Liquid formulations of indacaterol and glycopyrronium

Abstract

An aqueous formulation of indacaterol and glycopyrronium is disclosed. The formulations may be used to treat respiratory disorders, inflammatory disorders or obstructive airway diseases. The present disclosure also encompasses methods of using the formulations and kits comprising the formulations.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 325,510, filed on March 30, 2022, the entire contents of which are incorporated herein by reference. Background Art

[0002] The inhalation dosage forms currently on the market for the symptomatic treatment of COPD typically contain active agents (APIs) as long-acting beta agonists (LABAs), long-acting muscarinic antagonists (LAMAs) and / or inhaled corticosteroids (ICS). These APIs (alone or in combination) are typically administered to the lungs via dry powder inhalers (DPIs), pressure metered dose inhalers (pMDIs) or soft mist inhalers (SMIs). Although these inhaled drug delivery devices are sufficient for most patients, a portion of COPD populations (e.g., the elderly) may be difficult to effectively use these devices, thereby resulting in insufficient treatment of particularly vulnerable patient populations. This may be due to challenges in generating enough inhalation efforts for DPIs or inadequate coordination of device actuation / inhalation for MDI / SMIs. Alternative compositions that are more easily administered are needed, particularly for patient populations that cannot effectively utilize currently available treatments. Summary of the invention

[0003] Provided herein are aqueous pharmaceutical compositions comprising indacaterol and glycopyrronium or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 20 weight percent to 99.9 weight percent of water, 10 μg / mL to 2 mg / mL of indacaterol or a pharmaceutically acceptable salt thereof, and 10 μg / mL to 1 mg / mL of glycopyrronium or a pharmaceutically acceptable salt thereof. In some embodiments, the glycopyrronium is present in a form different from glycopyrronium bromide, or the composition further comprises an anti-crystallization agent; or the glycopyrronium is present in a form different from glycopyrronium bromide, and the composition further comprises an anti-crystallization agent.

[0004] In some embodiments, the indacaterol or a pharmaceutically acceptable salt thereof is present as a free base or as a citrate. In some embodiments, the concentration of indacaterol is 200 μg / mL to 1.5 mg / mL. In some embodiments, the glycopyrronium or a pharmaceutically acceptable salt thereof is present as glycopyrronium chloride or glycopyrronium citrate. In some embodiments, the glycopyrronium is present at a concentration of 200 μg / mL to 500 μg / mL.

[0005] In some embodiments, the anti-crystallization agent is present. In some embodiments, the anti-crystallization agent is a polymer or a surfactant. In some embodiments, the anti-crystallization agent prevents crystallization of indacaterol, glycopyrronium, or a pharmaceutically acceptable salt thereof.

[0006] In some embodiments, the composition further comprises a solubilizing agent. In some embodiments, the solubilizing agent is a cyclodextrin.

[0007] In some embodiments, the composition further comprises one or more tension regulators. In some embodiments, the one or more tension regulators are mannitol. In some embodiments, the one or more tension regulators are sodium chloride. In some embodiments, the composition comprises two or more tension regulators, each of which is present individually at a concentration of about 1mM to about 500mM. In some embodiments, the first tension regulator is present at a concentration of about 100mM to about 300mM. In some embodiments, the second tension regulator is present at a concentration of about 1mM to about 50mM. In some embodiments, the composition further comprises mannitol at a concentration of about 100mM to about 300mM and sodium chloride at a concentration of about 1mM to about 20mM.

[0008] In some embodiments, the composition further comprises a cosolvent. In some embodiments, the cosolvent is an alcohol. In some embodiments, the cosolvent is selected from ethanol and ethylene glycol. In some embodiments, the cosolvent is present in an amount of about 0.1% v / v to about 10% v / v. In some embodiments, the composition does not contain a cosolvent.

[0009] In some embodiments, the composition further comprises a buffer. In some embodiments, the buffer comprises anions selected from the following: acetate, bromide, chloride, citrate, furoate, fumarate, maleate, malate, propionate, succinate, sulfate, tartrate and xinafoate. In some embodiments, the buffer is prepared by a combination of citric acid and trisodium citrate or a combination of citric acid and sodium hydroxide. In some embodiments, the pH of the composition is 2 to 6. In some embodiments, the pH of the composition is 2.5 to 4.5. In some embodiments, the pH of the composition is 3.0 to 4.0. In some embodiments, the pH of the composition is 3.0 to 4.5.

[0010] In some embodiments, the composition further comprises one or more additional agents. In some embodiments, the additional agent is an inhaled corticosteroid. In some embodiments, the inhaled corticosteroid is mometasone or a pharmaceutically acceptable salt thereof. In some embodiments, the inhaled corticosteroid is mometasone.

[0011] In some embodiments, the indacaterol or a pharmaceutically acceptable salt thereof exhibits less than 5% degradation over a period of at least 90 days. In some embodiments, the composition is stored at a temperature of about 25°C and a relative humidity of about 60%. In some embodiments, the composition is stored at a temperature of about 5°C.

[0012] In some embodiments, the composition further comprises one or more tension modifiers and a buffer. In some embodiments, the one or more tension modifiers are mannitol and sodium chloride, and the buffer comprises citrate. In some embodiments, mannitol is present at a concentration of 100mM to 400mM, sodium chloride is present at a concentration of 1mM to 20mM, and the pH is 3 to 4. In some embodiments, indacaterol is present at about 500μg / mL, glycopyrronium is present at about 350μg / mL, mannitol is present at a concentration of about 200mM; sodium chloride is present at a concentration of about 10mM, and the pH is 3.0 to 3.5.

[0013] In some embodiments, the composition is free of particles after storage at 5°C for at least 26 weeks.

[0014] Also provided herein is a method for treating a respiratory disorder, an inflammatory disorder or an obstructive airway disease, the method comprising delivering any of the above-mentioned pharmaceutical compositions to the lungs of a patient in need thereof. In some embodiments, the respiratory disorder, inflammatory disorder or obstructive airway disease is COPD. In some embodiments, the composition has been stored for a period of at least 52 weeks. In some embodiments, the entire period of the composition is stored at room temperature all the time. In some embodiments, a breath-actuated vibrating mesh nebulizer is used to aerosolize the pharmaceutical composition.

[0015] Also provided herein is a method of aerosolizing any of the above pharmaceutical compositions, the method comprising contacting a vibrating mesh screen with the liquid formulation. Also provided is a method of aerosolizing the pharmaceutical composition by a jet nebulizer, an ultrasonic nebulizer, or a soft mist inhaler.

[0016] Also provided herein are kits comprising any of the above-described pharmaceutical compositions and a device for aerosolizing the pharmaceutical composition. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 is an interleaved chromatogram of an indacaterol sample from the forced degradation experiment in Example 1, showing minimal degradation of the indacaterol sample over time in aqueous solution.

[0018] Figure 2Ais a graph of the pH of Formulations F2-F9 at various time points during 90 days of storage at low temperature, showing that the pH was stable over the duration of the storage period.

[0019] Figure 2B is a graph of the pH of Formulations F2-F9 at various time points during 90 days of storage at room temperature, showing that the pH was stable over the duration of the storage period.

[0020] Figure 2C is a graph of the pH of Formulations F2-F9 at various time points during 90 days of storage at elevated temperature, showing that the pH was stable over the duration of the storage period.

[0021] Figure 3A is a graph of indacaterol concentrations in Formulations F2-F9 at various time points during 90 days of storage at low temperature, showing that the concentration of indacaterol was maintained during storage.

[0022] Figure 3B is a graph of indacaterol concentrations in Formulations F2-F9 at various time points during 90 days of storage at room temperature, showing that the concentration of indacaterol was maintained during storage.

[0023] Figure 3C is a graph of indacaterol concentrations in Formulations F2-F9 at various time points during 90 days of storage at elevated temperature, showing that indacaterol concentrations were maintained during storage.

[0024] Figure 4 is a chromatogram showing product related impurities associated with Formulation F5 and impurities in the indacaterol starting material.

[0025] Figure 5 is a graph of delivered dose versus fill volume for several aqueous indacaterol compositions.

[0026] Figure 6 is a graph of deposited dose versus packing volume for several aqueous indacaterol formulations.

[0027] Figure 7 is a chromatogram showing indacaterol and its impurities from formulation G7.

[0028] Figure 8 is a chromatogram showing glycopyrronium and its impurities from formulation G9. DETAILED DESCRIPTION

[0029] The present disclosure encompasses aqueous compositions of indacaterol or a pharmaceutically acceptable salt thereof and glycopyrronium or a pharmaceutically acceptable salt thereof (which may also be referred to herein as aqueous formulations), which in some embodiments may contain one or more excipients, which are particularly useful for modifying the solubility of indacaterol and / or glycopyrronium, adjusting tonicity, and controlling pH. The present disclosure also relates to methods of using the compositions to treat respiratory disorders, methods of preparing the compositions, and kits containing the compositions.

[0030] The present disclosure relates to aqueous compositions of indacaterol or a pharmaceutically acceptable salt thereof and glycopyrronium or a pharmaceutically acceptable salt thereof, and to the treatment of patients suffering from respiratory diseases, including chronic obstructive pulmonary disease (COPD) and asthma. The present invention further minimizes or eliminates the need for patient coordination and inspiratory effort by allowing the administration of indacaterol and glycopyrronium or their pharmaceutically acceptable salts with a device such as a breath-actuated vibrating mesh nebulizer. Due to the relatively low water solubility reported for these compounds, particularly indacaterol, it may appear that a suspension formulation is required. However, solution compositions provide specific advantages, such as easier preparation and higher compound concentrations. Liquid compositions of indacaterol and glycopyrronium are provided, having sufficiently high concentrations of active agents to ensure short dosing times, and having sufficient stability to be stored at room temperature. In some embodiments, a base form of indacaterol and / or glycopyrronium is used to allow solubility and stability evaluations to be performed without the action of counterions.

