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WO2019142214A1 - Composition pharmaceutique comprenant du tiotropium destinée à être inhalée - Google Patents

Composition pharmaceutique comprenant du tiotropium destinée à être inhalée Download PDF

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Publication number
WO2019142214A1
WO2019142214A1 PCT/IN2019/050045 IN2019050045W WO2019142214A1 WO 2019142214 A1 WO2019142214 A1 WO 2019142214A1 IN 2019050045 W IN2019050045 W IN 2019050045W WO 2019142214 A1 WO2019142214 A1 WO 2019142214A1
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Prior art keywords
pharmaceutically acceptable
formulation
acid
acceptable salt
tiotropium
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English (en)
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Geena Malhotra
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Cipla Ltd
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Cipla Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—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
    • A61K31/33—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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • 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

Definitions

  • the present invention relates to pharmaceutical compositions comprising a long acting muscarinic antagonist (LAMA) and at least one long-acting beta adrenergic agonist (LABA) for inhalation via nebulization, and processes for preparing the compositions.
  • LAMA long acting muscarinic antagonist
  • LABA beta adrenergic agonist
  • the invention also relates to methods of treatment and/or prevention of respiratory, inflammatory or obstructive airway disease and the use of the said composition.
  • COPD chronic obstructive pulmonary disease
  • Airflow limitation in COPD is persistent and incompletely reversible, which leads to potentially distressing symptoms, decreased exercise tolerance, and poor quality of life. It has been estimated that in 2030, COPD will be the fourth leading cause of death worldwide resulting in an economic and social burden that is both substantial and increasing.
  • the clinical manifestations of COPD include severity of respiratory symptoms, frequency of exacerbations, severity of spirometric abnormalities and type of co-morbidity cause a gradual decline in functional ability and greater dependence upon health and social care support with both aging and disease progression.
  • COPD is associated with mucus hyper secretion, emphysema, bronchiolitis.
  • Asthma is also common respiratory disease in the world and is a significant cause of morbidity worldwide. It is a chronic inflammatory disorder of the airways associated with airway hyper responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing. An increased inflammatory response is a major part of the pathophysiology of acute asthma and regular preventive treatment of the same is very important. Current medical treatment to treat COPD and asthma aims to manage symptoms, maintain physical activity and pulmonary function, and prevent exacerbations. Bronchodilators are the mainstay of pharmacologic therapy for chronic obstructive pulmonary disease (COPD), and asthma.
  • COPD chronic obstructive pulmonary disease
  • the principal bronchodilator treatments include administration of beta-agonists, muscarinic antagonists and methylxanthines.
  • Short-acting agents are usually used for immediate relief of symptoms, whereas long-acting inhaled agents are generally preferred and are more convenient for maintenance treatment of COPD.
  • Long-acting inhaled bronchodilators used for treatment of stable chronic obstructive pulmonary disease (COPD) include two classes of pharmacological agents: long acting beta-agonists (LAB A) and long acting muscarinic antagonists (LAMA).
  • LABAs Long-acting beta-agonist bronchodilators
  • Long acting muscarinic antagonists are anticholinergics that act by competing with acetylcholine for the receptor sites at vagus nerve or nerve-muscle junctions. This prevents the transmission of reflexes that are induced by asthma stimuli.
  • Use of anticholinergics provides an advantage in elderly patients as the responsiveness of anticholinergics does not decline with old age.
  • Monotherapy with some of these pharmacotherapeutic agents may give rise to side effects such as general malaise, cough, agitation, insomnia, anxiety, trembling fingers, sweating and headaches.
  • combination therapy is recommended.
  • the advantages of combination therapy include better lung function and improved symptoms.
  • combination therapy reduces the cost and 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. Specifically, as airflow obstruction becomes more severe, both a long-acting muscarinic antagonist (LAMA) plus a long-acting beta-agonist (LABA) can be used.
  • LAMA long-acting muscarinic antagonist
  • LAA long-acting beta-agonist
  • the treatment of asthma and COPD need quick onset of action of drugs, longer duration of action of drugs, improved control of obstructive or inflammatory airway diseases, reduction in the exacerbations of the diseases and minimum dosage administration especially in pediatric & elderly patients. Even from the patient compliance point of view, the treatment requires for the patient to comply with different dosage regimens, different frequencies of administration etc. Efforts to improve compliance have been aimed at by simplifying the medication packaging, providing effective medication reminders, improving patient education and limiting the number of medications prescribed simultaneously. The use of combination of long acting bronchodilators provides these benefits along with reduction in frequency of drug administration and providing patient compliance.
  • LAMA long-acting b agonist
  • LAMA long acting muscarinic antagonist
  • LAMA long acting muscarinic antagonist
  • WO2015173153 discloses combination product comprising an inhalable long- acting muscarinic antagonist (LAMA) composition combined with an inhalable fixed-dose composition comprising budesonide and formoterol.
