liquid composition suitable for administering via nebulizer for treating a pulmonary disorder in a subject in need thereof, comprising: i) a fixed dose combination of (a) glycopyrronium or its pharmaceutically acceptable form(s) thereof, (b) formoterol or its pharmaceutically acceptable salt(s) thereof, (c) budesonide or its pharmaceutically acceptable salt(s) or ester(s) thereof; and ii) a pharmaceutically acceptable excipient(s) thereof; Wherein the composition provides one or more characteristics in the subject selected from (i) improvement of trough FEV1 in the subject from about 6% to about 10% from the baseline, and (ii) improvement of trough FEV1 from the nebulized composition comprising the fixed dose composition is comparable to meter dose inhaler comprising the fixed dose combination.

[0182] In a preferred embodiment, the pulmonary disorder is selected from asthma, and COPD. In a preferred embodiment, the pulmonary disorder is COPD or one or more symptoms of COPD. The symptom of COPD is selected from breathlessness, chronic cough, chest tightness, wheezing and any combination(s) of foregoing.

[0183] In a preferred embodiment, the present application relates to an inhalable liquid composition suitable for administering via nebulizer for treating COPD in a subject in need thereof, comprising: i) a fixed dose combination of (a) glycopyrronium or its pharmaceutically acceptable form(s) thereof, (b) formoterol or its pharmaceutically acceptable salt(s) thereof, (c) budesonide or its pharmaceutically acceptable salt(s) or ester(s) thereof; and ii) a pharmaceutically acceptable excipient(s) thereof; Wherein the composition provides one or more characteristics in the subject selected from (i) improvement of trough FEV1 in the subject from about 6% to about 10% from the baseline, and (ii) improvement of trough FEV1 from the nebulized composition comprising the fixed dose composition is comparable to meter dose inhaler comprising the fixed dose combination.

[0184] In a preferred embodiment, the present application relates to an inhalable liquid composition suitable for administering via nebulizer for treating COPD in a subject in need thereof, comprising: i) a fixed dose combination of (a) glycopyrronium or its pharmaceutically acceptable form(s) thereof, (b) formoterol or its pharmaceutically acceptable salt(s) thereof, (c) budesonide or its pharmaceutically acceptable salt(s) or ester(s) thereof; and ii) a pharmaceutically acceptable excipient(s) thereof; Wherein the composition provides one or more characteristics in the subject selected from (i) improvement of trough FEV1 in the subject from about 6% to about 10% from the baseline, and (ii) improvement in one or more symptom(s) of COPD selected from breathlessness, wheezing, chest tightness, and chronic cough within 3 hours of dosing to the subject.

[0185] In a preferred embodiment, the present application relates to an inhalable liquid composition suitable for administering via nebulizer for treating one or more symptoms of COPD in a subject in need thereof, comprising: i) a fixed dose combination of (a) glycopyrronium or its pharmaceutically acceptable form(s) thereof, (b) formoterol or its pharmaceutically acceptable salt(s) thereof, (c) budesonide or its pharmaceutically acceptable salt(s) or ester(s) thereof; and ii) a pharmaceutically acceptable excipient(s) thereof; wherein the composition provides improvement in one or more symptom(s) of COPD selected from breathlessness, wheezing, chest tightness, and chronic cough within 3 hours of dosing to the subject. In a preferred embodiment, the present application relates to an inhalable liquid composition suitable for administering via nebulizer for treating one or more symptoms of COPD in a subject in need thereof, comprising: i) a fixed dose combination of (a) glycopyrronium or its pharmaceutically acceptable form(s) thereof, (b) formoterol or its pharmaceutically acceptable salt(s) thereof, (c) budesonide or its pharmaceutically acceptable salt(s) or ester(s) thereof; and ii) a pharmaceutically acceptable excipient(s) thereof; wherein composition provide relief to the symptoms of COPD 2 hours after first dosing the subject.

[0186] The following examples further illustrate various embodiment of the present application, but are not limiting to any specific disclosure.

