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WO2024206662A1 - Formulations liquides d'indacatérol et de glycopyrronium - Google Patents

Formulations liquides d'indacatérol et de glycopyrronium Download PDF

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Publication number
WO2024206662A1
WO2024206662A1 PCT/US2024/022018 US2024022018W WO2024206662A1 WO 2024206662 A1 WO2024206662 A1 WO 2024206662A1 US 2024022018 W US2024022018 W US 2024022018W WO 2024206662 A1 WO2024206662 A1 WO 2024206662A1
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WO
WIPO (PCT)
Prior art keywords
composition
indacaterol
concentration
pharmaceutically acceptable
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/022018
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English (en)
Inventor
Mei-Chang Kuo
Keith Try Ung
John Nigel Pritchard
Blaine Bueche
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AeroRx Therapeutics Inc
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AeroRx Therapeutics Inc
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Filing date
Publication date
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Publication of WO2024206662A1 publication Critical patent/WO2024206662A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • API active pharmaceutical agent
  • LAA long acting beta agonist
  • LAMA long acting muscarinic antagonist
  • ICS inhaled corticosteroid
  • DPIs dry powder inhalers
  • pMDIs metered dose pressurized inhalers
  • SMIs soft mist inhalers
  • compositions that can be more easily administered are desired, particularly for patient populations that cannot effectively take advantage of currently available treatments.
  • compositions of indacaterol, or a pharmaceutically acceptable salts thereof, and glycopyrronium, or pharmaceutically acceptable salts thereof are provided herein.
  • the present case claims formulations with high concentrations of active pharmaceutical with long-term stability and solubility upon storage, including storage a low temperatures.
  • the ability of the compositions to maintain a high concentration over long periods of storage a low temperature is an advantage to usability over similar compositions that exhibit crystallization or precipitation over long periods of storage at low temperature, as that crystallization and/or precipitation negatively impacts drug concentration and, by extension, drug efficacy over time.
  • the low concentration of chloride results in the lack of crystallization and/or precipitation upon long-term storage at low temperature, such as 5 °C.
  • a pharmaceutical composition comprising from about 20 weight percent to 99.9 weight percent water; indacaterol, or a pharmaceutically acceptable salt thereof, present at a concentration of about 100 pg/mL to about 2 mg/mL; glycopyrronium, or a pharmaceutically acceptable salt thereof, present at a concentration of about 50 pg/mL to about 1.5 mg/mL; and wherein the composition has a concentration of chloride ion of less than about 10 mM.
  • a pharmaceutical composition comprising from about 20 weight percent to 99.9 weight percent water; indacaterol, or a pharmaceutically acceptable salt thereof, present at a concentration of about 100 pg/mL to about 2 mg/mL; glycopyrronium, or a pharmaceutically acceptable salt thereof, present at a concentration of about 50 pg/mL to about 1.5 mg/mL; and wherein the composition is free of precipitate after 25 weeks of storage at 5 °C.
  • the indacaterol or pharmaceutically acceptable salt thereof is from a source of indacaterol free base, indacaterol citrate, or indacaterol acetate.
  • concentration of indacaterol or pharmaceutically acceptable salt thereof is about 200 pg/mL to about 475 pg/mL.
  • concentration of indacaterol or pharmaceutically acceptable salt thereof is about 300 pg/mL to about 450 pg/mL.
  • the concentration of indacaterol or pharmaceutically acceptable salt thereof is about 375 pg/mL to about 425 pg/mL.
  • the concentration of indacaterol or pharmaceutically acceptable salt thereof is about 400 pg/mL. In some embodiments, the concentration of indacaterol or pharmaceutically acceptable salt thereof is about 900 pg/mL to about 1.5 mg/mL.
  • the glycopyrronium or pharmaceutically acceptable salt thereof is from a source of glycopyrronium bromide.
  • the concentration of glycopyrronium or pharmaceutically acceptable salt thereof is about 100 pg/mL to about 300 pg/mL.
  • the concentration of glycopyrronium or pharmaceutically acceptable salt thereof is about 150 pg/mL to about 250 pg/mL.
  • the concentration of glycopyrronium or pharmaceutically acceptable salt thereof is about 175 pg/mL to about 225 pg/mL.
  • the concentration of glycopyrronium or pharmaceutically acceptable salt thereof is about 200 pg/mL.
  • the concentration of glycopyrronium or pharmaceutically acceptable salt thereof is about 400 pg/mL to about 800 pg/mL.
  • the composition further comprises a tonicity modifier.
  • the tonicity modifier is mannitol.
  • the tonicity modifier is present at a concentration of about 50 mM to about 300 mM.
  • the tonicity modifier is present at a concentration of about 100 mM to about 200 mM.
  • the tonicity modifier is present at a concentration of about 125 mM to about 175 mM.
  • the tonicity modifier is present at a concentration of about 150 mM.
  • the tonicity modifier is present at a concentration of about 100 mM to about 500 mM.
  • the composition comprises a co-solvent in an amount of 0% v/v to about 5% v/v co-solvent. In some embodiments, the composition comprises a cosolvent in an amount of 0% v/v to about 2% v/v organic solvent. In some embodiments, the composition is free of a co-solvent or comprises a co-solvent only as a contaminant.
  • the composition comprises a co-solvent.
  • the co-solvent is ethanol or ethylene glycol.
  • the cosolvent is present in an amount of about 5% v/v to about 50% v/v of the composition.
  • the co-solvent is present in an amount of about 15% v/v to about 35% v/v.
  • the composition comprises 0 mM to about 5 mM chloride ion.
  • the composition comprises 0 mM to about 2 mM chloride ion.
  • the composition comprises 0 mM to about 1 mM chloride ion.
  • the composition is free of chloride or comprises chloride only as a contaminant.
  • the glycopyrronium or pharmaceutically acceptable salt thereof is from a source of glycopyrronium other than glycopyrronium bromide.
  • the composition has a concentration of halide ion of 0 mM to about 5 mM. In some embodiments, the composition has a concentration of halide ion of 0 mM to about 2 mM. In some embodiments, the composition has a concentration of halide ion of 0 to about 1 mM. In some embodiments, the composition is free of halide ion or comprises halide ion only as a contaminant.
  • the composition further comprises a buffer.
  • the buffer comprises an anion selected from the group consisting of acetate, citrate, furoate, fumarate, maleate, malate, propionate, succinate, sulfate, tartrate, or xinafoate.
  • the buffer comprises a citrate or acetate ion.
  • the buffer comprises a citrate ion.
  • the buffer comprises an acetate ion.
  • the composition has a pH of about 2 to about 5.
  • the composition has a pH of about 2.5 to about 4.
  • the composition has a pH of about 3.0 to about 3.5.
  • the composition further comprises an anti-crystallization agent.
  • the anti-crystallization agent is a polymer or surfactant.
  • the anti-crystallization agent is hydroxypropyl methylcellulose (HPMC).
  • the composition further comprises a solubilizing agent.
  • the solubilizing agent is a cyclodextrin.
  • the indacaterol or pharmaceutically acceptable salt thereof is present at a concentration of 350 pg/mL to 450 pg/mL; the glycopyrronium or pharmaceutically acceptable salt thereof is present at a concentration of 150 pg/mL to 250 pg/mL; the composition further comprises mannitol at a concentration of 100 pg/mL to 200 pg/mL; and the composition is buffered at a pH of 3.0 to 3.5.
  • the indacaterol or pharmaceutically acceptable salt thereof is present at a concentration of about 400 pg/mL; glycopyrronium or pharmaceutically acceptable salt thereof is present at a concentration of about 200 pg/mL; the composition further comprises mannitol at a concentration of about 150 mM; and the composition is buffered at a pH of 3.2 to 3.4.
  • the indacaterol or pharmaceutically acceptable salt thereof exhibits less than 5% degradation for a period of at least 90 days.
  • 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. In some embodiments, the indacaterol or pharmaceutically acceptable salt thereof in the composition does not crystallize for a period of 25 weeks. In some embodiments, the composition is stored at a temperature of about 22 °C. In some embodiments, the composition is stored at a temperature of about 5 °C.
  • a method of treating a respiratory disorder, inflammatory disorder, or obstructive airway disease comprising delivering the pharmaceutical composition of any one of claims 1 to 58 to the lungs of a patient in need thereof.
  • the respiratory disorder, inflammatory disorder, or obstructive airway disease is COPD.
  • the composition has been stored for a period of at least 52 weeks.
  • the composition has been stored for the full period of time at a temperature of about 22 °C.
  • the composition has been stored for the full period of time at about 5 °C.
  • a breath-actuated vibrating mesh nebulizer is used to aerosolize the pharmaceutical composition.
  • a method of aerosolizing the composition of any one of claims 1 to 58 comprising aerosolizing the composition via a jet nebulizer, ultrasonic nebulizer, or a soft mist inhaler.
