WO2016178019A1 - Solution de nébulisation de tiotropium stable - Google Patents

Solution de nébulisation de tiotropium stable Download PDF

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Publication number
WO2016178019A1
WO2016178019A1 PCT/GB2016/051277 GB2016051277W WO2016178019A1 WO 2016178019 A1 WO2016178019 A1 WO 2016178019A1 GB 2016051277 W GB2016051277 W GB 2016051277W WO 2016178019 A1 WO2016178019 A1 WO 2016178019A1
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WO
WIPO (PCT)
Prior art keywords
formulation
tiotropium
solution
nebuliser
acid
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PCT/GB2016/051277
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English (en)
Inventor
Kevin Hawkins
David Edwards
Jennifer WALLEY
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Norton Healthcare Ltd
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Publication date
Application filed by Norton Healthcare Ltd filed Critical Norton Healthcare Ltd
Publication of WO2016178019A1 publication Critical patent/WO2016178019A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • 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

Definitions

  • the present invention relates to a stable tiotropium nebuliser solution and more specifically to a solution formulation of tiotropium for inhalation by a nebuliser.
  • Tiotropium is a long-acting anticholinergic bronchodilator indicated as a maintenance bronchodilator to relieve symptoms of patients with chronic obstructive pulmonary disease (COPD) or asthma.
  • COPD chronic obstructive pulmonary disease
  • COPD is the name for a collection of lung diseases including chronic bronchitis, emphysema and chronic obstructive airways disease. Patients with COPD have difficulties breathing, primarily due to the narrowing of their airways, this is called airflow obstruction. Typical symptoms of COPD include increased breathlessness during activity, a persistent cough with phlegm and frequent chest infections. The main cause of COPD is smoking, but other causes include air pollution and genetic disorders.
  • Asthma is a common chronic inflammatory disease of the airways characterised by reversible airway obstruction and bronchospasm. Typical symptoms of asthma include wheezing, coughing, chest tightness, and shortness of breath. Tiotropium is indicated as an add-on maintenance bronchodilator treatment in patients already undergoing treatment with inhaled corticosteroids and long-acting p 2 -agonists.
  • Tiotropium has the following chemical structure, with X " denoting a counter ion:
  • Spiriva® is available as a dry powder inhalation (DPI) formulation, or as an aqueous solution for use with the Respimat® soft mist inhaler.
  • the aqueous formulation has a pH of 2.7.
  • the DPI formulation is formulated with lactose carrier and is contained in capsules, each containing 22.5 microgram tiotropium bromide monohydrate equivalent to 18 microgram tiotropium.
  • the delivered dose is 10 microgram tiotropium.
  • Respimat® delivers 2.5 ⁇ g tiotropium per puff (2 puffs comprise one medicinal dose) and is equivalent to 3.124 microgram tiotropium bromide monohydrate.
  • DPI formulations have the disadvantage that the amount of medicament delivered to the patient's lungs is dependent on a sufficiently strong inspiration force. This is not always possible in patients suffering from COPD owing to their compromised lung function. A further problem is achieving a high homogeneity of the blend of active ingredient and carrier, typically lactose.
  • Aqueous formulations such as Respimat® overcome these problems to a certain extent.
  • the amount of medicament delivered to the lungs is less dependent on the inspirational force.
  • the homogeneity problems may be circumvented if the active ingredient is in solution. This is the case for tiotropium, which has a high solubility in water.
  • aqueous formulations have drawbacks of their own. In the case of tiotropium for example, preservatives and stabilisers are required.
  • Spiriva Respimat® also contains a preservative (benzalkonium chloride) and multiple stabilising agents (including sodium edetate), see US 2004/0019073 and US 2002/01 1 1363 in the name of Boehringer Ingelheim.