[0187] Example- 1 : Compositions containing glycopyrronium, formoterol and budesonide

[0188] TABLE 1

[0189] TABLE la

[0190] Example-2: Compositions containing glycopyrronium, formoterol and budesonide

[0191] TABLE 2 The compositions of Example 1 and 2 were prepared by method generally known to the

[0192] Example-3 : The formulation of example-2 was stored in LDPE smartule and evaluated for its stability; stability results are given below:

[0193] TABLE 3

[0194] TABLE 3 (cont.)

[0195] Manufacturing process:

[0196] Preparation of Initial Solution:

[0197] Sodium chloride, citric acid, sodium citrate, and edetate disodium were dissolved in Water for Injection (WFI) under stirring. The clarity of the solution was checked, and its pH was measured.

[0198] Addition of Glycopyrronium and Formoterol Fumarate:

[0199] Glycopyrronium and formoterol fumarate were accurately weighed and added to the solution from step 1 while stirring. The stirring continued until a clear solution was obtained, and then the solution was filtered through a 0.22-micron PES / PVDF filter.

[0200] Preparation of Budesonide Slurry:

[0201] Polysorbate 80 was dissolved in WFI under stirring to form a clear solution. Budesonide was added while stirring to create a uniform slurry. This phase could be autoclaved if a non-sterile API was used; in the case of a sterile API, autoclaving was not necessary. This slurry was then added to the solution from step 2 under stirring until a uniform suspension was obtained.

[0202] Final Volume Adjustment:

[0203] The volume of the suspension was made up with additional Water for Injection.

[0204] Filling into Nebules:

[0205] The suspension bulk was filled into LDPE nebulization containers. The resulting nebulization compositions could be filled into single-chamber, dual-chamber, or triple-chamber containers. Single chamber container The composition illustrated above can be filled into a single container. The contents of the container need to be emptied into the reservoir of the nebulizer before administering to the subject.

[0206] Dual chamber container

[0207] The following table illustrates the different combinations which can be filled into chamber 1 and chamber 2 of the dual chamber container

[0208] TABLE 4

[0209] 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 the compositions. The contents in both the chamber may be mixed before adding to the reservoir of the nebulizer or alternatively, they may be added sequentially into the reservoir of the nebulizer.

[0210] Triple chamber container

[0211] The nebulization compositions of formoterol, glycopyrronium and budesonide may be filled in individual chambers respectively. The glycopyrronium composition may be filled in one chamber, formoterol composition in another chamber and budesonide composition in the last chamber of the triple chamber container. The contents in the three chambers may be mixed before adding to the reservoir of the nebulizer or alternatively, they may be added sequentially into the reservoir of the nebulizer.

[0212] Example 4 - The composition of the Example 3 was evaluated for In-vitro nebulization parameters for breath simulator and next generation impactor using any suitable Jet Nebulizer and the result were provided in the below table

[0213] There were 3 batches manufactured using the manufacturing process described

[0214] TABLE 5

[0215] BRS (Breath-Responsive System) data: measures how a nebulizer or inhalation device responds to patient breathing — e.g., whether it senses inhalation to trigger aerosol generation, adjusts output with inspiratory flow, or times aerosol bursts to inhalation. BRS data typically reports trigger sensitivity, latency, delivered dose per breath, inhalation: exhalation dosing ratio, and overall emitted dose during simulated breathing patterns (adult / paediatric, normal / rapid). It shows device performance under realistic patient breathing conditions.

[0216] NGI (Next Generation Impactor) data: characterizes aerosol particle size distribution by measuring mass or count of drug deposited across staged impactor plates corresponding to aerodynamic diameters (commonly reported as MMAD — mass median aerodynamic diameter, GSD — geometric standard deviation, and fine particle fraction, FPF, typically <5 pm). NGI testing is performed using standardized flow rates to determine where droplets / particles deposit, which predicts lung deposition (central vs peripheral) and bioavailability.

[0217] Example 5 - A randomized, double blind, double dummy clinical trial to assess efficacy and safety of fixed dose combination of glycopyronium 25 mcg, formoterol 20 mcg, and budesonide 500 mcg inhalation suspension in subjects with COPD in comparison with glycopyrronium 7.2 mcg, formoterol 5 mcg, and budesonide 160 mcg Metered dose inhaler.