  • kits comprising the composition of any one of claims 1 to 58; and a device for aerosolizing the pharmaceutical composition.
  • a method of preparing an aqueous composition of indacaterol, or a pharmaceutically acceptable salt thereof, and glycopyrronium, or a pharmaceutically acceptable salt thereof comprising steps a) and b): a) adding indacaterol, or a pharmaceutically acceptable salt thereof, and glycopyrronium, or a salt thereof, to a liquid to form a mixture; and b) adjusting a pH of the mixture by adding citric acid or acetic acid to obtain the composition.
  • FIG. 1 is a staggered chromatogram of indacaterol samples from the forced degradation experiment in Example 1 showing the minimal degradation of indacaterol samples in aqueous solutions over time.
  • FIG. 2A is a graph of the pH of formulas F2-F9 at various time points during a 90 day storage at low temperature showing that the pH is stable for the duration of the storage period.
  • FIG. 2B is a graph of the pH of formulas F2-F9 at various time points during a 90 day storage at room temperature showing that the pH is stable for the duration of the storage period.
  • FIG. 2C is a graph of the pH of formulas F2-F9 at various time points during a 90 day storage at high temperature showing that the pH is stable for the duration of the storage period.
  • FIG. 3 A is a graph of indacaterol concentration in formulas F2-F9 at various time points during a 90 day storage period at low temperature showing that the concentration of indacaterol is maintained during the storage period.
  • FIG. 3B is a graph of indacaterol concentration in formulas F2-F9 at various time points during a 90 day storage period at room temperature showing that the concentration of indacaterol is maintained during the storage period.
  • FIG. 3C is a graph of indacaterol concentration in formulas F2-F9 at various time points during a 90 day storage period at high temperature showing that the concentration of indacaterol is maintained during the storage period.
  • FIG. 4 is a chromatogram showing product-related impurities associated with Formulation F5 and impurities in the indacaterol raw material.
  • FIG. 5 is a graph of delivered dose vs. charge volume for several aqueous indacaterol compositions.
  • FIG. 6 is a graph of deposited dose vs. charge volume for several aqueous indacaterol formulations.
  • FIG. 7 is a chromatogram showing indacaterol and its impurities from Formulation G7.
  • FIG. 8 is a chromatogram showing glycopyrronium and its impurities from Formulation G9.
  • the disclosure encompasses aqueous compositions (which may also be referred to herein as aqueous formulations) of indacaterol, or a pharmaceutically acceptable salt thereof, and glycopyrronium, or a pharmaceutically acceptable salt thereof, that can, in some embodiments, include one or more excipients that are used, among other things, to modify indacaterol and/or glycopyrronium solubility, adjust tonicity, or control pH.
  • the disclosure also relates to methods of treating respiratory disorders using the compositions, to methods of making the compositions, and to kits that contain the compositions.
  • the present disclosure relates to aqueous compositions of indacaterol, or a pharmaceutically acceptable salt thereof, and glycopyrronium, or a pharmaceutically acceptable salt thereof, to treat patients with respiratory diseases, including chronic obstructive pulmonary disorder (COPD) and asthma.
  • COPD chronic obstructive pulmonary disorder
  • the present invention further minimizes or eliminates the need for patient coordination and inspiratory effort by allowing the indacaterol and glycopyrronium, or pharmaceutically acceptable salts thereof, to be administered with devices such as breath-actuated vibrating mesh nebulizers. Due to the relatively low aqueous solubility reported for these compounds, particularly indacaterol, a suspension formulation may seem desirable. However, solution compositions offer particular advantages, such as an easier formulation and a higher concentration of the compounds.
  • a liquid composition of indacaterol and glycopyrronium is provided with a sufficiently high concentration of the active agents to ensure a short dosing time and sufficient stability to be stored at room temperature.
  • the base form of indacaterol and/or glycopyrronium is used to allow solubility and stability evaluation without the effect of counter ions.
  • the base form of both indacaterol and glycopyrronium is used to allow solubility and stability evaluation without the effect of counter ions.
  • liquid composition of indacaterol and glycopyrronium is provided with a sufficiently high concentration of the active agents to ensure a short dosing time and sufficient stability to be stored at low temperature, for example, at 5 °C.
  • Precipitate in solutions that are stored cold will reduce efficacy of formulations due to a reduction in drug available to be aerosolized by a device. Therefore, solutions that can withstand long durations of storage at cold temperatures without precipitation or degradation would useful.
  • compositions are non-trivial due to solubility issues with the compounds, particularly indacaterol.
  • aqueous solutions disclosed herein can be tuned to be isotonic, which would allow them to be safely and effectively administered to patients, even those with significant breathing difficulties.
  • many other commonly used LABA pharmaceuticals e.g., formoterol
  • LABA pharmaceuticals are not stable in aqueous solution at room temperature (see WO 2001/89480, incorporated herein by reference), thereby requiring refrigerated storage during distribution and use.
  • the aqueous compositions of indacaterol in the present disclosure are stable at room temperature for long periods of time.
  • indacaterol e.g., indacaterol and glycopyrronium
  • the disease is COPD.
  • the disease is asthma.
  • a composition is administered to an individual with insufficient inspiratory effort for DPIs or having insufficient device actuation / inhalation coordination for MDIs / SMIs.
  • the composition is administered to an individual via a breath-actuated vibrating mesh nebulizer.
  • the individual being treated is a human.
  • Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, descriptions referring to “about X” includes descriptions of “X” per se and descriptions referring to from “about X” to “about Y” includes descriptions of from “X” to “Y” per se.
  • treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired results include, but are not limited to, one or more of the following: decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease, and/or prolonging survival of individuals.
  • the term “individual” or “patient” is a mammal, including humans.
  • a patient includes, but is not limited to, human, bovine, horse, feline, canine, rodent, or primate.
  • the patient is human.
  • the patient (such as a human) may have advanced disease or lesser extent of disease.
  • an effective amount intends such amount of a composition which should be effective in a given therapeutic form.
  • an effective amount may be in one or more doses, z.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint.
  • An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
  • Suitable doses of any of the co-administered composition may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the composition.
  • “pharmaceutically acceptable,” refer to a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • weight percent refers to the percentage of a component of a composition by weight. A component that is present at “5 weight percent” takes up 5%, by weight, of the total weight of the composition.
  • % w/v refers to a concentration defined by “g solute / 100 mL of solution.” For example, a composition that comprises 0.5 % w/v of cyclodextrin contains 0.5 g of cyclodextrin per 100 mL of solution.
  • % v/v refers to a concentration of a liquid in another liquid by comparing their relative volumes. For example, a composition that comprises 20% v/v of ethanol contains 20 mL of ethanol per 100 mL of the total solution.
  • chloride and “chloride ion” refer to the solubilized ion CF, which is commonly present in aqueous solutions.
  • the source of CF in solutions can be. for example, ionic compounds, such as NaCl, which are known to separate into solubilized Na + and CF ions upon dissolving in aqueous solutions.
  • halide and “halide ion” refer to solubilized halide ions such as CF, Br , and F’.
  • Sources of halide ions in solutions can be, for example, ionic compounds, such as NaCl, KBr, and NaF, wherein the solids are known to separate into cations and anions upon dissolving in aqueous solutions.
  • references to a source of a particular chemical mean that the chemical was added from a particular stock that may not be chemically conserved the chemical environment of the composition at equilibrium.
  • the sodium is from a source a NaCl means that while sodium is in the composition, and it was added in the form of NaCl, it may exist in another form in the composition at equilibrium (such as dissolved Na + ) ions
  • “from a source of indacaterol free base” means that the free base of indacaterol was used to make the composition, but it is not claimed that the indacaterol must remain in that form (as a free base) in given composition to fall within the scope of that language.
  • references to “from a source of x” herein includes (and describes) variations comprising x per se.
  • descriptions referring to “the indacaterol is from a source of indacaterol free base” include descriptions wherein “the indacaterol is present in the form of a free base” per se.
  • the term “contaminant” refers to an undesirable component of a mixture or composition.
  • a contaminant is preferably excluded from the composition, but may be present in trace amounts due to impurities in the sources of chemicals used to prepare the mixture or composition.
  • the term “the composition is free of x or comprises x only as a contaminant” means that x has not been intentionally added to the composition and therefore may be absent or may be present in trace amounts, but, if present in trace amounts, does not have a significant impact on the properties of the composition.
  • indacaterol refers to (R)-5-[2-(5,6-Diethylindan-2-ylamino)-l- hydroxyethyl]-8hydroxy-lH-quinolin-2-one, which may exist as the free base form or a salt thereof.
  • salts of indacaterol are indacaterol maleate, indacaterol acetate, and indacaterol citrate. The structure of indacaterol is shown below:
  • glycoscopyrronium refers to the (l,l-dimethylpyrrolidin-l-ium-3-yl) 2- cyclopentyl-2-hydroxy-2-phenylacetate ion, which contains two chiral centers and is often administered therapeutically as a racemic mixture of the (R, S)' and (S,R) enantiomers.