[0031] Due to the solubility problem of compound (particularly indacaterol), the design of such composition is meaningful. Although it is known that indacaterol is soluble in organic solvents, including alcohol (for example, methanol and ethanol), a large amount of these solvents are incompatible with safe and effective inhalable formulations. Ethanol formulations have a high osmotic pressure that can induce cough in some cases, thereby limiting its effectiveness in inhalable formulations. In contrast, the aqueous solution disclosed herein can be adjusted to isotonic, which will allow them to be safely and effectively applied to patients, even those with significant dyspnea. It is worth noting that many other commonly used LABA drugs (for example, formoterol) are unstable in aqueous solution at room temperature (see WO 2001 / 89480, incorporated herein by reference), thus requiring refrigerated storage during distribution and use. In contrast, the aqueous composition of indacaterol in the present disclosure is stable for a long period of time at room temperature. The stability of the indacaterol composition also supports the use of other medicaments to be added, to produce a stable composition with a drug combination (for example, indacaterol and glycopyrronium).

[0032] In addition to the compositions provided herein, methods of using the compositions to treat disease, methods of preparing the compositions, and kits comprising the compositions are also described.

[0033] It should be understood that embodiments described herein as "comprising" may include "consisting of" and / or "consisting essentially of" the aspects and variations.

[0034] The disclosures of all publications, patents, and patent applications mentioned herein are hereby incorporated by reference in their entirety. definition

[0035] References herein to "about" a value or parameter include (and describe) variations to that value or parameter itself. For example, descriptions referring to "about X" include descriptions of "X" itself and descriptions referring to from "about X" to "about Y" include descriptions of from "X" to "Y" itself.

[0036] As used herein, "treatment" or "treating" is a method for obtaining beneficial or desired results (including clinical results). For example, beneficial or desired results include, but are not limited to, one or more of the following: reducing symptoms caused by the disease, improving the quality of life of patients with the disease, reducing the dose of other drugs required to treat the disease, delaying disease progression, and / or prolonging the survival of an individual.

[0037] As used herein, the term "patient" is a mammal, including a human. Patients include, but are not limited to, humans, cattle, horses, cats, dogs, rodents, or primates. In some embodiments, the patient is a human. The patient (such as a human) may have an advanced disease or a less severe disease.

[0038] As used herein, the term "effective amount" is intended to refer to the amount of the composition that should be effective under a given treatment form. As understood in the art, an effective amount can be one or more doses, i.e., a single dose or multiple doses may be required to reach the desired treatment endpoint. In the case of administering one or more therapeutic agents, an effective amount can be considered, and a single agent can be considered to be given in an effective amount if it can achieve or achieve the desired or beneficial result in combination with one or more other agents. Due to the combined effects of the composition (e.g., additive or synergistic effects), the appropriate dose of any co-administered composition can be optionally reduced.

[0039] As used herein, "pharmaceutically acceptable" refers to materials that are not biologically or otherwise undesirable, for example, materials that can be incorporated into pharmaceutical compositions administered to patients without causing any significant undesirable biological effects or interacting in a harmful manner with any other component of the composition in which they are placed. Pharmaceutically acceptable carriers or excipients preferably meet the required standards for toxicology and production testing and / or are included according to the Inactive Ingredient Guide compiled by the U.S. Food and Drug Administration.

[0040] As used herein, "unit dosage form" refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Unit dosage forms may contain single or combined therapies.

[0041] As used herein, "weight percent" refers to the percentage of a component of a composition by weight. A component present at "5 weight percent" accounts for 5% by weight of the total weight of the composition. As used herein, "% w / v" refers to the concentration defined by "g solute / 100 mL solution". For example, a composition comprising 0.5% w / v of cyclodextrin contains 0.5 g cyclodextrin / 100 mL solution. As used herein, "% v / v" refers to the concentration of a liquid in another liquid as determined by comparing the relative volumes of the other liquid. For example, a composition comprising 20% ​​v / v ethanol contains 20 mL ethanol / 100 mL total solution.

[0042] The term "indacaterol" refers to (R)-5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8hydroxy-1H-quinolin-2-one, which may exist in the form of a free base or a salt thereof. An example of an indacaterol salt is indacaterol maleate. The structure of indacaterol is shown below:

[0043] The term "glycopyrronium" refers to the (1,1-dimethylpyrrolidin-1-ium-3-yl) 2-cyclopentyl-2-hydroxy-2-phenylacetate ion, which contains two chiral centers and is usually administered therapeutically as a racemic mixture of (R, S) and (S, R) enantiomers. Glycopyrronium is also known as glycopyrrolate. An example of a salt of glycopyrronium is glycopyrrolate. The structure of glycopyrronium is shown below: Composition

[0044] The compositions provided are noteworthy in that indacaterol and glycopyrronium are substantially soluble in aqueous solution and stable for a considerable period of time. In some embodiments, stability and / or degree of degradation are assessed by the appearance of the composition. In some embodiments, stability and / or degree of degradation are assessed by the pH of the composition. In some embodiments, stability and / or degree of degradation are assessed by the concentration of indacaterol and / or glycopyrronium in the composition. In some embodiments, stability and / or degree of degradation are assessed by the concentration or amount of impurities in the composition. In some embodiments, stability and / or degree of degradation are assessed by the weight molar osmotic pressure concentration of the composition. These examples are not intended to be limiting, as those skilled in the art may be aware of other methods for assessing stability and / or degree of degradation. In some embodiments, provided herein is an aqueous composition comprising indacaterol or a pharmaceutically acceptable salt thereof, wherein the composition exhibits less than 10%, 20%, 30%, 40% or 50% indacaterol degradation after storage for a period of one year. In some embodiments, the composition exhibits less than 10%, 20%, 30%, 40%, or 50% degradation of indacaterol after a storage period of 2 years. In some embodiments, the composition exhibits less than 10%, 20%, 30%, 40%, or 50% degradation of indacaterol after a storage period of 5 years. In some embodiments, the composition exhibits less than 10%, 20%, 30%, 40%, or 50% degradation of indacaterol after a storage period of 10 years. In some embodiments, indacaterol is in base form. In some embodiments, indacaterol is present as a pharmaceutically acceptable salt. In some embodiments, indacaterol is present as indacaterol maleate. In some embodiments, the storage conditions are 40°C and 75% relative humidity. In some embodiments, the storage conditions are 25°C and 60% relative humidity. In some embodiments, the storage conditions are 5°C. In some embodiments, the composition exhibits less than 10%, 20%, 30%, 40% or 50% degradation of indacaterol after a period of storage of 30, 60 or 90 days. In some embodiments, the composition exhibits less than 10%, 20%, 30%, 40% or 50% degradation of indacaterol after a period of storage of 1, 2, 3, 4 or 5 weeks. In some embodiments, the composition exhibits less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% degradation of indacaterol, glycopyrronium or both within a storage period of 8 weeks, 26 weeks, 52 weeks or 104 weeks. In some embodiments, storage is storage at room temperature. In some embodiments, storage is storage at 40°C and 75% relative humidity. In some embodiments, storage is storage at 25°C and 60% relative humidity. In some embodiments, storage is storage at 5°C.

[0045] In some embodiments, the composition comprising indacaterol or a pharmaceutically acceptable salt thereof and glycopyrronium or a pharmaceutically acceptable salt thereof remains particle-free during the storage period. In some embodiments, the storage period is at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 26 weeks, at least 52 weeks, or at least 104 weeks. In some embodiments, the composition is stored at room temperature throughout the storage period. In some embodiments, the composition is not refrigerated (including frozen) throughout the duration of the storage period. In some embodiments, storage is storage at room temperature. In some embodiments, storage is storage at 40°C and 75% relative humidity. In some embodiments, storage is storage at 25°C and 60% relative humidity. In some embodiments, storage is storage at 5°C. In some embodiments, glycopyrronium exists in a form other than bromide (such as glycopyrronium chloride, glycopyrronium acetate, or glycopyrronium citrate). In some embodiments, the composition further comprises an anti-crystallization agent. In some embodiments, glycopyrronium exists in a form other than bromide, and the composition further comprises an anti-crystallization agent.

[0046] Without wishing to be bound by theory, it is believed that high concentrations of indacaterol (e.g., 200 μg / mL or more, 300 μg / mL or more, 400 μg / mL or more of indacaterol) dissolved in aqueous compositions are attributed to specific features of the aqueous compositions. In some embodiments, indacaterol is added to the composition in its free base form so that high concentrations of indacaterol can be dissolved in the composition. In some embodiments, the presence of a solubilizing agent (e.g., cyclodextrin) enables high concentrations of indacaterol to be dissolved in the composition. In some embodiments, indacaterol is used in its free base form and a solubilizing agent is included in the aqueous composition so that high concentrations of indacaterol can be dissolved in the composition.