  • LAMA long- acting muscarinic antagonist
  • US20150258021 discloses solution formulation for inhalation which contain one or more active substances in a solvent selected from among water, ethanol and water- ethanol mixtures; and at least one inert, non-volatile excipient.
  • W02015181360 discloses an inhalable medicament of solid amorphous particles comprising an intimate admixture of two or three active ingredients selected from a long-acting muscarinic antagonist (LAMA), a long-acting beta- agonist (LABA) and an inhaled corticosteroid (ICS), together with a pharmaceutically acceptable co-solid.
  • LAMA long-acting muscarinic antagonist
  • LABA long-acting beta- agonist
  • ICS inhaled corticosteroid
  • EP2999460 discloses a suspension composition for respiratory delivery of a long- acting muscarinic antagonist (LAMA), a long-acting beta adrenergic agonist (LABA), and an inhaled corticosteroid (ICS) from a metered dose inhaler (MDI).
  • LAMA long- acting muscarinic antagonist
  • LABA long-acting beta adrenergic agonist
  • MDI metered dose inhaler
  • US20040132759 describes inhalable powders of Tiotropium and Indacaterol for the treatment of inflammatory or obstructive diseases of the respiratory tract, particularly asthma and/or COPD.
  • US9757365 discloses pharmaceutical composition
  • composition comprising Tiotropium or a pharmaceutically acceptable salt thereof, water, a complexing agent, the complexing agent being disodium EDTA and 0.9% by weight of sodium chloride, the pH of the composition ranges from 2.5 to 3.0 and the said composition is free of preservative, and the composition is contained in a prefilled container.
  • compositions comprising combination of Tiotropium or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof with at least one long acting beta adrenergic agonists (LAB A) or a pharmaceutically acceptable salt, solvate , physiological ly functional derivative thereof such as Indacaterol or its pharmaceutically acceptable salts or Vilanterol or its pharmaceutically acceptable salts for inhalation via nebulization.
  • LAB A long acting beta adrenergic agonists
  • inhalable pharmaceutical compositions comprising Tiotropium bromide with at least one long-acting beta adrenergic agonist (LABA) such as Indacaterol or its salts, or Vilanterol or its salts which are stable, easy to manufacture, convenient to handle and simplify the dosage regimen by administering an effective amount of Indacaterol maleate with Tiotropium bromide or Vilanterol trifenatate with Tiotropium bromide once or twice daily and can be administered with the help of a nebulizer (e.g. high efficiency nebulizer) for relieving symptoms associated with COPD, asthma and related respiratory disorders.
  • a nebulizer e.g. high efficiency nebulizer
  • An object of the present invention is to provide a pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one long acting beta adrenergic agonists or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof selected from indacaterol or its pharmaceutically acceptable salt or vilanterol or its pharmaceutically acceptable salt for inhalation via nebulization.
  • Another object of the present invention is to provide an inhalable pharmaceutical composition comprising Tiotropium or its pharmaceutically acceptable salt and at least one long acting beta adrenergic agonists or its pharmaceutically acceptable salt for once or twice daily administration.
  • Yet another object of present invention is to provide an inhalable pharmaceutical composition
  • an inhalable pharmaceutical composition comprising Tiotropium or its or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one LAB A or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and minimum pharmaceutically acceptable excipients in pharmaceutically acceptable amount, thus reducing the unwanted interaction among the actives and excipient.
  • Another object of the present invention is to provide a mode of administration of an inhalable pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one LABA or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof using simple, user friendly and inexpensive nebulizer device.
  • the object of the present invention is to provide an inhalable pharmaceutical composition
  • an inhalable pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one LABA or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof selected from indacaterol or its or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof or vilanterol or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof for administration via nebulization in the prevention or treatment of respiratory, inflammatory or obstructive airway disease.
  • Yet another object of the present invention is to provide a simple process for preparing the pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one LABA or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and one or more pharmaceutically acceptable excipients.
  • a further object of the present invention is to provide a method for the treatment or prevention of asthma, COPD or a related respiratory disorder, which method comprises administering a pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt, solvate, physiologically functional derivative thereof and at least one LABA or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof
  • a pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one LAB A or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof selected from indacaterol or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof or vilanterol or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof for inhalation via nebulization.
  • an inhalable pharmaceutical composition comprising Tiotropium or pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one long acting beta adrenergic agonist (LABA) or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof for once or twice daily administration.
  • an inhalable pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one long acting beta adrenergic agonist or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and minimum pharmaceutically acceptable excipients in pharmaceutically acceptable amount, thus reducing the unwanted interaction among the actives and excipient.
  • a mode of administration of a stable inhalable pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one long acting beta adrenergic agonist or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof using simple, user friendly and inexpensive nebulizer device.
