WO2020148638A1 - Composition de nébulisation comprenant du glycopyrrolate et de l'arformotérol - Google Patents

Composition de nébulisation comprenant du glycopyrrolate et de l'arformotérol Download PDF

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Publication number
WO2020148638A1
WO2020148638A1 PCT/IB2020/050248 IB2020050248W WO2020148638A1 WO 2020148638 A1 WO2020148638 A1 WO 2020148638A1 IB 2020050248 W IB2020050248 W IB 2020050248W WO 2020148638 A1 WO2020148638 A1 WO 2020148638A1
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Prior art keywords
nebulization
composition
arformoterol
nebulization composition
meg
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PCT/IB2020/050248
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English (en)
Inventor
Sunil Chaudhari
Ulhas Rameshchandra Dhuppad
Suresh RAJURKAR
Nilesh Jain
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Glenmark Specialty S.A.
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Publication of WO2020148638A1 publication Critical patent/WO2020148638A1/fr

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    • 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
    • A61K31/16—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

Definitions

  • the present invention relates to a nebulization composition comprising glycopyrrolate and arformoterol for the treatment of inflammatory or obstructive airway disease and a process for preparing the composition.
  • 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®.
  • Arformoterol is approved under the brand name Brovana® as a nebulization composition.
  • US 6,667,344 covers a nebulization composition of arformoterol.
  • US 7,473,710 and US 7,541,385 covers a method of treating bronchoconstriction by adding to a nebulizer an inhalation solution of arformoterol.
  • WO2010144628 relates to inhalation solutions for administration of beta 2-agonists or combinations of muscarinic antagonists and beta 2-agonists with a high efficiency nebulizer.
  • the reference discloses high concentration inhalation solutions and require to be administered with a high efficiency nebulizer.
  • the inventors of the present invention has surprisingly found that a combination of glycopyrrolate and arformoterol provides a stable formulation suitable for administration as inhalation.
  • the present invention provides a nebulization composition of glycopyrrolate and arformoterol for the treatment of COPD or asthma.
  • the present invention relates to a composition comprising a fixed dose combination of the two drugs in a single ampule or keeping the two drugs in separate ampules and mixing them together in the nebulizer before administration to a patient.
  • the term“combination of’ includes both fixed dose combination of the two drugs in a single ampule or keeping the two drugs in separate ampules and mixing them together in the nebulizer before administration to a patient.
  • the present invention provides a nebulization composition comprising a combination of glycopyrrolate or a pharmaceutically acceptable salt thereof and arformoterol or a pharmaceutically acceptable salt thereof.
  • the nebulization composition comprises glycopyrronium bromide and arformoterol tartarate.
  • the nebulization composition comprises a fixed dose composition of glycopyrronium bromide and arformoterol tartarate in a single ampule.
  • the nebulization composition comprises mixing of glycopyrronium bromide and arformoterol tartarate which are kept in separate ampules to be mixed together in a nebulizer prior to the administration to a patient.
  • the glycopyrrolate and arformoterol 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 arformoterol 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 arformoterol or a pharmaceutically acceptable salt thereof in a weight ratio of about 1 : 128 to about 400: 1.
  • the nebulization composition comprises glycopyrronium bromide, arformoterol tartarate, buffering /pH adjusting agent, and an isotonicity agent.
  • the nebulization composition may optionally further include a chelating agent, a pharmaceutically acceptable vehicle, or any combination thereof.
  • the nebulization composition is free, or substantially free, of a preservative (such as a benzalkonium salt, e.g., benzalkonium chloride).
  • 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, arformoterol tartarate, buffer, isotonicity agent and sterile water.
  • the nebulization composition comprises glycopyrronium bromide, arformoterol tartarate, citric acid, sodium citrate, sodium chloride and sterile water.
  • the nebulization composition comprises glycopyrronium bromide, arformoterol tartarate, citric acid, sodium citrate, sodium chloride, ethylene diamine tetra-acetic acid and sterile water
  • One more embodiment is a nebulization solution comprising glycopyrronium bromide, arformoterol tartarate, sodium chloride, sodium citrate and citric acid, hydrochloric acid, sodium hydroxide, water and optionally edetate disodium.