  • glycopyrrolate is also known as glycopyrrolate.
  • glycopyrronium bromide is glycopyrronium bromide. The structure of glycopyrronium is shown below:
  • compositions provided are notable in that indacaterol and glycopyrronium are substantially dissolved and stable over a significant period of time in an aqueous solution under a variety of conditions.
  • the stability and/or extent of degradation is assessed by appearance of the composition.
  • the stability and/or extent of degradation of indacaterol and/or glycorronium, or a pharmaceutically acceptable salt of either of the foregoing is assessed by pH of the composition.
  • the stability and/or extent of degradation of indacaterol and/or glycorronium, or a pharmaceutically acceptable salt of either of the foregoing is assessed by concentration of indacaterol and/or glycopyrronium in the composition.
  • the stability and/or extent of degradation of indacaterol and/or glycorronium, or a pharmaceutically acceptable salt of either of the foregoing is assessed by the concentration or amount of impurities in the composition. In some embodiments, the stability and/or extent of degradation of indacaterol and/or glycorronium, or a pharmaceutically acceptable salt of either of the foregoing, is assessed by osmolality of the composition.
  • aqueous compositions comprising indacaterol, or a pharmaceutically acceptable salt thereof, wherein the compositions exhibit less than 10%, 20%, 30%, 40%, or 50% indacaterol degradation upon storage for a period of a year. In some embodiments, the compositions exhibit less than 10%, 20%, 30%, 40%, or 50% indacaterol degradation upon storage for a period of 2 years. In some embodiments, the compositions exhibit less than 10%, 20%, 30%, 40%, or 50% indacaterol degradation upon storage for a period of 5 years.
  • the compositions exhibit less than 10%, 20%, 30%, 40%, or 50% indacaterol degradation upon storage for a period of 10 years.
  • the indacaterol is in the free base form.
  • the indacaterol is present as a pharmaceutically acceptable salt.
  • the indacaterol is present as indacaterol maleate, indacaterol citrate, or indacaterol acetate, or a mixture of the foregoing.
  • the storage conditions are 40 °C with 75% relative humidity. In some embodiments, the storage conditions are 25 °C with 60% relative humidity. In some embodiments, the storage conditions is 5 °C.
  • the compositions exhibit less than 10%, 20%, 30%, 40%, or 50% indacaterol degradation upon storage for a period of 30, 60, or 90 days. In some embodiments, the compositions exhibit less than 10%, 20%, 30%, 40%, or 50% indacaterol degradation upon storage for a period of 1, 2, 3, 4, or 5 weeks. In some embodiments, the compositions exhibit less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% degradation of indacaterol, glycopyrronium, or both over a storage period of 8 weeks, 26 weeks, 52 weeks, or 104 weeks. In some embodiments, the storage is storage at room temperature. In some embodiments, the storage is storage at 40 °C and 75% relative humidity.
  • the storage is 25 °C and 60% relative humidity. In some embodiments, the storage is at 5 °C. In some embodiments, the compositions exhibit less than 10% degradation of indacaterol, or a pharmaceutically acceptable salt thereof, and glycopyrronium, or a pharmaceutically acceptable salt thereof, over a period of at least 25 or 52 weeks when stored at room temperature, 22 °C or at 5 °C. In some embodiments, the compositions exhibit less than 10% degradation of indacaterol when stored for at least 52 weeks at 5 °C.
  • the composition comprises 300 pg/mL to 500 pg/mL indacaterol free base, is free of chloride or contains chloride only as a contaminant, exhibits less than 10% degradation over at least 52 weeks at 5 °C, and is free of precipitate and particulate matter when stored for 52 weeks at 5 °C.
  • the composition comprising indacaterol, or a pharmaceutically acceptable salt thereof, and glycopyrronium, or a pharmaceutically acceptable salt thereof remains free of particulates over a storage period.
  • 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 long.
  • the storage period is at least 12 weeks or at least 25 weeks.
  • the compositions are stored at room temperature for the entirety of the storage period.
  • the compositions are not refrigerated (including frozen) for the full duration of the storage period.
  • the storage is storage at room temperature.
  • the storage is storage at 40 °C and 75% relative humidity. In some embodiments, the storage is 25 °C and 60% relative humidity. In some embodiments, the storage is at 5 °C. In some embodiments, the storage is at 22 °C.
  • 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, glycopyrronium is present in a form other than bromide and the composition further comprises an anti-crystallization agent.
  • the indacaterol is from a source of indacaterol free base or is present in the form of indacaterol free base and the glycopyrronium is from a source of glycopyrronium bromide or is present in the form of glycopyrronium bromide.
  • the high concentration of indacaterol dissolved in the aqueous compositions is believed to be attributed to particular characteristics of the aqueous composition.
  • adding indacaterol to the composition in its free base form enables the high concentration of indacaterol dissolved in the composition.
  • the presence of a solubilizing agent for example, cyclodextrin
  • indacaterol in its free base form and including a solubilizing agent in the aqueous composition enables the high concentration of indacaterol dissolved in the composition.
  • a low concentration of chloride ions, including compositions that are free of chloride ion or only comprise chloride as a contaminant enables the high concentration of indacaterol dissolved in the composition.
  • indacaterol and glycopyrronium are used in order to meet those requirements.
  • indacaterol free base and glycopyrronium bromide are used in a composition that has a low concentration of chloride ions, including compositions that are free of chloride ion or only comprise chloride as a contaminant, to enables the high concentrations of indacaterol and glycorpyrronium required to meet dosing requirements.
  • a concentration of indacaterol greater than 300 pg/mL is necessary to meet treatment targets and/or guidelines.
  • a concentration of indacaterol greater than 300 pg/mL and a glycopyrronium concentration greater than 150 pg/mL are required to meet dosing requirements.
  • a concentration of indacaterol greater than 800 pg/mL is necessary to meet treatment targets and/or guidelines.
  • a concentration of indacaterol greater than 800 pg/mL and a glycopyrronium concentration greater than 300 pg/mL are required to meet dosing requirements.
  • the composition may have a low concentration of chloride, including compositions that are free of chloride ion or only comprise chloride as a contaminant, and may be stable and resist formation of precipitate upon storage at 5 °C for at least 25, 26, or 52 weeks.
  • the device used to deliver the composition is a vibrating mesh device.
  • a concentration of indacaterol greater than 300 pg/mL and a glycopyrronium concentration greater than 150 pg/mL are required to meet dosing requirements for the vibrating mesh device.
  • the composition may have a low concentration of chloride, including compositions that are free of chloride ion or only comprise chloride as a contaminant, and may be stable and resist formation of precipitate upon storage at room temperature, 22 °C, 25 °C, or 5 °C for at least 25, 26, or 52 weeks.
  • the composition may have a low concentration of chloride, including compositions that are free of chloride ion or only comprise chloride as a contaminant, and may be stable and resist formation of precipitate upon storage at 5 °C for at least 25 weeks.
  • the indacaterol may be from a source of indacaterol free base and/or the glycopyrronium may be from a source of glycopyrronium bromide.
  • the device used to deliver the composition is a soft mist inhaler device.
  • a concentration of indacaterol greater than 700 pg/mL and a glycopyrronium concentration greater than 300 pg/mL are required to meet dosing requirements for the soft mist inhaler device.
  • the composition may have a low concentration of chloride, including compositions that are free of chloride ion or only comprise chloride as a contaminant, and may be stable and resist formation of precipitate upon storage at room temperature, 22 °C, 25 °C, or 5 °C for at least 25, 26, or 52 weeks.
  • the composition may have a low concentration of chloride, including compositions that are free of chloride ion or only comprise chloride as a contaminant, and may be stable and resist formation of precipitate upon storage at 5 °C for at least 25 weeks.
  • the indacaterol may be from a source of indacaterol free base and/or the glycopyrronium may be from a source of glycopyrronium bromide.
  • the aqueous compositions comprising indacaterol and glycopyrronium, or pharmaceutically acceptable salts thereof comprise 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 compositions comprising indacaterol and glycopyrronium, or pharmaceutically acceptable salts thereof, comprise more than about any one of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% water by weight.
  • the aqueous compositions comprising indacaterol and glycopyrronium, or pharmaceutically acceptable salts thereof comprise about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% water by weight. In some embodiments, the compositions comprise from about any one of 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% to about 99.9% water by weight. In some embodiments, the compositions comprise from about any one of 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% to about 95% water by weight. In some embodiments, the compositions comprise from about any one of 20%, 30%, 40%, 50%, 60%, 70% or 80% to about 90% water by weight.
