NZ707754B2 - Combination of glycopyrrolate and a beta2 -agonist - Google Patents

Combination of glycopyrrolate and a beta2 -agonist Download PDF

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Publication number
NZ707754B2
NZ707754B2 NZ707754A NZ70775412A NZ707754B2 NZ 707754 B2 NZ707754 B2 NZ 707754B2 NZ 707754 A NZ707754 A NZ 707754A NZ 70775412 A NZ70775412 A NZ 70775412A NZ 707754 B2 NZ707754 B2 NZ 707754B2
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New Zealand
Prior art keywords
pharmaceutical composition
glycopyrrolate
composition according
glycopyrronium
furoate
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NZ707754A
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NZ707754A (en
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Geena Malhotra
Shrinivas Madhukar Purandare
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Cipla Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
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    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
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    • 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
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
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    • A61K9/0012—Galenical forms characterised by the site of application
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    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
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    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
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    • 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
    • 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
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Provided are pharmaceutical compositions comprising glycopyrrolate, a beta2-adrenergic agonist, and optionally a corticosteroid. Preferred beta2-adrenergic agonists include indacaterol, formoterol, vilanterol, carmoterol and olodaterol. Preferred corticosteroids include fluticasone and mometasone. Particularly preferred compositions consist of glycopyrrolate, formoterol fumarate dihydrate and fluticasone furoate; glycopyrrolate, vilanterol trifenatate and fluticasone furoate; or glycopyrrolate and olodaterol hydrochloride monohydrate. The compositions can be used in the treatment of respiratory, inflammatory or obstructive airway diseases. articularly preferred compositions consist of glycopyrrolate, formoterol fumarate dihydrate and fluticasone furoate; glycopyrrolate, vilanterol trifenatate and fluticasone furoate; or glycopyrrolate and olodaterol hydrochloride monohydrate. The compositions can be used in the treatment of respiratory, inflammatory or obstructive airway diseases.

Description

PATENTS FORM NO. 5 Our ref: CLM 236617NZPR DIVISIONAL APPLICATION FILED OUT OF NZG13915 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Combination of glycopyrrolate and a beta2 -agonist We, Cipla Limited of Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg, Lower Parel, L. B. S. Marg, Vikhroli (W), Mumbai, , India hereby declare the invention, for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following ent: (Followed by page 121) 103609857_1.docx:CLM:ewa Combination of glycopyrrrolate and a beta2 -agonist Field of Invention The present invention relates to pharmaceutical compositions for inhalation which comprise one or more bronchodilators and optionally an inhaled corticosteroid. There is also provided a process for preparing such compositions and the use thereof in the treatment and/or prevention of respiratory, inflammatory or obstructive airway disease, particularly chronic obstructive pulmonary disease.
The present application is a divisional application out of NZ 613915. The description of the present invention and the description of the invention of NZ 613915 are both retained herein for clarity and completeness.
Background of Invention c obstructive pulmonary e (COPD) is a severe respiratory condition that is sing its prevalence worldwide. In India, the estimated prevalence is about 12.36 n. It is currently the fourth leading cause of death in the UK & US, and predicted to rank third in the global impact of disease by the year 2020.
COPD is a preventable and treatable disease state characterized by air flow limitation that is not fully reversible. The airflow ction is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. gh COPD affects the lungs it also produces significant systemic consequences.
COPD is associated with mucus hyper secretion, emphysema, iolitis.
The major goals of COPD therapy include smoking cessation, relief of symptoms, improvement in physiological functions and ng complications, such as abnormal gas exchange and bation of disease. However, an integrated ch to the treatment of COPD, involves a combination of healthcare maintenance such as smoking cessation, nce of indoor, outdoor pollutants and ens, and avoidance of occupational exposure to allergens, use of drugs and supplemental therapies in a step-wise fashion as (Followed by page 2) 2012/000171 Currently, y for the treatment or prevention of COPD and asthma includes the use of one or more long acting bronchodilators and an inhaled corticosteroid (ICS).
Inhaled bronchodilators are the foundation in the therapy of COPD e of their capacity to alleviate symptoms, decrease exacerbations of disease and improve quality of life. These drugs also improve airflow limitation and hyperinflation, thereby decreasing the work of ing and improving exercise tolerance. In addition, bronchodilators may reduce respiratory muscle fatigue and improve mucociliary clearance.
More specifically, the choice of bronchodilators es betaz-agonists and anticholinergics. Further, betag—agonists can be short acting for ate relief, or long acting for long term prevention of asthma symptoms.
Long acting betaz-agonists (LABAS) improve lung function, reduce symptoms and protect against se-induced dyspnea in patients with asthma and COPD. LABAs induce odilation by causing prolonged relaxation of airway smooth muscle. In addition to prolonged bronchodilation, LABAs exert other effects such as inhibition of airway smooth-muscle cell proliferation and inflammatory mediator release, as well as non smooth—muscle effects, such as stimulation of mucociliary transport, cytoprotection ofthe respiratory mucosa and attenuation of neutrophil recruitment and activation.
Also, use of a LABA s the frequency of drug administration. Commercially available LABAs include salmeterol and fonnoterol.
Anticholinergic agents also act as bronchodilators and are potential alternatives to beta agonists, particularly LABAs. However, anticholinergics can also be administered along with LABAs for the management of asthma. Anticholinergics act by competing with acetylcholine for the receptor sites at vagus nerve or nerve-muscle junctions. This ts the transmission of reflexes that are induced by asthma stimuli.
W0 2012/1 10770 PCTIGB2012/000171 Use of anticholinergics provides an advantage in elderly ts as the siveness of beta2~agonists declines with old age. Further it would be advantageous to use anticholinergics in patients who are intolerant to the use of betaz-agonists.
Even though it is known that agonists provide a symptomatic relief in bronchoconstriction, another component of COPD, which is inflammation, requires a separate treatment such as with steroids. Most of the inhaled corticosteroids need to be administered in multiple dosage ns.
Corticosteroids exhibit tory effects on inflammatory cells and inflammatory mediators involved in the pathogenesis of respiratory disorders such as COPD.
Treatment with a corticosteroid/glucocorticoid is considered one of the most potent and effective therapies currently available for COPD.
However, the use of corticosteroids has been limited due to ial side effects associated with their use, including suppression of the Hypothalamic-Pituitary-Adrenal (HPA) axis, adverse effects on bone growth in children and on bone density in the elderly, ocular complications (cataract formation and glaucoma) and skin atrophy.
Commercially available corticosteroids include beclomethasone, nide, fluticasone, mometasone, ciclesonide and inolone.
Currently, there are several commercially available pharmaceutical itions for inhalation comprising combinations of LABA and inhaled corticosteroid (ICS).
Examples of such combinations for the treatment of asthma and chronic obstructive pulmonary disease (COPD) are salmeterol/fluticasone propionate (Advair® diskus®, Advair® HFA), and formoterol fumarate dehydrate/budesonide (Symbicort®).
Thus combination therapy of a bronchodilator with an ICS es pulmonary efficiency, reduces inflammatory response and provides symptomatic relief as ed to higher doses of ICS alone in ts affected by respiratory disorders such as COPD.
W0 2012l110770 The selection of a specific bronchodilator and ICS plays a very important role in ation of fixed dose combination therapies.
Further, combination therapy reduces the cost and also provides control of respiratory disorders. Reducing the dose frequency to the minimum is a main step in simplifying COPD management for improving patient adherence to the therapy.
U82009088408 discloses pharmaceutical compositions of anticholinergics, corticosteroids and betamimetics and their use in the treatment of respiratory diseases.
The examples of this application are inhalable powders or suspension aerosol compositions which n tiotropium or ipratropium bromide.
U82005042174 discloses a combination of doses of a betaz-agonist, an anticholinergic agent and an anti—inflammatory d.
W02006105401 discloses anticholinergic in combination with a corticosteroid, and a long acting beta t, for simultaneous or sequential administration in the prevention or treatment of a atory, inflammatory or ctive airway disease.
U82008279948 discloses a medicament comprising a betaz-agonist, a yrronium salt and mometasone furoate. The examples of this application contain the betaz-agonist indacaterol maleate.
U82008286363 discloses a ment comprising a betaz-agonist (such as indacaterol maleate), a glycopyrronium salt and a corticosteroid. The examples of this application contain the corticosteroid 3-methy1-thiophenecarboxylic acid (68,9R, 1 03,1 1 S, 1 3 S,16R,17R)chloro—6-fluoro—1 1—hydroxymethoxycarbonyl- , 13,16-trimethyl-3—oxo-6,7,8,9, 10, l l,12,13,14,15,16,17-dodecahydro-3H~cyclopenta- [alphenanthrenyl ester.
U8201016667l discloses a medicament comprising an scarinic agent, a beta;- t and a corticosteroid. The examples of this application contain yrronioum, formoterol fumarate and mometasone furoate.
US7439393 discloses certain phenethanolamine derivatives for the treatment of respiratory diseases. The use of such compounds in combination therapy with other therapeutic agents is also disclosed.
USZOO80041369 ses propellant—free aerosol formulations comprising inter alia olodaterol, a corticosteroid such as budesonide, beclomethasone or fluticasone and an anticholinergic such as tiotropium, oxitropium or ipratropium. 0239778 discloses medicament combinations comprising inter alia olodaterol and at least one other active substance, such as a steroid.