  • an inhalable pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one long acting beta adrenergic agonist or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof selected from indacaterol or its pharmaceutically acceptable salt or vilanterol or its pharmaceutically acceptable salt for administration via nebulization in the prevention or treatment of respiratory, inflammatory or obstructive airway disease.
  • a simple process for preparing the pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one longacting beta adrenergic agonist or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and one or more pharmaceutically acceptable excipients.
  • LAB A beta adrenergic agonist
  • LAMA long acting muscarinic antagonist
  • selecting a combination of a LABA and LAMA is critical since both drugs should be capable of being administered once or twice daily. It is as well critical to select a limited set of excipients and evaluate its compatibility with the specific LABA and LAMA for the purposes of ensuring stability, and whether such stable inhalation formulation is capable of being administered without much effort using a simple, and user friendly nebulizer device. It is also necessary that such stable inhalation formulation has suitable characteristics so that the nebulizer device used to deliver the formulation should not block the device orifice or cause any damage to the componentry of the device resulting in nonuniformity of dose of actives during administration.
  • compositions comprising Tiotropium or its pharmaceutically acceptable salt and selected LABA with selective set of excipients are stable and can be administered once or twice a day achieving required therapeutic effect relatively easily with the help of simple, user friendly device via nebulization.
  • the singular forms“a,”“an” and“the” include plural referents unless the context clearly dictates otherwise.
  • Ranges may be expressed herein as from“about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent“about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
  • the long acting muscarinic antagonist is Tiotropium.
  • Tiotropium is used in broad sense to include not only “Tiotropium” per se but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable esters, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complex, pharmaceutically acceptable co-crystals etc.
  • Tiotropium salts include acid addition salts such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid and p-toluenesulfonic.
  • acid addition salts such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,
  • the Tiotropium salt in the pharmaceutical composition described herein is Tiotropium bromide, such as Tiotropium bromide monohydrate ((la,2p,4p,7P)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9- azoniatricyclo [3.3.l.02,4]nonane bromide, monohydrate).
  • Tiotropium bromide monohydrate ((la,2p,4p,7P)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9- azoniatricyclo [3.3.l.02,4]nonane bromide, monohydrate).
  • the pharmaceutical composition of the present invention may include from about 0.0001% to about 1% w/w of Tiotropium or its salt (such as Tiotropium bromide). In an embodiment, the pharmaceutical composition of the present invention preferably may include from about 0.001% to about 0.05% w/w of Tiotropium or its salt (such as Tiotropium bromide).
  • the LABA include ,but are not limited to arformoterol, bambuterol, clenbuterol, formoterol, salmeterol, abediterol, carmoterol, Indacaterol , olodaterol , Vilanterol and any combinations thereof.
  • the LABA in the present invention is Indacaterol or its pharmaceutically acceptable salt. More preferably, LABA in the present invention is Indacaterol maleate.
  • the amount of LABA in the formulation of present invention is from about 0.001% to 1.0% w/w. In one embodiment, the amount of Indacaterol maleate that can be included in the formulation of present invention is from about 0.01% to about 0.9% w/w. Preferably, the amount of Indacaterol maleate that can be included in the present invention is from about 0.03% to about 0.75% w/w. In yet another preferred embodiment, the LABA in the present invention is Vilanterol or its pharmaceutically acceptable salt.
  • the LABA in the present invention is Vilanterol trifenatate.
  • the amount of Vilanterol trifenatate that can be included in the formulation of present invention is from about 0.001% to about 1.0 % w/w.
  • the amount of vilanterol trifenatate in the present invention is from about 0.005% to about 0.5% w/w .
  • Tiotropium bromide in inhalable combination formulation with Indacaterol maleate or Vilanterol trifenatate provides relief from respiratory disorders while simultaneously reducing the frequency of dosage administration when administered via nebulizer.
  • the present invention thus provides a novel combination for inhalation comprising Tiotropium or its pharmaceutically acceptable salt in combination with Indacaterol or its pharmaceutically acceptable salt, or Vilanterol or its pharmaceutically acceptable salt for the prevention or treatment of respiratory, inflammatory or obstructive airway disease while simultaneously reducing the frequency of dosage administration.
  • a single dose may provide the daily dose.
  • the daily dose may comprise multiple doses of the composition, e.g. two doses, which can be taken at the same time if administered once a day
  • both the doses may provide the daily dose.
  • the daily dose may comprise multiple doses of composition e.g two or more than two doses and can be taken at different times if administered twice a day.
  • the dose of tiotropium bromide delivered in per inhalation of formulation is 0.001 to 0.01% w/w of total formulation when the formulation is administered once or twice a day.
  • the dose of indacaterol or its pharmaceutically acceptable salt delivered in per inhalation of formulation is 0.001 to 0.01% w/w of total formulation when the formulation is administered once or twice a day in one or multiple doses.