[0047] In some embodiments, the aqueous composition comprising indacaterol and glycopyrronium or their pharmaceutically acceptable salts comprises at least 5% and up to about any one of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 99.9% water by weight. In some embodiments, the aqueous composition comprising indacaterol and glycopyrronium or their pharmaceutically acceptable salts comprises more than about any one of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% water by weight. In some embodiments, the aqueous composition comprising indacaterol and glycopyrronium or their pharmaceutically acceptable salts comprises about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% water by weight. In some embodiments, the composition comprises about 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% by weight any one to about 99.9% water. In some embodiments, the composition comprises about 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% by weight any one to about 95% water. In some embodiments, the composition comprises about 20%, 30%, 40%, 50%, 60%, 70% or 80% by weight any one to about 90% water. In some embodiments, the composition comprises about 20%, 30%, 40%, 50%, 60%, 70% or 80% by weight any one to about 80% water. In some embodiments, the composition comprises about 20%, 30%, 40%, 50% or 60% by weight any one to about 70% water. In some embodiments, the composition comprises any one of about 20%, 30%, 40%, or 50% to about 60% water by weight. In some embodiments, the composition comprises any one of about 20%, 30%, or 40% to about 50% water by weight.

[0048] In some embodiments, an aqueous composition comprising indacaterol and glycopyrronium or a pharmaceutically acceptable salt thereof is provided, wherein indacaterol is present at a concentration of about 10 μg / mL to about 2 mg / mL. In some embodiments, indacaterol is present at a concentration of up to about 2 mg / mL, up to about 1.5 mg / mL, up to about 1 mg / mL, up to about 800 μg / mL, up to about 600 μg / mL, up to about 400 μg / mL, up to about 200 μg / mL, up to about 50 μg / mL, or up to about 10 μg / mL. In some embodiments, the concentration of indacaterol is about 10 μg / mL to about 2 mg / mL, about 10 μg / mL to about 1.5 mg / mL, about 10 μg / mL to about 1 mg / mL, about 10 μg / mL to about 800 μg / mL, about 10 μg / mL to about 600 μg / mL, about 10 μg / mL to about 400 μg / mL, about 10 μg / mL to about 200 μg / mL, about 50 μg / mL to about 1 mg / mL, about 50 μg / mL to about 800 μg / mL, about 50 μg / mL to about 600 μg / mL, about 50 μg / mL to about 400 μg / mL, about 10 μg / mL to about 200 μg / mL, about 50 μg / mL to about 1 mg / mL, about 50 μg / mL to about 800 μg / mL, about 50 μg / mL to about 600 μg / mL, about 50 μg / mL to about mL to about 400 μg / mL, about 50 μg / mL to about 200 μg / mL, about 200 μg / mL to about 1 mg / mL, about 200 μg / mL to about 800 μg / mL, about 200 μg / mL to about 600 μg / mL, about 200 μg / mL to about 400 μg / mL, about 400 μg / mL to about 1 mg / mL, about 400 μg / mL to about 800 μg / mL, about 400 μg / mL to about 600 μg / mL, about 600 μg / mL to about 1 mg / mL, or about 600 μg / mL to about 800 μg / mL. In some embodiments, indacaterol is present at a concentration of about 200 μg / mL to about 400 μg / mL, about 600 μg / mL, about 800 μg / mL, about 1 mg / mL, about 1.25 mg / mL, about 1.5 mg / mL, about 1.75 mg / mL, or about 2 mg / mL. In some embodiments, indacaterol is present at a concentration of about 400 μg / mL to about 600 μg / mL, about 800 μg / mL, about 1 mg / mL, about 1.25 mg / mL, about 1.5 mg / mL, about 1.75 mg / mL, or about 2 mg / mL. In some embodiments, indacaterol is present at a concentration of about 600 μg / mL to about 800 μg / mL, about 1 mg / mL, about 1.25 mg / mL, about 1.5 mg / mL, about 1.75 mg / mL, or about 2 mg / mL. In some embodiments, indacaterol is present at a concentration of about 1 mg / mL to about 1.25 mg / mL, about 1.5 mg / mL, about 1.75 mg / mL, or about 2 mg / mL.In some embodiments, indacaterol is present at a concentration of about 1.25 mg / mL to about 1.5 mg / mL, about 1.75 mg / mL, or about 2 mg / mL. In some embodiments, indacaterol is present at a concentration of about 1.5 mg / mL to about 1.75 mg / mL, or about 2 mg / mL.

[0049] In some embodiments, an aqueous composition comprising indacaterol and glycopyrronium or a pharmaceutically acceptable salt thereof is provided, wherein glycopyrronium is present at a concentration of about 10 μg / mL to about 1 mg / mL, calculated as glycopyrronium ion. In some embodiments, the concentration is any of about 10 μg / mL to about 50 μg / mL, about 100 μg / mL, about 150 μg / mL, about 200 μg / mL, about 250 μg / mL, about 300 μg / mL, about 350 μg / mL, about 400 μg / mL, about 450 μg / mL, about 500 μg / mL, about 550 μg / mL, about 600 μg / mL, about 650 μg / mL, about 700 μg / mL, about 750 μg / mL, or about 800 μg / mL. In some embodiments, the concentration is any of about 50 μg / mL to about 100 μg / mL, about 150 μg / mL, about 200 μg / mL, about 250 μg / mL, about 300 μg / mL, about 350 μg / mL, about 400 μg / mL, about 450 μg / mL, about 500 μg / mL, about 550 μg / mL, about 600 μg / mL, about 650 μg / mL, about 700 μg / mL, about 750 μg / mL, or about 800 μg / mL. In some embodiments, the concentration is any of about 100 μg / mL to about 150 μg / mL, about 200 μg / mL, about 250 μg / mL, about 300 μg / mL, about 350 μg / mL, about 400 μg / mL, about 450 μg / mL, about 500 μg / mL, about 550 μg / mL, about 600 μg / mL, about 650 μg / mL, about 700 μg / mL, about 750 μg / mL, or about 800 μg / mL. In some embodiments, the concentration is any of about 150 μg / mL to about 200 μg / mL, about 250 μg / mL, about 300 μg / mL, about 350 μg / mL, about 400 μg / mL, about 450 μg / mL, about 500 μg / mL, about 550 μg / mL, about 600 μg / mL, about 650 μg / mL, about 700 μg / mL, about 750 μg / mL, or about 800 μg / mL. In some embodiments, the concentration is any of about 200 μg / mL to about 250 μg / mL, about 300 μg / mL, about 350 μg / mL, about 400 μg / mL, about 450 μg / mL, about 500 μg / mL, about 550 μg / mL, about 600 μg / mL, about 650 μg / mL, about 700 μg / mL, about 750 μg / mL, or about 800 μg / mL.In some embodiments, the concentration is about 250 μg / mL to about 300 μg / mL, about 350 μg / mL, about 400 μg / mL, about 450 μg / mL, about 500 μg / mL, about 550 μg / mL, about 600 μg / mL, about 650 μg / mL, about 700 μg / mL, about 750 μg / mL, or about 800 μg / mL. In some embodiments, the concentration is about 300 μg / mL to about 350 μg / mL, about 400 μg / mL, about 450 μg / mL, about 500 μg / mL, about 550 μg / mL, about 600 μg / mL, about 650 μg / mL, about 700 μg / mL, about 750 μg / mL, or about 800 μg / mL. In some embodiments, the concentration is about 350 μg / mL to about 400 μg / mL, about 450 μg / mL, about 500 μg / mL, about 550 μg / mL, about 600 μg / mL, about 650 μg / mL, about 700 μg / mL, about 750 μg / mL, or about 800 μg / mL. In some embodiments, the concentration is about 400 μg / mL to about 450 μg / mL, about 500 μg / mL, about 550 μg / mL, about 600 μg / mL, about 650 μg / mL, about 700 μg / mL, about 750 μg / mL, or about 800 μg / mL. In some embodiments, the concentration is about 500 μg / mL to about 550 μg / mL, about 600 μg / mL, about 650 μg / mL, about 700 μg / mL, about 750 μg / mL, or about 800 μg / mL. In some embodiments, the concentration is about 550 μg / mL to about 600 μg / mL, about 650 μg / mL, about 700 μg / mL, about 750 μg / mL, or about 800 μg / mL. In some embodiments, the concentration is about 600 μg / mL to about 650 μg / mL, about 700 μg / mL, about 750 μg / mL, or about 800 μg / mL. In some embodiments, the concentration is about 650 μg / mL to about 700 μg / mL, about 750 μg / mL, or about 800 μg / mL. In some embodiments, the concentration is about 700 μg / mL to about 750 μg / mL or about 800 μg / mL. In some embodiments, the concentration is about 750 μg / mL to about 800 μg / mL. It should be understood that any concentration range listed for indacaterol and glycopyrronium can be used together in a formulation, as if each combination was explicitly and individually listed. In some embodiments, glycopyrronium is present in a form other than bromide (such as glycopyrronium chloride, glycopyrronium acetate, or glycopyrronium citrate). In some embodiments, the composition further comprises an anticrystallization agent.In some embodiments, the glycopyrronium is present in a form other than the bromide, and the composition further comprises an anticrystallization agent.

[0050] It should be understood that in the context of the present disclosure, all concentrations of indacaterol are given for indacaterol free base, and are independent of the form of indacaterol added to the composition. For example, a composition prepared using 500 μg / mL indacaterol maleate contains 384.6 μg / mL of indacaterol free base (the molecular weight of indacaterol maleate is 508.6 g / mol, and the molecular weight of indacaterol free base is 392.5 g / mol, 508.6 g / mol / 392.5 g / mol=1.3, and 500 μg / mL / 1.3=384.6 μg / mL). Similarly, it should be understood that in the context of the present disclosure, all dosages mentioned herein are given for indacaterol free base, and are independent of the form of indacaterol administered.