U820080317862 discloses medicaments comprising an antimuscarinic agent and a corticosteroid for the treatment of atory or obstructive airways diseases. In particular, this application discloses l compositions comprising glycopyrronium and mometasone furoate.
U820060069073 discloses a combination of glycopyrronium and one or more steroids as a second active substance.
W02005110402 discloses medicaments comprising yrrolate in combination with betaz-agonist such as indacaterol maleate. 074900 discloses a combination of an anticholinergic such as glycopyrronium and a long-acting beta-mimetic agent such as erol or salmeterol.
Thus, there is still a need to develop suitable combinations comprising a beta agonist, an anticholinergic agent and/or an inhaled corticosteroid that alleviate COPD.
W0 2012I110770 2012/000171 Hence, there still exits a need to formulate pharmaceutical compositions comprising a beta agonist, an anticholinergic agent and an inhaled corticosteroid exhibiting reduced side s and which can be administered once a day.
Objects of the Invention The object of the present invention is to provide pharmaceutical compositions for inhalation comprising one or more bronchodilators and an d corticosteroid for administration in the prevention or treatment of respiratory, inflammatory or obstructive airway e.
Another object of the present invention is to provide pharmaceutical compositions for inhalation comprising one or more bronchodilators and an inhaled corticosteroid for once daily administration for the tion or treatment of respiratory, inflammatory or obstructive airway disease.
Yet another object of the present invention is to provide a process for preparing the pharmaceutical compositions comprising one or more bronchodilators and an inhaled corticosteroid for administration in the prevention or treatment of respiratory, inflammatory or ctive airway disease.
A further object of the present invention is to provide a method for prophylaxis or treatment of COPD which comprises administering pharmaceutical compositions comprising one or more bronchodilators and an inhaled corticosteroid. y ofthe Invention According to a first aspect of the present invention, there is provided a pharmaceutical composition comprising glycopyrrolate and a betaz-agonist.
Preferably the composition r comprises one or more inhaled corticosteroids.
According to a second aspect of the present invention, there is provided a pharmaceutical ition comprising glycopyrrolate and erol.
According to a third aspect of the present invention, there is provided a pharmaceutical composition comprising glycopyrrolate and olodaterol.
According to a fourth aspect of the present invention, there is provided a pharmaceutical composition sing glycopyrrolate and carmoterol.
According to a fifih aspect of the present invention, there is provided a pharmaceutical composition comprising yrrolate, olodaterol and fluticasone, especially an ester of fluticasone, in particular fluticasone furoate.
According to a sixth aspect of the present invention, there is provided a pharmaceutical composition comprising yrrolate, olodaterol and mometasone, ally an ester of mometasone, in particular mometasone furoate. ing to a seventh aspect of the present invention, there is ed a pharmaceutical composition comprising glycopyrrolate, vilanterol and sone, especially an ester of fluticasone, in particular fluticasone furoate.
According to a eighth aspect of the present invention, there is provided a pharmaceutical composition comprising glycopyrrolate, fomoterol and fluticasone, especially an ester of fluticasone, in particular fluticasone furoate.
According to a ninth aspect of the present invention, there is provided a pharmaceutical composition comprising glycopyrrolate, indacetrol and fluticasone, especially an ester of fluticasone, in particular fluticasone e.
According to a tenth aspect of the present invention, there is provided a process for preparing the pharmaceutical itions described above.
According to a eleventh aspect of the present ion, there is provided a method for prophylaxis or treatment of asthma, COPD or a related respiratory disorder which comprises administering a ceutical compositions described above.
According to a twelfih aspect of the present invention there is provided a use in treating disorders or conditions that respond to, or are prevented, ameliorated or eliminated by, the administration of pharmaceutical compositions described above.
Detailed Description ofthe Invention As sed above, the ion of a specific betaz-agonist, anticholinergic agent and inhaled osteroid (lCS) plays a very important role in formulation of fixed dose combinations.
The present invention thus es pharmaceutical compositibns for inhalation comprising or ting of glycopyrrolate, a betag-agonist, and an inhaled corticosteroid.
In one embodiment, there is provided a pharmaceutical composition for inhalation comprising or consisting of: (a) glycopyrrolate; (b) a betaz-agonist selected from the group consisting of carmoterol, formoterol, indacaterol, olodaterol, vilanterol; and, optionally, when the LABA is selected from formoterol, indacaterol, olodaterol, vilanterol; (c) an inhaled osteroid (ICS) selected from the group consisting of fluticasone, mometasone; preferably wherein (a), (b) and (c) are formulated for simultaneous, separate or tial administration; and provided that the composition does not comprise glycopyrrolate, mometasone furoate and terol maleate or formoterol fumarate.
W0 2012410770 PCTIGB2012/000171 A particularly preferred pharmaceutical composition of the present invention comprises, or ts of, (a) glycopyrrolate (b) indacaterol and (c) fluticasone (especially fluticasone furoate).
A further particularly preferred ceutical composition of the present ion comprises, or consists of, (a) glycopyrrolate, (b) formoterol and (c) fluticasone (especially fluticasone furoate).
A further particularly preferred ceutical composition of the t invention comprises, or consists of, (a) glycopyrrolate (b) vilanterol and (c) fluticasone (especially fluticasone furoate). , A further particularly red pharmaceutical composition of the present invention comprises, or consists of, (a) glycopyrrolate, (b) olodaterol and (c) fluticasone (especially fluticasone furoate).
A still further particularly preferred pharmaceutical composition of the present invention comprises, or consists of, (a) glycopyrrolate, (b) erol and (c) mometasone.
In an alternative preferred ment of the invention, there is provided a pharmaceutical composition comprising or consisting of glycopyrrolate and a beta;- agonist.
In a still further preferred ment of the ion, there is provided a pharmaceutical composition comprising or consisting of (a) glyc0pyrroiate; and (b) a betaz-agonist selected from the group consisting of carmoterol, olodaterol, vilanterol; preferably wherein (a) and (b) are formulated for simultaneous, separate or sequential administration.
A particularly preferred pharmaceutical composition of the present invention comprises, or consists of, (a) glycopyrrolate and (b) vilanterol.
A further particularly preferred pharmaceutical composition of the present invention comprises, or consists-of, (a) yrrolate and (b) olodaterol.
A still further ularly preferred pharmaceutical composition of the present invention comprises, or ts of, (a) glycopyrrolate and (b) carmoterol.
Our inventors have found that the above-mentioned pharmaceutical compositions are effective for ng inflammatory and/or obstructive es of the respiratory tract, particularly asthma or chronic obstructive pulmonary disease (COPD). rmore, the pharmaceutical compositions of the present invention advantageously provide a rapid onset of action, longer duration of action and improved control of ctive or inflammatory airway diseases, or reduction in the exacerbations of the diseases.
Also, the pharmaceutical compositions of the t invention advantageously reduce the risk of rable side effects as compared to the repeated re of the steroid alone involved in the treatment of inflammatory or obstructive airways diseases.
Another advantage of the pharmaceutical compositions ofthe present invention is that the invention facilitates the treatment of an obstructive and inflammatory airway disease with a single medicament.
Further the pharmaceutical compositions of the present invention provide for the administration of combination therapies by use of a single inhaler for patients who currently have to make use of multiple inhalers. By way of example, ts may administer pharmaceutical compositions of the present invention from a single inhaler instead of administering from three different inhalers, one for corticosteroid, one for W0 2012!]10770 anticholinergic and one for a long acting betaz-agonist. This is particularly important in case of elderly patients who may get confused between the inhalers and who also suffer from several other medical conditions such as heart disease and arthritis, and are receiving multiple other medications.
In a preferred embodiment, the ceutical compositions of the present ion are ated for once daily administration.
The pharmaceutical compositions of the present invention comprise glycopyrrolate. The word “glycopyrrolate” can be interchangeably used with “glycopyrronium”.
Glycopyrrolate belongs to the class of quaternary ammonium anticholinergic drugs and antagonizes the neurotransmitter acetylcholine at its muscarinic receptors. This effect leads to a erable smooth muscle relaxation resulting in a prolonged bronchodilating effect. More specifically it inhibits acetylcholine g to M3 inic receptors thereby inhibiting bronchoconstriction.
Glycopyrrolate is a quaternary ammonium salt. Suitable counter ions are pharmaceutically acceptable counter ions including, for e, fluoride, chloride, e, iodide, nitrate, e, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p—chlorobenzoate, diphenyl-acetate or triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, l- hydroxynaphthalene-Z-carboxylate, 3-hydroxynaphthalene-Z—carboxylate, methanesulfonate and benzenesulfonate. A particularly preferred salt of glycopyrrolate the bromide salt thereof. The bromide salt of glycopyrrolate is chemically known as {3- [(Cyclopentyl-hydroxyphenylacetyl) oxy]-1, l-dimethylpynrolidinium bromide}.
Glycopyrrolate has two centers of asymmetry (chiral centers), and can exist in four stereoisometric forms namely (3R, 2'R)-, (3S, 2'R)», (3R, 2'S)- and (38, 2'8), i. , two enantiomeric pairs of diastereomers. The two di~ astereomer pairs have been separated from one another. Commercially ble formulations of glycopyrrolate contain both the (R, S)~glycopyrrolate and (S, R)-glycopyrrolate enantiomers.
Glycopyrrolate is currently available marketed in the form of oral tablets for tive therapy in the treatment of peptic ulcer, as an injectable for therapy in the treatment of peptic ulcer and as a preoperative scarinic to reduce secretions and as a capsule for reducing chronic severe drooling in patients aged between 3 to 16 years with ogic conditions associated with problem drooling.