  • the glycopyrronium bromide and arformoterol tartarate are in solubilized form.
  • the nebulization solution is preferably free, or substantially free, of benzalkonium salts.
  • the nebulization composition contains not more than about 0.5% of Impurity C of glycopyrrolate or pharmaceutically acceptable salt thereof.
  • the nebulization composition contains not more than about 0.5% of total impurities of glycopyrrolate or pharmaceutically acceptable salt thereof.
  • the nebulization composition contains not more than about 0.4% of amine impurity of aformoterol or pharmaceutically acceptable salt thereof.
  • the nebulization composition contains not more than about 4% of Impurity A (deshydroxy impurity) of aformoterol or pharmaceutically acceptable salt thereof.
  • the nebulization composition contains not more than about 0.3% of deshydroxy impurity of aformoterol or pharmaceutically acceptable salt thereof.
  • the nebulization composition contains not more than about 5% of total impurities of aformoterol or pharmaceutically acceptable salt thereof.
  • 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 arformoterol tartarate.
  • Yet another embodiment is a method of treating an inflammatory or obstructive airway disease by administering a nebulization composition of the present invention.
  • the nebulization composition comprises glycopyrronium bromide and arformoterol tartarate.
  • the present invention relates to a nebulization composition
  • a nebulization composition comprising glycopyrrolate or a pharmaceutically acceptable salt thereof and arformoterol or a pharmaceutically acceptable salt thereof.
  • the nebulization composition is useful for the treatment of an inflammatory or obstructive airway disease.
  • Glycopyrronium bromide an anticholinergic is a quaternary ammonium salt with the following chemical name: (3RS)-3-[(2SR)-(2-cyclopentyl-2-hydroxy-2-phenylacetyl) oxy]-l,l- dimethylpyrrolidinium bromide.
  • the quaternary ammonium compound inhibits acetyl choline binding to M3 muscarinic receptor is represented by structural formula.
  • Glycopyrrolate can be prepared using the procedures described in U.S. Pat. No.2956062.
  • the present invention embraces using one or more of these isomeric forms, especially the 3S,2'R isomer, the 3R,2'R isomer or the 2S,3'R isomer, thus including single enantiomers, or racemates, especially the (3S,2'R/2S,3'R) racemate.
  • glycopyrrolate and glycopyrronium are used interchangeably.
  • Arformoterol is a long-acting, beta 2-adrenergic receptor agonist. It is a (R,R) -enantiomer of formoterol.
  • the tartarate salt of arformoterol is chemically described as formamide, N-[2- hydroxy-5-[(lR)-l-hydroxy-2-[[(lR)-2-(4-methoxyphenyl)-l-methylethyl]amino]ethyl]phenyl]- ,(2R,3R)-2,3-dihydroxybutanedioate (1: 1 salt).
  • Arformoterol tartarate has a molecular formula of C19H24N2C C4H6O6 and the following structure:
  • the nebulization composition may contain Form A, Form B, Form C or mixtures thereof of arformoterol or its pharmaceutically acceptable salts thereof.
  • Salts of arformoterol include, but are not limited to, acid addition salts and base salts thereof.
  • Suitable salts of arformoterol include, but are not limited to, salts of mineral acids, such as hydrochlorides and sulfates, and salts of organic acids, such as acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates and tartarates.
  • One preferred salt of arformoterol for the nebulization composition is arformoterol tartarate.
  • the nebulization compositions may contain glycopyrronium bromide and arformoterol tartarate in solubilized form in a sterile unit dosage form.
  • the nebulization composition may contain glycopyrronium bromide in an amount of about 2.5 mcg/ml to about 1000 mcg/ml.
  • 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 arformoterol tartarate in an amount of about 2.5 mcg/ml to about 320 mcg/ml.
  • the composition contains arformoterol tartarate in amounts of 2.5 mcg/ml, 5 mcg/ml, 10 mcg/ml, 20 mcg/ml, 40 mcg/ml, 80 mcg/ml, 160 mg/ml, and 320 mg/ml.
  • the nebulization composition may contain 5 mcg/ml, 10 mcg/ml, 15 mcg/ml, 20 mcg/ml of arformoterol tartarate.