  • the dose of indacaterol or its pharmaceutically acceptable salt delivered in per inhalation of formulation is 0.001 to 0.01% w/w of total formulation when the formulation is administered once or twice a day in one or multiple doses.
  • the dose of vilanterol or its pharmaceutically acceptable salt delivered in per inhalation of formulation is 0.001 to 0.01% w/w of total formulation when the formulation is administered once or twice a day in one or multiple doses.
  • the ratio of Indacaterol maleate to Tiotropium bromide in the composition of the invention is preferably from about 50: 1 to about 0.5: 1, preferably from about 25: 1 to about 5: 1.
  • the ratio of Vilanterol trifenatate to Tiotropium bromide in the composition of the invention is preferably from about 50: 1 to about 0.5: 1, preferably from about 25: 1 to about 5: 1.
  • the inhalable pharmaceutical composition is a unit dose nebulizable pharmaceutical composition for inhalation comprising Tiotropium or its salt with at least one LABA.
  • the pharmaceutical composition of present invention may be administered in nebulized form to relieve bronchospasm in a subject, such as a subject suffering from COPD. Nebulization is a safe therapy to deliver or deposit medications directly into the respiratory tract and hence achieve higher drug concentrations. It is easy to use, does not require co-ordination or much effort and works much more rapidly than medicines taken by mouth.
  • the inhalable pharmaceutical composition comprising Tiotropium or its pharmaceutically acceptable salt and at least one LABA administered via nebulizer is in the form of suspension, solution and the like.
  • the nebulizable composition of present invention comprising Tiotropium or its pharmaceutically acceptable salt and at least one LABA further comprises one or more pharmaceutically acceptable excipients selected from stabilizer (or complexing agent), isotonic agent or tonicity adjusting agent, pH modifier, buffer, vehicle, preservatives and the combinations thereof.
  • the pharmaceutical composition of the present invention thus may be administered through nebulizers.
  • the stabilizers or complexing agents, according to the present invention may comprise, but are not limited to, edetic acid (EDTA) or one of the known salts thereof, e.g.
  • the stabilizers or complexing agent are used in the formulation of present invention in an amount from about 0.01% to 0.5 % about w/w.
  • the formulations according to the invention contain a complexing agent in an amount from about 0.025% to about 0.3 % w/w.
  • Tonicity agents that may be used, comprise sodium chloride, potassium chloride, zinc chloride, calcium chloride, boric acid and the like or combinations thereof.
  • Other tonicity agents may also include, but are not limited to, mannitol, glycerol, and dextrose and the like or combinations thereof.
  • the tonicity agents are used in the formulation of present invention in an amount from about 0.05% to 1.0 % w/w.
  • the pH may be adjusted by the addition of pharmacologically acceptable acids.
  • Pharmacologically acceptable inorganic acids or organic acids may be used for this purpose. Examples of preferred inorganic acids are selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and phosphoric acid.
  • the inhalation composition has a pH from about 2.0 to about 6.0. In another embodiment, the composition has a pH from about 2.0 to about 4.0.
  • the preferred pH range of Tiotropium bromide and Indacaterol maleate composition or Tiotropium bromide and Vilanterol trifenatate composition is from about 2.0 to about 4.5, preferably from about 2.5 to 3.5.
  • the inhalation composition of the present invention may contain sodium citrate at a concentration of about 0.1 to about 1.0% w/w and citric acid at a concentration of about 0.1 to 1.0% w/w to control pH.
  • the inhalation composition may optionally include a buffer.
  • a buffer in the pH range of about 2.0 to about 8.0 include, but are not limited to, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, Mcllvaine, phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen), veronal acetate, MES, BIS-TRIS, ADA, ACES, PIPES, MOPSO, BIS-TRIS PROPANE, BES, MOPS, TES, HEPES, DIPSO, MOBS, TAPSO, TRIZMA, HEPPSO, POPSO, TEA, EPPS, TRICINE, GLY-GLY, BICINE, HEPBS, TAPS, and AMPD buffers.
  • the preservative may comprise one or more of benzalkonium chloride, benzoic acid, benzoates such as sodium benzoate and the like or combinations thereof and such other preservatives which may be known to the person having a skill in the art.
  • the nebulizable compositions of the present invention are formulated with a pharmacologically acceptable fluid acting as a vehicle for the dissolution of the actives to facilitate nebulization and delivery of the actives into the lungs of a patient.
  • Pharmacologically suitable fluids include, but are not limited to, polar solvents, including, but not limited to, water or alcohols, such as ethanol, isopropanol, and glycols including propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol and polyoxyethylene alcohols or combination thereof.
  • the preferred vehicle is water in an amount sufficient to maintain Tiotropium or its pharmaceutically acceptable salt and at least one LABA or its pharmaceutically acceptable salt in liquid form such as suspension or solution for a considerable amount of time.
