WO2020084549A1 - Composition de nébulisation comprenant du glycopyrrolate et du formotérol - Google Patents

Composition de nébulisation comprenant du glycopyrrolate et du formotérol Download PDF

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Publication number
WO2020084549A1
WO2020084549A1 PCT/IB2019/059106 IB2019059106W WO2020084549A1 WO 2020084549 A1 WO2020084549 A1 WO 2020084549A1 IB 2019059106 W IB2019059106 W IB 2019059106W WO 2020084549 A1 WO2020084549 A1 WO 2020084549A1
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Prior art keywords
nebulization
composition
nebulization composition
formoterol
composition according
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Inventor
Sunil Chaudhari
Ulhas Dhuppad
Suresh RAJURKAR
Chandrakant DHATRAK
Nilesh Jain
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Glenmark Specialty SA
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Glenmark Specialty SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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

Definitions

  • the present invention relates to a nebulization composition comprising glycopyrrolate and formoterol for the treatment of inflammatory or obstructive airway disease and a process for preparing the composition.
  • Asthma and chronic obstructive pulmonary disease (COPD) are the common life threatening respiratory disorders.
  • Emphysema and chronic bronchitis are the two states of COPD. Emphysema is primarily characterized by irreversible enlargement of the air spaces distal to the terminal bronchioles leading to alveolar wall destruction. Chronic bronchitis on the other hand, is characterized by persistent productive cough in absence of any other cause of excessive sputum generation. All of these effects lead to clogging of the airways making it difficult for the patient to breathe.
  • Asthma is a chronic disease and is triggered by allergies, tobacco smoke and multiple such reasons. Asthma is characterized by tightening of the airway muscles, narrowing of the airway muscles, swollen or inflamed lining of the airways and excessive mucus production. Common symptoms of asthma include coughing, wheezing, and shortness of breath.
  • the commonly available dosage forms for the treatment of asthma and COPD include metered dose inhalation, dry powder inhalation and nebulization compositions.
  • the user has to synchronize with the patient’s breathing pattern and the device characteristics in case of metered dose inhalation and dry powder inhalation. This often requires the patient to be trained with the device.
  • the nebulization compositions do not require any specialized training or synchronization. This is of ultimate convenience to pediatric and geriatric patients. Nebulized drugs are deposited directly into the respiratory tract and thus higher drug concentrations can be achieved in the bronchial tree and pulmonary bed with fewer adverse effects.
  • Currently available treatment options include corticosteroids, beta agonists, anticholinergic agents, and expectorants.
  • dosage forms available such as nebulization, dry powder inhalers, and metered dose inhalers.
  • Glycopyrrolate is approved in the U.S. as nebulization dosage form under the brand name Lonhala Magnair Kit®.
  • Formoterol is approved under the brand name Perforomist® as a nebulization composition.
  • US6667344 covers a nebulization composition of formoterol.
  • US20160166506 relates to a method of treating chronic obstructive pulmonary disease with nebulized anticholinergics.
  • the anticholinergic agents are administered with a high efficiency nebulizer to achieve an effect for a prolonged period.
  • a combination of Formoterol and Glycopyrrolate metered dose inhaler-Bevispi Aerosphere® is available in US as a twice-daily, fixed-dose dual bronchodilator combining glycopyrrolate and formoterol fumarate.
  • US8808713 discloses the composition of glycopyrrolate and formoterol in a metered dose inhaler.
  • US20160374987 relates to inhalation solutions for administration of beta 2-agonists or combinations of muscarinic antagonists and beta 2-agonists with a high efficiency nebulizer.
  • the patent application provides a broad disclosure about co- administration of the two drugs for the treatment of chronic obstructive pulmonary disease.
  • glycopyrrolate and formoterol fumarate for the treatment of chronic obstructive pulmonary disease, as this combination would add the efficacy of both the drugs together, giving a synergistic effect and would possibly lead to dose reduction and eventually reducing the adverse effects.
  • the present invention relates to a composition
  • a composition comprising a fixed dose combination of the two drugs in a single ampule or keeping the two drugs in separate ampules and mixing them together in the nebulizer before administration to a patient.