  • the ratio of glycopyrronium bromide and arformoterol tartarate in the nebulization composition may range from about 1 : 128 to about 400: 1.
  • the nebulization composition may additionally comprise one or more pharmaceutically acceptable excipients.
  • suitable pharmaceutically acceptable excipients include, but are not limited to, pH adjusting agents, buffering agents, isotonicity agents, optionally chelating agents, surfactants, anti-oxidants, and pharmaceutically acceptable vehicles.
  • 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.
  • benzalkonium chloride may be present in a concentration less than 0.008% w/w based on total weight of the composition.
  • the term “substantially free of preservative” denotes that preservative is not an amount sufficient to materially act as a preservative for the nebulization composition.
  • 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.
  • the nebulization compositions of the present invention may be provided without benzalkonium chloride, thereby making them suitable for repeated administration over a short period of time.
  • 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 arformoterol. Such a nebulization composition can be contained in a single chamber container. Such a single composition comprising both glycopyrronium and arformoterol (such as the combination glycopyrronium bromide and arformoterol tartarate) is stable under during long term storage.
  • the pharmaceutical composition or solution may contain greater than about 80%, such as greater than about 85%, greater than about 90%, greater than about 95% or greater than about 98% of the initial amount of glycopyrronium /arformoterol or salts thereof in the nebulization composition after being stored for 3 or 6 months or 1, 2 or 3 years at 2-8° C and 25° C when stored in a suitable container.
  • the two active agents can also be separately formulated and contained in separate containers, which are then mixed prior to administration to a patient.
  • a composition comprising glycopyrronium bromide and one or more pharmaceutically acceptable excipients is contained in one chamber and another composition comprising arformoterol tartarate and one or more pharmaceutically acceptable excipients is contained in a separate chamber.
  • This combination comprising separate compositions of glycopyrronium bromide and arformoterol tartarate can be contained in a dual chamber container.
  • the two chambers of the dual chamber container may be separate or may be connected by a common septum.
  • the dual chamber container with a common septum may contain a common top which when broken would provide simultaneous access to both compositions.
  • composition comprising glycopyrronium bromide may be mixed with the composition comprising arformoterol tartarate 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 arformoterol tartarate 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 arformoterol nebulization composition is between about 3 to about 6, preferably about 5.5.
  • the pH of the nebulization composition containing both glycopyrrolate and arformoterol is about 3 to about 6, preferably about 5.5.
  • the pH may be adjusted by the addition of one or more pharmaceutically acceptable acids.
  • suitable pharmaceutically acceptable acids include inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid, and any combination of any of the foregoing.
  • Non-limiting examples of other suitable pharmacologically acceptable acids include organic acids, such as ascorbic acid, citric acid, malic acid, maleic acid, tartaric acid, succinic acid, fumaric acid, acetic acid, formic acid, propionic acid, and any combination of any of the foregoing.
  • the pH adjusting agents may be selected from one or more organic acids selected from ascorbic acid, fumaric acid and citric acid.
  • a preferred organic acid is citric acid.
  • Mixtures of the abovementioned acids may also be used, particularly in the case of acids which have other properties in addition to their acidifying properties, e.g., those which act as flavorings or antioxidants, such as citric acid or ascorbic acid.
  • the nebulization composition may contain sodium citrate, for example, at a concentration of about 0.0001% w/v to about 2.20% w/v, and citric acid, for example, at a concentration of about 0.0001% w/v to about 0.53% w/v, to control pH.
  • the pharmaceutically acceptable vehicle in the nebulization composition includes water and optionally a cosolvent.
  • Any cosolvent that is suitable for inhalation and capable of dissolving or solubilizing the glycopyrronium or arformoterol in the mixture of cosolvent and water can be used.
  • 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.
  • Suitable surfactants include, but are not limited to, C 5-20 -fatty alcohols, Cs- 20 -fatty acids, C 5-20 -fatty acid esters, lecithin, glycerides, propylene glycol esters, polyoxyethylenes, polysorbates, sorbitan esters, carbohydrates, and any combination of any of the foregoing.
  • C 5-20 - fatty acids, propylene glycol diesters of the Cv 20 -fatty acids, triglycerides of the Cs- 20 -fatty acids, and sorbitans of the Cs- 20 -fatty acids are preferred.