  • the compositions comprise from about any one of 20%, 30%, 40%, 50%, 60% or 70% to about 80% water by weight. In some embodiments, the compositions comprise from about any one of 20%, 30%, 40%, 50% or 60% to about 70% water by weight. In some embodiments, the compositions comprise from about any one of 20%, 30%, 40%, or 50% to about 60% water by weight. In some embodiments, the compositions comprise from about any one of 20%, 30%, or 40% to about 50% water by weight. In some embodiments, the composition comprises from about 20% to about 30% water by weight. In some embodiments, the composition comprises from about 20% to about 40% water by weight.
  • the indacaterol may be from a source of indacaterol free base and/or the glycopyrronium may be from a source of glycopyrronium bromide.
  • the water used may be deionized or purified, including ultrapure water such as “Milli-Q” water.
  • an aqueous composition comprising indacaterol and glycopyrronium, or pharmaceutically acceptable salts thereof, wherein the indacaterol is present at a concentration from about 100 pg/mL to about 2 mg/mL.
  • the indacaterol or pharmaceutically acceptable salt thereof is present at a concentration up to about 2 mg/mL, up to about 1.5 mg/mL, up to about 1 mg/mL, up to about 900 pg/mL, up to about 800 pg/mL, up to about 700 pg/mL, up to about 600 pg/mL, up to about 500 pg/mL, up to about 400 pg/mL, up to about 300 pg/mL, up to about 200 pg/mL, up to about 150 pg/mL, or up to about 100 pg/mL.
  • the indacaterol or pharmaceutically acceptable salt thereof is at a concentration from about 100 pg/mL to about 2 mg/mL, to about 1.5 mg/mL, to about 1 mg/mL, to about 900 pg/mL, to about 800 pg/mL, to about 700 pg/mL, to about 600 pg/mL, to about 500 pg/mL, to about 400 pg/mL, to about 300 pg/mL, to about 200 pg/mL, or to about 150 pg/mL.
  • the indacaterol or pharmaceutically acceptable salt thereof is present at a concentration from about 150 pg/mL to about 2 mg/mL, to about 1.5 mg/mL, to about 1 mg/mL, to about 900 pg/mL, to about 800 pg/mL, to about 700 pg/mL, to about 600 pg/mL, to about 500 pg/mL, to about 400 pg/mL, to about 300 pg/mL, or to about 200 pg/mL.
  • the indacaterol or pharmaceutically acceptable salt thereof is present from about 200 pg/mL to about 2 mg/mL, to about 1.5 mg/mL, to about 1 mg/mL, to about 900 pg/mL, to about 800 pg/mL, to about 700 pg/mL, to about 600 pg/mL, to about 500 pg/mL, to about 400 pg/mL, or to about 300 pg/mL.
  • the indacaterol or pharmaceutically acceptable salt thereof is present from about 300 pg/mL to about 2 mg/mL, to about 1.5 mg/mL, to about 1 mg/mL, to about 900 pg/mL, to about 800 pg/mL, to about 700 pg/mL, to about 600 pg/mL, to about 500 pg/mL, or to about 400 pg/mL.
  • the indacaterol or pharmaceutically acceptable salt thereof is present from about 400 pg/mL to about 2 mg/mL, to about 1.5 mg/mL, to about 1 mg/mL, to about 900 pg/mL, to about 800 pg/mL, to about 700 pg/mL, to about 600 pg/mL, or to about 500 pg/mL.
  • the indacaterol or pharmaceutically acceptable salt thereof is present from about 500 pg/mL to about 2 mg/mL, to about 1.5 mg/mL, to about 1 mg/mL, to about 900 pg/mL, to about 800 pg/mL, to about 700 pg/mL, or to about 600 pg/mL. In some embodiments, the indacaterol or pharmaceutically acceptable salt thereof is present from about 600 pg/mL to about 2 mg/mL, to about 1.5 mg/mL, to about 1 mg/mL, to about 900 pg/mL, to about 800 pg/mL, or to about 700 pg/mL.
  • the indacaterol or pharmaceutically acceptable salt thereof is present from about 700 pg/mL to about 2 mg/mL, to about 1.5 mg/mL, to about 1 mg/mL, to about 900 pg/mL, or to about 800 pg/mL. In some embodiments, the indacaterol or pharmaceutically acceptable salt thereof is present from about 800 pg/mL to about 2 mg/mL, to about 1.5 mg/mL, to about 1 mg/mL, or to about 900 pg/mL. In some embodiments, the indacaterol or pharmaceutically acceptable salt thereof is present from about 900 pg/mL to about 2 mg/mL, to about 1.5 mg/mL, or to about 1 mg/mL.
  • the indacaterol or pharmaceutically acceptable salt thereof is present from about 1 mg/mL to about 2 mg/mL or to about 1.5 mg/mL. In some embodiments, the indacaterol or pharmaceutically acceptable salt thereof is present from about 1.5 mg/mL to about 2 mg/mL.
  • the indacaterol or pharmaceutically acceptable salt thereof is present at a concentration of about 2 mg/mL, about 1.5 mg/mL, about 1 mg/mL, about 900 pg/mL, about 800 pg/mL, about 700 pg/mL, about 600 pg/mL, about 500 pg/mL, about 400 pg/mL, about 300 pg/mL, about 200 pg/mL, about 150 pg/mL, or about 100 pg/mL.
  • the indacaterol or pharmaceutically acceptable salt thereof is present at a concentration of about 500 pg/mL, about 400 pg/mL, about 300 pg/mL, or about 200 pg/mL. In some embodiments, the indacaterol or pharmaceutically acceptable salt thereof is present at a concentration of about 500 pg/mL or about 400 pg/mL. In some embodiments, the indacaterol or pharmaceutically acceptable salt thereof is present at a concentration of about 400 pg/mL.
  • the concentrations of indacaterol above may be enabled by using indacaterol from a source of indacaterol free base and/or by reducing the concentration or eliminating chloride and/or halide. In any of the foregoing embodiments, the concentrations of indacaterol above may be enabled by using indacaterol from a source of indacaterol free base and/or by adding a co-solvent, such as ethanol, in an amount from 10% v/v to 40% v/v.
  • a co-solvent such as ethanol
  • an aqueous composition comprising indacaterol and glycopyrronium, or pharmaceutically acceptable salts thereof, is provided, wherein the glycopyrronium or pharmaceutically acceptable salt thereof is present at a concentration from about 50 pg/mL to about 1.5 mg/mL, as determined for the glycopyrronium ion. In some embodiments, the concentration is from about 50 pg/mL to any of about 100 pg/mL, about
  • the concentration is from about 100 pg/mL to any of about 150 pg/mL, about 200 pg/mL, about 250 pg/mL, about 300 pg/mL, about 350 pg/mL, about 400 pg/mL, about 450 pg/mL, about 500 pg/mL, about 550 gg/mL, about 600 gg/mL, about 650 gg/mL, about 700 gg/mL, about 750 gg/mL, about 800 gg/mL, about 900 gg/mL, about 1 mg/mL, about 1.25 mg/mL, or about 1.5 mg/mL.
  • the concentration is from about 150 gg/mL to any of about 200 gg/mL, about 250 gg/mL, about 300 gg/mL, about 350 gg/mL, about 400 gg/mL, about 450 gg/mL, about 500 gg/mL, about 550 gg/mL, about 600 gg/mL, about 650 gg/mL, about 700 gg/mL, about 750 gg/mL, about 800 gg/mL, about 900 gg/mL, about 1 mg/mL, about 1.25 mg/mL, or about 1.5 mg/mL.
  • the concentration is from about 200 gg/mL to any of about 250 gg/mL, about 300 gg/mL, about 350 gg/mL, about 400 gg/mL, about 450 gg/mL, about 500 gg/mL, about 550 gg/mL, about 600 gg/mL, about 650 gg/mL, about 700 gg/mL, about 750 gg/mL, about 800 gg/mL, about 900 gg/mL, about 1 mg/mL, about 1.25 mg/mL, or about 1.5 mg/mL.
  • the concentration is from about 250 gg/mL to any of about 300 gg/mL, about 350 gg/mL, about 400 gg/mL, about 450 gg/mL, about 500 gg/mL, about 550 gg/mL, about 600 gg/mL, about 650 gg/mL, about 700 gg/mL, about 750 gg/mL, about 800 gg/mL, about 900 gg/mL, about 1 mg/mL, about 1.25 mg/mL, or about 1.5 mg/mL.
  • the concentration is from about 300 gg/mL to any of about 350 gg/mL, about 400 gg/mL, about 450 gg/mL, about 500 gg/mL, about 550 gg/mL, about 600 gg/mL, about 650 gg/mL, about 700 gg/mL, about 750 gg/mL, about 800 gg/mL, about 900 gg/mL, about 1 mg/mL, about 1.25 mg/mL, or about 1.5 mg/mL.
  • the concentration is from about 350 gg/mL to any of about 400 gg/mL, about 450 gg/mL, about 500 gg/mL, about 550 gg/mL, about 600 gg/mL, about 650 gg/mL, about 700 gg/mL, about 750 gg/mL, or about 800 gg/mL.