  • the term“combination of’ includes both fixed dose combination of the two drugs in a single ampule or keeping the two drugs in separate ampules and mixing them together in the nebulizer before administration to a patient.
  • the present invention provides a nebulization composition comprising a combination of glycopyrrolate or a pharmaceutically acceptable salt thereof and formoterol or a pharmaceutically acceptable salt thereof.
  • the nebulization composition comprises glycopyrronium bromide and formoterol fumarate.
  • the nebulization composition comprises a fixed dose composition of glycopyrronium bromide and formoterol fumarate in a single ampule.
  • the nebulization composition comprises mixing of glycopyrronium bromide and formoterol fumarates are kept in seperate ampules and are mixed together in a nebulizer prior to the administration to a patient.
  • the glycopyrrolate and formoterol are present in the nebulization composition in solubilized form.
  • One embodiment relates to a nebulization composition
  • a nebulization composition comprising a combination of glycopyrrolate or a pharmaceutically acceptable salt thereof and formoterol or a pharmaceutically acceptable salt thereof for the treatment of an inflammatory or obstructive airway disease.
  • the nebulization composition is a sterile, unit dose composition.
  • the nebulization composition comprises glycopyrrolate or a pharmaceutically acceptable salt thereof and formoterol or a pharmaceutically acceptable salt thereof in a weight ratio of 1 : 128 to 400: 1.
  • the nebulization composition comprises glycopyrronium bromide, formoterol fumarate, buffering /pH adjusting agent, and an isotonicity agent.
  • the nebulization composition may optionally further include a chelating agent, a pharmaceutically acceptable vehicle, or any combination thereof.
  • the nebulization composition is free, or substantially free, of a preservative (such as a benzalkonium salt, e.g., benzalkonium chloride).
  • the nebulization composition is free, or substantially free, of a complexing agent (such as ethylene diamine tetra-acetic acid (EDTA) or a salt thereof).
  • a complexing agent such as ethylene diamine tetra-acetic acid (EDTA) or a salt thereof.
  • the nebulization composition is free, or substantially free, of (a) EDTA or a salt thereof and (b) a benzalkonium salt, such as benzalkonium chloride.
  • the nebulization composition comprises glycopyrronium bromide, formoterol fumarate, buffer, isotonicity agent, and water.
  • the nebulization composition comprises glycopyrronium bromide, formoterol fumarate, citric acid, sodium chloride, and water.
  • the nebulization composition comprises glycopyrronium bromide, formoterol fumarate, citric acid, sodium citrate, sodium chloride, and water.
  • the nebulization composition comprises glycopyrronium bromide, formoterol fumarate, buffer, complexing agent, isotonicity agent, and water.
  • the nebulization composition comprises glycopyrronium bromide, formoterol fumarate, citric acid, sodium chloride, ethylene diamine tetra-acetic acid and water.
  • the nebulization composition comprises glycopyrronium bromide, formoterol fumarate, citric acid, sodium citrate, sodium chloride, ethylene diamine tetra-acetic acid and sterile water.
  • One more embodiment is a nebulization solution comprising glycopyrronium bromide, formoterol fumarate, sodium chloride, sodium citrate and citric acid, hydrochloric acid, sodium hydroxide, water and optionally edetate disodium.
  • the glycopyrronium bromide and formoterol fumarate are in solubilized form in the solution.
  • the nebulization solution is preferably free, or substantially free, of benzalkonium salts.
  • the nebulization composition is administered once a day or twice a day to a subject in need thereof.
  • a further embodiment is a kit comprising a nebulizer and a nebulization composition of the present invention.
  • the nebulization composition comprises glycopyrronium bromide and formoterol fumarate.
  • Yet another embodiment is a method of treating an inflammatory or obstructive airway disease by administering a nebulization composition of the present invention.
  • the nebulization composition comprises glycopyrronium bromide and formoterol fumarate.
  • the present invention relates to a nebulization composition
  • a nebulization composition comprising glycopyrrolate or a pharmaceutically acceptable salt thereof and formoterol or a pharmaceutically acceptable salt thereof.
  • the nebulization composition is useful for the treatment of an inflammatory or obstructive airway disease.