  • a stable aqueous tiotropium nebuliser formulation can be provided without requiring preservatives and multiple stabilising agents.
  • the formulation is well-tolerated by patients providing a benefit of greater patient compliance.
  • the present invention provides a solution formulation for inhalation by a nebuliser consisting of tiotropium, water, sodium chloride, and an acid selected from hydrochloric acid, citric acid, or a mixture thereof.
  • a solution formulation for inhalation from a nebuliser comprising tiotropium, water, sodium chloride, and an acid selected from hydrochloric acid, citric acid, or a mixture thereof; wherein the formulation is substantially free of preservatives and further stabilisers.
  • the present invention provides a nebuliser comprising a reservoir, wherein the reservoir contains the above-mentioned formulations.
  • Fig. 1 shows an assay for tiotropium bromide content over time at two pH values at (a) 40 ⁇ 2°C/25 ⁇ 5% RH and (b) 25 ⁇ 2°C/40 ⁇ 5% RH;
  • Fig. 2 shows the variation in pH over time at two pH values at (a) 40 ⁇ 2°C/25 ⁇ 5% RH and (b) 25 ⁇ 2°C/40 ⁇ 5% RH;
  • Fig. 3 shows an assay for tiotropium bromide content over time at 40 ⁇ 2°C/25 ⁇ 5% RH over a range of pH values.
  • the formulations of the present invention contain the tiotropium cation as the active agent. Any pharmaceutically acceptable counter ion is suitable for use in the formulations of the invention.
  • the tiotropium is tiotropium bromide.
  • the tiotropium bromide may be in the form of a tiotropium bromide solvate (e.g. as described in WO 2006/1 17300 and in WO 2006/1 17299), a tiotropium bromide hydrate e.g. tiotropium bromide monohydrate (e.g. as described in WO 02/030928), anhydrous tiotropium bromide (e.g. as described in WO 03/000265, WO 2005/042527, WO 2006/1 17299 and form 1 1 as described in WO 2007/075858) or amorphous tiotropium bromide prior to dissolution.
  • the amount of tiotropium will vary depending on the particular product, medical indication and patient. Typically, the amount of tiotropium (i.e. based on the weight of tiotropium) per inhalation is from 5 to 100 ⁇ g, more preferably 10 to 25 ⁇ g. Suitable doses include 5, 15, 30, 45, 60, 75 and 90 ⁇ g.
  • the volume of solution per inhalation is typically 0.5-5 ml_, more preferably 0.5-3.5 ml_. This volume is preferably provided as a unit dose.
  • each dose is presented as a unit dose containing 5 to 100 ⁇ g of tiotropium, more preferably 10 to 25 ⁇ g, in 0.5-5 ml_, preferably 0.5-3.5 ml_, of solution.
  • the droplet size (d90) is preferably less than 15 ⁇ , more preferably from 0.5 ⁇ to 15 ⁇ , even more preferably, from 1 ⁇ to 15 ⁇ , and most preferably, from 2 ⁇ to 15 ⁇ .
  • the formulations of the present invention also contain an acid.
  • the acid lowers the pH of the formulation, providing chemical stability to the tiotropium.
  • the acid may be hydrochloric acid, citric acid, or a mixture of hydrochloric acid and citric acid.
  • the amount of acid required depends on the desired pH of the formulation.
  • a nebuliser formulation having a pH range of 2 to 8 is acceptable to the patient.
  • the pH of the formulation of the present invention is preferably from 2 to 4, more preferably from 2.5 to 3.3, more preferably 2.6 to 3.1 and most preferably 2.7 to 3.0.
  • the above ranges are preferred for stability. However, an elevated pH is also preferable for patient compliance. In one embodiment, the preferred pH range to balance stability and patient compliance is 2.8 to 3.1 .
  • the formulations of the present invention also contain sodium chloride to provide the appropriate tonicity.
  • the amount of sodium chloride is from 8 to 10 g/L, and more preferably 9 g/L.
  • the present invention provides a solution formulation for inhalation from a nebuliser comprising tiotropium, water, sodium chloride, and an acid selected from HCI, citric acid, or a mixture thereof; wherein the formulation is substantially free of preservatives and further stabilisers.
  • preservatives which are not present are benzalkonium chloride, benzoic acid or benzoates such as sodium benzoate.
  • the formulation is substantially free of benzalkonium chloride.