  • the concentration is from about 400 gg/mL to any of about 450 gg/mL, about 500 gg/mL, about 550 gg/mL, about 600 gg/mL, about 650 gg/mL, about 700 gg/mL, about 750 gg/mL, about 800 gg/mL, about 900 gg/mL, about 1 mg/mL, about 1.25 mg/mL, or about 1.5 mg/mL.
  • the concentration is from about 450 gg/mL to any of about 500 gg/mL, about 550 gg/mL, about 600 gg/mL, about 650 gg/mL, about 700 gg/mL, about 750 gg/mL, about 800 gg/mL, about 900 gg/mL, about 1 mg/mL, about 1.25 mg/mL, or about 1.5 mg/mL.
  • the concentration is from about 500 gg/mL to any of about 550 gg/mL, about 600 gg/mL, about 650 gg/mL, about 700 gg/mL, about 750 gg/mL, about 800 gg/mL, about 900 gg/mL, about 1 mg/mL, about 1.25 mg/mL, or about 1.5 mg/mL.
  • the concentration is from about 550 gg/mL to any of about 600 gg/mL, about 650 gg/mL, about 700 gg/mL, about 750 gg/mL, about 800 gg/mL, about 900 gg/mL, about 1 mg/mL, about 1.25 mg/mL, or about 1.5 mg/mL. In some embodiments, the concentration is from about 600 gg/mL to any of about 650 gg/mL, about 700 pg/mL, about 750 pg/mL, about 800 pg/mL, about 900 pg/mL, about 1 mg/mL, about 1.25 mg/mL, or about 1.5 mg/mL.
  • the concentration is from about 650 pg/mL to any of about 700 pg/mL, about 750 pg/mL, about 800 pg/mL, about 900 pg/mL, about 1 mg/mL, about 1.25 mg/mL, or about 1.5 mg/mL. In some embodiments, the concentration is from about 700 pg/mL to any of about 750 pg/mL, about 800 pg/mL, about 900 pg/mL, about 1 mg/mL, about 1.25 mg/mL, or about 1.5 mg/mL.
  • the concentration is from about 750 pg/mL to any of about 800 pg/mL, about 900 pg/mL, about 1 mg/mL, about 1.25 mg/mL, or about 1.5 mg/mL. In some embodiments, the concentration is from about 800 pg/mL to any of about 900 pg/mL, about 1 mg/mL, about 1.25 mg/mL, or about 1.5 mg/mL. In some embodiments, the concentration is from about 900 pg/mL to any of about 1 mg/mL, about 1.25 mg/mL, or about 1.5 mg/mL. In some embodiments, the concentration is from about 1 mg/mL to about 1.25 mg/mL or about 1.5 mg/mL. In any of the foregoing embodiments, the glycopyrronium may be present from a source of glycopyrronium bromide.
  • the indacaterol is present at a concentration of about 100 pg/mL to about 2 mg/mL and the glycopyrronium is present at a concentration of about 50 pg/mL to about 1.5 mg/mL. In some embodiments, the indacaterol is present at a concentration of about 100 pg/mL to about 700 pg/mL and the glycopyrronium is present at a concentration of about 50 pg/mL to about 500 pg/mL.
  • the indacaterol is present at a concentration of about 300 pg/mL to about 500 pg/mL and the glycopyrronium is present at a concentration of about 100 pg/mL to about 300 pg/mL. In some embodiments, the indacaterol is present at a concentration of about 300 pg/mL to about 500 pg/mL and the glycopyrronium is present at a concentration of about 100 pg/mL to about 300 pg/mL, the composition is free of chloride or comprises chloride only as a contaminant, and is stable upon storage at 5 °C for a period of at least 25 weeks.
  • the indacaterol is from a source of indacaterol free base and is present at a concentration of about 300 pg/mL to about 500 pg/mL
  • the glycopyrronium is from a source of glycopyrronium bromide and is present at a concentration of about 100 pg/mL to about 300 pg/mL
  • the composition is free of chloride or comprises chloride only as a contaminant, and is stable upon storage at 5 °C for a period of at least 25 weeks concentration.
  • the composition may be suitable for use with a vibrating mesh device.
  • the composition may be used to treat a respiratory disorder, including COPD, by delivery to a subject in need thereof, including a human, by a vibrating mesh device.
  • a respiratory disorder including COPD
  • the indacaterol is present at a concentration of about 800 pg/mL to about 2 mg/mL and the glycopyrronium is present at a concentration of about 300 pg/mL to about 1 mg/mL.
  • the indacaterol is present at a concentration of about 900 pg/mL to about 1.5 mg/mL and the glycopyrronium is present at a concentration of about 400 pg/mL to about 900 pg/mL.
  • the indacaterol is present at a concentration of about 900 pg/mL to about 1.5 mg/mL and the glycopyrronium is present at a concentration of about 400 pg/mL to about 900 pg/mL, the composition is free of chloride or comprises chloride only as a contaminant, and is stable upon storage at 5 °C for a period of at least 25 weeks.
  • the indacaterol is from a source of indacaterol free base and is present at a concentration of about 900 pg/mL to about 1.5 mg/mL
  • the glycopyrronium is from a source of glycopyrronium bromide and is present at a concentration of about 400 pg/mL to about 900 pg/mL
  • the composition is free of chloride or comprises chloride only as a contaminant, and is stable upon storage at 5 °C for a period of at least 25 weeks concentration.
  • the composition may be suitable for use with a soft mist inhaler device.
  • the composition may be used to treat a respiratory disorder, including COPD, by delivery to a subject in need thereof, including a human, by a soft mist inhaler device.
  • glycopyrronium is present in a form other than bromide, such as glycopyrronium chloride, glycopyrronium acetate, or glycopyrronium citrate.
  • the composition further comprises an anticrystallization agent.
  • the glycopyrronium in the composition is from a source of glycopyrronium bromide.
  • the indacaterol in the composition is from a source of indacaterol free base and the glycopyrronium in the composition is from a source of glycopyrronium bromide.
  • all dosages referred to herein are given for the indacaterol free base, regardless of the form of indacaterol that is administered.
  • the indacaterol is from a source of an indacaterol salt.
  • the indacaterol salt is a water soluble salt of indacaterol.
  • the indacaterol salt has a solubility in water of at least 100 pg/mL, at least 200 pg/mL, at least 300 pg/mL, or at least 400 pg/mL in water.
  • the indacaterol salt has a solubility of at least 200 or at least 300 pg/mL in water.
  • the indacaterol salt has a solubility of at least 100 pg/mL, at least 200 pg/mL, at least 300 pg/mL, or at least 400 pg/mL in water at a pH of 3. In some embodiments, the indacaterol salt has a solubility of at least 100 pg/mL, at least 200 pg/mL, or at least 300 pg/mL at a pH of 4. In some embodiments, the indacaterol salt has a solubility of at least 100 pg/mL at a pH of 5.
  • glycopyrronium in the composition is from a source of a glycopyrronium salt.
  • the salt is a water soluble salt of glycopyrronium.
  • the glycopyrronium is from a source of glycopyrronium bromide.
  • glycopyrronium is from a source other than glycopyrronium bromide.
  • the glycopyrronium is from a source of glycopyrronium chloride, glycopyrronium acetate, or glycopyrronium citrate.
  • the composition remains free of particulate a storage period of 8 weeks, 26 weeks, 52 weeks, or 104 weeks.
  • the storage is storage at room temperature.
  • the storage is storage at 40 °C and 75% relative humidity.
  • the storage is 25 °C and 60% relative humidity.
  • the storage is at 5 °C.
  • the cyclodextrin is present from about 0.1 % w/v to about 1 % w/v. In some embodiments, the cyclodextrin is present from about 0.25 % w/v to about 1 % w/v. In some embodiments, the cyclodextrin is present from about 0.25 % w/v to about 5 % w/v. In some embodiments, the cyclodextrin is present from about 0.25 % w/v to about 10 % w/v. In some embodiments, the aqueous composition does not comprise solubilizing agent.
  • the aqueous composition comprises one or more tonicity modifiers.
  • the one or more tonicity modifiers are sodium chloride and mannitol.
  • the one or more tonicity modifier is either sodium chloride or mannitol.
  • the one or more tonicity modifier is mannitol.
  • the aqueous composition is isotonic.
  • the one or more tonicity modifier is present at a concentration from about any one of 10 mM, 20 mM, 30 mM, 50 mM, 100 mM, 200 mM, 300 mM or 400 mM to about 500 mM.
  • the one or more tonicity modifier is present at a concentration from about any one of 10 mM, 20 mM, 30 mM, 50 mM, 100 mM, 200 mM or 300 mM to about 400 mM. In some embodiments, the one or more tonicity modifier is present at a concentration from 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 modifier is present at a concentration from about 10 mM, 20 mM, 30 mM, 50 mM, or 100 mM, to about 200 mM. In some embodiments, two or more tonicity modifiers may each be individually present at any of ranges disclosed for a single tonicity modifier.