  • Glycopyrronium bromide an anticholinergic is a quaternary ammonium salt with the following chemical name: (3RS)-3-[(2SR)-(2-cyclopentyl-2-hydroxy-2-phenylacetyl) oxy]- l, l-dimethylpyrrolidinium bromide.
  • the quaternary ammonium compound inhibits acetyl choline binding to M3 muscarinic receptor is represented by structural formula.
  • Glycopyrrolate can be prepared using the procedures described in U.S. Pat.
  • the present invention embraces using one or more of these isomeric forms, especially the 3S,2'R isomer, the 3R,2'R isomer or the 2S,3'R isomer, thus including single enantiomers, or racemates, especially the (3S,2'R/2S,3'R) racemate.
  • glycopyrrolate and glycopyrronium are used interchangeably.
  • Formoterol is a long-acting, beta 2-adrenergic receptor agonist.
  • Formoterol has a molecular formula of C19H24N2O4 and the following structure:
  • the term“formoterol”, unless otherwise indicated, includes, but is not limited to, formoterol in any physical form such as the amorphous form and crystalline forms (e.g., anhydrous, hydrate, and other solvate forms).
  • Salts of formoterol include, but are not limited to, acid addition salts and base salts thereof.
  • Suitable salts of formoterol include, but are not limited to, salts of mineral acids, such as hydrochlorides and sulfates, and salts of organic acids, such as acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates and fumarates.
  • One preferred salt of formoterol for the nebulization composition is formoterol fumarate, such as in the form of its dihydrate salt (formoterol fumarate dihydrate).
  • the nebulization compositions may contain glycopyrronium bromide and formoterol fumarate in solubilized form in a sterile unit dosage form.
  • the nebulization composition may contain glycopyrronium bromide in an amount of about 2.5 mcg/ml to about 1000 mcg/ml.
  • the composition contains glycopyrronium bromide in amounts of 2.5 mcg/ml, 5 mcg/ml, 10 mcg/ml, 20 mcg/ml, 40 mcg/ml, 80 mcg/ml, 160 mcg/ml, 320 mcg/ml, 500 mcg/ml, 750 mcg/ml and 1000 mcg/ml.
  • the nebulization composition may contain 12.5 mcg/ml, 25 mcg/ml, 50 mcg/ml of glycopyrronium bromide.
  • the nebulization composition may contain formoterol fumarate in an amount of about 2.5 mcg/ml to about 320 mcg/ml.
  • the composition contains formoterol fumarate in amounts of 2.5 mcg/ml, 5 mcg/ml, 10 mcg/ml, 20 mcg/ml, 40 mcg/ml, 80 mcg/ml, 160 mg/ml, and 320 mg/ml.
  • the nebulization composition may contain 5 mcg/ml, 10 mcg/ml, 15 mcg/ml, 20 mcg/ml of formoterol fumarate.
  • the ratio of glycopyrronium bromide and formoterol fumarate in the nebulization composition may range from 1: 128 to 400: 1.
  • the nebulization composition may additionally comprise one or more pharmaceutically acceptable excipients.
  • suitable pharmaceutically acceptable excipients include, but are not limited to, pH adjusting agents, buffering agents, isotonicity agents, optionally chelating agents, surfactants, anti-oxidants, and pharmaceutically acceptable vehicles.
  • the composition includes a buffering/ pH adjusting agent, isotonicity agent, pharmaceutically acceptable vehicle, and optionally a chelating agent.
  • the nebulization composition is substantially free of preservative (such as benzalkonium and salts thereof), preferably substantially benzalkonium chloride free.
  • preservative such as benzalkonium and salts thereof
  • a composition is “substantially benzalkonium chloride free” or “substantially free of benzalkonium chloride” when the amount of benzalkonium chloride is not an amount sufficient to materially act as a preservative for the nebulization composition i.e less than 0.1 %w/w.
  • benzalkonium chloride may be present in a concentration less than 0.008% w/w based on total weight of the composition.
  • preservative is not an amount sufficient to materially act as a preservative for the nebulization composition.
  • the preservative may be present in a concentration less than 0.008% w/w based on total weight of the composition.
  • nebulization compositions contain a preservative such as benzalkonium chloride.