  • compositions of the present invention may or may not comprises of stabilizer or complexing agent.
  • the composition comprises.
  • the inhalable composition comprises Tiotropium or its pharmaceutically acceptable salt, at least one LABA or its pharmaceutically acceptable salt selected from indacaterol or vilanterol , pharmaceutically acceptable excipients selected from isotonic agent or tonicity adjusting agent, pH modifier, buffer, vehicle, preservatives or the combinations thereof and water.
  • the inhalable composition comprises Tiotropium or its pharmaceutically acceptable salt, at least one LABA or its pharmaceutically acceptable salt selected from indacaterol or vilanterol , pharmaceutically acceptable excipients selected from stabilizer (or complexing agent), isotonic agent or tonicity adjusting agent, pH modifier, buffer, vehicle, preservatives or the combinations thereof and water.
  • compositions according to the present invention may be packed in suitable containers provided with means of enabling the delivery /deposition of the contained formulation to the respiratory tract.
  • composition of the present invention is a prepackaged, sterile, premixed, premeasured composition comprising Tiotropium bromide and at least one LABA or its pharmaceutically acceptable salt for inhalation administered via nebulizer.
  • the composition of the present invention is a ready-to-use composition which does not require any mixing or dilution by the subject prior to administration via nebulizer.
  • the composition may be administered via nebulizer for the relief of bronchospasm in a subject suffering from COPD.
  • Yet another embodiment is a method of administering pharmaceutical composition of present invention comprising Tiotropium or its pharmaceutically acceptable salt and at least one LAB A by inhalation via a nebulizer to a subject a pharmaceutical composition of the present invention.
  • Yet another embodiment is a method of relieving bronchospasm (such as that associated with COPD) comprising administering by inhalation via nebulizer to a subject in need thereof a pharmaceutical composition of the present invention.
  • Another embodiment of the present invention is a kit having one or more prefilled containers containing a pharmaceutical composition of the present invention.
  • each container comprises a single unit dose of pharmaceutical inhalation composition of the present invention comprising a therapeutically effective amount of Tiotropium or its salt and at least one LABA or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients.
  • the kit and/or system comprises an inhalation composition of the present invention comprising a therapeutically effective amount of Tiotropium or its salt and at least one LABA or its pharmaceutically acceptable salt in a prepackaged, premeasured, premixed and/or single unit dose.
  • the prepackaged inhalation kit and/or system comprises one or more premixed, premeasured single unit dose vials comprising a pharmaceutical composition of the present invention comprising a therapeutically effective amount of Tiotropium or its pharmaceutically acceptable salt and at least one LABA or its pharmaceutically acceptable salt), and instructions for using the same.
  • kit and/or system comprises an inhalation composition of the present invention comprising a therapeutically effective amount of Tiotropium or its salt and Indacaterol or its pharmaceutically acceptable salt in a prepackaged, premeasured, premixed and/or single unit dose form.
  • kit and/or system comprises an inhalation composition of the present invention comprising a therapeutically effective amount of Tiotropium or its salt and Vilanterol or its pharmaceutically acceptable salt in a prepackaged, premeasured, premixed and/or single unit dose form .
  • another embodiment of the present invention is a kit having container containing a pharmaceutical composition of the present invention.
  • the container comprises multiple doses of pharmaceutical composition of the present invention comprising a therapeutically effective amount of Tiotropium or its salt and at least one LAB A or its pharmaceutically acceptable salt.
  • the kit and/or system comprises an inhalation composition of the present invention comprising a therapeutically effective amount of Tiotropium or its salt and at least one LABA or its pharmaceutically acceptable salt in a prepackaged, premeasured, premixed for multiple dose form.
  • the prepackaged inhalation kit and/or system comprises one or more premixed, premeasured for multiple dose vials comprising a pharmaceutical composition of the present invention comprising a therapeutically effective amount of Tiotropium or its pharmaceutically acceptable salt and at least one LABA or its pharmaceutically acceptable salt and instructions for using the same.
  • kit and/or system comprises an inhalation composition of the present invention comprising a therapeutically effective amount of Tiotropium or its salt and Indacaterol or its pharmaceutically acceptable salt in a prepackaged, premeasured, premixed and/or for multiple dose form.
  • kit and/or system comprises an inhalation composition of the present invention comprising a therapeutically effective amount of Tiotropium or its salt and Vilanterol or its pharmaceutically acceptable salt in a prepackaged, premeasured, premixed for multiple dose form.
  • kits comprising a nebulizer, instructions for using the nebulizer and the unit dose vials containing the pharmaceutical compositions of the present invention.