  • the surfactant is selected from oleic acid, sorbitan mono-, di- or trioleates, and any combination of any of the foregoing.
  • nebulization compositions described herein may optionally include a buffer.
  • Suitable general and biological buffers that may be used, such as those in the pH range of about 2 to about 8 include, but are not limited to, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, Mcllvaine, phosphate, Prideaux-Ward, phosphate, citrate, borate, succinate, citrate -phosphate -borate (Teorell-Stanhagen), veronal acetate, 2-(N- morpholino)ethanesulfonic acid (MES), BIS-TRIS, N-(2-Acetamido)iminodiacetic acid, N-(2- Acetamido)-2-aminoethanesulfonic acid (ADA), piperazine-N,N'-bis(2-ethanesulfonic acid) (PIPES), P-Hydroxy-4-morpholinepropanes
  • 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.
  • 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.
  • the nebulization composition may comprise of one or more prefilled containers containing a nebulization composition of the present invention. Each container comprises a single unit dose of a nebulization composition of the present invention.
  • One embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide and 10 meg arformoterol tartarate.
  • the nebulization composition may additionally contain a buffer, an isotonicity agent and optionally a complexing agent.
  • One more embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide and 10 meg arformoterol tartarate.
  • the nebulization composition may additionally contain citric acid and sodium citrate as buffer and sodium chloride as isotonicity agent.
  • Yet another embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide and 10 meg arformoterol tartarate.
  • the nebulization composition may additionally contain citric acid as buffer and ethylene diamine tetra-acetic acid (EDTA) as a complexing agent and sodium chloride as isotonicity agent.
  • EDTA ethylene diamine tetra-acetic acid
  • Another embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide, about 15 meg arformoterol tartarate.
  • the nebulization composition may additionally contain citric acid as buffer and sodium chloride as isotonicity agent.
  • One more embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide and 15 meg arformoterol tartarate.
  • the nebulization composition may additionally contain citric acid and sodium citrate as buffer and sodium chloride as isotonicity agent.
  • Yet another embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide and 15 meg arformoterol tartarate.
  • the nebulization composition may additionally contain citric acid as buffer and ethylene diamine tetra-acetic acid (EDTA) as a complexing agent and sodium chloride as isotonicity agent.
  • EDTA ethylene diamine tetra-acetic acid
  • One embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide and 20 meg arformoterol tartarate.
  • the nebulization composition may additionally contain a buffer, an isotonicity agent and optionally a complexing agent.
  • One more embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide and 20 meg arformoterol tartarate.
  • the nebulization composition may additionally contain citric acid and sodium citrate as buffer and sodium chloride as isotonicity agent.
  • An embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 25 meg of glycopyrronium bromide and 20 meg arformoterol tartarate.
  • the nebulization composition may additionally contain citric acid and sodium citrate as buffer and ethylene diamine tetra-acetic acid (EDTA) as a complexing agent and sodium chloride as isotonicity agent.
  • EDTA ethylene diamine tetra-acetic acid
  • One embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 10 meg arformoterol tartarate.
  • the nebulization composition may additionally contain a buffer, an isotonicity agent and optionally a complexing agent.
  • Another embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide, about 10 meg arformoterol tartarate.
  • the nebulization composition may additionally contain citric acid as buffer and sodium chloride as isotonicity agent.
  • An embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 10 meg arformoterol tartarate.
  • the nebulization composition may additionally contain citric acid and sodium citrate as buffer and ethylene diamine tetra-acetic acid (EDTA) as a complexing agent.
  • EDTA ethylene diamine tetra-acetic acid
  • One embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 15 meg arformoterol tartarate.
  • the nebulization composition may additionally contain a buffer, an isotonicity agent and optionally a complexing agent.
  • Another embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide, about 15 meg arformoterol tartarate.
  • the nebulization composition may additionally contain citric acid as buffer and sodium chloride as isotonicity agent.
  • One more embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 15 meg arformoterol tartarate.
  • the nebulization composition may additionally contain citric acid and sodium citrate as buffer and sodium chloride as isotonicity agent.