Glycopyrrolate also t the effects resulting from passage of impulses through the parasympathetic nerves. This action results from their ability to inhibit the action of the neurotransmitter acetylcholine by blocking its g to muscarinic cholinergic receptors. Further, inhaled glycopyrrolate exhibits low systemic absorption, and therefore is not associated with typical systemic antimuscarinic adverse effects. ing to the present invention, glycopyrrolate may be t in an amount of from about 50mcg to about 200mcg.
Bronchodilators used according to the present invention may be beta-agonists and/or anticholinergics. According to the present invention, beta ts may comprise, one or more, short acting beta agonist(s), long acting beta agonist(s) and/or ultra long acting beta agonist(s).
In addition to glycopyrrolate, the pharmaceutical compositions of the present invention further comprise a beta2~agonist, ably selected from the group comprising carmoterol, formoterol, indacaterol, olodaterol, vilanterol.
Carmoterol is chemically known as 8~hydroxy~5 - (1-hydroxy—2-(N—(2-(4- methoxyzphenyi) methyl:ethyi) amino)ethyl)~2 (lH)-quinolinone. Carmoterol is a long acting betaz-agonist characterized by having a rapid onset of action, prolonged duration of action and also having a high selectivity towards the beta adrenoreceptor. rmore, carrnoterol is more potent than other LABAs such as formoterol and salmeterol. A particularly preferred pharmaceutically able salt of cannoterol is PCT/G32012/000171 cannoterol hydrochloride. According to the t invention, carmoterol may be present in an amount of from about lmcg to about 4mcg.
Forrnoterol is chemically known as (i)-2—hydroxy[(lRS)—l-hydroxy—2~[[(1RS)~2~(4v methoxyphenyl)-lmethylethyl]-amino] ethyl] formanilide. Forrnoterol is a selective LABA. erol exhibits a quick onset of action (1-3 minutes) which helps to achieve an immediate therapeutic response. Furthermore formoterol exhibits a long on of action of more than 12 hours. A particularly preferred pharmaceutically acceptable ester of formoterol is formoterol fumarate. A particularly preferred ceutically able ester of formoterol is formoterol fumarate dihydrate. According to the present invention, formoterol may be present in an amount of from about 12 to about 24mcg, preferably about 24mcg.
Indacaterol is chemically known as (R)[2~[(5,6—Diethyl-2,3-dihydro-lH-inden-Z- no]—l-hydroxyethyl]—8-hydroxyquinolin-2(1H)—0ne is a ultra-long acting betaz- t. Indacaterol has a fast onset of action which is similar to that of formoterol and faster than that of salmeterol. Furthermore, indacaterol exhibits a longer duration of action than salmeterol as well as has greater cardiovascular safety margin as compared to erol and formoterol. A particularly preferred pharmaceutically acceptable salt of terol is indacterol maleate. According to the present invention, indacaterol may be present in an amount of from about 25mcg to about 800mcg.
Olodaterol is chemically known as 6-hydroxy—8—[(1R)¥l~hydroxy—2-[[2-(4- methoxyphenyl)- 1 , l -dimethylethyl]amino]ethyl]-2H- l ,4-benzoxazin-3(4H)- one. A particularly preferred pharmaceutically acceptable salt of Olodaterol is Olodaterol hydrochloride monohydrate. According to the present invention, Olodaterol may be present in an amount of from about 3mcg to about 50mcg.
Vilanterol is chemically known as 4-{(1R)‘2—[(6-{2-[(2,6~ dichlorobenzyl)oxy]ethoxy}hexy1)amino]~1-hydroxyethyl}(hydroxymethyl)phenol is a long acting beta2-agonist. A particularly preferred ceutically acceptable salt of WO 10770 2012/000171 vilanterol is vilanterol trifenatate. According to the present invention, vilanterol may be present in an amount of from about 3mcg to about 50mcg.
In addition to glycopyrrolate and a betaz-agonist, the pharmaceutical compositions of the t invention may also comprise a corticosteroid; preferably selected from the group ting ofmometasone, fluticasone.
Fluticasone is currently commercially available as a furoate salt and a propionate salt. asone furoate is a novel corticosteroid which substantially overcomes the potential side effects that are generally produced by the use of conventional corticosteroids.
Moreover fluticasone furoate exhibits a 1.7 times higher binding affinity for the human glucocorticoid receptor as compared to that of fluticasone propionate and also provides prolonged protection up to 26 hours against airway hyperresponsiveness as ed to fluticasone propionate. Fiuticasone furuoate has a longer on of action with an elimination half life of 15.1 hrs. asone furoate is a synthetic fluorinated corticosteroid that has been developed as an intranasai treatment for patients with symptoms of rhinitis and has an enhanced affinity towards the glucocorticoid receptor. Further, fluticasone furoate has r potency than other clinically used corticosteroids such as sone furoate, budesonide, fiuticasone propionate, ciclesonide for the glucocorticoid receptor'and t the proinflammatory ription factors nuclear factor KB (NF-KB), activation protein-1, and tumor is factor~ induced interleukin-8 cytokine production. Chronic inflammation which is commonly associated with asthma is managed by fluticasone furoate.
Particularly preferred pharmaceutically acceptable esters of fluticasone are fluticasone furoate and fluticasone propionate, most preferably fluticasone furoate. According to the present invention, fluticasone furoate may be present in an amount of from about 25mcg to about 800mcg. 2012/000171 Mometasone furoate is ally known as (11[B], 16[a})-9, 21-dichloro-l7-[(2~ furanylcarbonyl) oxy]-l oxymethylpregna-l ,4-diene-3,20-dione. Mometasone furoate is a synthetic 17—heterocyclic corticosteroid and exhibits a long duration of action A particularly preferred pharmaceutically acceptable ester of mometasone is mometasone furoate. Acc0rding to the present invention, mometasone furoate may be present in an amount of from about 400mcg to about 800mcg.
As used herein the terms “glycopyrronium”, “glycopyrrolate”, "fluticasone furoate”, “mometasone furoare”, “carmoterol”, terol, “vilanterol’, ”formoterol” and “indacaterol” are used in broad sense to include not only “glycopyxronium”, “glycopyrrolate” “fluticasone furoate” “mometasone furoare”, “carmoterol”, “olodaterol, “vilanterol’, ”formoterol” and l“indacaterol” per se but also their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable es, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, ceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, etc.
In on to active ceutical ients, the ceutical compositions of the present invention typically comprise one or more pharmaceutically acceptable ents.
The active ingredients may be used as separate formulations or as a single combined formulation. When combined in the same formulation, it will be appreciated that the active ingredients must be stable and compatible with each other and the other components of the formulation.
The pharmaceutical compositions of the present invention are formulated for inhalation and may therefore be administered by any suitable methods used for ry of the drugs to the respiratory tract. For example, the composition of the present invention may be in the form of an aerosol composition, a nasal spray, nasal drops or an insufflation powder.
Such aerosol compositions may be administered by any conventional means, for example using a metered dose inhaler (MDI), dry powder inhaler (DPI) or nebulizer.
The various dosage forms ing to the present invention may comprise carriers/excipients suitable for formulating the same.
In one embodiment, the pharmaceutical compositions of the present invention are in a form suitable for administration by a MDI, for example, in the form of an l composition. Such compositions may comprise one or more pharmaceutically acceptable excipients, in particular selected from the group of HFC/HFA lants, co-solvents, bulking agents, non~volatile components, buffers/pH adjusting agents, surface active agents, vatives, complexing agents, or combinations thereof.
Suitable pmpellants are those which, when mixed with the cosolvent(s), form a homogeneous propellant system in which a eutically effective amount of the medicament can be dissolved. The HFC/HFA propellant must be toxicologically safe and must have a vapor pressure which is suitable to enable the medicament to be administered via a rized MDI. ' According to the present invention, the HFC/HFA propellants may comprise, one or more of l,l,1,2-tetrafluoroethane (HFA-l34(a)) and 1,1,1,2,3,3,3,—heptafluoropropane (HFA- 227), HFC~32 (difluoromethane), HFC-l43(a) (1,1,1-trifluoroethane), HFC~134 ,2— tetrafluoroethane), and 2a (1,1-difluoroethane) or combinations thereof and such other prOpellants which may be known to the person having a skill in the art.
In the context of the present invention, the term “co-solvent” means any solvent which is miscible in the ation in the amount desired and which, when added provides a formulation in which the medicament can be ved. The function of the co-solvent is to increase the solubility of the ment and the excipients in the formulation.
According to the present invention, the co-solvent may comprise one or more of, C2. C5 aliphatic alcohols, such as, but not limited to, ethyl alcohol and isopmpyl alcohol; glycols such as but not limited to propylene glycol, polyethylene glycols, polypropylene glycols, glycol ethers, and block mers of oxyethylene and oxypropylene; and other W0 2012f110770 substances, such as, but not limited to, glycerol, polyoxyethylene alcohols, and polyoxyethylene fatty acid esters; hydrocarbons such as but not limited to n—propane, n~ butane, isobutane, n-pentane, iso-pentane, ntane, and n-hexane; and ethers such but not limited to diethyl ether and combinations f.
Suitable surfactants which may be employed in an aerosol composition of the present invention include those which may serve to stabilize the solution formulation and improve the performance of valve systems of the metered dose inhaler. Preferred surfactants include one or more ionic and/or non- ionic surfactants.