  • substantially free means less than 5 mg/100 mL, preferably less than 1 mg/mL, and even more preferably less than 0.1 mg/mL. Most preferably the formulation does not contain benzalkonium chloride (0 mg/mL).
  • further stabiliser is meant a stabiliser other than the hydrochloric and/or citric acid which is already present.
  • An example of a further stabiliser which is not present is ethylenediaminetetraacetic acid (EDTA) or a salt such as the sodium salt, sodium edetate.
  • EDTA ethylenediaminetetraacetic acid
  • the formulation is substantially free of sodium edetate.
  • Another example of a further stabiliser which is not present is a magnesium salt, such as magnesium chloride.
  • substantially free means less than 5 mg/100 mL, preferably less than 1 mg/mL, and most preferably less than 0.1 mg/mL. Most preferably the formulation does not contain further stabiliser (0 mg/mL).
  • the formulations of the present invention are preferably sterile.
  • Sterilisation may be carried out by heating, gamma irradiation or filtration.
  • the formulations are sterilised by filtration.
  • the formulation may be a multi-dose or single-dose formulation, and preferably a single-dose formulation.
  • the formulation is typically provided in a container and hence the present invention also provides a container containing the formulation as defined herein.
  • the single-dose formulation may be provided in an ampule, such as an LDPE ampule.
  • the formulations of the present invention have surprisingly been found to be stable without recourse to components previously considered to be essential, like benzalkonium chloride and EDTA. This surprising stability means that the resulting formulation is better tolerated by patients and leads to improved patient compliance.
  • the present invention provides a nebuliser comprising a reservoir, wherein the reservoir contains the above described formulations.
  • the nebuliser may be a jet nebuliser, a vibrating mesh nebuliser, an ultrasonic wave nebuliser, a soft-mist nebuliser or a high- efficiency nebuliser.
  • Preferred are a jet nebuliser, a vibrating mesh nebuliser, an ultrasonic wave nebuliser or a high-efficiency nebuliser, and in this embodiment the nebuliser formulation is advantageously administered to the patient via a face mask.
  • the nebuliser is most preferably a jet nebuliser, which are also known as "atomisers". Jet nebulizers are connected by tubing to a compressor which causes compressed air or oxygen to flow at high velocity through the liquid medicament to turn it into an aerosol, which is then inhaled by the patient.
  • a suitable jet nebuliser is the Pari LC®. Nebulisers are well known in the art; see, for example, Drug Delivery to the Respiratory Tract, Eds. D. Ganderton and T. Jones, VCH Publishers, 1987, pages 124-132.
  • the inhalation time is typically 1 -15 mins.
  • the present invention also provides a kit comprising the formulation as defined herein, a nebuliser and a face mask.
  • the kit contains at least two unit doses of the formulation, more preferably at least five unit doses of the formulation.
  • the formulation of the present invention is a solution formulation and hence the active ingredient, the salt and the liquid phase form a single homogeneous phase.
  • the active ingredient and the salt are dissolved in the liquid phase. Therefore, the active ingredient and the salt must be soluble in the liquid phase.
  • the formulation can be cooled to 4°C and then re-heated to ambient temperature without precipitation of the active ingredient.
  • the formulation of the present invention is typically used for the treatment of COPD and/or asthma.
  • the present invention provides a method of treating COPD and/or asthma comprising administering the formulation of the present invention to a patient in need thereof.
  • the formulation is typically administered once or twice per day, and preferably once per day.
  • Example 1 A study into the stability of tiotropium bromide was performed.
  • a bulk solution of tiotropium bromide anhydrous form 1 1 (12.5 ⁇ 9/ ⁇ _, equivalent to 10 ⁇ g/mL as tiotropium, as described in WO 2007/075858), water and sodium chloride (9 g/L) was prepared.