  • benzalkonium chloride A common problem with benzalkonium chloride is that it may cause paradoxic bronchoconstriction if the solution is administered repeatedly over short intervals, and frequent exposure to benzalkonium chloride may lead to occupational asthma. Another problem is that, when inhaled by patients, the benzalkonium chloride can cause dose- dependent bronchoconstriction.
  • nebulization compositions of the present invention may be provided without benzalkonium chloride, thereby making them suitable for repeated administration over a short period of time. Also, administering a substantially benzalkonium chloride-free nebulization composition to a patient reduces the concomitant liability of adverse effects associated with benzalkonium chloride alone or in combination with other excipients and/or the active agents. It also negates the toxicity and other side effects associated with benzalkonium chloride.
  • the nebulization composition may be free, or substantially free, of complexing agents such as ethylene diamine tetra-acetic acid (EDTA) and salts thereof.
  • EDTA ethylene diamine tetra-acetic acid
  • the nebulization composition or solution may contain less than about 0.1% by weight of complexing agent such as EDTA. The absence of or reduction in the concentration of the additive EDTA and its salts helps to reduce the paradoxic effect associated with cough.
  • the nebulization composition may be formulated as a single composition comprising glycopyrrolate and formoterol. Such a nebulization composition can be contained in a single chamber container. Such a single composition comprising both glycopyrronium and formoterol (such as the combination glycopyrronium bromide and formoterol fumarate) is stable under during long term storage.
  • the pharmaceutical composition or solution may contain greater than about 80%, such as greater than about 85%, greater than about 90%, greater than about 95% or greater than about 98% of the initial amount of glycopyrronium /formoterol or salts thereof in the nebulization composition after being stored for 3 or 6 months or 1, 2 or 3 years at 2-8° C and 25° C when stored in a suitable container.
  • the two active agents can also be separately formulated and contained in separate containers, which are then mixed prior to administration to a patient.
  • a composition comprising glycopyrronium bromide and one or more pharmaceutically acceptable excipients is contained in one chamber and another composition comprising formoterol fumarate and one or more pharmaceutically acceptable excipients is contained in a separate chamber.
  • This combination comprising separate compositions of glycopyrronium bromide and formoterol fumarate can be contained in a dual chamber container.
  • the two chambers of the dual chamber container may be separate or may be connected by a common septum.
  • the dual chamber container with a common septum may contain a common top which when broken would provide simultaneous access to both compositions.
  • composition comprising glycopyrronium bromide may be mixed with the composition comprising formoterol fumarate before being added to the reservoir of the nebulizer.
  • the composition comprising glycopyrronium bromide may be added to the reservoir of the nebulizer followed by addition of the composition comprising formoterol fumarate and vice versa.
  • the two compositions would be mixed in the reservoir of the nebulizer device and then administered to the patient.
  • the pH of the nebulization composition may vary from about 1 to about 7.
  • the pH of the glycopyrrolate nebulization composition is preferably between about 3 to about 6, preferably about 4.5.
  • the pH of the formoterol nebulization composition is between about 3 to about 6, preferably about 5.5.
  • the pH of the nebulization composition containing both glycopyrrolate and formoterol is about 3 to about 6, preferably about 5.5.
  • the pH may be adjusted by the addition of one or more pharmaceutically acceptable acids.
  • suitable pharmaceutically acceptable acids include inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid, and any combination of any of the foregoing.
  • suitable pharmacologically acceptable acids include organic acids, such as ascorbic acid, citric acid, malic acid, maleic acid, tartaric acid, succinic acid, fumaric acid, acetic acid, formic acid, propionic acid, and any combination of any of the foregoing.
  • the pH adjusting agents may be selected from one or more organic acids selected from ascorbic acid, fumaric acid and citric acid.
  • a preferred organic acid is citric acid.
  • Mixtures of the abovementioned acids may also be used, particularly in the case of acids which have other properties in addition to their acidifying properties, e.g., those which act as flavorings or antioxidants, such as citric acid or ascorbic acid.
  • the nebulization composition may contain sodium citrate, for example, at a concentration of about 0.0001% w/v to about 2.20% w/v, and citric acid, for example, at a concentration of about 0.0001% w/v to about 0.53% w/v, to control pH.