  • kit suitable for once daily administration via inhalation, which comprises:
  • kits suitable for once or twice daily administration via inhalation, which comprises:
  • kits suitable for once or twice daily administration via inhalation, which comprises:
  • kits suitable for once or twice daily administration via inhalation, comprising:
  • a nebulizable composition comprising (a) Tiotropium or its pharmaceutically acceptable salt
  • stabilizer comprising one or more of EDTA, ascorbic acid, or citric acid
  • kits suitable for once or twice daily administration via inhalation, comprising:
  • stabilizer comprising one or more of EDTA, ascorbic acid, sodium metabisulfite or citric acid
  • compositions provided herein are intended for administration to a subject in need of such treatment via nebulization.
  • Nebulizers that nebulize liquid formulations containing no propellant are suitable for use with the compositions provided herein.
  • Suitable nebulizers include, but not limited to, a jet nebulizer, an ultrasonic nebulizer, vibrating mesh nebulizer and breadth actuated nebulizer.
  • the nebulizer is a jet nebulizer connected to an air compressor with adequate airflow.
  • the nebulizer is a jet nebulizer connected to an air compressor with adequate airflow.
  • the nebulizer being equipped with a mouthpiece or suitable face mask.
  • the inhalation solution may be administered by nebulizers manufactured, designed or sold by Philips Respironics, such as Philips InnoSpire Go or I-neb Advance or InnoSpire Essence nebulizer system or InnoSpire Elegance nebulizer system.
  • Philips Respironics such as Philips InnoSpire Go or I-neb Advance or InnoSpire Essence nebulizer system or InnoSpire Elegance nebulizer system.
  • Other nebulizers may also include those manufactured, designed, or sold by Aerogen such as Aerogen Solo or Aerogen Ultra or Aerogen Pro.
  • the formulations described herein can also be nebulized using inhalers other than those described above, for example jet-stream inhalers.
  • a further embodiment of the present invention is to provide a process for making an inhalation composition comprising Tiotropium or its pharmaceutically acceptable salt, at least one LABA or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients.
  • the process comprises dissolving Tiotropium or its salt in stabilizing agent (pH 3.0 maintained by suitable pH adjusting agent). Adding LABA in above solution of Tiotropium salt and stirring well to obtain clear solution.
  • Suitable pharmaceutically acceptable excipients such as a buffer, tonicity adjusting agent, or any combination thereof, to the solution of Tiotropium salt and LABA prepared above, and optionally adjusting the pH of the mixture with a pharmaceutically acceptable acid followed by filtering the formulation (for example, with a 0.2 micron filter); and filling a suitable container with the formulation.
  • the process comprises the steps of (a) dissolving stabilizing agent in water with suitable pH; (b) adding Tiotropium or its salt to the above solution; (c) adding Indacaterol or its salt to the above solution and maintaining the pH; (d) optionally addition of pharmaceutically acceptable excipients such as a buffer, tonicity adjusting agent, or any combination thereof, to the solution of step (d);
  • the process comprises the steps of (a) dissolving stabilizing agent in water with suitable pH; (b) adding Tiotropium or its salt to the above solution (c) adding Vilanterol or its salt to the above solution and maintaining the pH (d) optionally addition of pharmaceutically acceptable excipients such as a buffer, tonicity adjusting agent, or any combination thereof, to the solution of step (d); (e) optionally adjusting the pH of the solution with a pharmaceutically acceptable acid; (f) optionally filtering the solution (for example, with a 0.2 micron filter); and (e) filling a suitable container with the formulation .
  • the process comprises the steps of dissolving tiotropium or its salt in water at suitable pH , adding LABA selected from Indacaterol or Vilanterol or its pharmaceutically acceptable salt to the above solution and maintaining the pH, optionally addition of pharmaceutically acceptable excipients such as a buffer, tonicity adjusting agent, or any combination thereof, to the solution and adjusting the pH of the solution with a pharmaceutically acceptable acid; optionally filtering the solution (for example, with a 0.2 micron filter) and filling a suitable container with the formulation .
  • LABA selected from Indacaterol or Vilanterol or its pharmaceutically acceptable salt
  • pharmaceutically acceptable excipients such as a buffer, tonicity adjusting agent, or any combination thereof
  • a pharmaceutical composition suitable for administration with a nebulizer comprising: a) about 0.001% to about 0.05 % w/w Tiotropium or its pharmaceutically acceptable salt thereof; b) about 0.03% to about 0.75% w/w Indacaterol or its pharmaceutically acceptable salt thereof; c) about 0.01% to about 0.5 % w/w stabilizing agent comprising di sodium EDTA, ascorbic acid, sodium metabisulfite or citric acid; d) about 0.05% to about 1.0% w/w sodium chloride; e) water for injection; and f) other pharmaceutically acceptable excipients wherein the pH of the pharmaceutical composition is about 2 to about 4.