[0051] In some embodiments, indacaterol is present in the form of an indacaterol salt. In some embodiments, the indacaterol salt is a water-soluble salt of indacaterol. In some embodiments, the solubility of the indacaterol salt in water is at least 100 μg / mL, at least 200 μg / mL, at least 300 μg / mL, or at least 400 μg / mL in water. In some embodiments, the solubility of the indacaterol salt in water is at least 200 μg / mL or at least 300 μg / mL. In some embodiments, the solubility of the indacaterol salt in water at a pH of 3 is at least 100 μg / mL, at least 200 μg / mL, at least 300 μg / mL, or at least 400 μg / mL. In some embodiments, the solubility of the indacaterol salt in water at a pH of 4 is at least 100 μg / mL, at least 200 μg / mL, or at least 300 μg / mL. In some embodiments, the indacaterol salt has a solubility of at least 100 μg / mL at pH 5. In some embodiments, the indacaterol salt is selected from indacaterol acetate, indacaterol tartrate, and indacaterol citrate. In some embodiments, the indacaterol salt is indacaterol citrate. Also provided herein is a pharmaceutical composition comprising an indacaterol salt such as indacaterol citrate. In some embodiments, the pharmaceutical composition is an aqueous pharmaceutical composition suitable for inhalation. Any method described in detail herein may comprise an indacaterol salt such as indacaterol citrate, or a pharmaceutical composition comprising an indacaterol salt. In some embodiments, the indacaterol salt is any pharmaceutically acceptable salt other than maleate. In any embodiment of indacaterol or its salt described herein, an embodiment in which the indacaterol is present as indacaterol base or its salt is considered, wherein the salt is not maleate.

[0052] In some embodiments, glycopyrronium is present in the composition as a glycopyrronium salt. In some embodiments, the salt is a water-soluble salt of glycopyrronium. In some embodiments, glycopyrronium is present in a form other than glycopyrronium bromide. In some embodiments, the glycopyrronium is present in the form of glycopyrronium chloride, glycopyrronium acetate, or glycopyrronium citrate. In some embodiments, the composition remains particle-free over a storage period of 8 weeks, 26 weeks, 52 weeks, or 104 weeks. In some embodiments, storage is storage at room temperature. In some embodiments, storage is storage at 40°C and 75% relative humidity. In some embodiments, storage is storage at 25°C and 60% relative humidity. In some embodiments, storage is storage at 5°C.

[0053] In some embodiments, the aqueous composition comprises a solubilizing agent. In some embodiments, the solubilizing agent is a cyclodextrin. In some embodiments, the cyclodextrin is a sulfobutyl ether-β-cyclodextrin (SBE-β-CD). In some embodiments, the cyclodextrin is present in an amount of about 0.1% w / v to about 10% w / v. In some embodiments, the cyclodextrin is present in an amount of about 0.1% w / v to about 5% w / v. In some embodiments, the cyclodextrin is present in an amount of about 0.1% w / v to about 1% w / v. In some embodiments, the cyclodextrin is present in an amount of about 0.1% w / v to about 1% w / v. In some embodiments, the cyclodextrin is present in an amount of about 0.25% w / v to about 1% w / v. In some embodiments, the cyclodextrin is present in an amount of about 0.25% w / v to about 5% w / v. In some embodiments, the cyclodextrin is present in an amount of about 0.25% w / v to about 10% w / v. In some embodiments, the aqueous composition does not comprise a solubilizing agent.

[0054] In some embodiments, the aqueous composition comprises one or more tension regulators. In some embodiments, the one or more tension regulators are sodium chloride and mannitol. In some embodiments, the one or more tension regulators are sodium chloride or mannitol. In some embodiments, the one or more tension regulators are mannitol. In some embodiments, the aqueous composition is isotonic. In some embodiments, the one or more tension regulators are present in a concentration of about 10mM, 20mM, 30mM, 50mM, 100mM, 200mM, 300mM or 400mM to about 500mM. In some embodiments, the one or more tension regulators are present in a concentration of about 10mM, 20mM, 30mM, 50mM, 100mM, 200mM or 300mM to about 400mM. In some embodiments, the one or more tonicity adjusters are present at a concentration of about 10 mM, 20 mM, 30 mM, 50 mM, 100 mM or 200 mM to about 300 mM. In some embodiments, the one or more tonicity adjusters are present at a concentration of about 10 mM, 20 mM, 30 mM, 50 mM or 100 mM to about 200 mM. In some embodiments, two or more tonicity adjusters can each independently be present in any range disclosed for a single tonicity adjuster.

[0055] In some embodiments, the sexual composition comprises sodium chloride. In some embodiments, sodium chloride is present in a concentration of any one of about 5mM to about 15mM, about 30mM, about 50mM, about 80mM, about 100mM or about 150mM. In some embodiments, sodium chloride is present in an amount of any one of about 15mM to about 30mM, about 50mM, about 80mM, about 100mM or about 150mM. In some embodiments, sodium chloride is present in an amount of any one of about 30mM to about 50mM, about 80mM, about 100mM or about 150mM. In some embodiments, sodium chloride is present in an amount of any one of about 50mM to about 80mM, about 100mM or about 150mM. In some embodiments, sodium chloride is present in an amount of about 80mM to about 100mM or about 150mM. In some embodiments, sodium chloride is present at a concentration of about 5 mM to about 20 mM.

[0056] In some embodiments, the aqueous composition comprises mannitol. In some embodiments, the mannitol exists with a concentration of any one of about 100mM to about 150mM, about 200mM, about 250mM, about 300mM, about 350mM, about 400mM or about 500mM. In some embodiments, the mannitol exists with a concentration of any one of about 150mM to about 200mM, about 250mM, about 300mM, about 350mM, about 400mM or about 500mM. In some embodiments, the mannitol exists with a concentration of any one of about 200mM to about 250mM, about 300mM, about 350mM, about 400mM or about 500mM. In some embodiments, the mannitol is present in a concentration of about 250mM to about 300mM, about 350mM, about 400mM or about 500mM. In some embodiments, the mannitol is present in a concentration of about 300mM to about 350mM, about 400mM or about 500mM. In some embodiments, the mannitol is present in a concentration of about 350mM to about 400mM or about 500mM. In some embodiments, the mannitol is present in a concentration of about 150mM to about 300mM. In some embodiments, the mannitol is present in a concentration of about 200mM to about 300mM.

[0057] In some embodiments, the aqueous composition comprises both sodium chloride and mannitol. It should be understood that the two tension modifiers can be present together at any concentration described above for each of these components, as if each combination is clearly and individually listed. In some embodiments, the sodium chloride is present at a concentration of about 5mM to about 15mM, and the mannitol is present at a concentration of about 150mM to about 300mM. In some embodiments, the sodium chloride is present at a concentration of about 5mM to about 15mM, and the mannitol is present at a concentration of about 200mM to about 300mM.

[0058] In some embodiments, the aqueous composition comprises a buffer. In some embodiments, the buffer is a citrate-containing buffer. In some embodiments, the buffer is prepared from citric acid and trisodium citrate. In some embodiments, the buffer is prepared from citric acid and a strong base. In some embodiments, the composition is buffered to a pH of 2 to 6. In some embodiments, the composition is buffered to a pH of 3 to 6. In some embodiments, the composition is buffered to a pH of 4 to 6. In some embodiments, the composition is buffered to a pH of 5 to 6. In some embodiments, the composition is buffered to a pH of 2 to 5. In some embodiments, the composition is buffered to a pH of 3 to 5. In some embodiments, the composition is buffered to a pH of 4 to 5. In some embodiments, the composition is buffered to a pH of 2 to 4. In some embodiments, the composition is buffered to a pH of 3 to 4. In some embodiments, the composition is buffered to a pH of 2 to 3. In some embodiments, the composition is buffered to a pH of 3.5 to 4.5. In some embodiments, the composition is buffered to a pH of about 4. In some embodiments, the composition is buffered to a pH of less than 8. In some embodiments, the composition is buffered to a pH of 2 to 8.

[0059] In some embodiments, the aqueous composition comprises a cosolvent. In some embodiments, the cosolvent is ethanol or ethylene glycol. In some embodiments, the cosolvent is present in an amount of about 0% to about 0.1%, 0.5%, 1%, 2.5%, 5% or 10%. In some embodiments, the cosolvent is present in an amount of about 0.1% v / v to about 10% v / v, about 0.1% v / v to about 5% v / v, about 0.1% v / v to about 2.5% v / v, about 0.1% v / v to about 1% v / v, about 0.5% v / v to about 5% v / v, about 0.5% v / v to about 2.5% v / v, about 0.5% v / v to about 1% v / v, about 1% v / v to about 5% v / v, or about 1% v / v to about 2.5% v / v. In some embodiments, the aqueous composition does not comprise a cosolvent. In some embodiments, the aqueous composition does not comprise ethanol.

[0060] In some embodiments, the aqueous composition comprises a preservative. In some embodiments, the preservative comprises benzalkonium chloride. In some embodiments, the preservative comprises ethylenediaminetetraacetic acid (EDTA). In some embodiments, the composition comprises two or more preservatives. In some embodiments, the composition comprises benzalkonium chloride and EDTA. In some embodiments, the preservative is present in a concentration of about 0.001% to about 0.1%. In some embodiments, the preservative is present in a concentration of about 0.01% to about 0.1%. In some embodiments, the preservative is present in a concentration of about 0.001% to about 0.01%. In some embodiments, the preservative is present in a concentration of about 0.001% to about 0.01%. In the case of having multiple preservatives, each preservative can exist independently in any one of the ranges listed above. In some embodiments, the aqueous composition does not comprise a preservative.