  • the aqueous composition comprises a tonicity modifier.
  • the tonicity modifier is mannitol.
  • mannitol is present at a concentration of 50 mM to any of about 100 mM, 150 mM, 200mM, 250 mM, or 300 mM.
  • mannitol is present at a concentration of 100 mM to any of about of about 150 mM, 200 mM, 250 mM, or 300 mM.
  • mannitol is present at a concentration of about 150 mM to any of about 200 mM, 250 mM, or 300 mM.
  • mannitol is present at a concentration of about 200 mM to 250 mM or 300 mM. In some embodiments, mannitol is present at a concentration of 250 mM to about 300 mM. In some embodiments, mannitol is present at a concentration of about 125 mM to about 175 mM. In some embodiments, mannitol is present at a concentration of about 150 mM.
  • the concentration of chloride or halide ion is from 0 mM to about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, or about 9 mM.
  • the mannitol is present at a concentration of about 200 mM to any of about 250 mM, about 300 mM, about 350 mM, about 400 mM, or about 500 mM. In some embodiments, the mannitol is present at a concentration of about 250 mM to any of about 300 mM, about 350 mM, about 400 mM, or about 500 mM. In some embodiments, the mannitol is present at a concentration of about 300 mM to any of about 350 mM, about 400 mM, or about 500 mM. In some embodiments, the mannitol is present at a concentration of about 350 mM to about 400 mM or about 500 mM.
  • mannitol is present at a concentration of about 150 mM to any of about 200 mM, 250 mM, or 300 mM. In some embodiments, mannitol is present at a concentration of about 200 mM to 250 mM or 300 mM. In some embodiments, mannitol is present at a concentration of about 250 mM to about 300 mM. In some embodiments, mannitol is present at a concentration of about 125 mM to about 175 mM. In some embodiments, mannitol is present at a concentration of about 150 mM.
  • the aqueous composition comprises a co-solvent.
  • the co-solvent is ethanol or ethylene glycol.
  • the cosolvent is present in an amount from about 0% v/v to about 0.1% v/v, 0.5% v/v, 1% v/v, 2.5% v/v, 5% v/v, or 10% v/v.
  • the co-solvent is present in an amount from about 15% v/v to any of about 20% v/v, about 25% v/v, about 30% v/v, about 35% v/v, about 40% v/v, about 45% v/v, or about 50% v/v. In some embodiments, the co-solvent is present in an amount from about 20% v/v to any of about 25% v/v, about 30% v/v, about 35% v/v, about 40% v/v, about 45% v/v, or about 50% v/v.
  • the co-solvent is present in an amount from about 25% v/v to any of about 30% v/v, about 35% v/v, about 40% v/v, about 45% v/v, or about 50% v/v. In some embodiments, the co-solvent is present in an amount from about 30% v/v to any of about 35% v/v, about 40% v/v, about 45% v/v, or about 50% v/v. In some embodiments, the co-solvent is present in an amount from about 35% v/v to any of about 40% v/v, about 45% v/v, or about 50% v/v.
  • the aqueous composition comprises a preservative.
  • the preservative comprises benzalkonium chloride.
  • the preservative comprises ethylenediaminetetraacetic acid (EDTA).
  • the composition comprises two or more preservatives.
  • the composition comprises benzalkonium chloride and EDTA.
  • the preservative is present at a concentration from about 0.001% to about 0.1%.
  • the preservative is present at a concentration of about 0.01% to about 0.1%.
  • the preservative is present at a concentration of about 0.001% to about 0.01%. In cases with multiple preservatives, each preservative may be individually present at any of the ranges recited above.
  • the aqueous compositions does not comprise a preservative.
  • the aqueous composition comprises an anti-crystallization agent.
  • the anti-crystallization agent is a polymer or surfactant.
  • the anti-crystallization agent is selected from the group consisting of a polyethylene glycol, a povidone, glycerin, propylene glycol, a polysorbate, or a poloxamer.
  • the anti-crystallization agent is Solutol HS 15, Kolliphor EL, ELP, or RH 40, HPMC (hydroxypropylmethylcellulose), Tween 20, Tween 80, or Poloxamer 124, 188, 237, 338, or 407.
  • anti-crystallization agent prevents precipitation, even in cases where the precipitate is not crystalline. In some embodiments, the anti-crystallization agent also prevents the formation of amorphous precipitate. In some embodiments, the anti-crystallization agent prevents crystallization or precipitation of indacaterol and/or glycopyrronium, or a pharmaceutically acceptable salt of either of the foregoing. In some embodiments, the anti-crystallization agent prevents crystallization or precipitation of indacaterol and/or glycopyrronium, or a pharmaceutically acceptable salt of either of the foregoing, from aqueous solution.
  • the anti-crystallization agent prevents crystallization or precipitation of indacaterol and/or glycopyrronium, or a pharmaceutically acceptable salt of either of the foregoing 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.
  • the aqueous composition comprises water and indacaterol as a free base.
  • the aqueous composition comprises water and a pharmaceutically acceptable salt of indacaterol, such as indacaterol maleate.
  • the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, and a solubilizing agent.
  • the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, and a buffer.
  • 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 modifier. 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 co-solvent. 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 modifier.
  • the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a buffer, and a co-solvent. 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 modifier. 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 co-solvent.
  • the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a solubilizing agent, a tonicity modifier, and a co-solvent.
  • the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a buffer, a tonicity modifier, and a co-solvent.
  • the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, and a preservative.
  • 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.
  • the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a buffer, and a preservative.
  • the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a tonicity modifier, and a preservative.
  • the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a co-solvent, and a preservative.
  • 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.
  • the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a solubilizing agent, a tonicity modifier, and a preservative.
  • the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a solubilizing agent, a co-solvent, and a preservative.
  • the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a buffer, a tonicity modifier, and a preservative.
  • the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a buffer, a co-solvent, and a preservative.
  • the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a tonicity modifier, a co-solvent, and a preservative.
  • 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 tonicity modifier, and a preservative.
  • 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 co-solvent, and a preservative.
  • the aqueous composition comprises water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, a solubilizing agent, a tonicity modifier, a co-solvent, and a preservative.
  • 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 tonicity modifier, a co-solvent, and a preservative.
  • 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 to be considered as though each were specifically and individually listed.
  • the aqueous composition comprises indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, one or more tonicity modifiers, a buffer, and an anti-crystallization agent.
  • the aqueous composition comprises indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, two tonicity modifiers, and a buffer.
  • the aqueous composition comprises indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, two tonicity modifiers, a buffer, and an anti-crystallization agent.
  • the aqueous composition comprises indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, one or more tonicity 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 the water, indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, solubilizing agent, buffer, tonicity modifier, co-solvent, and preservative may be present in any amounts as disclosed herein.
  • the composition comprises indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium and a pharmaceutically acceptable salt thereof, a tonicity modifier, and a buffer.
  • the composition comprises indacaterol or a pharmaceutically acceptable salt thereof, glycopyrronium and a pharmaceutically acceptable salt thereof, a tonicity modifier, and a buffer and is free of chloride ion or comprises chloride ion only as a contaminant.
  • the composition comprises indacaterol from a source of indacaterol free base, glycopyrronium from a source of glycopyrronium free base, mannitol, and a buffer comprising citrate or acetate.
  • the composition comprises indacaterol from a source of indacaterol free base, glycopyrronium from a source of glycopyrronium free base, mannitol, and a buffer comprising citrate or acetate and is free of chloride ion or comprises chloride ion only as a contaminant.
  • the composition comprises indacaterol from a source of indacaterol free base, glycopyrronium from a source of glycopyrronium free base, mannitol, and a buffer comprising citrate or acetate, wherein the composition is buffered to a pH of 3.0 to 3.5.
  • the composition comprises indacaterol from a source of indacaterol free base, glycopyrronium from a source of glycopyrronium free base, mannitol, and a buffer comprising citrate or acetate, wherein the composition is buffered to a pH of 3.0 to 3.5, and is free of chloride ion or comprises chloride ion only as a contaminant.
  • the composition comprises indacaterol and an additional pharmaceutical agent.
  • the additional pharmaceutical agent is an inhaled corticosteroid.
  • the inhaled corticosteroid is mometasone or a pharmaceutically acceptable salt thereof.
  • an aqueous combination provided herein comprising indacaterol or a pharmaceutically acceptable salt thereof further comprises two additional pharmaceutical agents.
  • an aqueous composition provided herein comprises indacaterol, glycopyrronium, and mometasone or pharmaceutically acceptable salts of any of the foregoing.
  • the additional pharmaceutical agent or salt thereof is free of bromide.