  • Yet another embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 15 meg arformoterol tartarate.
  • the nebulization composition may additionally contain citric acid as buffer and ethylene diamine tetra-acetic acid (EDTA) as a complexing agent and sodium chloride as isotonicity agent.
  • EDTA ethylene diamine tetra-acetic acid
  • An embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 15 meg arformoterol tartarate.
  • the nebulization composition may additionally contain citric acid and sodium citrate as buffer and ethylene diamine tetra-acetic acid (EDTA) as a complexing agent and sodium chloride as isotonicity agent.
  • EDTA ethylene diamine tetra-acetic acid
  • One embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 20 meg arformoterol tartarate.
  • the nebulization composition may additionally contain a buffer, an isotonicity agent and optionally a complexing agent.
  • Yet another embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 20 meg arformoterol tartarate.
  • the nebulization composition may additionally contain citric acid as buffer and ethylene diamine tetra-acetic acid (EDTA) as a complexing agent and sodium chloride as isotonicity agent.
  • EDTA ethylene diamine tetra-acetic acid
  • An embodiment is a prefilled container containing about 2 ml of the nebulization composition comprising about 50 meg of glycopyrronium bromide and 20 meg arformoterol tartarate.
  • the nebulization composition may additionally contain citric acid and sodium citrate as buffer and ethylene diamine tetra-acetic acid (EDTA) as a complexing agent and sodium chloride as isotonicity agent.
  • EDTA ethylene diamine tetra-acetic acid
  • the nebulization composition contains not more than about 0.5% of Impurity C of glycopyrrolate or pharmaceutically acceptable salt thereof.
  • the nebulization composition contains not more than about 0.5% of total impurities of glycopyrrolate or pharmaceutically acceptable salt thereof.
  • the nebulization composition contains not more than about 0.4% of amine impurity of aformoterol or pharmaceutically acceptable salt thereof.
  • the nebulization composition contains not more than about 0.3% of deshydroxy impurity of aformoterol or pharmaceutically acceptable salt thereof.
  • the nebulization composition contains not more than about 5% of total impurities of aformoterol or pharmaceutically acceptable salt thereof.
  • the nebulization compositions described herein can also comprise a prefilled container containing a nebulization composition comprising glycopyrronium bromide and arformoterol tartarate, and optionally one or more pharmaceutically acceptable excipients, wherein the nebulization composition is in a solid dosage form, e.g. powder form which can be reconstituted prior to nebulization, with an appropriate diluent supplied in another prefilled container.
  • the solid dosage form can be prepared by various methods, such as dry mixing, spray drying, lyophilization and the like.
  • the nebulization composition can be prepared as follows.
  • composition comprising Glycopyrronium and Arformoterol together
  • a nebulization composition of arformoterol can be prepared in a similar manner as illustrated above.
  • B.3 Mixing of the compositions B.l and B.2
  • Nebulization compositions B.l and B.2 can be separately added to the reservoir of the nebulizer device and mixed to form a nebulization composition B.3
  • the nebulization composition provided herein has a long shelf life, i.e., it is stable during long term storage.
  • the composition may contain greater than about 80%, such as greater than about 85%, greater than about 90%, greater than about 95% or greater than about 98% of the initial amount of glycopyrronium (or its salt) and arformoterol (or its salt) in the composition after being stored for 3 or 6 months or 1, 2 or 3 years at 2-8 0 C and 25° C when stored in a suitable container (such as a LDPE container in an aluminium pouch).
  • 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 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
  • any of the nebulization compositions described herein, when administered by a nebulizer provides a mass median aerodynamic diameter (MMAD) of below about 10 microns, such as between about 3 and about 6 microns.
  • MMAD mass median aerodynamic diameter
  • any of the nebulization compositions described herein, when administered by a nebulizer provides a geometric standard deviation (GSD) of below about 5, such as between about 1 and about 3.
  • GSD geometric standard deviation
  • any of the nebulization compositions described herein when administered by a nebulizer device provides a fine particle dose which is not less than about 10%.
  • the fine particle fraction (FPF) obtained following administration of the nebulizable composition in a nebulizer is about 30% to about 70%.
  • the time taken to nebulize the nebulizable composition from the nebulizer device is about 1 to about 10 minutes.