[0061] In some embodiments, the aqueous composition comprises anticrystallization agent. In some embodiments, the anticrystallization agent is a polymer or a surfactant. In some embodiments, the anticrystallization agent is selected from polyethylene glycol, povidone, glycerol, propylene glycol, polysorbate or poloxamer. In some embodiments, the anticrystallization agent is Solutol HS15, Kolliphor EL, ELP or RH 40, HPMC (hydroxypropyl methylcellulose), Tween 20, Tween 80 or poloxamer 124, 188, 237, 338 or 407. It should be understood that anticrystallization agent prevents precipitation, even when the precipitate is not crystalline. In some embodiments, the anticrystallization agent also prevents the formation of amorphous precipitates. In some embodiments, the anticrystallization agent prevents the crystallization or precipitation of a pharmaceutically acceptable salt of indacaterol and / or glycopyrronium or any of the foregoing. In some embodiments, the anticrystallization agent prevents indacaterol and / or glycopyrronium, or a pharmaceutically acceptable salt of any of the foregoing, from crystallizing or precipitating from an aqueous solution. In some embodiments, the anticrystallization agent prevents indacaterol and / or glycopyrronium, or a pharmaceutically acceptable salt of any of the foregoing, from crystallizing or precipitating from a solution comprising at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% water by weight.

[0062] In some embodiments, the aqueous composition comprises water and indacaterol as a free base. In some embodiments, the aqueous composition comprises water and a pharmaceutically acceptable salt of indacaterol, such as indacaterol maleate. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, and a solubilizing agent. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, and a buffer. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, and a tension modifier. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, and a cosolvent. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a solubilizing agent, and a buffer. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a solubilizing agent, and a tonicity adjusting agent. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a solubilizing agent, and a cosolvent. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a buffer, and a tonicity adjusting agent. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a buffer, and a cosolvent. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a solubilizing agent, a buffer, and a tonicity adjusting agent. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a solubilizing agent, a buffer, and a cosolvent. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a solubilizing agent, a tension regulator, and a cosolvent. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a buffer, a tension regulator, and a cosolvent. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, and a preservative. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a solubilizing agent, and a preservative. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a buffer, and a preservative.In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a tension modifier, and a preservative. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a cosolvent, and a preservative. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a solubilizing agent, a buffer, and a preservative. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a solubilizing agent, a tension modifier, and a preservative. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a solubilizing agent, a cosolvent, and a preservative. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a buffer, a tension adjuster, and a preservative. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a buffer, a cosolvent, and a preservative. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a tension adjuster, a cosolvent, and a preservative. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a solubilizing agent, a buffer, a tension adjuster, and a preservative. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a solubilizing agent, a buffer, a cosolvent, and a preservative. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a solubilizer, a tension regulator, a cosolvent and a preservative. In some embodiments, the aqueous composition comprises one or more of water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a buffer, a tension regulator, a cosolvent and a preservative. In some embodiments, the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, and one or more of the components listed above. Each possible combination of three or more components is considered to be specifically and individually listed. In some embodiments, the aqueous composition comprises indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, one or more tension regulators, a buffer and an anti-crystallization agent. In some embodiments, the aqueous composition comprises indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, two tension regulators and a buffer.In some embodiments, the aqueous composition comprises indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, two tension modifiers, a buffer, and an anti-crystallization agent. In some embodiments, the aqueous composition comprises indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, one or more tension modifiers, a buffer, and an anti-crystallization agent. In some embodiments, the aqueous composition comprises indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, and an anti-crystallization agent. In some embodiments, the aqueous composition comprises indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, and an anti-crystallization agent. Each of water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, solubilizer, buffer, tension modifier, cosolvent, and preservative may be present in any amount as disclosed herein.

[0063] In some embodiments, the composition comprises indacaterol and another medicament. In some embodiments, the other medicament is an inhaled corticosteroid. In some embodiments, the inhaled corticosteroid is mometasone or a pharmaceutically acceptable salt thereof. In some embodiments, the aqueous composition provided herein comprising indacaterol or a pharmaceutically acceptable salt thereof further comprises two other medicaments. In some embodiments, the aqueous composition provided herein comprises indacaterol, glycopyrronium and mometasone or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the other medicament or its salt does not contain bromide.

[0064] In some embodiments, the additional agent is present at a concentration of about 10 μg / mL to about 2 mg / mL. In some embodiments, the additional agent is present at a concentration of up to about 2 mg / mL, up to about 1 mg / mL, up to about 800 μg / mL, up to about 600 μg / mL, up to about 400 μg / mL, up to about 200 μg / mL, up to about 50 μg / mL, or up to about 10 μg / mL. In some embodiments, the additional agent is present at about 10 μg / mL to about 2 mg / mL, about 10 μg / mL to about 1.5 mg / mL, about 10 μg / mL to about 1 mg / mL, about 10 μg / mL to about 800 μg / mL, about 10 μg / mL to about 600 μg / mL, about 10 μg / mL to about 400 μg / mL, about 10 μg / mL to about 200 μg / mL, about 50 μg / mL to about 1 mg / mL, about 50 μg / mL to about 800 μg / mL, about 50 μg / mL to about 600 μg / mL, about 50 μg / mL to about The invention relates to a method for treating a leukemia or a diabetic patient. The method comprises: providing a leukemia or a diabetic patient with at least one ...

[0065] In certain embodiments, the composition is a pharmaceutical formulation in unit dosage form. In one variation, the unit dosage form comprises one or more additional pharmaceutical agents. Preparation method

[0066] Provided herein are methods for preparing the compositions described herein. In some embodiments, the method for preparing the compositions described herein comprises steps a) to f): a) adding indacaterol or a pharmaceutically acceptable salt thereof and glycopyrronium or a pharmaceutically acceptable salt thereof to a liquid comprising water to form a mixture; and b) adjusting the pH of the mixture to obtain the composition. In some embodiments, the mixture further comprises one or more excipients selected from a buffer, a cosolvent, a tension regulator, and a preservative. In some embodiments, step b) includes waiting for the mixture to reach equilibrium. In some embodiments, step b) lasts for a period of 12 to 72 hours. In some embodiments, pH is adjusted using strong acids and strong bases. In some embodiments, the strong acid is HCl. In some embodiments, the strong base is NaOH. In some embodiments, step b) further includes adding an acid or an acid-form buffer. In some embodiments, an acid or an acid-form buffer is added until the pH of the mixture is equal to or less than 4.0, 3.0, or 2.0. In some embodiments, an acid or an acid-form buffer is added until the pH of the mixture is equal to or less than 2.0. In some embodiments, an acid or an acid-form buffer is added until the pH of the mixture is equal to or less than 2.0, and then the mixture is waited for to reach equilibrium. In some embodiments, the acid or an acid-form buffer is citric acid. How to use

[0067] In some embodiments, the aqueous composition is used to treat a patient. In some embodiments, the composition is delivered to a patient in need as an aerosol. In some embodiments, the aerosol is generated by contacting the aqueous composition with a vibrating mesh screen. In some embodiments, the API of the aqueous composition is delivered to the lungs of a patient in need. In some embodiments, the composition acts as a bronchodilator.

[0068] In some embodiments, a method for delivering indacaterol to the lungs of a patient in need is provided, wherein the delivery is completed by low tidal breathing. In some embodiments, the patient has difficulty in producing enough inhalation effort to properly use a dry powder inhaler or has a significant cough caused by dry powder stimulation. In some embodiments, the patient is difficult to produce a pressure drop of 1kPa or more (Clark, AR et al., J Aerosol Med Pulm Drug Deliv, (2020) 33, 1-11). In some embodiments, the patient is difficult to achieve the coordination of device actuation and inhalation required for the correct use of a dry powder inhaler, a pressure metered dose inhaler and / or a soft mist inhaler. In some embodiments, the patient is an elderly or pediatric patient. In some embodiments, the elderly patient is 65 years old or older. In some embodiments, the elderly patient is 75 years old or older. In some embodiments, the elderly patient is between 75 and 100 years old. In some embodiments, the patient is an adult. In some embodiments, the patient is less than 65 years old. In some embodiments, the patient is less than 50 years old. In some embodiments, the patient is less than 40 years old. In some embodiments, the patient is a young adult. In some embodiments, the patient is less than 30 years old. In some embodiments, the patient is less than 25 years old. In some embodiments, the patient is less than 20 years old. In some embodiments, the patient is a teenager. In some embodiments, the patient is less than 15 years old. In some embodiments, the patient is greater than 2 years old. In some embodiments, the patient suffers from COPD and / or asthma and / or emphysema.

[0069] In some embodiments, the aqueous composition is used to treat patients with respiratory disorders. In some embodiments, the aqueous composition is used to treat patients with inflammatory disorders (such as inflammatory disorders of the airways and / or lungs). In some embodiments, the aqueous composition is used to treat patients with obstructive airway disease. In some embodiments, the patient suffers from one or more of respiratory disorders, inflammatory disorders and / or obstructive airway diseases. In some embodiments, the aqueous composition is used to treat COPD. In some embodiments, the aqueous composition is used to treat asthma. In some embodiments, the aqueous composition is used to treat COPD and asthma. In some embodiments, the aqueous composition is used to treat emphysema. In some embodiments, the composition is used to treat COPD and emphysema. In some embodiments, treatment includes preventing symptoms associated with respiratory disorders, inflammatory disorders or obstructive airway diseases or delaying their occurrence, such as in patients at risk of developing such symptoms.