  • the additional pharmaceutical agent is present at a concentration from about 10 pg/mL to about 2 mg/mL. In some embodiments, the additional pharmaceutical agent is present at a concentration up to about 2 mg/mL, up to about 1 mg/mL, up to about 800 pg/mL, up to about 600 pg/mL, up to about 400 pg/mL, up to about 200 pg/mL, up to about 50 pg/mL, or up to about 10 pg/mL.
  • the additional pharmaceutical agent is present at a concentration from about 10 pg/mL to about 2 mg/mL, from about 10 pg/mL to about 1.5 mg/mL, from about 10 pg/mL to about 1 mg/mL, from about 10 pg/mL to 800 pg/mL, from about 10 pg/mL to about 600 pg/mL, from about 10 pg/mL to about 400 pg/mL, from about 10 pg/mL to about 200 pg/mL, from about 50 pg/mL to about 1 mg/mL, from about 50 pg/mL to about 800 pg/mL, from about 50 pg/mL to about 600 pg/mL, from about 50 pg/mL to about 400 pg/mL, from about 50 pg/mL to about 200 pg/mL, from about 200 pg/mL to about 1 mg/mL, from about 200 pg/m
  • the composition is a pharmaceutical formulation which is present in a unit dosage form.
  • the unit dosage form comprises one or more additional pharmaceutical agents.
  • the method of making a composition as 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 a pH of the mixture by adding citric acid or acetic acid to obtain the composition.
  • the mixture further comprises one or more excipients are selected from the group consisting of a buffer, a co-solvent, a tonicity modifier, and a preservative.
  • step b) comprises waiting for the mixture to reach equilibrium. In some embodiments, step b) lasts a period of time from 12 to 72 hours.
  • the pH is adjusted using citric or acetic acid and a strong base. In some embodiments, the strong base is NaOH.
  • the citric or acetic acid is added until the mixture has a pH equal to or below 4.0, 3.0, or 2.0. In some embodiments, the acid is added until the mixture has a pH equal to or below 2.0. In some embodiments, the acid is added until the mixture has a pH equal to or below 2.0 before waiting for the mixture to reach equilibrium.
  • the aqueous composition is used to treat a patient.
  • the composition is delivered to a patient in need thereof as an aerosol.
  • the aerosol is generated by contacting the aqueous composition with a vibrating mesh.
  • the API of the aqueous composition is delivered to the lungs of a patient in need thereof.
  • the composition acts as a bronchodilator.
  • a method for the delivery of indacaterol to the lungs of a patient in need thereof, wherein the delivery is accomplished via low tidal breathing.
  • the patient has difficulty generating sufficient inspiratory effort to properly use dry powder inhalers or has significant cough caused by the irritation of dry powders.
  • the patient has difficulty generating a pressure drop of 1 kPa or more (Clark, A. R., et al., J Aerosol Med Pulm Drug Deliv, (2020) 33, 1-11).
  • the patient has difficulty with the coordination of device actuation and inhalation that is required for proper usage of dry powder inhalers, metered dose pressurized inhalers, and/or soft mist inhalers.
  • 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 younger than 65 years old. In some embodiments, the patient is younger than 50 years old. In some embodiments, the patient is younger than 40 years old. In some embodiments, the patient is a young adult.
  • the patient is younger than 30 years old. In some embodiments, the patient is younger than 25 years old. In some embodiments, the patient is younger than 20 years old. In some embodiments, the patient is a teenager. In some embodiments, the patient is younger than 15 years old. In some embodiments, the patient is older than 2 years old. In some embodiments, the patient has COPD and/or asthma and/or emphysema.
  • the aqueous compositions are used in the treatment of a patient with a respiratory disorder. In some embodiments, the aqueous compositions are used in the treatment of patient with an inflammatory disorder, such as an inflammatory disorder of the airways and/or lungs.
  • the aqueous compositions are used in the treatment of patient with an obstructive airway disease.
  • the patient has one or more of a respiratory disorder, an inflammatory disorder, and/or an obstructive airway disease.
  • the aqueous compositions are used to treat COPD.
  • the aqueous compositions are used to treat asthma.
  • the aqueous compositions are used to treat COPD and asthma.
  • the aqueous compositions are used to treat emphysema.
  • the compositions are used to treat COPD and emphysema.
  • the treatment includes the prevention or delayed occurrence of symptoms related to the respiratory disorder, inflammatory disorder, or obstructive airway disease, such as in a patient at risk of developing such symptoms.
  • the composition is administered to the patient in an effective amount to treat the desired respiratory disorder, inflammatory disorder, or obstructive airway disease.
  • the composition is administered to the patient daily.
  • the composition is administered to the patient twice daily.
  • the dose of indacaterol is from 20 to 800 pg.
  • the dose of indacaterol is from 50 to 650 pg.
  • the dose of indacaterol is from 100 to 600 pg.
  • the dose of indacaterol is from 200-500 pg.
  • the dose of indacaterol is from 70 to 80 pg.
  • the dose of indacaterol is 75 pg.
  • the composition is intended as a maintenance treatment of a respiratory disorder, inflammatory disorder such as asthma, or obstructive airway disease such as COPD.
  • the dose of indacaterol is from about 20 pg/mL to about 120 pg/mL and the dose of glycopyrronium is from about 10 pg/mL to about 60 pg/mL. In some embodiments, the dose of indacaterol is from about 20 pg/mL to about 35 pg/mL and the dose of glycorpyrronium is from about 10 pg/mL to about 20 pg/mL.
  • the dose of indacaterol is from about 20 pg/mL to about 35 pg/mL
  • the dose of glycorpyrronium is from about 10 pg/mL to about 20 pg/mL
  • the device used to deliver the dose is a vibrating mesh device.
  • the dose of indacaterol is from about 100 pg/mL to about 120 pg/mL and the dose of glycorpyrronium is from about 40 pg/mL to about 60 pg/mL.
  • the dose of indacaterol is from about 100 pg/mL to about 120 pg/mL
  • the dose of glycorpyrronium is from about 40 pg/mL to about 60 pg/mL
  • the device used to deliver the dose is a soft mist inhaler device.
  • the composition is intended as a maintenance treatment of a respiratory disorder, inflammatory disorder such as asthma, or obstructive airway disease such as COPD.
  • the patient receiving the composition is the subject of one or more additional therapies and/or treatments for a respiratory disorder.
  • the respiratory disorder is asthma.
  • the respiratory disorder is COPD.
  • the respiratory disorder is emphysema.
  • the respiratory disorder is seasonal allergies.
  • the composition can be administered to a patient in need thereof with a variety of devices.
  • the device is an inhaler device or a nebulizer.
  • the device is a soft mist inhaler, a jet nebulizer, an ultrasonic nebulizer, or a vibrating mesh device.
  • the device is a jet nebulizer.
  • the device is a soft mist inhaler.
  • the device is a mesh nebulizer.
  • the device is a breath actuated nebulizer.
  • the aqueous composition is included as part of a kit that includes a device used to aerosolize the formulation.
  • the device comprises a vibrating mesh.
  • the kit comprises indacaterol or a pharmaceutically acceptable salt thereof, a solubilizing agent and instructions for preparing an aqueous liquid composition thereof.
  • the kit comprises indacaterol or a pharmaceutically acceptable salt thereof and the solubilizing agent in the same or separate containers.
  • a kit provided herein may comprise a container, such as an ampule, vial, or cartridge, comprising an aqueous liquid composition comprising indacaterol or a pharmaceutically acceptable salt thereof, a solubilizing agent and water in an amount to provide an aqueous liquid composition.
  • the kit further comprises a device for aerosolizing an aqueous liquid composition.
  • the aqueous liquid composition comprises water in an amount of about 20 weight percent to 99.9 weight percent.
  • the composition may be suitable for use with a vibrating mesh device.
  • the concentration of indacaterol or a pharmaceutically acceptable salt thereof is between 800 pg/mL and 2 g/mL
  • the composition may be suitable for use with a soft mist inhaler device.
  • kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses.
  • kits may be provided that contain sufficient dosages of a composition as disclosed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
  • Kits may also include multiple unit doses of the composition and instructions for use.
  • Indacaterol base was purchased from Cayman Chemicals. Indacaterol maleate was purchased from AChemBlock.
  • a degraded sample panel was prepared to identify indacaterol degradation pathways and products. Stress conditions are outlined in Table 1.
  • Example 2 Aqueous solubility of indacaterol
  • Indacaterol was insoluble in water at pH 7.1. The change in pH for the sample is likely due to dissolved environmental CO2. The pH of the indacaterol maleate solution is attributed primarily to the dissolution of the salt and formation of maleic acid and indacaterol free base.