Examples of le surfactants include, but are not limited to, oleic acid, sorbitan trioleate, lecithin, pylmyristate, tyloxapol, nylpyrrolidone, polysorbates such as polysorbate 80, vitamin E—TPGS, and macrogol hydroxystearates such as macrogoH5~hydroxystearate and combinations thereof.
In the context of the t invention, the term “non-volatile component” refers to the suspended or dissolved constituents of the pharmaceutical composition that would remain after evaporation of the solvent(s) present.
According to the present invention, the non-volatile component may comprise one or more of ccharides such as, but not limited to, glucose, arabinose; disaccharides such as lactose, maltose; oligosaccharides and polysaccharides such as, but not d to, dextrans; polyalcohol such as, but not limited to, glycerol, sorbitol, mannitol, xylitol; salts such as, but not limited to, ium de, magnesium chloride, magnesium te, sodium chloride, sodium citrate, sodium phosphate, sodium hydrogen phosphate, sodium hydrogen carbonate, potassium citrate, potassium phosphate, potassium hydrogen phosphate, potassium hydrogen carbonate, calcium carbonate and calcium de and combinations thereof.
Suitable bulking agents may be employed in the pharmaceutical compositions of the invention, in particular aerosol compositions that are intended for administration using an MDI. The bulking agent may comprise one or more of saccharides, including W0 20121110770 monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, terhalose, lactose, maltose, starches, dextran or mannitol and combinations f. le buffers or pH adjusting agents may be employed in the pharmaceutical compositions of the invention, in particular l compositions that are intended for administration using an MDl. The buffer or the pH adjusting agent may comprise one or more of organic or inorganic acids such as, but not limited to, citric acid, ascorbic acid, hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid and combinations thereof.
Suitable preservatives may be employed in in the ceutical compositions of the invention, in ular aerosol compositions that are intended for administration using an MDI, to protect the ation from contamination with pathogenic ia. The preservative may comprise one or more of benzalkonium chloride, benzoic acid, benzoates such as sodium benzoate and such other preservatives which may be known to the person having a skill in the art and combinations thereof.
Suitable complexing agents may be employed in the pharmaceutical compositions of the invention, in particular aerosol compositions that are intended for administration using an MDI, e of forming complex bonds. The complexing agent may se one or more of, but not limited to, sodium EDTA or disodium EDTA and ations thereof.
In one embodiment, the pharmaceutical itions of the present invention are in a form suitable for administration by a dry powder inhaler (DPI).
The ceutically acceptable excipients suitable for dry powder inhalation according to the present invention may be selected from suitable carriers which include, but are not d to, sugars such as glucose, saccharose, lactose and fructose, starches or starch derivatives, oligosaccharides such as dextrins, cyclodextrins and their derivatives, polyvinylpyrrolidone, alginic acid, tylose, silicic acid, cellulose, cellulose derivatives (for example cellulose ether), sugar alcohols such as mannitol or sorbitol, calcium carbonate, W0 2012I110770 calcium phosphate, etc. lactose, lactitol, dextrates, , dextrose, extrin, saccharides including monosaccharides, disaccharides, polysaccharides; sugar alcohols such as arabinose, ribose, mannose, sucrose, trehalose, maltose, dextran and combinations thereof.
In an alternative embodiment, the pharmaceutical itions of the present invention are in a form suitable for administration by nebulization.
Nebulization therapy has an advantage over other inhalation y, since it is easy to use and does not e co-ordination or much effort. It also works much more rapidly than medicines taken by mouth. Such compositions may comprise suitable ents such as one or more, but not limited to, ty agents, pH regulators, and chelating agents in a suitable vehicle.
Examples of suitable isotonicity-adjusting agents include sodium de, potassium de, zinc chloride, m chloride and mixtures thereof. Other isotonicity- adjusting agents may also include, but are not limited to, mannitol, glycerol, and dextrose and mixtures thereof.
The pH of pharmaceutical compositions of the invention may be adjusted by the addition of one or more pH regulators such as pharmacologically acceptable acids.
Pharmacologically acceptable inorganic acids or c acids may be used for this purpose. Examples of preferred inorganic acids include one or more acids selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and phosphoric acid and ations thereof. Examples of particularly suitable organic acids include one or more acids selected from the group consisting of ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinicacid, fumaric acid, acetic acid, formic acid and propionic acid and combinations thereof.
Examples of suitable chelating agents for use in a ceutical compositions of the invention include editic acid (EDTA) or a salt thereof, e.g. sodium EDTA or disodium EDTA dihydrate (sodium edetate), and mixtures of such compounds.
W0 2012f110770 In addition to the excipients such as icity-adjusting agents, pH regulators, chelating agents covered under nebulization therapy, the dosage forma as nasal spay and nasal drops may comprise thickening agents.
Examples of suitable thickening agents may for use in a ceutical compositions of the ion include ose derivatives (for e cellulose ether) in which the ose-hydroxy groups are partially zed with lower unsaturated aliphatic alcohols and/or lower unsaturated tic ohols (for example methyl cellulose, carboxymethyl cellulose, hyd'roxypropylmethylcellulose), gelatin, polyvinylpyrrolidone, tragacanth, ethoxose (water soluble binding and thickening agents on the basis of ethyl cellulose), alginic acid, polyvinyl alcohol, polyacrylic acid, pectin and equivalent agents.
Should these substances contain acid groups, the corresponding physiologically acceptable salts may also be used.
In addition to the aforementioned excipients, one or more anti-microbial preservative agents may also be added to the pharmaceutical compositions of the invention, in particular for multi-dose packages.
In an alternative embodiment, the composition according to the present invention may be included in one or more suitable containers provided with means enabling the application of the contained formulation to the respiratory tract.
Where the pharmaceutical compositions of the invention are in the form of a powder for inhalation and are intended to be administered by a DP], it may be encapsulated in capsules of gelatin or HPMC, or in blisters. In an alternative embodiment, the dry powder may be ned as a reservoir either in a single dose or multi-dose dry powder inhalation device. In a further alternative ment, the powder for inhalation may be suspended in a suitable liquid vehicle and packed in an aerosol container along with suitable propellants or mixtures thereof. In still a further alternative embodiment, the powder for inhalation may be sed in a suitable gas stream to form an aerosol composition.
PCTfGB2012/000171 Where the pharmaceutical compositions of the invention are in the form of an aerosol composition for administration using an MDI, it may be packed in plain aluminium cans or SS less steel) cans or any such cans suitable for MDI delivery. Some aerosol drugs tend to adhere to the inner es, i.e., walls of the cans and valves, of the MDI.
This can lead to the patient getting significantly less than the ibed amount of the active agent upon each activation of the MIDI. Such cans may be suitably treated to avoid any adherence of the active on the walls thereof using techniques known in the art, for example coating the inner surface of the container with a suitable polymer can reduce this adhesion problem. Suitable coatings include fluorocarbon copolymers such as FEP-PES (fluorinated ne propylene and polyethersulphone) and PFA-PES (perfluoroalkoxyalkane and polyethersulphone), epoxy and ethylene. Alternatively, the inner surfaces of the cans may be anodized, plasma treated or plasma coated.
Where the pharmaceutical compositions of the ion are in the form of nasal sprays and nasal drops for administration into the nasal passages it may be done by means of a dropper (or pipette) that includes a glass, plastic or metal dispensing tube. Fine droplets and sprays can be ed by an asal pump dispenser or squeeze bottle as well known in the art.
The pharmaceutical compositions of the present invention may r comprise, in addition to those pharmaceutically active ingredients detailed above, one or more active(s) selected from the group comprising of , antihistamines, antiallergics or leukotriene antagonists, or their pharrnaceutically acceptable salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof.
The pharmaceutical compositions of the present invention comprise glycopyrrolate, a agonist and, optionally, a osteroid. These active ingredients are formulated for simultaneous, separate or sequential administration. When the active ingredients are administered sequentially, either glycopyrrolate the long acting betaz-agonist, or where present, the corticosteroid, may be administered first. When stration is aneous, the active ingredients may be administered either in the same or different WO 10770 pharmaceutical compositions. Adjunctive y, i.e. where one active ingredient is used as the primary treatment and the other active ingredient(s) is/are used to assist that primary treatment is also an embodiment of the present invention.
According to a further embodiment of the invention, there is provided a product comprising (a) glycopyrrolate; (b) a beta2~agonist selected from the group comprising carmoterol, olodaterol, vilanterol; as a combined preparation for simultaneous, separate or sequential use for treatment and /or prevention of respiratory, inflammatory or obstructive airway disease According to a another embodiment of the invention, there is provided a product comprising (a) glycopyrrolate; (b) a betaz-agonist selected from the group comprising olodateroi, vilanterol, formoterol, indacaterol (c) a corticosteroid selected from the group consisting of fluticasone, sone, as a combined ation for simultaneous, separate or sequential use for treatment and /or tion of respiratory, inflammatory or obstructive airway disease Compositions for use according to the present invention may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredients. These may for example, comprise metal or plastic foil, such as a blister pack. Where compositions are intended for stration as two separate compositions these may be presented in the form ofa twin pack.
Pharmaceutical compositions may also be prescribed in “patient packs” containing the whole course of treatment in a single package. The ion of a package insert has been shown to improve patient ance with the ibing physician’s instructions. ing to a further embodiment of the present invention, there is provided a patient pack sing at least one active ingredient of the combination according to the ion and an information insert containing directions to use the combination of the invention. In one embodiment, the present invention provides a fixed dose combination.