[0070] The composition is administered to the patient in an amount effective to treat the respiratory disorder, inflammatory disorder or obstructive airway disease that needs to be treated. In some embodiments, the composition is administered to the patient every day. In some embodiments, the composition is administered to the patient twice a day. In some embodiments, the dose of indacaterol is 20 μg to 800 μg. In some embodiments, the dose of indacaterol is 50 μg to 650 μg. In some embodiments, the dose of indacaterol is 100 μg to 600 μg. In some embodiments, the dose of indacaterol is 200-500 μg. In some embodiments, the dose of indacaterol is 70 μg to 80 μg. In some embodiments, the dose of indacaterol is 75 μg. In some embodiments, the composition is intended as a maintenance treatment for respiratory disorders, inflammatory disorders such as asthma, or obstructive airway diseases such as COPD.

[0071] In some embodiments, the patient receiving the composition is a subject receiving one or more additional therapies and / or treatments for a respiratory disorder. In some embodiments, the respiratory disorder is asthma. In some embodiments, the respiratory disorder is COPD. In some embodiments, the respiratory disorder is emphysema. In some embodiments, the respiratory disorder is seasonal allergies.

[0072] The composition can be administered to a patient in need using a variety of devices. In some embodiments, the device is an inhaler device or a nebulizer. In some embodiments, the device is a soft mist inhaler, a jet nebulizer, an ultrasonic nebulizer, or a vibrating mesh device. In some embodiments, the device is a jet nebulizer. In some embodiments, the device is a soft mist inhaler. In some embodiments, the device is a mesh nebulizer. In some embodiments, the device is a breath-actuated nebulizer.

[0073] In some embodiments, the aqueous composition is included as a part of a test kit, and the test kit includes a device for aerosolization preparation. In some embodiments, the device includes a vibrating mesh screen. In some embodiments, the test kit includes indacaterol or its pharmaceutically acceptable salt, a solubilizing agent and instructions for preparing its aqueous liquid composition. In some embodiments, the test kit includes indacaterol or its pharmaceutically acceptable salt and a solubilizing agent in the same or separate container. The test kit provided herein can include a container (such as an ampoule, a vial or a cartridge), a solubilizing agent and water providing a required amount of an aqueous liquid composition, and the container includes an aqueous liquid composition containing indacaterol or its pharmaceutically acceptable salt. In some embodiments, the test kit further includes a device for aerosolization aqueous liquid composition. In some embodiments, the aqueous liquid composition includes water in an amount of about 20 weight percent to 99.9 weight percent.

[0074] The kit can be a unit dosage form, bulk packaging (e.g., multi-dose packaging) or sub-unit dosage. For example, a kit containing a sufficient dose of a composition as disclosed herein can be provided to provide effective treatment for an individual over an extended period of time, such as 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months or any of a longer period of time. The kit can also include multiple unit doses of the composition and instructions for use. Example

[0075] Unless otherwise stated, the materials used below were purchased commercially. Indacaterol (base) was purchased from Cayman Chemicals. Indacaterol maleate was purchased from AChemBlock. Example 1 - Forced Degradation Study

[0076] A degradation sample set was prepared to identify the degradation pathways and products of indacaterol. Table 1 summarizes the stress conditions. Table 1. Characteristics of samples used in forced degradation studies

[0077] One of 6N HCl, 6N NaOH or 30% H2O2 (aqueous solution) was added to a suitable volume of 100 μg / mL indacaterol and diluted with water: methanol (50:50, v:v) to reach a final indacaterol concentration of 10 μg / mL. Samples were stored at ambient temperature. At the specified time point, acidic and alkaline hydrolysis (1N HCl and 1N NaOH, respectively) samples were neutralized (without quenching H2O2 samples), and reverse phase high performance liquid chromatography (RP-HPLC) was used to quantify indacaterol impurities. Prior to RP-HPLC analysis, all samples were diluted to 5 μg / mL. Table 2 summarizes the method parameters. Table 2. RP-HPLC impurity method parameters (Examples 1-7)

[0078] The total impurities (process related and product related) of the samples from the forced degradation study of Indacaterol are presented in Table 3. The forced degradation impurity peaks were identified based on the relative retention time (RRT) to the Indacaterol peak. The impurity peaks already present in Indacaterol (control at T0; approximately 2% of the total peak area) were considered to be process related, while the additional peaks formed after degradation were considered to be product related. Table 3. Results of forced degradation experiments

[0079] The total impurity percentages in the 1 N HCl and 1 N NaOH samples stored at ambient temperature for 15 hours were the same (approximately 7% to 8%), while the total impurities in the 1.2% H2O2 sample stored for 29 hours were approximately 9%. Figure 1 Interleaved chromatograms of forced degradation samples of Indacaterol are shown. The peak at the column void volume in the oxidized sample is attributed to water from the H2O2 solution and is excluded from the total impurity percentages. Overall, the results indicate that the RP-HPLC method provides good separation of Indacaterol impurities. Example 2 - Water Solubility of Indacaterol

[0080] The solubility study of indacaterol and indacaterol maleate was carried out using the orbital shaking method. An excess of indacaterol was placed in a glass vial filled with water. The initial pH of the water was 7.1. The sample was shaken for 12 hours to ensure that equilibrium was reached. After a period of 12 hours, the vial was taken out of the shaking table and allowed to stand for 30 minutes. Then, the sample was filtered using a 0.2 μM polyvinylidene fluoride (PVDF) syringe filter; the initial 0.5 mL filtrate was discarded. The pH was then measured, and the concentration of indacaterol was assessed by UV-Vis. The results are shown in Table 4. Table 4. Maximum solubility of indacaterol and indacaterol maleate

[0081] Indacaterol is insoluble in water at pH 7.1. The pH changes of the samples may be due to dissolved ambient CO2. The pH of the indacaterol maleate solution is mainly attributed to the dissolution of the salt and the formation of maleic acid and indacaterol free base. Example 3 - Water solubility of indacaterol at different pH

[0082] The solubility study of indacaterol in solutions of different pH was carried out using the orbital shaking method. An excess of indacaterol was placed in a glass vial containing an aqueous citrate buffer solution (5mM; prepared by citric acid and NaOH). The sample was shaken for 12 to 24 hours to ensure that equilibrium was reached, then the pH was checked and adjusted (using 1M HCl and NaOH) and the sample was returned to the orbital shaking table for another 12 hours. This process was repeated up to twice or until the desired pH was obtained. After reaching the desired pH, the vial was removed from the shaking table and allowed to stand for 30 minutes. Then, the sample was filtered using a 0.2 μM PVDF syringe filter; the initial 0.5 mL filtrate was discarded. The pH was then measured, and the concentration of indacaterol was evaluated by UV-Vis. The results are shown in Table 5. It was found that the solubility of indacaterol increased with decreasing pH. Table 5. Solubility of Indacaterol in Citrate Buffer. Example 4 - Aqueous Solubility of Indacaterol in Different Buffers

[0083] The solubility study of indacaterol in solutions of different pH and different buffers was carried out using the orbital shaking method. Excess indacaterol was placed in a glass vial containing water and appropriate buffer and 300mM mannitol. The sample was shaken for 12 to 24 hours to ensure that equilibrium was reached, then the pH was checked and adjusted (using 1M HCl and NaOH) and the sample was placed back in the orbital shaking table for another 12 hours. This process was repeated up to twice or until the desired pH was obtained. After reaching the desired pH, the vial was taken out of the shaking table and allowed to stand for 30 minutes. Then, the sample was filtered using a 0.2 μM PVDF syringe filter; initial 0.5 mL filtrate was discarded. pH was then measured, and the concentration of indacaterol was assessed by UV-Vis. The results are shown in Table 6. Table 6. Effect of buffer type and pH on the solubility of indacaterol. Example 5 - Solubility of Indacaterol in Formulations with Tonicity Modifiers and Cosolvents

[0084] The solubility study of indacaterol in solutions of different pH and tension regulators was carried out using the orbital shaking method. Excess indacaterol was placed in a glass vial containing water, 5mM citrate and a variety of tension regulators and / or cosolvents. The sample was shaken for 12 to 24 hours to ensure that equilibrium was reached, then the pH was checked and adjusted (using 1M HCl and NaOH) and the sample was returned to the orbital shaking table for another 12 hours. This process was repeated up to 2 times or until the desired pH was obtained. After reaching the desired pH, the vial was taken out of the shaking table and allowed to stand for 30 minutes. Then, the sample was filtered using a 0.2 μM PVDF syringe filter; the initial 0.5 mL filtrate was discarded. The pH was then measured, and the concentration of indacaterol was assessed by UV-Vis. The results are shown in Table 7. Table 7. Solubility of Indacaterol in Solutions with Various Tonicity Modifiers and Cosolvents Example 6 - Solubility of Indacaterol in Formulations Containing Cyclodextrins

[0085] The solubility study of the effect of cyclodextrin on indacaterol aqueous solution was carried out using the orbital shaking method (preparations 6.1-6.11). Excess indacaterol was placed in a glass vial containing water, 5mM citrate, mannitol or NaCl and sulfobutyl ether β-cyclodextrin (SBE-β-CD). The sample was shaken for 12 to 24 hours to ensure that equilibrium was reached, then the pH was checked and adjusted (using 1M HCl and NaOH) and the sample was returned to the orbital shaking table for another 12 hours. This process was repeated up to 2 times or until the desired pH was obtained. After reaching the desired pH, the vial was removed from the shaking table and allowed to stand for 30 minutes. Then, the sample was filtered using a 0.2 μM PVDF syringe filter; the initial 0.5 mL filtrate was discarded. The pH was then measured, and the concentration of indacaterol was assessed by UV-Vis. The results are shown in Table 8.