  • Example 3 Aqueous solubility of indacaterol with varying pH
  • Example 4 Aqueous solubility of indacaterol with various buffers
  • Example 5 Solubility of indacaterol in formulations with tonicity modifiers and co-solvents
  • Example 6 Solubility of indacaterol in formulations including a cyclodextrin
  • the vial was removed from the shaker and allowed to settle for 30 minutes. Then, the sample was filtered using a 0.2 pM PVDF syringe filter; the initial 0.5 mL of filtrate was discarded. The pH was then measured and the concentration of the indacaterol was evaluated by UV-Vis. Results shown in Table 8.
  • a series of formulations of indacaterol were prepared for the stability study. Each formulation was transferred to a glass bottle, then excess indacaterol was added. The bottles were capped, placed horizontally on an orbital shaker set to 200 rpm overnight. The following day, the pH of each formulation was measured and subsequently adjusted with 1 N NaOH and/or 1 N HC1 to maintain target pH. Bottles were placed back onto the shaker overnight. The bottles were then removed 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 pH adjusted with 1 M NaOH and/or 1 M HC1 to maintain target pH.
  • each formulation was filtered through a PVDF filter membrane to minimize particulate load and transferred to a biosafety cabinet (BSC) for vial filling.
  • BSC biosafety cabinet
  • the osmolality and viscosity of the formulations were tested (see Table 9).
  • Indacaterol concentration was determined by RP-HPLC. Table 9. Liquid formulations of indacaterol for stability studies.
  • Table 10 Summary of % change (90d vs TO) in indacaterol main peak and total product-related impurities for indacaterol liquid formulations stored at various conditions.
  • a series of formulations of indacaterol in combination with glycopyrronium were prepared for the stability study. Each formulation was initially prepared in a concentrated form and with a low pH to maximize the rate of indacaterol solubilization. Each formulation was transferred to a glass bottle, then indacaterol and glycopyrronium was added. The formulation in the bottles were stirred by magnetic stirrer until the indacaterol had solubilized. The pH of each formulation was measured and subsequently adjusted with 2 N NaOH and/or 2 N HC1 to the target pH. The stirring was allowed to stir for another 30 minutes. Water was added up to the target volume and the pH was checked to ensure target pH was maintained.
  • Table 17 Appearance, pH and concentration of indacaterol and glycopyrronium liquid formulations stored at 25°C / 60% RH for 4 weeks.
  • Table 19 Summary of % change (4 weeks or 5 weeks vs TO) in indacaterol main peak and total product-related impurities for indacaterol liquid formulations stored at various conditions. Detection at 254 nm.
  • Table 20 % main peak and % impurities for indacaterol liquid formulations stored at 40°C / 75% RH for 5 weeks. Detection at 254 nm.
  • Table 21 % main peak and % impurities for indacaterol liquid formulations stored at 25°C / 60% RH for 5 weeks. Detection at 254 nm.
  • Table 22 % main peak and % impurities for indacaterol liquid formulations stored at 5°C for 5 weeks. Detection at 254 nm.
  • DD Delivered Dose
  • a breathing simulator pre-set to a tidal breathing pattern (500 mL tidal volume, Inspiratory to Expiratory ratio (I:E) of 1 : 1, 15 BPM, sinusoidal waveform) as per USP ⁇ 1601> (United States Pharmacopeia, section 1601), was used to draw inspiratory and expiratory airflow through the DD collection filter.
  • the nebulizer positioned as intended for use, was connected to the filter inlet, charged with drug product solution and nebulization initiated for the specified duration. The drug content was determined by RP-HPLC. Results are presented in Table 23, Table 24, and Figures 5 and 6.
  • LC Sprint is an air-jet nebulizer. InnoSpire Go and FLYP are vibrating mesh nebulizers. The LC Sprint, InnoSpire Go, and FLYP nebulizers are not breath-actuated.
  • VNN vibrating mesh nebulizer
  • BA breath-actuated
  • VNN vibrating mesh nebulizer
  • BA breath-actuated
  • VNN vibrating mesh nebulizer
  • BA breath-actuated
  • VNN vibrating mesh nebulizer
  • BA breath-actuated
  • a series of formulations of indacaterol in combination with tiotropium were prepared for the stability study. Each formulation was initially prepared in a concentrated form and with a low pH to maximize the rate of indacaterol solubilization. Each formulation was transferred to a glass bottle, then indacaterol and tiotropium was added. The formulation in the bottles were stirred by magnetic stirrer until the indacaterol had solubilized. The pH of each formulation was measured and subsequently adjusted with 2 N NaOH and/or 2 N HC1 to the target pH. The stirring were allowed to stir for another 30 minutes. The volume was made up to the target volume using water and the pH was checked to ensure target pH was maintained.
  • Each formulation was filtered through a PVDF filter membrane to minimize particulate and microbial load and transferred to a biosafety cabinet (BSC) for vial filling.
  • BSC biosafety cabinet
  • the osmolality and viscosity of the formulations were tested (see Table 25).
  • Example 8 The formulations from Example 8 continued to be monitored for a 26-week period. Indacaterol and glycopyrronium concentration and impurities were determined by RP-HPLC. RP-HPLC method parameters are outlined in Table 26.
  • Tables 30 and 31 show the indacaterol and glycopyrronium concentration, main peak and impurities data for all formulations stored under various conditions. “MP” refers to “Main Peak,” “ISR” refers to “Indacaterol Related Substance”, and “GSR” refers to “Glycopyrronium Related Substance.”
  • Figure 7 and Figure 8 show an example chromatogram for indacaterol and glycopyrronium. 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.
  • G7, G8, and G9 stored at 40°C / 75% RH, 25°C / 60% RH and 5°C for 52 weeks.
  • a series of formulations of indacaterol in combination with glycopyrronium were prepared for the stability study. Each formulation was transferred to a glass bottle, then indacaterol and glycopyrronium were added. The formulation in the bottles were stirred by magnetic stirrer until the indacaterol had solubilized. The pH of each formulation was measured and subsequently adjusted with 2 N NaOH and/or 2 N citric or acetic acid to the target pH. The stirring was allowed to stir for another 30 minutes. Water was added up to the target volume and the pH was checked to ensure target pH was maintained. Each formulation was filtered through a PVDF filter membrane to minimize particulate and microbial load and transferred to a biosafety cabinet (BSC) for vial filling. The contents of the formulations are shown in Table 32 below. Table 32. Contents of IndglyAA and IndGlyCA
  • Example 13 52-week stability of G7. G8. and G9 [0123] The formulations G7, G8, and G9 continued to be monitored.

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Abstract

L'invention divulgue des formulations aqueuses d'indacatérol et de glycopyrronium. Les formulations peuvent être utilisées dans le traitement de troubles respiratoires, de troubles inflammatoires ou de maladies liées à l'obstruction des voies respiratoires. La divulgation comprend également des méthodes d'utilisation des formulations et des kits contenant les formulations.
PCT/US2024/022018 2023-03-30 2024-03-28 Formulations liquides d'indacatérol et de glycopyrronium Pending WO2024206662A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12419883B2 (en) 2020-09-29 2025-09-23 Aerorx Therapeutics, Inc. Liquid formulations of indacaterol

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000075114A1 (fr) * 1999-06-04 2000-12-14 Novartis Ag Agonistes du recepteur beta 2-adrenergique
US20110023876A1 (en) * 2009-05-29 2011-02-03 Pearl Therapeutics, Inc. Compositions for pulmonary delivery of long-acting muscarinic antagonists and associated methods and systems
WO2020217116A2 (fr) * 2019-03-28 2020-10-29 Orbicular Pharmaceutical Technologies Pvt Ltd Compositions d'indacatérol inhalables à action prolongée
WO2022073009A1 (fr) * 2020-09-29 2022-04-07 iPharma Labs, Inc. Formulations liquides d'indacatérol
WO2024033626A1 (fr) * 2022-08-08 2024-02-15 Verona Pharma Plc Ensifentrine (rpl-554) pour diminution de fréquence et/ou de gravité d'exacerbations de bpco

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000075114A1 (fr) * 1999-06-04 2000-12-14 Novartis Ag Agonistes du recepteur beta 2-adrenergique
US20110023876A1 (en) * 2009-05-29 2011-02-03 Pearl Therapeutics, Inc. Compositions for pulmonary delivery of long-acting muscarinic antagonists and associated methods and systems
WO2020217116A2 (fr) * 2019-03-28 2020-10-29 Orbicular Pharmaceutical Technologies Pvt Ltd Compositions d'indacatérol inhalables à action prolongée
WO2022073009A1 (fr) * 2020-09-29 2022-04-07 iPharma Labs, Inc. Formulations liquides d'indacatérol
WO2024033626A1 (fr) * 2022-08-08 2024-02-15 Verona Pharma Plc Ensifentrine (rpl-554) pour diminution de fréquence et/ou de gravité d'exacerbations de bpco

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12419883B2 (en) 2020-09-29 2025-09-23 Aerorx Therapeutics, Inc. Liquid formulations of indacaterol

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