  • the solution was prepared by charging a beaker with a proportion of purified water, adding sodium chloride to the water and mixing until dissolved using a magnetic stirrer and magnetic stirrer bar.
  • the API was then added and stirred until dissolved.
  • This solution was split into two samples named TF1 and TF2 and dilute hydrochloric acid was added to each in order to provide the required pH.
  • the solution was made up to the required volume and the final pH checked.
  • the samples were contained in glass scintillation vials (approx. 10 to 30 ml_) and wrapped in foil to protect from light.
  • a control sample of 9 g/L saline at pH 2 was also prepared to account for any erroneous results which may occur over the course of the study.
  • the pH was also monitored and the results are shown in Figs. 2(a) and 2(b).
  • the pH was monitored by rinsing two clean glass beakers with a small volume of sample by emptying two ampoules into each of the beakers. The remaining ampoules were subdivided into two lots. One lot of the ampoules was emptied into one of the glass beakers and the beaker labelled #1 . The rest of the ampoules were emptied into the second beaker, labelled #2.
  • the pH electrode was first rinsed using deionised water, then the pH electrode was rinsed by immersion into the sample in beaker #1 . The electrode was then stirred in the solution. Once the electrode has been rinsed in the sample, the electrode was placed into beaker #2. The sample solution in beaker #2 was stirred with the pH electrode and the pH reading allowed to settle before recording the result.
  • the total impurity content was also measured over time.
  • the impurities detected were known impurities A, C, E and F, as defined in the European Pharmacopoeia, 8th Edition. In each case, the experiments were performed at (a) 40 ⁇ 2°C/25 ⁇ 5% RH and (b) 25 ⁇ 2°C/40 ⁇ 5% RH.
  • the detection was performed chromatographically and all solutions were protected from light.
  • the column was Zorbax SB-C3, 3.5 ⁇ , 150 x 3.0mm (Agilent, part number 863954-309).
  • the mobile phase A was buffer and the mobile phase B was buffer/acetonitrile/methanol 50:40:10 (v/v/v).
  • the sample diluent was 0.01 M HCI.
  • the gradient elution is set out in the following table. Time (min) Mobile Phase A (%) Mobile Phase (%) Curve
  • the flow rate was 0.9 mL/min.
  • the column temperature was 30°C.
  • the autosampler temperature was 4°C. Detection was at 240 nm.
  • the run time was 50 mins.
  • the integration time was 35 mins.
  • the injection volume was 200 ⁇ _.
  • Buffer was prepared by weighing 1 .0 g of sodium methanesulfonate and 5.0 g of potassium phosphate monobasic in 1000 ml_ of water. The pH was adjusted to 3.0 ⁇ 0.1 with 85% orthophosphoric acid. The test solution (formulation strength 20 ⁇ g/2 ml_) was injected neat.
  • the stock standard solution was prepared in duplicate by transferring 5 mg of tiotropium bromide (94002) into a 50 ml_ volumetric flask to dissolve then making up to volume with diluent (cone. 100 ⁇ g/mL).
  • the working standard solution, the stock system suitability solution, the working system suitability solution, the stock impurity F solution, the working impurity F solution, the stock API Solution and the working API solution were prepared in duplicate in an analogous manner.
  • the chromatographic procedure was as follows: Perform 1 priming injection followed by a further 6 injections of Working Standard B / Perform duplicate injection of Working Standard A / Perform a single injection working system suitability solution / Perform a single injection of working impurity F solution / Perform single injection of LOD/LOQ solution & diluent / Bracket injections of test solutions & Working API solution (up to a maximum of 8) with duplicate injections of Working Standard A.
  • Impurities were identified in accordance with the following table. Sample peak Retention time Relative retention Relative response (min) time factor
  • the total impurities after 12 weeks at 40 ⁇ 2°C/25 ⁇ 5% RH was less than 0.70% and after 12 weeks at 25 ⁇ 2°C/40 ⁇ 5% RH was less than 0.40%.
  • Figs. 1 (a) and 1 (b) show that the amount of tiotropium bromide remains almost constant over 12 weeks, even under the accelerated stability testing set out in Fig. 1 (a).