[0086] For Examples 6.12 and 6.13, an excess of indacaterol was placed in a glass vial containing water, 5 mM citrate, and sulfobutyl ether β-cyclodextrin (SBE-β-CD). The sample was stirred at 250 rpm for up to 24 hours to ensure equilibrium. The vial was removed from the shaker and allowed to stand for approximately 24 hours. The sample was then filtered using a 0.2 μM PVDF syringe filter; the initial 0.5 mL of filtrate was discarded. The pH was then measured, and the concentration of indacaterol was assessed by UV-Vis. The results are shown in Table 8. Table 8. Solubility of Indacaterol in formulations with SBE-β-CD. Example 7 - Stability Study of Liquid Indacaterol Formulation

[0087] A series of indacaterol formulations were prepared for stability studies. Each formulation was transferred to a glass bottle, and then additional indacaterol was added. The bottle was capped and placed horizontally on an orbital shaker set to 200 rpm overnight. The next day, the pH of each formulation was measured, and then adjusted with 1N NaOH and / or 1N HCl to maintain the target pH. The bottle was placed back on the shaker overnight. The bottle was then taken out from the shaker and checked to ensure that the pH was stable. Each formulation was filtered through a PVDF filter membrane to remove excess indacaterol and diluted to 75% concentration using the corresponding formulation buffer. The pH of each formulation was measured, and the pH was adjusted with 1M NaOH and / or 1M HCl to maintain the target pH. Finally, each formulation was filtered through a PVDF filter membrane to minimize particle load, and transferred to a biosafety cabinet (BSC) for vial filling. The weight molar osmotic pressure concentration and viscosity of the test formulation (see Table 9) were determined by RP-HPLC. Indacaterol concentration was determined by RP-HPLC. Table 9. Indacaterol liquid formulations used in stability studies.

[0088] The formulations were stored under various conditions, and pH and concentration were tested at different time points to evaluate the stability of the formulations. For all formulations, the pH remained relatively unchanged over a 90-day period. Figure 2 shows the data for all formulations stored under various conditions. For all formulations, the concentration of indacaterol remained relatively unchanged over a 90-day period. Figure 3 shows the indacaterol concentration of each formulation under all storage conditions. For all formulations, product-related impurities were identified at relative retention times of approximately 0.425, 0.626, 0.734, 0.877, 0.915, and 1.217 (see Figure 4 A summary of the percentage changes (90d compared to T0) of the main indacaterol peak and total product-related impurities is shown in Table 10. Table 10. Summary of % change (90d compared to T0) of indacaterol main peak and total product-related impurities for indacaterol liquid formulations stored under various conditions.

[0089] The complete impurity data for stability samples stored at 40°C, 25°C and 5°C for up to 90 days are presented in Tables 11-13. Table 11. Major peak impurities % of indacaterol liquid formulations stored at 40°C / 75% RH for 90 days. Table 12. Major peak impurities % of indacaterol liquid formulations stored at 25°C / 60% RH for 90 days. *RRT = relative retention time Table 13. Major peaks and % impurities of indacaterol liquid formulations stored at 5°C for 90 days. Example 8 - Stability Study of Liquid Indacaterol and Glycopyrronium Formulations

[0090] A series of formulations of indacaterol combined with glycopyrronium were prepared for stability studies. Each formulation was initially prepared in concentrated form and low pH to maximize the dissolution rate of indacaterol. Each formulation was transferred to a glass bottle, and then indacaterol and glycopyrronium were added. The formulations in the bottle were stirred with a magnetic stirrer until indacaterol dissolved. The pH of each formulation was measured and then adjusted to the target pH with 2N NaOH and / or 2N HCl. Stirring was allowed to proceed for another 30 minutes. Water was added to the target volume, and the pH was checked to ensure that the target pH was maintained. Each formulation was filtered through a PVDF filter membrane to minimize particle and microbial loads, and transferred to a biological safety cabinet (BSC) for vial filling. The weight molar osmotic pressure concentration and viscosity of the test formulations were (see Table 14). Indacaterol and glycopyrronium concentrations and impurities were determined by RP-HPLC. Table 15 summarizes the RP-HPLC method parameters.

[0091] The formulations were stored under various conditions, and appearance, pH, concentration, and impurities were tested at different time points to evaluate the stability of the formulations. For all formulations, except G1, the appearance remained relatively unchanged over a 90-day period. For all formulations, the pH remained relatively unchanged over a 90-day period. For all formulations, the concentrations of indacaterol and glycopyrronium remained relatively unchanged over a 5-week period. Tables 16, 17, and 18 show the appearance, pH, and drug concentration data of all formulations stored under various conditions. For all formulations, the impurities at relative retention times of approximately 0.25, 0.29, 0.33, 0.60, 0.73, 0.83, 1.03, 1.10, and 1.15 remained relatively unchanged over a 5-week period. Only under 40°C storage conditions was a small increase in the amount of impurities with a relative retention time of 0.83 observed for formulations G7, G8, and G9. A summary of the percent change (90d compared to T0) of the indacaterol main peak and total impurities is shown in Table 19, and the full impurity data is shown in Table 20, Table 21, and Table 22. Table 14. Indacaterol and glycopyrronium liquid formulations used in stability studies. Table 15. RP-HPLC concentration and impurity method parameters (Examples 8-10) Table 16. Appearance, pH and concentration of indacaterol and glycopyrronium liquid formulations stored at 40°C / 75% RH for up to 5 weeks. *% change in value relative to week 0 at the final time point tested. TBD = To be determined. Table 17. Appearance, pH and concentration of indacaterol and glycopyrronium liquid formulations stored at 25°C / 60% RH for 4 weeks. *% change in value relative to week 0 at the final time point tested. Table 18. Appearance, pH and concentration of indacaterol and glycopyrronium liquid formulations stored at 5°C for 4 weeks. *% change from week 0 value at final time point tested. Table 19. Summary of % change (4 or 5 weeks compared to T0) of indacaterol main peak and total product-related impurities for indacaterol liquid formulations stored under various conditions. Detection at 254 nm. 1 % change at 5 weeks compared to time 0 2 % change at 4 weeks compared to time 0 Table 20. Main peak % and impurity % of indacaterol liquid formulations stored at 40°C / 75% RH for 5 weeks. Detection was at 254 nm. Table 21. Main peak % and impurity % of indacaterol liquid formulations stored at 25°C / 60% RH for 5 weeks. Detection was at 254 nm. Table 22. Main peak % and impurity % of indacaterol liquid formulations stored at 5°C for 5 weeks. Detection at 254 nm. Example 9 - Aerosol Performance Study of Liquid Indacaterol Formulation

[0092] Aerosol performance studies of single-drug (indacaterol) and combination (indacaterol and glycopyrronium) solution formulations delivered using various liquid inhalation devices were conducted using laser diffraction and delivered dose (DD) methods. For laser diffraction, a specified volume of each formulation was placed in a test nebulizer reservoir and aerosolized to determine the droplet size distribution (DSD). For delivered dose (DD), the droplet size distribution (DSD) was determined according to USP. <1601> (United States Pharmacopeia, Section 1601) A breathing simulator pre-set to a tidal breathing mode (500 mL tidal volume, 1:1 inspiratory-expiratory ratio (I:E), 15 BPM, sinusoidal waveform) was used to draw inspiratory and expiratory airflow through the DD collection filter. A nebulizer (positioned as intended for use) was connected to the filter inlet, loaded with drug product solution, and nebulization was started for the specified duration. Drug content was determined by RP-HPLC. The results are presented in Tables 23, 24, and Figure 5 and Figure 6LC Sprint is a jet nebulizer. InnoSpire Go and FLYP are vibrating mesh nebulizers. LC Sprint, InnoSpire Go and FLYP nebulizers are not breath actuated. Table 23. Laser diffraction testing of indacaterol liquid formulations used for aerosol performance studies. Results are means (n=3) with one standard deviation in parentheses. 1 Indacaterol free base. 2 A vibrating mesh nebulizer (VMN) with breath actuation (BA) from Device Company 1 was studied. 3 A vibrating mesh nebulizer (VMN) with breath actuation (BA) from Device Company 2 was studied. Table 24. Delivery testing of indacaterol liquid formulations for aerosol performance studies. 1 Indacaterol free base content in indacaterol maleate. 2 A vibrating mesh nebulizer (VMN) with breath actuation (BA) from Device Company 1 was studied. 3 A vibrating mesh nebulizer (VMN) with breath actuation (BA) from Device Company 2 was studied. 4 For G 7 and G 8 The test was run three times. The measured data are the average of three runs, and the relative standard deviation is given in brackets after the average. TBD = To be determined Example 10 - Liquid Indacaterol and Tiotropium Formulation

[0093] Prepare a series of formulations of indacaterol and tiotropium combination for stability study. Initially prepare each formulation in concentrated form and low pH to maximize the dissolution rate of indacaterol. Each formulation is transferred to a glass bottle, and then indacaterol and tiotropium are added. The formulation in the bottle is stirred with a magnetic stirrer until indacaterol dissolves. The pH of each formulation is measured, and then adjusted to the target pH with 2N NaOH and / or 2N HCl. Allow stirring for another 30 minutes. Use water to make up the volume to the target volume, and check pH to ensure that the target pH is maintained. Each formulation is filtered through a PVDF filter membrane to minimize particles and microbial load, and transferred to a biosafety cabinet (BSC) for vial filling. The weight molar osmotic pressure concentration and viscosity of the test formulation are (see Table 25). Table 25. Indacaterol liquid formulations used in stability studies. Example 11 - Liquid Indacaterol and Tiotropium Formulation

[0094] The formulation of Example 8 was monitored for a period of 26 weeks. Indacaterol and glycopyrronium concentrations and impurities were determined by RP-HPLC. Table 26 summarizes the RP-HPLC method parameters.