  • the pharmaceutically acceptable vehicle in the nebulization composition includes water and optionally a cosolvent.
  • Any cosolvent that is suitable for inhalation and capable of dissolving or solubilizing the glycopyrronium in the mixture of cosolvent and water can be used.
  • suitable cosolvents include, for example, alcohols, ethers, hydrocarbons, and perfluorocarbons.
  • the cosolvent is a short chain polar alcohol. More preferably, the cosolvent is an aliphatic alcohol having from one to six carbon atoms, such as ethanol or isopropanol.
  • a preferred cosolvent is ethanol.
  • Non-limiting examples of suitable hydrocarbons include n-butane, isobutane, pentane, neopentane and isopentanes.
  • suitable ethers include dimethyl ether and diethyl ether.
  • suitable perfluorocarbons include perfluoropropane, perfluorobutane, perfluorocyclobutane, and perfluoropentane.
  • Suitable surfactants include, but are not limited to, C 5- 20-fatty alcohols, C 5- 20-fatty acids, C 5- 20-fatty acid esters, lecithin, glycerides, propylene glycol esters, polyoxyethylenes, polysorbates, sorbitan esters, carbohydrates, and any combination of any of the foregoing.
  • C 5- 20-fatty acids, propylene glycol diesters of the C 5- 20-fatty acids, triglycerides of the C5-20- fatty acids, and sorbitans of the C 5- 20-fatty acids are preferred.
  • the surfactant is selected from oleic acid, sorbitan mono-, di- or trioleates, and any combination of any of the foregoing.
  • the nebulization composition may optionally include a buffer.
  • Buffers in the pH range of about 2.0 to about 8.0 include, but are not limited to, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, Mcllvaine, phosphate, Prideaux-Ward, succinate, citrate -phosphate-borate (Teorell-Stanhagen), veronal acetate, MES, BIS-TRIS, ADA, ACES, PIPES, MOPSO, BIS-TRIS PROPANE, BES, MOPS, TES, HEPES, DIPSO, MOBS, TAPSO, TRIZMA, HEPPSO, POPSO, TEA, EPPS, TRICINE, GLY-GLY, BICINE, HEPBS, TAPS, and AMPD buffers.
  • the osmolality of the nebulization composition may be from about 200-500 mOsm/kg.
  • the nebulization composition may comprise a tonicity adjusting agent, such as an ionic salt (e.g., about 0.0001% w/v to about 264% w/v ionic salt).
  • Suitable tonicity adjusting agents include, but are not limited to, ammonium carbonate, ammonium chloride, ammonium lactate, ammonium nitrate, ammonium phosphate, amonium sulfate, ascorbic acid, bismuth sodium tartrate, boric acid, calcium chloride, calcium disodium edetate, calcium gluconate, calcium lactate, citric acid, dextrose, diethanolamine, dimethyl sulfoxide, edetate disodium, edetate trisodium monohydrate, fluorescein sodium, fructose, galactose, glycerin, lactic acid, lactose, magnesium chloride, magnesium sulfate, mannitol, polyethylene glycol, potassium acetate, potassium chlorate, potassium chloride, potassium iodide, potassium nitrate, potassium phosphate, potassium sulfate, propylene glycol, silver nitrate, sodium acetate, sodium bicarbonate, sodium biphosphat
  • Suitable osmotic adjusting agents include, but are not limited to, sodium chloride, potassium chloride, zinc chloride, calcium chloride and any combination of any of the foregoing.
  • Other osmotic adjusting agents include, but are not limited to, mannitol, glycerol, dextrose and any combination of any of the foregoing.
  • the nebulization compositions may contain osmolality adjusting agents such as sodium chloride in amount of about 0.375% to about 1.125%, preferably about 0.9%.
  • Suitable antioxidants include, but are not limited to, ascorbic acid, vitamin A, vitamin E, tocopherols, and any combination of any of the foregoing.
  • a nebulization composition of the present invention may have a fill volume of from about 0.5 ml to about 5 ml.
  • the nebulization composition has a fill volume of 2 ml.
  • the nebulization composition may be contained in a prefilled, unit-dose, low-density polyethylene (LDPE) container.