[0218] Subjects: Age 40-75 yrs, subjects with Moderate-to- Severe COPD, post-BD FEV1 >30% and <80% predicted, exposure to tobacco or biomass smoke

[0219] Treatment Arms: 1) Inhalation composition comprising FDC combination of Glycopyrronium 25 mcg / Formoterol 20 mcg / Budesonide 500 mcg; was administered twice daily using Jet nebulizer; and 2) glycopyrronium 7.2 mcg, formoterol 5 mcg, and budesonide 160 mcg Metered dose inhaler. This multicenter, randomized, double-blind, double-dummy, parallel-group non-inferiority study in COPD subjects included a 1-7 day screening, a 2-week open-label run-in during which eligible subjects stopped prior COPD meds and received formoterol 20 mcg / budesonide 500 mcg respule twice daily (jet nebulizer) with salbutamol MDI as rescue; subjects with >80% diary / ICS-LABA compliance were randomized 1 : 1 to 12 weeks of either glycopyrronium 25 mcg + formoterol 20 mcg + budesonide 500 mcg respule twice daily (nebulizer) or formoterol 5 mcg + glycopyrronium 7.2 mcg + budesonide 160 mcg pMDI two puffs twice daily (no spacer). Clinic visits occurred at Weeks 4, 8 and 12 (end-of-treatment) with spirometry and mMRC assessments, while subjects kept diaries of AEs, exacerbations, compliance and medication changes; a telephone follow-up was done one week after EOT during which usual physician-directed care was permitted.

[0220] The treatment period is 12 weeks and the primary endpoint was measured for change in trough FEV1 from baseline at the end ofweek 12. The total subjects undergone for the treatment were 314 subjects with COPD.

[0221] In a randomized, controlled clinical study, subjects were administered either (i) a nebulized formulation of glycopyrronium / formoterol / budesonide (GB / FF / BUD Neb) or (ii) a metered-dose inhaler formulation of glycopyrronium / formoterol / budesonide (GB / FF / BUD MDI) over a 12-week treatment period.

[0222] Primary Endpoint: In the per-protocol (PP) population, the GB / FF / BUD Neb group exhibited a statistically significant improvement in least-squares (LS) mean (standard error, SE) change from baseline in trough FEVi at Week 12 of 0.10 (0.018) L (P < 0.001). The LS mean (SE) difference between the GB / FF / BUD Neb and GB / FF / BUD MDI groups was -0.00 (0.021) L with a 95% confidence interval (CI) of -0.04 to 0.04. As the lower bound of the CI was above the predefined non-inferiority margin of -0.08 L, the GB / FF / BUD Neb formulation was concluded to be non-inferior to the GB / FF / BUD MDI formulation (P < 0.001 for non- inferiority). mITT Population Analysis: Non-inferiority was also demonstrated in the modified intent-to- treat (mITT) population, with LS mean change from baseline in trough FEVi at Week 12 of 0.13 (0.021) L in the GB / FF / BUD Neb group and 0.11 (0.020) L in the GB / FF / BUD MDI group. The LS mean (SE) difference between groups was 0.02 (0.024) L (95% CI, -0.02 to 0.07; P < 0.001).

[0223] TABLE 6

[0224]

Claims

We Claim:

1. An inhalable liquid composition suitable for nebulization comprising:(i) a fixed dose combination of (a) glycopyrronium or its pharmaceutically acceptable form(s) thereof, (b) formoterol or its pharmaceutically acceptable salt(s) thereof, (c) budesonide or its pharmaceutically acceptable salt(s) or ester(s) thereof; and (ii) a pharmaceutically acceptable excipient(s) thereof; wherein the composition comprises glycopyrronium and formoterol are in solubilized form and budesonide in suspended form; 50% of the total budesonide particles are less than about 5 microns; and wherein the composition has one or more characteristics selected from (i) osmolality of the composition from about 200 mOsm / kg to about 400 mOsm / kg; (ii) pH from about 3 to about 6; (iii) impurity(ies) present in the composition less than about 5% and (iv) the composition is not aerosol composition.