The pharmaceutical compositions of the present invention may be conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art.
Suitable methods include the step of bringing into association the active ients with a carrier which tutes one or more pharrnaceutically acceptable excipients. In general, itions may be prepared by uniformly and intimately bringing into association the active ingredients with one or more liquid carriers or finely divided solid carriers, or both. It will be appreciated that when the active ingredients are administered independently, each may be administered by a different means.
The present invention also provides a process to cture the compositions according to the present invention.
In one ment, the t invention provides a s of preparing pharmaceutical itions for administration by a metered dose inhaler, which process comprises admixing a pharmaceutically acceptable carrier or excipient with one or more active pharmaceutical ingredients of the invention and a propellant, and thereafter transferring the composition to a suitable container, preferably a pre-crimped can.
In another embodiment, the invention es a process of preparing a pharmaceutical compositions for administration by dry powder inhalation, which process comprises admixing of a pharmaceutically acceptable carrier or excipient with one or more active pharmaceutical ingredients of the invention and providing the composition as a dry powder.
In a further embodiment, the ion provides a process of ing pharmaceutical compositions for administration by nebulisation, which process comprises dissolving the drugs, optionally chelating , osmotic/isotonicity adjusting agents and any other suitable ingredients in the vehicle and adjusting the pH using a suitable pH adjusting agent.
In a r embodiment, the invention also provides a method for the prevention and/or treatment of a respiratory, inflammatory or obstructive airway disease, in particular chronic obstructive pulmonary disease, in a mammal, such as a human, which method comprises administration of a therapeutically effective amount of pharmaceutical compositions according to the present invention.
The present invention also provides pharmaceutical compositions according to the t invention for use in preventing and/or treating disorders or conditions that respond to, or are prevented, rated or eliminated by, the administration one or more bronchodilators and an d corticosteroid (ICS), such as a respiratory, inflammatory or obstructive airway disease, in particular chronic obstructive ary disease.
The following examples are for the purpose of illustration of the invention only and not intended in any way to limit the scope of the present invention.
Example 1 Process: 1) Fluticasone e, yrronium and Tiotropium were nized with part quantity ofHFA. 2) The suspension obtained in step 1 was transferred to the mixing vessel where remaining quantity ofHFA was added. 3) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
WO 2012!]10770 2012/000171 Example 2 Process: 1) Fluticasone furoate, Indacaterol and yrronium were homogenized with lactose and part quantity ofHFA. 2) The suspension obtained in step i was transferred to the mixing vessel where remaining quantity of HFA was added. 3) The resulting suspension was mixed, ulated and filled in into pre-crimped aluminum cans.
Example 3 Ingredients 1. Fluticasone Furoate mi Glycopyrroniumlndacaterol IPEG400/1000 formulation PVP K 25 0.001% oftotal formulation _HFA134A OR HFA227 _ Process: 1) PVP was dissolved in PEG and part quantity of HFA134A or HFA22’7.
W0 110770 2) The solution obtained in Step 1 was transferred to a mixing . 3) Fluticasone furoate, Indacaterol and Glycopyrronium were homogenized with a part quantity of HFA. 4) The suspension obtained in step 3 was transferred to the mixing vessel where remaining ty ofHFA was added.
) The resulting total suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 4 Sr. No Ingredients .
Fluticasone Furoate 2. yrronium 50 mcg Ethanol 15-20% of total formulation . Glycerol 1% of total formulation HCL ( 0.08N) pH 2.5 - 3.5 Process: 1) Glycerol was dissolved in ethanol and required quantity ofHCl was added. 2) Fluticasone fiJroate, Indacaterol and Glycopyrronium were dissolved in the solution obtained in step 1. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
WO 10770 Example 5 4. Ethanol 15-20% of total formulation HCL ( 0.08N) pH 2.5-3.5 Process: 1) Required quantity ofHCl was added to ethanol. 2) asone fiiroate, Indacaterol and Glycopyrronium were dissolved in the solution ed in step 1. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, recirculated and filled in into pre~crimped aluminum cans.
Example 6 4. Ethanol 15-20% of total formulation . Glycerol 1% of total formulation mCitric acid anhydrous pH 2.5 — 3.5 Process: 1) Citric acid anhydrous and glycerol were dissolved in ethanoir 2) Fluticasone furoate, Indacaterol and Glycopyrronium were dissolved in the solution obtained in step (1). 3) The solution obtained in step (2) was transferred to the main mixing vessel where it was mixed with entire quantity ofHFA134a. 4) The resulting sion was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 7 Ingredients -Fluticasone e ol4. 15-20% of total formulation -5. Citric acid ous pH 2.5 - 3.5 Process: 1) Citric acid anhydrous was dissolved in ethanol. 2) Fluticasone furoate, Indacaterol and Glycopyrronium were dissolved in the solution obtained in step (1). 3) The solution obtained in step (2) was transferred to the main mixin‘g‘vessel where it was mixed with entire ty of HFA134a. 4) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 8 Indacaterol formulation _HFAl34a or HFA227 _ Process: 1) Lecithin was ved in ethanol. 2) Glycopyrronium and Indacaterol were nized with part ty of HFA and transferred to the mixing vessel. 3) Fluticasone furoate was homogenized with lecithin and ethanol. 4) The suspension obtained instep (3) was transferred to the main mixing vessel where the remaining quantity ofHFA was added.
) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 9 Process: 1) Oleic acid was ved in ethanol. 2) Glyeopyrronium and Indacaterol were homogenized with part quantity of HFA and erred to the mixing vessel. 3) Fluticasone furoate was homogenized with oleic acid and ethanol. 4) The suspension obtained instep (3) was transferred to the main mixing vessel where the ing quantity ofHFA was added; ) The resulting suspension was mixed, recirculated and filled in into pre~crimped aluminum cans.
Example 10 --—2, --mn-3.
-Lactose monohydrate IP/Ph.Eur/NF4.
Process: 1) Glycopyrronium, Indacaterol and Fluticasone furoate were sified with a part ty of lactose. 2) The co-sift of step 1 was then sifted with the remaining quantity of lactose and blended. 3) The blend of step 2 was then filled in capsules.
W0 20121110770 Example 1 1 -—Sr.No. Qty / unit (mg) Process: 1) Glycopyrronium, terol and Fluticasone furoate were sifted with a part quantity of lactose. 2) The co-sifi of step I was then sifted with the remaining quantity of lactose and blended. 3) The blend of step 2 was then filled in capsules.
Example 12 Process: 1) Glycopyrronium, terol and Fluticasone furoate were sifted with a part quantity of lactose. 2) The co-sifi of step 1 was then sifted with the remaining quantity of lactose and blended. 3) The blend of step 2 was then filled in capsules.
Example 13 Qty ,SW HFA134A OR HFA227 _ Process: 1) Fluticasone‘fiiroate, Glycopyrronium and erol were homogenized with part quantity of HFA. 2) The suspension obtained in step 1 was transferred to the mixing vessel where remaining quantity ofHFA was added. 3) The resulting sion was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 14 HFA134A OR HFA227 _ Process: 1) Fluticasone furoate, Formoterol and Glycopyrronium were homogenized with lactose and part quantity ofHFA. 2) The suspension obtained in step 1 was transferred to the mixing vessel where ing quantity ofHFA was added.
W0 20121110770 3) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 15 4. PEG400/1000 0.3% of total formulation PVP K 25 0.001% oftotal ation HFA134A OR HFA227 _ Process: 1) PVP was dissolved in PEG and part quantity of HFA134A or HFA227. 2) The solution ed in Step 1 was erred to a mixing vessel. 3) Fluticasone furoate, Forrnoterol and Glycopyrronium were homogenized with a part quantity ofHFA. 4) The suspension obtained in step 3 was transferred to the mixing vessel where remaining quantity ofHFA was added.
) The resulting total suspension was mixed, recirculated and filled in into pre—crimped aluminum cans.
Example 16 W0 2012/‘110770 . Glycerol 1% of total ation _HCL ( 0.08N) pH 2.5 — 3.5 Process: 1) Glycerol was dissolved in ethanoland required quantity of HCl was added. 2) Fluticasone furoate, Formoterol and Glycopyrronium were dissolved in the solution obtained instep l. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The resulting sion was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 17 4. Ethanol 15-20% of total formulation HCL ( 0.08N) pH 2.5-3.5 Process: 1) Required quantity ofHCl was added to ethanol. 2) asone furoate, erol and Glyc0pyrronium were dissolved in the solution obtained in step 1. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 18 Ingredients -Fluticasone Furoate Glycopyrronium Formoterol formulation Lecithin 0.02 of the API mHFA134a or HFA227 Process: 1) Lecithin was dissolved in ethanol. 2) Glycopyrronium and Formoterol were homogenized with part quantity of HFA and transferred to the mixing vessel. 3) Fluticasoen furoate was homogenized with lecithin and ethanol. 4) The suSpension obtained instep (3) was erred to the main mixing vessel where the remaining quantity of HFA was added.
) The resulting suspension was mixed, recirculated and filled in into pre—crimped aluminum cans. e 19 4 l 1-2% of total formulation .‘ Oleic acid 0.02 —- 5% of the 2012/000171 Process: 1) Oleic acid was dissolved in ethanol. 2) Glycopyrronium and erol were homogenized with part quantity of HFA and erred to the mixing vessel. 3) Fluticasone furoate was homogenized with oleic acid and ethanol. 4) The suspension obtained instep (3) was transferred to the main mixing vessel where the remaining quantity ofHFA was added.
) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 20 Qty/um Lactose monohydrate IP/Ph.Eur/NF 24.844 Process: 1) Glycopyrronium, Formoterol and Fluticasone furoate were sifted with a part quantity of lactose. 2) The co-sifi of step 1 was then sifted with the remaining quantity of e and blended. 3) The blend of step 2 was then filled in capsules.
Example 21 Process: 1) Glycopyrronium, Formoterol and Fluticasone furoate were sifted with a part quantity of lactose. 2) The co-sifi of step 1 was then sified with the remaining quantity of e and 3) The blend of step 2 was then filled in capsules.
Example 22 Fluticasone Furoate Process: 1) Glycopyrronium, Formoterol and Fluticasone furoate were sifted with a part quantity of lactose. 2) The co-sifi of step I was then sified with the remaining quantity of lactose and blended.
W0 20121’110770 2012/000171 3) The blend of step 2 was then filled in capsules.
Example 23 Process: 1) Fluticasone fiiroate, Glycopyrronium and erol were homogenized with part quantity of HFA. 2) The suspension obtained in step 1 was transferred to the mixing vessel where remaining quantity of HFA was added. 3) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 24 HFA134A OR HFA227 * _ Process: 1) Fluticasone firroate, Vilanterol and Glycopyrronium were homogenized with e and part quantity of HFA. 2) The suspension ed in step 1 was transferred to the mixing vessel where remaining quantity ofHFA was added. 3) The resulting suspension was mixed, recirculated and filled in into imped aluminum cans.
Example 25 PEG400/1000 0.3% oftotal ation PVP K 25 0.001% oftotal formulation _HFA134A OR HFA227 _ Process: 1) PVP was dissolved in PEG and part quantity of HFA134A or HFA227. 2) The solution obtained in Step 1 was transferred to a mixing vessel. 3) Fluticasone furoate, Vilanterol and Glycopyrronium were homogenized with a part quantity of HFA. 4) The suspension obtained in step 3 was transferred to the mixing vessel where remaining quantity ofHFA was added.
) The ing total suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 26 4. Ethanol 15-20% of total formulation . Glycerol 1% of total formulation _HCL( 0.08N) pH 2.5 - 3.5 Process: 1) Glycerol was dissolved in ethanol and ed quantity ofHCl was added. 2) Fluticasone furoate, Vilanterol and Glycopyrronium were ved in the solution obtained in step 1. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, recirculated and filled in into pre—crimped aluminum cans.
Example 27 Glycopyrronium 50 meg 4. Ethanol 15-20% of total formulation .
HCL ( 0.08N) pH 2.5—3.5 Process: 1) Required ty of HCl was added to ethanol. 2) Fluticasone furoate, Vilanterol and Glycopyrronium were dissolved in the on obtained in step 1. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 28 Ingredients Qty /Spray 4. Ethanol 142% of total formulation Process: l) Lecithin was dissolved in ethanol. 2) Glycopyrronium and Vilanterol were homogenized with part quantity of HFA and erred to the mixing . 3) Fluticasoen furoate was homogenized with lecithin and ethanol. 4) The suspension obtained instep (3) was transferred to the main mixing vessel where the remaining quantity of HFA was added.
) The resulting suspension was mixed, recirculated and filled in into pre—crimped aluminum cans.
Example 29 4. Ethanol 1-2% of total formulation WO 10770 0.02 — 5% of the Process: 1) Oleic acid was dissolved in ethanol. 2) Glycopyrronium and Vilanterol were homogenized with part quantity of HFA and transferred to the mixing vessel. 3) Fluticasoen furoate was homogenized with oleic acid and ethanol. 4) The suspension ed instep (3) was transferred to the main mixing vessel where the remaining quantity of HFA was added.
) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 30 Lactose monohydrate IP/Ph.Eur/NF 24.844 1) Glycopyrronium, Vilanterol Trifenatate and Fluticasone e were sified with a part quantity of lactose. 2) The co-sifi of step 1 was then sifted with the remaining quantity of lactose and blended. 3) The blend ofstep 2 was then filled in capsules.
Example 31 Ingredients Process: 1) Glycopyrronium, Vilanterol Trifenatate and Fluticasone furoate were sified with a part quantity of e. 2) The co-sifi of step 1 was then sified with the remaining quantity of lactose and blended. 3) The blend of step 2 was then filled in capsules.
Example 32 Process: 1) Glycopyrronium, Vilanterol atate and Fluticasone furoate were sifted with a part quantity of lactose. 2) The co-sifi of step I was then sifted with the remaining quantity of lactose and blended. 3) The blend of step 2 was then filled in capsules.
Example 33 Qty /Spray Process: 1) Fluticasone furoate, Glycopyrronium and Olcdaterol were nized with part quantity ofHFA. 2) The suspension obtained in step 1 was transferred to the mixing vessel where remaining quantity of HFA was added. 3) The resulting suspension was mixed, recirculated and filled in into imped aluminum cans.
Example 34 Process: 1) Fluticasone furoate, Olodaterol and Glycopyrronium were homogenized with lactose and part quantity ofHFA. '2) The suspension obtained in step 1 was transferred to the mixing vessel where remaining quantity ofHFA was added. 3) The ing suspension was mixed, ulated and filled in into pre-crimped um cans.
Example 35 4. PEG400/1000 0.3% oftotal formulation . PVP K 25 0.001% of total formulation Process: 1) PVP was dissolved in PEG and part quantity of HFA134A or HFA227. 2) The solution obtained in Step 1 was transferred to a mixing vessel. 3) Fluticasone furoate, Olodaterol and Glycopyrronium were nized with a part quantity ofHFA. 4) The suspension obtained in step 3 was transferred to the mixing vessel where remaining quantity ofHFA was added.
) The resulting total suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
W0 2012/‘110770 Example 36 ISNo 4. Ethanol 15-20% of total formulation . Glycerol 1% of total ation HCL ( 0.08N) ' pH 2.5 — 3.5 Process: 1) Glycerol was dissolved in ethanol and required quantity of HCl was added. 2) Fluticasone furoate, Olodaterol and Glycopyrronium were dissolVed in the solution obtained in step 1. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, recirculated and filled in into imped aluminum cans.
Example 37 Glycopyrronium 50 mcg 4. Ethanol 15-20% of total ation HCL ( 0.08N) pH 2.5-3.5 PCT/G32012/000171 Process: 1) Required ty of HCl was added to ethanol. 2) Fluticasone e, erol and Glycopyrronium were dissolved in the solution obtained in step 1. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, ulated and filled in into pre-crimped aluminum cans.
Example 38 Glycopyrronium 50 meg Olodaterol 5 meg 4. Ethanol 1-2% oftotal formulation _HFA134a or HFA227 Process: 1) Lecithin was dissolved in ethanol. 2) Glycopyrronium and Olodaterol were homogenized with part quantity of EPA and transferred to the mixing vessel. 3) Fluticasone furoate was homogenized with in and ethanol. 4) The suspension obtained instep (3) was transferred to the main mixing vessel where the remaining quantity ofHFA was added.
) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
W0 2012I110770 Example 39 -Ethanol 1-2% of total ation . Oleic acid 0.02 —— 5% ofthe HFA134a or HFA227 Prdcess: 1) Oleic acid was dissolved in ethanol. 2) Glycopyrronium and erol were homogenized with part quantity of HFA and erred to the mixing vessel. 3) FIuticasone furoate was homogenized with oleic acid and ethanol. 4) The suspension obtained instep (3) was transferred to the main mixing vessel where the remaining quantity ofHFA was added.
) The resulting suspension was mixed, recirculated and filled in into pre—crimped aluminum cans.
Example 40 W0 2012.1‘1 10770 2012/000171 Process: 1) Glycopyrronium, Olodaterol and Fluticasone furoate were sifted with a part quantity of lactose. 2) The co-sifi of step 1 was then sifted with the remaining quantity of lactose and blended. 3) The blend of step 2 was then filled in capsules.
Example 41 Qty / unit (mg) Process: 1) GlycoPyrronium, Olodaterol and asone furoate were sifted with a part quantity of lactose. 2) The co-sifi of step 1 was then sifted with the ing quantity of lactose and blended. 3) The blend of step 2 was then filled in capsules.
Example 42 Lactose monohydrate IP/Ph.Eur/NF 2012/000171 Process: 1) Glycopyrronium, Oiodaterol and Fluticasone furoate were sifted with a part quantity of lactose. 2) The co—sifi of step 1 was then sifted with the remaining ty of lactose and blended. 3) The blend of step 2 was then filled in capsules.
Example 43 Process: 1) Mometasone furoate, Glycopyrronium and Olodaterol were homogenized with part quantity of HFA. 2) The suspension obtained in step 1 was erred to the mixing vessel where remaining quantity of HFA was added. 3) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 44 WO 10770 Process: 1) Mometasone furoate, Olodaterol and Glycopyrronium were homogenized with lactose and part quantity ofHFA. 2) The suspension obtained in step 1 was transferred to the mixing vessel where remaining quantity ofHFA was added. 3) The resulting sion was mixed, recirculated and filled in into precrimped aluminum cans.