  • LDPE low-density polyethylene
  • Each unit-dose container may be disposed in a foil pouch, and each foil pouch may contain one or more unit-dose containers.
  • Each foil pouch containing the unit dose container may be disposed in a shelf carton.
  • the container may have a TWIST-FLEX TM top, such top comprising an easy-to-grip tab-like handle such that the container may be opened, for example, by twisting off the tab by hand.
  • the TWIST-FLEX TM top is advantageous in that it allows for easy dispensing of the solution, prevents spillage and eliminates the need to open the container by cutting or tearing off the top, thereby reducing cross-contamination.
  • Dispensing vials may include, but are not limited to, any container comprising glass, low density polyethylene, or any other material capable of preventing the solution from leaking out of the container.
  • the vial may be enclosed by any conventional means including, but not limited to, screw cap, heat seal, snap-on top, flip- top, twist-off stopper, and peel away top.
  • the nebulization composition may comprise of one or more prefilled containers containing a nebulization composition of the present invention. Each container comprises a single unit dose of a nebulization composition of the present invention.
  • One embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide and 10 meg formoterol fumarate.
  • the nebulization composition may additionally contain a buffer, an isotonicity agent and optionally a complexing agent.
  • the nebulization composition further comprises citric acid, sodium chloride, and water.
  • the nebulization composition further comprises citric acid, sodium citrate, sodium chloride, and water.
  • the nebulization composition comprises citric acid, sodium chloride, ethylene diamine tetra-acetic acid and water.
  • the nebulization composition comprises citric acid, sodium citrate, sodium chloride, ethylene diamine tetra-acetic acid and water.
  • nebulization composition comprising about 25 meg of glycopyrronium bromide and 15 meg formoterol fumarate.
  • the nebulization composition may additionally contain a buffer, an isotonicity agent and optionally a complexing agent.
  • the nebulization composition further comprises citric acid, sodium chloride, and water.
  • the nebulization composition further comprises citric acid, sodium citrate, sodium chloride, and water.
  • the nebulization composition comprises citric acid, sodium chloride, ethylene diamine tetra-acetic acid and water.
  • the nebulization composition comprises citric acid, sodium citrate, sodium chloride, ethylene diamine tetra-acetic acid and water.
  • nebulization composition comprising about 25 meg of glycopyrronium bromide and 20 meg formoterol fumarate.
  • the nebulization composition may additionally contain a buffer, an isotonicity agent and optionally a complexing agent.
  • the nebulization composition further comprises citric acid, sodium chloride, and water.
  • the nebulization composition further comprises citric acid, sodium citrate, sodium chloride, and water.
  • the nebulization composition comprises citric acid, sodium chloride, ethylene diamine tetra-acetic acid and water.
  • the nebulization composition comprises citric acid, sodium citrate, sodium chloride, ethylene diamine tetra-acetic acid and water.
  • An embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 10 meg formoterol fumarate.
  • the nebulization composition may additionally contain a buffer, an isotonicity agent and optionally a complexing agent.
  • the nebulization composition further comprises citric acid, sodium chloride, and water.
  • the nebulization composition further comprises citric acid, sodium citrate, sodium chloride, and water.
  • the nebulization composition comprises citric acid, sodium chloride, ethylene diamine tetra-acetic acid and water.
  • the nebulization composition comprises citric acid, sodium citrate, sodium chloride, ethylene diamine tetra-acetic acid and water.
  • One more embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 15 meg formoterol fumarate.
  • the nebulization composition may additionally contain a buffer, an isotonicity agent and optionally a complexing agent.
  • the nebulization composition further comprises citric acid, sodium chloride, and water.
  • the nebulization composition further comprises citric acid, sodium citrate, sodium chloride, and water.
  • the nebulization composition comprises citric acid, sodium chloride, ethylene diamine tetra-acetic acid and water.
  • the nebulization composition comprises citric acid, sodium citrate, sodium chloride, ethylene diamine tetra-acetic acid and water.
  • nebulization composition comprising about 50 meg of glycopyrronium bromide and 20 meg formoterol fumarate.
  • the nebulization composition may additionally contain a buffer, an isotonicity agent and optionally a complexing agent.