  • the acceptable range is ⁇ 10% of the initial value, i.e. 9.00-1 1 .00 ⁇ g/mL.
  • the stability is also retained at both pH values.
  • Figs. 2(a) and 2(b) show that the pH is essentially constant. This indicates product stability since key degradation products of tiotropium bromide are less acidic and hence an unstable formulation would be expected to increase in pH over time. Again, stability is retained at both pH values.
  • the total impurity content provides a more detailed analysis of degradation behaviour by focussing on the low levels of impurities present in the samples. A slight increase in degradation products over the 12 weeks is observed, and this is to be expected for an unstable API like tiotropium bromide. However, even under the accelerated stability testing, the total impurity content remains well under the key value of 1 .5%. This suggests a shelf-life of at least 24 months at 25°C, which is the goal for this product.
  • the total impurity content of the commercial product, Spiriva® Respimat® is around 1 % after 18 months at 25°C.
  • the present invention therefore provides a stable product, without recourse to undesirable excipients.
  • Example 2 The tiotropium assay of Example 1 was repeated at two different pH values, namely 3.00 and 3.25. The results are shown in Fig. 3. The plots for the pH values set out in Fig. 1 (a) are included for comparison. The upper and lower cut off values at 9.00 and 1 1 .00 are also included for guidance. (The higher values at the four week time point are explained by experimental error - the amount of tiotropium bromide in the sample cannot increase with time.)
  • Example 3 The plots for the pH values set out in Fig. 1 (a) are included for comparison. The upper and lower cut off values at 9.00 and 1 1 .00 are also included for guidance. (The higher values at the four week time point are explained by experimental error - the amount of tiotropium bromide in the sample cannot increase with time.)
  • Example 3 The higher values at the four week time point are explained by experimental error - the amount of tiotropium bromide in the sample cannot increase with time.
  • Example 1 The study of Example 1 was followed, with citric acid in place of hydrochloric acid. Samples were prepared having a pH of 2.50, 2.70 and 3.00. Similar results were observed.
  • the mixing system, holding tank and filling machine are cleaned using hot WFI and sterilised at a minimum of 122.0°C and a maximum of 134.0°C using pure steam prior to batch manufacture and filling.
  • the holding tank and filling machine are continuously held under positive pressure, using sterile filtered compressed air, during subsequent batch hold and filling.
  • WFI is drawn from the site distribution ringmain and added, via an in-line flowmeter, into the mixing vessel.
  • the excipients (including pre-dispensed acid for pH adjustment) and the active substance are added to the circulating WFI via an additions hopper and are mixed for a minimum of 30 mins to form the drug product solution. All material additions take place in an ISO Class 7 area.
  • the bulk solution alert limit is 1 cfu/100 ml_ and the action limit is 10 cfu/100 ml_.
  • the drug product solution is filtered through a pre-use integrity tested sterile 0.2 ⁇ rated filter via the sterilised transfer line, into a pre-sterilised holding tank and maintained under positive pressure. At the end of batch transfer the 0.2 ⁇ rate filter is integrity tested.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pulmonology (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Dispersion Chemistry (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une formulation de solution à inhaler à partir d'un nébuliseur, constituée de tiotropium, d'eau, de chlorure de sodium et d'un acide choisi parmi HCl et l'acide citrique, ou un mélange de ceux-ci.
PCT/GB2016/051277 2015-05-05 2016-05-04 Solution de nébulisation de tiotropium stable WO2016178019A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB1507686.2A GB201507686D0 (en) 2015-05-05 2015-05-05 A stable tiotropium nebuliser solution
GB1507686.2 2015-05-05