[0095] The formulations were stored under various conditions, and the appearance, pH, concentration, and impurities were tested at different time points to evaluate the stability of the formulations. For all formulations, except for G8 and G9 stored at 5°C, the appearance remained relatively unchanged over a period of 26 weeks. For all formulations, the pH remained relatively unchanged over a period of 26 weeks. For all formulations, the concentrations of indacaterol and glycopyrronium remained relatively unchanged (≤2% change) over a period of 26 weeks, except for indacaterol in G8 stored at 5°C. Tables 27, 28, and 29 show the appearance and pH data of all formulations stored under various conditions. For all formulations, impurities remained relatively unchanged over a period of 26 weeks at 5°C and 25°C. Only under 40°C storage conditions was a small increase in the amount of impurities observed for all formulations. Tables 30, 31, and 32 show the indacaterol and glycopyrronium concentrations, main peaks, and impurity data for all formulations stored under various conditions. Figure 7 and Figure 8 Exemplary chromatograms of indacaterol and glycopyrronium are shown. The results indicate that formulations of indacaterol alone or in combination with glycopyrronium are stable at room temperature. Table 26. RP-HPLC concentration and impurity method parameters (Example 11) Table 27. Appearance and pH of indacaterol and glycopyrronium liquid formulations stored at 40°C / 75% RH for up to 26 weeks. Table 28. Appearance and pH of indacaterol and glycopyrronium liquid formulations stored at 25°C / 60% RH for up to 26 weeks. Table 29. Appearance and pH of indacaterol and glycopyrronium liquid formulations stored at 5°C for up to 26 weeks. Table 30. Concentrations, main peak % and impurity % of indacaterol liquid formulations (G7) stored at 40°C / 75% RH, 25°C / 60% RH and 5°C for 26 weeks. Changes in concentrations are percentages relative to T0. Table 31. Concentrations, main peak % and impurity % of indacaterol and glycopyrronium liquid formulations (G8) stored at 40°C / 75% RH, 25°C / 60% RH and 5°C for 26 weeks. Changes in concentrations are percentages relative to T0. Table 32. Concentrations, main peak % and impurity % of indacaterol and glycopyrronium liquid formulations (G9) stored at 40°C / 75% RH, 25°C / 60% RH and 5°C for 26 weeks. Changes in concentrations are percentages relative to T0.

[0096] Although the foregoing invention has been described in some detail by way of illustration and example for the purpose of clear understanding, it is clear to those skilled in the art that some minor changes and modifications may be practiced in view of the above teachings. Therefore, the description and embodiments should not be construed as limiting the scope of the present invention. All references in this disclosure are incorporated herein.

Claims

1. A pharmaceutical composition comprising About 20 weight percent to 99.9 weight percent water; Indacaterol or a pharmaceutically acceptable salt thereof present at a concentration of 10 μg / mL to 2 mg / mL; glycopyrronium or a pharmaceutically acceptable salt thereof present at a concentration of 10 μg / mL to 1 mg / mL; and wherein the glycopyrronium is present in a form different from glycopyrronium bromide.

2. A pharmaceutical composition comprising About 20 weight percent to 99.9 weight percent water; Indacaterol or a pharmaceutically acceptable salt thereof present at a concentration of 10 μg / mL to 2 mg / mL; glycopyrronium or a pharmaceutically acceptable salt thereof present at a concentration of 10 μg / mL to 1 mg / mL; and wherein the composition further comprises an anti-crystallization agent.

3. The pharmaceutical composition according to claim 2, wherein the glycopyrronium is present in a form different from glycopyrronium bromide.

4. The composition according to any one of claims 1 to 3, wherein the indacaterol or a pharmaceutically acceptable salt thereof is present as a free base or as a citrate salt.

5. The composition according to any one of claims 1 to 4, wherein the concentration of indacaterol is 200 μg / mL to 1.5 mg / mL.

6. The composition according to any one of claims 1 to 5, wherein the glycopyrronium or a pharmaceutically acceptable salt thereof is present as glycopyrronium chloride or glycopyrronium citrate.

7. The composition of any one of claims 1 to 6, wherein the concentration of glycopyrronium is 200 μg / mL to 350 μg / mL.

8. The composition according to any one of claims 2 to 7, wherein the anti-crystallization agent is a polymer or a surfactant.

9. The composition according to any one of claims 1 to 8, wherein the anticrystallization agent prevents crystallization of indacaterol, glycopyrronium or a pharmaceutically acceptable salt thereof.

10. The composition according to any one of claims 1 to 9, further comprising a solubilizer.

11. The composition of claim 10, wherein the solubilizing agent is cyclodextrin.

12. The composition according to any one of claims 1 to 11, further comprising one or more tonicity adjusting agents.

13. The composition of claim 12, wherein the composition further comprises sodium chloride and mannitol.

14. The composition of any one of claims 11 to 13, wherein the composition comprises two or more tonicity adjusting agents, each individually present at a concentration of about 1 mM to about 500 mM.

15. The composition of claim 14, wherein the first tonicity adjusting agent is present at a concentration of about 100 mM to about 300 mM.

16. The composition of claim 14 or 15, wherein the second tonicity adjusting agent is present at a concentration of about 1 mM to about 50 mM.

17. The composition according to any one of claims 1 to 16, further comprising a co-solvent.

18. The composition of claim 17, wherein the co-solvent is an alcohol.

19. The composition of claim 18, wherein the co-solvent is selected from ethanol and ethylene glycol.

20. The composition of any one of claims 17 to 19, wherein the co-solvent is present in an amount of about 0.1% v / v to about 10% v / v.

21. The composition of any one of claims 1 to 16, wherein the composition is free of a co-solvent.

22. The composition of any one of claims 1 to 21, further comprising a buffer.

23. The composition of claim 22, wherein the buffer comprises an anion selected from the group consisting of acetate, bromide, chloride, citrate, furoate, fumarate, maleate, malate, propionate, succinate, sulfate, tartrate, and xinafoate.

24. The composition of claim 22 or 23, wherein the buffer is prepared from a combination of citric acid and trisodium citrate or a combination of citric acid and sodium hydroxide.

25. The composition of any one of claims 1 to 24, wherein the pH of the composition is from 2 to 6.

26. The composition of any one of claims 1 to 25, wherein the pH of the composition is from 2.5 to 4.

5.

27. The composition of any one of claims 1 to 26, wherein the pH of the composition is from 3.0 to 4.

0.

28. The composition of any one of claims 1 to 27, further comprising one or more additional pharmaceutical agents.

29. The composition of claim 28, wherein the additional agent is an inhaled corticosteroid.

30. The composition of claim 29, wherein the inhaled corticosteroid is mometasone or a pharmaceutically acceptable salt thereof.

31. The composition of any one of claims 1 to 30, wherein the indacaterol or a pharmaceutically acceptable salt thereof exhibits less than 5% degradation over a period of at least 90 days.

32. The composition of claim 31, wherein the composition is stored at a temperature of about 25°C and a relative humidity of about 60%.

33. The composition of claim 31, wherein the composition is stored at a temperature of about 5°C.

34. A composition according to any one of claims 1 to 11, further comprising one or more tonicity adjusting agents; and Buffer.

35. The composition according to claim 34, wherein The one or more tonicity adjusting agents are mannitol and sodium chloride; and The buffer comprises citrate.

36. The composition according to claim 35, wherein Mannitol is present at a concentration of 100 mM to 400 mM; Sodium chloride is present at a concentration of 1 mM to 20 mM; and pH is 3 to 4.

37. The composition according to claim 36, wherein Indacaterol is present at approximately 500 μg / mL; Glycopyrronium was present at approximately 285 μg / mL; mannitol is present at a concentration of about 200 mM; and Sodium chloride is present at a concentration of about 10 mM; and The pH is 3.0 to 3.

5.

38. The composition of any one of claims 1-37, wherein the composition is free of particles after storage at 5°C for at least 26 weeks.

39. A method of treating a respiratory disorder, an inflammatory disorder or an obstructive airways disease, the method comprising delivering a pharmaceutical composition according to any one of claims 1 to 38 to the lungs of a patient in need thereof.

40. The method of claim 39, wherein the respiratory disorder, inflammatory disorder or obstructive airways disease is COPD.

41. The method of claim 39 or 40, wherein the composition has been stored for a period of at least 52 weeks.

42. The method of claim 41, wherein the composition is stored at room temperature for the entire period of time.

43. The method of any one of claims 39-42, wherein a breath-actuated vibrating mesh nebulizer is used to aerosolize the pharmaceutical composition.

44. A method of aerosolising a composition according to any one of claims 1 to 38, the method comprising contacting a vibrating mesh screen with the liquid formulation.

45. A method of aerosolising a composition according to any one of claims 1 to 38, the method comprising aerosolising the composition by means of a jet nebuliser, an ultrasonic nebuliser or a soft mist inhaler.

46. ​​A kit comprising A composition according to any one of claims 1 to 38; and A device for aerosolizing said pharmaceutical composition.

Images