. Example 45 Ingredients Mometasone furoate Glycopyrronium -Olodaterol 4. PEG400/1000 0.3% of total formulation PVP K 25 0.001% of total formulation HFA134A OR HFA227 _ Process: 1) PVP was ved in PEG and part quantity of HFA134A or HFA227. 2) The solution obtained in Step 1 was transferred to a mixing vessel. 3) Mometasone e, Olodaterol and Glycopyrronium were homogenized with a part quantity ofHFA. 4) The suspension obtained in step 3 was transferred to the mixing vessel where remaining ty of HFA was added.
) The resulting total suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 46 Ingredients Qty/Spray asone furoate 400 mcg Ethanol 15-20% oftotal formulation - Glycerol 1% of total formulation _HCL ( 0.08N) pH 2.5 —— 3.5 Process: 1) Glycerol was dissolved in ethanol and required quantity ofHCl was added. 2) Mometasone furoate, Olodaterol and yrronium were dissolved in the solution obtained in step 1. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 47 ‘4. Ethanol 15-20% of total formulation HCL ( 0.08N) pH 2.5-3.5 Process: 1) Required quantity ofHCl was added to ethanol. 2) Mometasone furoate, Olodaterol and Glycopyrronium were dissolved in the solution obtained in step 1. 3) The resulting solution was erred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 48 4. l 1-2% of total formulation Process: 1) Lecithin was dissolved in ethanol. 2) Glycopyrronium and erol were homogenized with part quantity of HFA and transferred to the mixing vessel. 3) Mometasone furoate was homogenized with lecithin and ethanol. 4) The suspension obtained instep (3) was transferred to the main mixing vessel where the remaining quantity ofHFA was added.
) The resulting suspension was mixed, ulated and filled in into pre-crimped aluminum cans.
W0 2012f110770 Example 49 4. Ethanol 1-2% of total formulation . Oleic acid 0.02 -— 5% ofthe ' Process: 1) Oleic acid was dissolved in ethanol. 2) Glycopyrronium and erol were nized with part quantity of HFA and transferred to the mixing vessel. 3) Mdmetasone furoate was homogenized with oleic acid and l. 4) The suspension obtained instep (3) was transferred to the main mixing vessel where the remaining quantity ofHFA was added.
) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 50 Lactose monohydrate IP/Ph.Eur/NF 24.390 W0 20121110770 Process: 1) Glycopyrronium, Olodaterol and Mometasone furoate were sifted with a part quantity of e. 2) The co-sifi of step 1 was then sifted with the remaining quantity of e and blended. 3) The blend of step 2 was then filled in capsules. e 51 Ingredients _Glycopyrronium bromide Vilanterol Trifenatate Process: 1) Glycopyrronium and Vilanterol Trifenatate were sified with a part quantity of e. 2) The co—sifi of step 1 was then sified with the remaining quantity of lactose blended. 3) The blend of step 2 was then filled in capsules.
Example 52 Ingredients Qty / unit (mg) _Glycopyrronium bromide 0.010 Vilanterol Trifenatate 0.025 Lactose monohydrate lP/Ph.Eur/NF 24.875 Process: 1) Glycopyrronium and Vilanterol Trifenatate were sifted with a part quantity of lactose. 2) The co-sifi of step 1 was then sifted with the remaining quantity of lactose and blended. 3) The blend of step 2 was then filled in capsules.
Example 53 Process: 1) Glycopyrronium and Vilanterol Trifenatate were sifted with a part quantity of lactose. 2) The co-sifi of step 1 was then sifted with the ing quantity of lactose and blended. 3) The blend of step 2 was then filled in capsules.
Example 54 Process: 1) Glycopyrronium and Vilanterol were homogenized with part quantity of HFA. 2) The sion obtained in step 1 was transferred to the mixing vessel where remaining quantity ofHFA was added.
W0 2012/‘110770 3) The resulting recirculated and . suspension was mixed, filled in into pre—crimped aluminum cans.
Example 55 HFA134A OR HFA227 _ Process: 1) Vilanterol and Glycopyrronium were homogenized with lactose and part quantity of HFA. 2) The suspension obtained in step 1 was transferred to the mixing vessel where ing quantity ofHFA was added. 3) The resulting suspension was mixed, recirculated and filled in into imped aluminum cans.
Example 56 2 12.5 mcg 3. /1000 0.3% of total 4. PVP K 25 0.001% of total Process: 1) PVP was dissolved in PEG and part quantity of HFA134A or HFA227. 2) The solution obtained in Step 1 was transferred to a mixing vessel. 3) erol and Glycopyrronium were homogenized with a part ty of HFA. 4) The suspension obtained in step 3 was transferred to the mixing vessel where remaining quantity ofHFA was added.
) The resulting total suspension was mixed, recirculated and filled in into pre-crimped aluminum cans. e 57 1. ‘ 3. Ethanol 15-20% of total formulation 4. Glycerol 1% oftotal formulation -HCL ( 0.08N)5. ' pH 2.5 — 3.5 We _ Process: 1) Glycerol was dissolved in ethanol and required'quantity of HCl was added. 2) Vilanterol and Glycopyrronium were dissolved in the solution ed in step 1. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 58 W0 20121110770 EHCL ( 0.08N) pH 2.5—3.5 Process: 1) Required quantity of HCl was added to ethanol. 2) Vilanterol and Glycopyrronium were dissolved in the solution obtained in step 1. 3) The'resulting solution was transferred to ing vessel where HFA was added. 4) The resulting suspension was mixed, ulated and filled in into pre—crimped aluminum cans.
Example 59 -Sr.No.
Glycopyrronium 50 meg 3. Ethanol l-2% of total formulation HFA134a or HFA227 l) Lecithin was dissolved in ethanol. 2) Glycopyrronium and Vilanterol were homogenized with part quantity of HFA and transferred to the mixing vessel. 3) The solution obtained in step (I) was homogenized with part quantity ofHFA 4) The mixture ed in step (3) was erred to the main mixing vessel where the remaining quantity ofHFA was added.
) The resulting suspension was mixed, recirculated and filled in into pre-Acrimped aluminum cans.
W0 2012l110770 PCT/G82012/000171 Example 60 Qty/sway 50 mcg 3. Ethanol 1-2% of total formulation 4. Oleic acid 0.02 —— 5% of the . API Process: 1) Oleic acid was dissolved in ethanol. 2) Glycopyrronium and Vilanterol were homogenized with part ty of HFA and transferred to the mixing vessel. 3) The solution obtained in step ( 1) was homogenized with part quantity ofHFA 4) The mixture obtained in step (3) was transferred to the main mixing vessel where the ing quantity ofHFA was added.
) The ing suspension was mixed, recirculated and filled in into pre—crimped aluminum cans.
Example 61 Ingredients Qty / unit (mg) yrronium bromide 0.100 Olodaterol ‘ 0.005 Lactose monohydrate IP/Ph.Eur/NF 24.944 Process: 1) GlyCOpyrronium and Olodaterol were sifted with a part quantity of lactose. 2) The co—sifi of step 1 was then sified with the remaining quantity of lactose and blended. 3) The blend of step 2 was then filled in capsules.
Example 62 Lactose monohydrate IP/Ph.Eur/NF 24.875 Process: 1) Glchpyrronium and Olodaterol were sifted with a part quantity of lactose. 2) The co-sifi of step 1 was then sifted with the remaining quantity of lactose and blended. 3) The blend of step 2 was then filled in es.
Example 63 Process: 1) Glycopyrronium and Olodaterol were homogenized with part quantity ofHFA. 2) The suspension obtained in step liwas transferred to the mixing vessel where remaining quantity ofHFA was added. 3) The ing suspension was mixed, ulated and filled in into pre-crimped aluminum cans. 2012/000171 e 64 Process: 1) Olodaterol and Glycopyrronium were homogenized with lactose and part quantity of HFA. 2) The suspension obtained in step 1 was transferred to the mixing vessel where remaining quantity ofHFA was added. 3) The resulting suspension was mixed, ulated and filled in into pre-crimped aluminum cans.
Example 65 Glycopyrronium 100 mcg PEG400/1000 0.3% of total formulation PVP K 25 0.001% of total formulation Process: 1) PVP was dissolved in PEG and part quantity of HFAl34A or HFA227. 2) The solution obtained in Step 1 was transferred to a mixing vessel. 3) Olodaterol and Glycopyrronium were homogenized with a part quantity of HFA.
B2012/000171 4) The suspension obtained in step 3 was transferred to the mixing vessel where remaining quantity of HFA was added.
) The resulting total suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 66 -Oldt2. Hoaero‘ mcg 3. Ethanol 15-20% of total formulation 4. Glycerol 1%. of total formulation -HCL ( 0.08N)5. pH 2.5 — 3.5 _E_- 1) Glycerol was dissolved in ethanol and required quantity of HCl was added. 2) erol and Glycopyrronium were dissolved in the solution obtained in step 1. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The resulting sion was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 67 Glycopyrronium -Olodaterol2 3. Ethanol 15—20% of total formulation HCL ( 0.08N) pH 2.5-3.5 W0 2012;110770 1) Required quantity of HCl was added to l. 2) Olodaterol and Glycopyrronium were dissolved in the solution obtained in step 1. 3) The resulting solution was transferred to the mixingvessel where HFA was added. 4) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 68 -Glycopyrromuml . i 100 mcg 3. Ethanol 1-2% of total formulation Process: 1) Lecithin was dissolved in ethanol. 2) Glycopyrronium and Olodaterol were nized with part quantity of HFA and transferred to the mixing vessel. 3) The solution obtained in step (1) was homogenized with part quantity ofHFA 4) The mixture obtained in step (3) was transferred to the main mixing vessel where the remaining quantity ofHFA was added.
) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Glycopyrronium 100 mcg 3. Ethanol 1~2% of total formulation 4. OICiC acid 0.02 -— 5% ofthe Process: 1) Oleic acid was ved in ethanol. 2) Glycopyrronium and Olodaterol were homogenized with part quantity of HFA and transferred to the mixing vessel. 3) The solution obtained in step (1) was homogenized with part quantity ofHFA 4) The mixture obtainedrin step (3) was transferred to the main mixing vessel where the remaining quantity ofHFA was added.
) The resulting suspension was mixed, recirculated and filled in into pre—crimped aluminum cans.
Example 70 1) Glycopyrronium and Cannoterol were sifted with a part quantity of lactose. 2) The co-sift of step 1 was then sifted with the remaining quantity of e and blended. 3) The blend of step 2 was then filled in capsules.
Example 71 Qty/um) -Total 25.000 Process: 1) Glycopyrronium and Carmoterol were sifted with a part quantity of lactose. 2) The co—sifi of step 1 was then sified with the remaining quantity of lactose and blended. 3) The blend of step 2 was then filled in capsules. e 72 Glycopyrronium 100 mcg Process: 1) Glycopyrronium and Carmoterol were homogenized with part quantity of HFA. 2) The suspension obtained in step 1 was transferred to the mixing vessel where remaining ty ofHFA was added. 3) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 73 _Glycopyrronium 100 mcg 100% ofthe drug A OR HFA227 Process: 1) Carmoterol and Glycopyrronium were nized with lactose and part quantity of HFA. 2) The suspension obtained in step 1 was transferred to the mixing vessel where remaining quantity ofHFA was added. 3) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 74 _Glycopyrronium 100 mcg PEG400/1000 0.3% oftotal formulation PVP K 25 0.001% oftotal formulation Process: 1) PVP was dissolved in PEG and part quantity of HFA134A or HFA227. 2) The solution obtained in Step 1 was transferred to a mixing . 3) Cannoterol and Glycopyrronium were homogenized with a part quantity of HFA.
WO 10770 4) The suspension obtained in step 3 was transferred to the mixing vessel where ing quantity ofHFA was added.
) The resulting total suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
Example 75 Qty [Spray _Glycopyrronium 100 mcg 3'. Ethanol 15-20% of total formulation 4. Glycerol 1% of total ’ r formulation HCL ( 0.08N) pH 2.5 — 3.5 Process: 1) Glycerol was dissolved in ethanol and required quantity of HCl was added. 2) Carmoterol and Glycopyrronium were dissolved in the on ed in step 1. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The resulting suspension was mixed, recirculated and filled in into pre—crimped aluminum cans.
Example 76 Glycopyrronium 100 mcg 3. Ethanol 15-20% of total formulation HCL ( 0.08N) pH 2.5-3.5 Process: 1) Required quantity of HCl was added to ethanol. 2) Carmoterol and Glycopyrronium were dissolved in the solution obtained in step 1. 3) The resulting solution was transferred to the mixing vessel where HFA was added. 4) The ing suspension was mixed, recirculated and filled in into pre-crimped aluminum cans. e 77 -Glycopyrromum 100 mcg 3. Ethanol 1—2% of total formulation Process: 1) Lecithin was dissolved in ethanol. 2) Glycopyrronium and Carmoterol were homogenized with part quantity of HFA and transferred to the mixing vessel. 3) The solution obtained in step (1) was homogenized with part ty ofHFA 4) The mixture obtained in step (3) was erred to the main mixing vessel where the remaining quantity ofHFA was added.
) The resulting suspension was mixed, recirculated and filled in into pre—crimped aluminum cans. e 78 -—_QtyISpray 3. Ethanol 1-2% of total formulation 4. Oleic acrd 0.02 ~ 5% of the Process: 1) Oleic acid was dissolved in ethanol. 2) Glycopyrronium and Cannoterol were homogenized with part quantity of HFA and erred to the mixing vessel. 3) The on obtained in step (1) was homogenized with part quantity ofHFA 4) The mixture obtained in step (3) was transferred to the main mixing vessel where the remaining quantity ofHFA was added.
) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.
It will be y apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that gh the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.
It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be ed as limiting. The use of “including,” “comprising,” or “having” and variations thereof herein is meant to encompass the items listed fter and equivalents thereof as well as additional items.
It must be noted that, as used in this specification and the appended claims, the singular forms "a,II I!an" and "the" include plural references unless the context y dictates otherwise. Thus, for example, reference to "an excipient" includes a single excipient as well as two or more different excipients, and the like.

Claims (25)

Claims 1.
1. A pharmaceutical composition consisting of: i) glycopyrrolate, formoterol fumarate dihydrate and fluticasone furoate; or ii) glycopyrrolate, vilanterol atate and asone furoate; or iii) glycopyrrolate and olodaterol hydrochloride monohydrate; and optionally one or more pharmaceutically acceptable excipients.
2. A pharmaceutical ition according to claim 1, wherein the glycopyrrolate is present in an amount ranging 50-200 mcg.
3. A pharmaceutical ition according to claim 1 or claim 2, wherein the asone furoate is present in an amount ranging from 25 —800 mcg.
4. A pharmaceutical composition according to any one of claims 1 to 3, wherein the formoterol fumarate dihydrate is present in an amount ranging from 12-25 mcg.
5. A pharmaceutical composition according to any one of claims 1 to 3, wherein the vilanterol trifenatate is present in an amount g from 3-50 mcg.
6. A pharmaceutical composition according to claim 1 or claim 2, wherein the olodaterol hydrochloride monohydrate is present in an amount ranging from 3-50 mcg.
7. A pharmaceutical composition according to any one of the preceding claims wherein the pharmaceutical composition along with any excipients are formulated in a single pharmaceutical composition.
8. A pharmaceutical composition according to any one of claims 1 to 7, ated as a composition for inhalation.
9. A pharmaceutical composition according to claim 8, ated as a composition for inhalation in the form of a metered dose inhaler (MDI), dry powder inhaler (DPI), nebulizer, nasal spray, nasal drops or an insufflation powder.
10. A ceutical composition according to any one of claims 1 to 8, formulated for use in a metered dose inhaler (MDI).
11. A pharmaceutical composition according to any one of claims 8 to 10, further comprising a propellant.
12. A pharmaceutical composition ing to any one of claims 8 to 11, further sing one or more excipients ed from a cosolvent, an antioxidant, a surfactant, a bulking agent and a lubricant.
13. A pharmaceutical composition according to any one of claims 1 to 8, formulated for use as a dry powder inhalation formulation.
14. A pharmaceutical composition ing to claim 13, further comprising at least one finely divided pharmaceutically acceptable carrier suitable for use in dry powder tion formulations.
15. A pharmaceutical composition according to claim 14, wherein said carrier includes a saccharide and/or a sugar alcohol.
16. A pharmaceutical composition according to any one of claims 1 to 8, formulated for use as an inhalation solution/suspension.
17. A pharmaceutical composition ing to claim 16, further comprising one or more excipients selected from a wetting agent, osmotic agent, a pH regulator, a buffering agent and a complexing agent, provided in a pharmaceutically acceptable e.
18. A pharmaceutical composition according to any one of the preceding claims for once daily administration.
19. A process for manufacturing a pharmaceutical composition according to any one of claims 1 to 18 comprising combining glycopyrrolate with: i) formoterol te dihydrate and fluticasone furoate; or ii) vilanterol trifenatate and fluticasone furoate; or iii) olodaterol hydrochloride monohydrate; and optionally one or more pharmaceutically acceptable ents.
20. The use of a pharmaceutical composition according to any one of claims 1 to 18 in the manufacture of a medicament for the prophylaxis or treatment of a respiratory, inflammatory or obstructive airway disease.
21. The use according to claim 20, wherein said medicament is adapted for once daily administration.
22. The use according to claim 20 or claim 21, wherein the disease is COPD or asthma.
23. A pharmaceutical composition according to claim 1, ntially as herein described with reference to the examples.
24. A process for making a pharmaceutical composition according to claim 19, substantially as herein described with reference to the examples.
25. Use according to claim 20, n the medicament is substantially as herein described with reference to the examples.
NZ707754A 2011-02-17 2012-02-17 Combination of glycopyrrolate and a beta2 -agonist NZ707754B2 (en)

Applications Claiming Priority (17)

Application Number Priority Date Filing Date Title
IN446MU2011 2011-02-17
IN446/MUM/2011 2011-02-17
IN694/MUM/2011 2011-03-11
IN694MU2011 2011-03-11
IN953/MUM/2011 2011-03-28
IN953MU2011 2011-03-28
IN1535MU2011 2011-05-19
IN1535/MUM/2011 2011-05-19
IN1534/MUM/2011 2011-05-19
IN1534MU2011 2011-05-19
IN1613MU2011 2011-05-31
IN1613/MUM/2011 2011-05-31
IN1965MU2011 2011-07-07
IN1966/MUM/2011 2011-07-07
IN1966MU2011 2011-07-07
IN1965/MUM/2011 2011-07-07
NZ613915A NZ613915B2 (en) 2011-02-17 2012-02-17 Combination of glycopyrrolate, fluticasone and indacaterol

Publications (2)

Publication Number Publication Date
NZ707754A NZ707754A (en) 2016-11-25
NZ707754B2 true NZ707754B2 (en) 2017-02-28

Family

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