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WO2016178019A1 true WO2016178019A1 (fr) 2016-11-10

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Cited By (7)

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US9757365B2 (en) 2015-05-18 2017-09-12 Glenmark Specialty S.A. Tiotropium inhalation solution for nebulization
WO2018094016A1 (fr) 2016-11-16 2018-05-24 Glenmark Specialty S.A. Tiotropium nébulisé
US9987260B2 (en) 2015-05-18 2018-06-05 Glenmark Specialty S.A. Tiotropium inhalation solution for nebulization
WO2019084478A1 (fr) * 2017-10-27 2019-05-02 Nephron Pharmaceuticals Corporation Solution d'inhalation de tiotropium à nébuliser
US10653683B2 (en) 2015-05-18 2020-05-19 Glenmark Specialty S.A. Tiotropium inhalation solution for nebulization
WO2020141472A1 (fr) * 2019-01-03 2020-07-09 Glenmark Specialty S.A. Composition de nébulisation comprenant du tiotropium et de l'indacatérol
US11844793B2 (en) 2020-09-29 2023-12-19 Aerorx Therapeutics Llc Liquid formulations of indacaterol

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WO2003084519A2 (fr) * 2002-04-11 2003-10-16 Boehringer Ingelheim Pharma Gmbh & Co.Kg Formulation d'aerosol contenant un sel de tiotropium pour administration par inhalation
US20040019073A1 (en) * 2002-04-11 2004-01-29 Boehringer Ingelheim Pharma Gmbh Co. Kg Aerosol formulation for inhalation containing a tiotropium salt
US20050058606A1 (en) * 2002-12-16 2005-03-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Tiotropium containing HFC solution formulations
EP2044967A1 (fr) * 2007-10-01 2009-04-08 Boehringer Ingelheim Pharma GmbH & Co. KG Pulvérisateur

Patent Citations (5)

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Publication number Priority date Publication date Assignee Title
US20030191151A1 (en) * 2001-10-26 2003-10-09 Imtiaz Chaudry Albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease
WO2003084519A2 (fr) * 2002-04-11 2003-10-16 Boehringer Ingelheim Pharma Gmbh & Co.Kg Formulation d'aerosol contenant un sel de tiotropium pour administration par inhalation
US20040019073A1 (en) * 2002-04-11 2004-01-29 Boehringer Ingelheim Pharma Gmbh Co. Kg Aerosol formulation for inhalation containing a tiotropium salt
US20050058606A1 (en) * 2002-12-16 2005-03-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Tiotropium containing HFC solution formulations
EP2044967A1 (fr) * 2007-10-01 2009-04-08 Boehringer Ingelheim Pharma GmbH & Co. KG Pulvérisateur

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9757365B2 (en) 2015-05-18 2017-09-12 Glenmark Specialty S.A. Tiotropium inhalation solution for nebulization
US10653683B2 (en) 2015-05-18 2020-05-19 Glenmark Specialty S.A. Tiotropium inhalation solution for nebulization
US9987260B2 (en) 2015-05-18 2018-06-05 Glenmark Specialty S.A. Tiotropium inhalation solution for nebulization
US10632109B2 (en) 2015-05-18 2020-04-28 Glenmark Specialty S.A. Tiotropium inhalation solution for nebulization
US10632108B2 (en) 2015-05-18 2020-04-28 Glenmark Specialty S.A. Tiotropium inhalation solution for nebulization
JP2019535714A (ja) * 2016-11-16 2019-12-12 グレンマーク・スペシャルティー・エスエー 噴霧チオトロピウム
KR20190085926A (ko) * 2016-11-16 2019-07-19 글렌마크 스페셜티 에스. 에이. 분무되는 티오트로피움
CN109963557A (zh) * 2016-11-16 2019-07-02 格兰马克专业公司 雾化的噻托铵
WO2018094016A1 (fr) 2016-11-16 2018-05-24 Glenmark Specialty S.A. Tiotropium nébulisé
KR102476726B1 (ko) * 2016-11-16 2022-12-12 글렌마크 스페셜티 에스. 에이. 분무되는 티오트로피움
WO2019084478A1 (fr) * 2017-10-27 2019-05-02 Nephron Pharmaceuticals Corporation Solution d'inhalation de tiotropium à nébuliser
WO2020141472A1 (fr) * 2019-01-03 2020-07-09 Glenmark Specialty S.A. Composition de nébulisation comprenant du tiotropium et de l'indacatérol
US11844793B2 (en) 2020-09-29 2023-12-19 Aerorx Therapeutics Llc Liquid formulations of indacaterol

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GB201507686D0 (en) 2015-06-17

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