  • the nebulization composition further comprises citric acid, sodium chloride, and water.
  • the nebulization composition further comprises citric acid, sodium citrate, sodium chloride, and water.
  • the nebulization composition comprises citric acid, sodium chloride, ethylene diamine tetra-acetic acid and water.
  • the nebulization composition comprises citric acid, sodium citrate, sodium chloride, ethylene diamine tetra-acetic acid and water.
  • the nebulization composition comprises glycopyrronium bromide, formoterol fumarate, buffer, isotonicity agent, and water.
  • the nebulization composition comprises glycopyrronium bromide, formoterol fumarate, citric acid, sodium chloride, and water.
  • the nebulization composition comprises glycopyrronium bromide, formoterol fumarate, citric acid, sodium citrate, sodium chloride, and water.
  • the nebulization composition comprises glycopyrronium bromide, formoterol fumarate, buffer, complexing agent, isotonicity agent, and water.
  • the nebulization composition comprises glycopyrronium bromide, formoterol fumarate, citric acid, sodium chloride, ethylene diamine tetra-acetic acid and water.
  • the nebulization composition comprises glycopyrronium bromide, formoterol fumarate, citric acid, sodium citrate, sodium chloride, ethylene diamine tetra-acetic acid and water.
  • the nebulization composition may contain 25 meg/ 15 meg or 25mcg/20 meg or 50 meg/ 10 meg or 50 mg/l5 meg or 50 mcg/20 meg of glycopyrronium bromide/formoterol fumarate.
  • the nebulization composition may additionally contain a buffer, isotonicity agent and optionally, a complexing agent.
  • the nebulization composition further comprises citric acid, sodium chloride, and water.
  • the nebulization composition further comprises citric acid, sodium citrate, sodium chloride, and water.
  • the nebulization composition comprises citric acid, sodium chloride, ethylene diamine tetra-acetic acid and water.
  • the nebulization composition comprises citric acid, sodium citrate, sodium chloride, ethylene diamine tetra-acetic acid and water.
  • the nebulization composition can be prepared as follows.
  • composition comprising Glycopyrronium and Formoterol in separate containers
  • a nebulization composition of glycopyrronium can be prepared in a similar manner as illustrated above.
  • a nebulization composition of formoterol can be prepared in a similar manner as illustrated above.
  • Nebulization compositions B.l and B.2 can be separately added to the reservoir of the nebulizer device and mixed to form a nebulization composition B.3
  • the nebulization composition provided herein has a long shelf life, i.e., it is stable during long term storage.
  • the composition may contain greater than about 80%, such as greater than about 85%, greater than about 90%, greater than about 95% or greater than about 98% of the initial amount of glycopyrronium (or its salt) and formoterol (or its salt) in the composition after being stored for 3 or 6 months or 1, 2 or 3 years at 2-8 0 C and 25° C when stored in a suitable container (such as a LDPE container in an aluminium pouch).
  • the stability may be determined using Arrhenius kinetics.
  • the nebulization composition may be administered by nebulizer.
  • Suitable nebulizers include, but are not limited to, a jet nebulizer, an ultrasonic nebulizer, vibrating mesh nebulizer and a breath actuated nebulizer.
  • the nebulization composition may be administered by nebulizers manufactured, designed or sold by Omron, such as the Omron MICRO AIR TM Ultrasonic Nebulizer or those manufactured, designed, or sold by Aerogen, or with the Nebu-Tec device, M-Neb ® or with the Zephair ® device from Aerosonix, or with the Fox inhaler ® from Vectura, or with the Alphazer ® device from Omega or with the e-flow device from Pari. Additionally, the nebulization compositions described herein can also be nebulized using inhalers other than those described above.
  • Omron such as the Omron MICRO AIR TM Ultrasonic Nebulizer or those manufactured, designed, or sold by Aerogen
  • the Nebu-Tec device M-Neb ® or with the Zephair ® device from Aerosonix, or with the Fox inhaler ® from Vectura, or with the Alphazer ® device from Omega or with the e-flow device from Pari
  • the nebulization compositions also may be provided as a kit wherein the kit comprises a nebulizer and the nebulization composition comprising glycopyrronium bromide and formoterol fumarate.