2. The inhalation composition of claim 1, wherein the fixed dose combination comprises (i) from about 0.001% w / v to about 0.01% w / v of glycopyrronium; (ii) from about 0.0005% w / v to about 0.002% w / v of formoterol; and (iii) 0.01% w / v to about 0.1 % w / v of budesonide.

3. The inhalation composition of claim 1, wherein the fixed dose combination comprises (i) from about 0.00125% w / v to about 0.005% w / v of glycopyrronium; (ii) from about 0.001% w / v to about 0.004% w / v; and (iii) 0.025% w / v to about 0.1% w / v.

4. The inhalation composition of claim 1, wherein volume of the composition is from about 0.5 ml to 4 ml.

5. The inhalation composition of claim 1, wherein volume of the composition is from about 1.5 ml to 3.5 ml.

6. The inhalation composition of claim 1, wherein volume of the composition is about 2 ml.

7. The inhalation composition of claim 1, wherein the fixed dose combination comprises (i) about 0.00125% w / v of glycopyrronium; (ii) about 0.001% w / v of formoterol; and (iii) about 0.025% w / v of budesonide and the volume of unit dose is about 2 ml.

8. The inhalation composition of claim 1, wherein the 50% of the total budesonide particles are less than about 4 microns.

9. The inhalation composition of claim 1, wherein the composition is free of isopropyl alcohol, propylene glycol, polyethylene glycol, polypropylene glycol, glycerol, polyoxyethylene alcohols, phospholipid and combinations thereof.

10. An inhalation nebulized composition comprising:(i) a fixed dose combination of (a) glycopyrronium or its pharmaceutically acceptable form(s) thereof, (b) formoterol or its pharmaceutically acceptable salt(s) thereof, (c) budesonide or its pharmaceutically acceptable salt(s) or ester(s) thereof; and (ii) a pharmaceutically acceptable excipient(s) thereof; wherein the composition exhibits one or more of characteristics when administered via standard jet nebulizer, are selected from (i) fine particle dose which is not less than about 10%; and (ii) delivered dose of each active(s) in the composition in the range of from about 10% to about 50%.

11. The Inhalation nebulized composition of claim 10, wherein the characteristics of the nebulized composition are measured in an in vitro method using next generation impactor.

12. The inhalation nebulized composition of claim 10, wherein the composition provides fine particle fraction from about 10% to about 60% when measured using breath simulator.

13. The inhalation composition of claim 10, wherein the fixed dose combination comprises (i) from about 0.001% w / v to about 0.01% w / v of glycopyrronium; (ii) 0.0005% w / v to about 0.002% w / v of formoterol; and (iii) 0.01% w / v to about 0.1 % w / v of budesonide.

14. The inhalation composition of claim 10, wherein the fixed dose combination comprises (i) from about 0.00125% w / v to about 0.005% w / v of glycopyrronium; (ii) from about 0.001% w / v to about 0.004% w / v; and (iii) 0.025% w / v to about 0.1% w / v.

15. The inhalation composition of claim 10, wherein the fixed dose combination comprises (i) about 0.00125% w / v of glycopyrronium; (ii) about 0.001% w / v of formoterol; and (iii) about 0.025% w / v of budesonide and the volume of the unit dose is about 2 ml.

16. An inhalable liquid composition suitable for administering via nebulizer for treating a pulmonary disorder in a subject in need thereof, comprising: a fixed dose combination of (i) glycopyrronium or its pharmaceutically acceptable form(s) thereof, (ii) formoterol or its pharmaceutically acceptable salt(s) thereof, (iii) budesonide or its pharmaceutically acceptable salt(s) or ester(s) thereof; and a pharmaceutically acceptable excipient(s) thereof; wherein the composition provides one or more characteristics in the subject selected from (i) improvement of trough FEV1 in the subject at least about 10% in a week from the baseline, and (ii) improvement of trough FEV1 from the nebulized composition comprising the fixed dose composition is comparable to meter dose inhaler comprising the fixed dose combination.

17. The inhalation composition of claim 16, wherein the composition provides at least 20% improvement in trough FEV1 from baseline.

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