  • a pharmaceutical composition suitable for administration with a nebulizer comprising: a) about 0.001 % to about 0.05% w/w Tiotropium or its pharmaceutically acceptable salt thereof; b) about 0.005 % to about 0.5% w/w Vilanterol or its pharmaceutically acceptable salt thereof; c) about 0.01% to about 0.5% w/w stabilizing agent comprising disodium EDTA, ascorbic acid, sodium metabisulfite or citric acid; d) about 0.05% to about 1.0% w/w sodium chloride; e) water for injection, and f) other pharmaceutically acceptable excipients, wherein the pH of the pharmaceutical composition is about 2 to about 4.
  • a pharmaceutical composition suitable for administration with a nebulizer comprising: a) about 0.001% to about 0.05 % w/w Tiotropium or its pharmaceutically acceptable salt thereof; b) about 0.03% to about 0.75% w/w Indacaterol or its pharmaceutically acceptable salt thereof; c) about 0.05% to about 1.0% w/w sodium chloride; e) water for injection; and f) other pharmaceutically acceptable excipients wherein the pH of the pharmaceutical composition is about 2 to about 4.
  • a pharmaceutical composition suitable for administration with a nebulizer comprising: a) about 0.001 % to about 0.05% w/w Tiotropium or its pharmaceutically acceptable salt thereof; b) about 0.005 % to about 0.5% w/w vilanterol or its pharmaceutically acceptable salt thereof; c) about 0.05% to about 1.0% w/w sodium chloride; e) water for injection, and f) other pharmaceutically acceptable excipients, wherein the pH of the pharmaceutical composition is about 2 to about 4.
  • the pharmaceutical compositions of the present invention may be also administered by any suitable methods used for delivery of the drugs to the respiratory tract.
  • the composition of the present invention may thus also be administered as metered dose inhalers (MDI), aerosol, drops, nasal drops, a nasal spray or an inhalation solution. and the like.
  • MDI metered dose inhalers
  • the various dosage forms as per the present invention may comprise one or more pharmaceutically acceptable carriers/excipients suitable for formulating the same selected from co- solvents, surfactants, non-volatile component, bulking agent, buffering agent, pH adjusting agent, preservative, complexing agent,
  • the composition of the present invention is stored and administered in a suitable container which, when in contact, do not hamper the stability of the pharmaceutical composition.
  • suitable containers as envisaged under the present invention are made of materials such as low density polyethylene (LDPE) or high density polyethylene (HDPE) or Polypropylene (PP), or PET or mixtures thereof.
  • the present invention also provides a method for the treatment in a mammal, such as a human, for treating chronic obstructive pulmonary disease and asthma, which method comprises administration of a therapeutically effective amount of a pharmaceutical composition according to the present invention.
  • a mammal such as a human
  • the present invention further provides a mode of administration to a mammal such as human for treating chronic obstructive pulmonary disease and asthma, which method comprises administration of a therapeutically effective amount of a pharmaceutical composition according to the present invention using nebulizer device.
  • the present invention also provides use of the pharmaceutical composition according to the present invention for the prevention or treatment of asthma, COPD or a related disorder.
  • the said pharmaceutical composition may further comprise additional active(s) selected from inhaled corticosteroids, antihistamines, antiallergics or leukotriene antagonist and the like or combinations thereof or their pharmaceutically acceptable salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof.
  • additional active(s) selected from inhaled corticosteroids, antihistamines, antiallergics or leukotriene antagonist and the like or combinations thereof or their pharmaceutically acceptable salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof.
  • Example 1 Tiotropium and Indacaterol inhalation composition
  • Table 1 Formulation of Tiotropium and Indacaterol inhalation composition
  • Example 2 Tiotropium and Indacaterol inhalation composition
  • Citric acid monohydrate was added to above solution and stirred to dissolve completely.
  • Example 3 Tiotropium and Indacaterol inhalation composition
  • Table 3 Formulation of tiotropium and Indacaterol inhalation composition
  • Example 4 Tiotropium and Indacaterol inhalation composition
  • Citric acid monohydrate and trisodium citrate dehydrate were added in Water for Injection and maintained the pH.
  • Example 5 Tiotropium and Vilanterol inhalation composition
  • Citric acid monohydrate was added to above solution and stirred to dissolve completely.
  • Example 7 Tiotropium and Vilanterol inhalation composition
  • Example 8 Tiotropium and Vilanterol inhalation composition
  • Citric acid monohydrate and trisodium citrate dehydrate were dissolved in Water for Injection and maintained the pH.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant du tiotropium ou un sel pharmaceutiquement acceptable de celui-ci et des agonistes bêta-adrénergiques à action prolongée ou leurs sels pharmaceutiquement acceptables correspondants destinés à être inhalés par un sujet par l'intermédiaire d'une nébulisation. L'invention concerne également un procédé de préparation de ladite composition pharmaceutique et son utilisation dans le traitement de maladies respiratoires, telles que la broncho-pneumopathie chronique obstructive (BPCO) chez un sujet.