  • the nebulization composition exhibits a delivered dose between about 40% to about 99%.
  • nebulization compositions of the present invention may be administered once a day or twice a day to a subject in need thereof.
  • the present invention includes methods of treating an inflammatory or obstructive airway disease such as asthma and COPD by administering to a patient a nebulization composition comprising glycopyrronium (or its salt) and arformoterol (or its salt) via a nebulizer.
  • compositions of the present invention comprising the combination of glycopyrrolate and arformoterol may be useful in cases where monotherapy i.e. glycopyrrolate or arformoterol alone have been ineffective in the treatment of inflammatory or obstructive airway disease such as asthma or COPD.
  • the nebulization composition of the present invention comprising glycopyrrolate and arformoterol provide a synergistic effect. Accordingly, it may be possible to reduce the effective daily dose of these agents, thus, reducing the adverse effects posed by these agents.
  • the nebulization composition provides a rapid onset of action and the effect may be extended for a long duration. A significant improvement in lung function leading to effective control of inflammatory or obstructive disease may be observed.
  • the methods of treating inflammatory or obstructive airway disease such as asthma or COPD by the nebulization compositions as per the present invention may eliminate the need for other concurrent treatment modalities.
  • Nebulization composition comprising Glycopyrronium bromide and Arformoterol tartarate in a single composition
  • the below table represents a stability data for the three replicate batches for Example 28.
  • FPM in-vitro aerodynamic particle size distribution
  • MB mass balance
  • MOC micro-orifice collector
  • IP induction port
  • S 1 to S7 refers to stages 1 through stage 7 respectively.
  • DD refers to drug delivery.
  • Nebulization composition comprising Glycopyrronium bromide and Arformoterol tartarate prepared separately and to be mixed prior to administration
  • compositions of glycopyrronium and arformoterol which are formulated separately and are mixed prior to administration to a patient.
  • Nebulization composition comprising Glycopyrronium bromide and Arformoterol tartarate prepared separately and to be mixed prior to administration
  • compositions of glycopyrronium and arformoterol which are formulated separately and are mixed prior to administration to a patient.
  • ampules C 1 and C2 are packaged together in a foil pouch.

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Abstract

La présente invention concerne une composition de nébulisation comprenant du glycopyrrolate et de l'arformotérol pour le traitement d'une maladie inflammatoire ou obstructive des voies respiratoires et un procédé de préparation de la composition.
PCT/IB2020/050248 2019-01-17 2020-01-14 Composition de nébulisation comprenant du glycopyrrolate et de l'arformotérol WO2020148638A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115475153A (zh) * 2021-11-30 2022-12-16 南京华盖制药有限公司 一种吸入用格隆溴铵药液及其应用
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 (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100055045A1 (en) * 2008-02-26 2010-03-04 William Gerhart Method and system for the treatment of chronic obstructive pulmonary disease with nebulized anticholinergic administrations
US20140018406A1 (en) * 2009-06-09 2014-01-16 Sunovion Respiratory Development, Inc. Treatment of Chronic Obstructive Pulmonary Disease With Nebulized Beta 2-Agonist or Combined Nebulized Beta 2-Agonist and Anticholinergic Administration
WO2016170518A1 (fr) * 2015-04-24 2016-10-27 Glenmark Specialty S.A. Compositions pharmaceutiques comprenant de l'arformotérol et du glycopyrronium

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100055045A1 (en) * 2008-02-26 2010-03-04 William Gerhart Method and system for the treatment of chronic obstructive pulmonary disease with nebulized anticholinergic administrations
US20140018406A1 (en) * 2009-06-09 2014-01-16 Sunovion Respiratory Development, Inc. Treatment of Chronic Obstructive Pulmonary Disease With Nebulized Beta 2-Agonist or Combined Nebulized Beta 2-Agonist and Anticholinergic Administration
WO2016170518A1 (fr) * 2015-04-24 2016-10-27 Glenmark Specialty S.A. Compositions pharmaceutiques comprenant de l'arformotérol et du glycopyrronium

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115475153A (zh) * 2021-11-30 2022-12-16 南京华盖制药有限公司 一种吸入用格隆溴铵药液及其应用
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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