  • nebulization compositions of the present invention may be administered once a day or twice a day to a subject in need thereof.
  • the present invention includes methods of treating an inflammatory or obstructive airway disease such as asthma and COPD by administering to a patient a nebulization composition comprising glycopyrronium (or its salt) and formoterol (or its salt) via a nebulizer.
  • compositions of the present invention comprising the combination of glycopyrrolate and formoterol may be useful in cases where monotherapy i.e. glycopyrrolate or formoterol alone have been ineffective in the treatment of inflammatory or obstructive airway disease such as asthma or COPD.
  • the nebulization composition of the present invention comprising glycopyrrolate and formoterol provide a synergistic effect. Accordingly, it may be possible to reduce the effective daily dose of these agents, thus, reducing the adverse effects posed by these agents.
  • the nebulization composition provides a rapid onset of action and the effect may be extended for a long duration. A significant improvement in lung function leading to effective control of inflammatory or obstructive disease may be observed.
  • the methods of treating inflammatory or obstructive airway disease such as asthma or COPD by the nebulization compositions as per the present invention may eliminate the need for other concurrent treatment modalities.
  • Nebulization composition comprising Glycopyrronium bromide and Formoterol fumarate in a single composition
  • Nebulization composition comprising Glycopyrronium bromide and Formoterol fumarate prepared separately and to be mixed prior to administration
  • the following examples illustrate the compositions of glycopyrronium and formoterol which are formulated separately and are mixed prior to administration to a patient.
  • B.l Nebulization compositions comprising Glycopyrronium bromide

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Abstract

La présente invention concerne une composition de nébulisation comprenant du glycopyrrolate et du formotérol pour le traitement d'une maladie inflammatoire ou obstructive des voies respiratoires et un procédé de préparation de la composition.
PCT/IB2019/059106 2018-10-25 2019-10-24 Composition de nébulisation comprenant du glycopyrrolate et du formotérol Ceased WO2020084549A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024051683A1 (fr) 2022-09-05 2024-03-14 立生医药(苏州)有限公司 Composition pharmaceutique pour inhalation destinée à prévenir ou à traiter une maladie respiratoire

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011076842A2 (fr) * 2009-12-23 2011-06-30 Chiesi Farmaceutici S.P.A. Préparation aérosol pour copd (bronchopneumopathie chronique obstructive)
EP2749280A2 (fr) * 2011-02-17 2014-07-02 Cipla Limited Composition pharmaceutique de glycopyrronium et formotérol
WO2015101576A1 (fr) * 2013-12-30 2015-07-09 Chiesi Farmaceutici S.P.A. Composition de solution d'aérosol stable, mise sous pression, de combinaison de bromure de glycopyrronium et de formotérol
WO2017077488A1 (fr) * 2015-11-04 2017-05-11 Glenmark Pharmaceuticals Limited Composition de poudre inhalable à dose fixe comprenant du glycopyrronium et du formotérol
WO2017089404A1 (fr) * 2015-11-25 2017-06-01 Jagotec Ag Composition pharmaceutique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011076842A2 (fr) * 2009-12-23 2011-06-30 Chiesi Farmaceutici S.P.A. Préparation aérosol pour copd (bronchopneumopathie chronique obstructive)
EP2749280A2 (fr) * 2011-02-17 2014-07-02 Cipla Limited Composition pharmaceutique de glycopyrronium et formotérol
WO2015101576A1 (fr) * 2013-12-30 2015-07-09 Chiesi Farmaceutici S.P.A. Composition de solution d'aérosol stable, mise sous pression, de combinaison de bromure de glycopyrronium et de formotérol
WO2017077488A1 (fr) * 2015-11-04 2017-05-11 Glenmark Pharmaceuticals Limited Composition de poudre inhalable à dose fixe comprenant du glycopyrronium et du formotérol
WO2017089404A1 (fr) * 2015-11-25 2017-06-01 Jagotec Ag Composition pharmaceutique

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024051683A1 (fr) 2022-09-05 2024-03-14 立生医药(苏州)有限公司 Composition pharmaceutique pour inhalation destinée à prévenir ou à traiter une maladie respiratoire

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