PCT/IN2019/050045 2018-01-19 2019-01-19 Composition pharmaceutique comprenant du tiotropium destinée à être inhalée Ceased WO2019142214A1 (fr)

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CN110613702A (zh) * 2019-09-30 2019-12-27 苏州弘森药业股份有限公司 一种克伦特罗雾化吸入用溶液制剂及其制备方法
WO2020105012A1 (fr) * 2018-11-22 2020-05-28 Glenmark Specialty S.A. Compositions stériles d'indacatérol appropriées pour la nébulisation
WO2020141472A1 (fr) 2019-01-03 2020-07-09 Glenmark Specialty S.A. Composition de nébulisation comprenant du tiotropium et de l'indacatérol
WO2021068961A1 (fr) * 2019-10-11 2021-04-15 四川海思科制药有限公司 Composition pharmaceutique de solution pour inhalation et son procédé de préparation
CN114073684A (zh) * 2020-08-10 2022-02-22 盈科瑞（天津）创新医药研究有限公司 三苯乙酸维兰特罗吸入溶液及其制备方法
US20220096536A1 (en) * 2020-05-01 2022-03-31 Tygrus, LLC THERAPEUTIC MATERIAL WITH LOW pH AND LOW TOXICITY ACTIVE AGAINST AT LEAST ONE PATHOGEN FOR ADDRESSING PATIENTS WITH RESPIRATORY ILLNESSES
WO2022073009A1 (fr) * 2020-09-29 2022-04-07 iPharma Labs, Inc. Formulations liquides d'indacatérol
CN115209884A (zh) * 2020-01-20 2022-10-18 广州谷森制药有限公司 含有格隆溴铵和盐酸奥达特罗的可吸入制剂
CN117679423A (zh) * 2022-09-05 2024-03-12 立生医药(苏州)有限公司 预防或治疗呼吸系统疾病的吸入用药物组合物
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WO2020105012A1 (fr) * 2018-11-22 2020-05-28 Glenmark Specialty S.A. Compositions stériles d'indacatérol appropriées pour la nébulisation
WO2020141472A1 (fr) 2019-01-03 2020-07-09 Glenmark Specialty S.A. Composition de nébulisation comprenant du tiotropium et de l'indacatérol
CN110613702A (zh) * 2019-09-30 2019-12-27 苏州弘森药业股份有限公司 一种克伦特罗雾化吸入用溶液制剂及其制备方法
WO2021068961A1 (fr) * 2019-10-11 2021-04-15 四川海思科制药有限公司 Composition pharmaceutique de solution pour inhalation et son procédé de préparation
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CN115209884A (zh) * 2020-01-20 2022-10-18 广州谷森制药有限公司 含有格隆溴铵和盐酸奥达特罗的可吸入制剂
CN115209884B (zh) * 2020-01-20 2024-05-28 广州谷森制药有限公司 含有格隆溴铵和盐酸奥达特罗的可吸入制剂
US20220096536A1 (en) * 2020-05-01 2022-03-31 Tygrus, LLC THERAPEUTIC MATERIAL WITH LOW pH AND LOW TOXICITY ACTIVE AGAINST AT LEAST ONE PATHOGEN FOR ADDRESSING PATIENTS WITH RESPIRATORY ILLNESSES
US11826382B2 (en) * 2020-05-01 2023-11-28 Tygrus, LLC Therapeutic material with low pH and low toxicity active against at least one pathogen for addressing patients with respiratory illnesses
US12042514B2 (en) 2020-05-01 2024-07-23 Tygrus, LLC Therapeutic material with low pH and low toxicity active against at least one pathogen for addressing patients with respiratory illnesses
CN114073684A (zh) * 2020-08-10 2022-02-22 盈科瑞（天津）创新医药研究有限公司 三苯乙酸维兰特罗吸入溶液及其制备方法
CN114073684B (zh) * 2020-08-10 2025-03-04 盈科瑞（天津）创新医药研究有限公司 三苯乙酸维兰特罗吸入溶液及其制备方法
WO2022073009A1 (fr) * 2020-09-29 2022-04-07 iPharma Labs, Inc. Formulations liquides d'indacatérol
CN116963715A (zh) * 2020-09-29 2023-10-27 艾罗克斯医疗有限责任公司 茚达特罗的液体配制品
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CN117679423A (zh) * 2022-09-05 2024-03-12 立生医药(苏州)有限公司 预防或治疗呼吸系统疾病的吸入用药物组合物
WO2024051683A1 (fr) * 2022-09-05 2024-03-14 立生医药(苏州)有限公司 Composition pharmaceutique pour inhalation destinée à prévenir ou à traiter une maladie respiratoire

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