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WO2016071862A1 - Composition pharmaceutique inhalable comportant du glycopyrronium - Google Patents

Composition pharmaceutique inhalable comportant du glycopyrronium Download PDF

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Publication number
WO2016071862A1
WO2016071862A1 PCT/IB2015/058550 IB2015058550W WO2016071862A1 WO 2016071862 A1 WO2016071862 A1 WO 2016071862A1 IB 2015058550 W IB2015058550 W IB 2015058550W WO 2016071862 A1 WO2016071862 A1 WO 2016071862A1
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WO
WIPO (PCT)
Prior art keywords
μπι
composition
lactose
glycopyrronium
range
Prior art date
Application number
PCT/IB2015/058550
Other languages
English (en)
Inventor
Ulhas Dhuppad
Sunil Chaudhari
Girish TRIVEDI
Ganesh JADHAV
Original Assignee
Glenmark Pharmaceuticals Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glenmark Pharmaceuticals Limited filed Critical Glenmark Pharmaceuticals Limited
Priority to BR112017009315A priority Critical patent/BR112017009315A2/pt
Publication of WO2016071862A1 publication Critical patent/WO2016071862A1/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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • 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
    • 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
    • A61K9/0075—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
    • 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

Definitions

  • the present invention relates to an inhalable pharmaceutical composition comprising glycopyrronium or its salt.
  • the present invention relates to an inhalable powder composition comprising an effective amount of glycopyrronium or its salt and lactose; a process of preparing such composition and its use in the treatment of respiratory disorders.
  • Respiratory disorders related to airway inflammation include a number of lung diseases such as chronic obstructive pulmonary disease (COPD) and asthma.
  • COPD chronic obstructive pulmonary disease
  • Asthma is a disease characterized by an increased responsiveness of the trachea and bronchi to various stimuli, and manifested by widespread narrowing of the airways that changes in severity either spontaneously or as a result of treatment.
  • the events leading to airway obstruction in asthma include edema of airway walls, infiltration of inflammatory cells into the lung, production of various inflammatory mediators and increased mucous production.
  • the current therapy for asthma includes bronchodilator drugs, corticosteroids and leukotriene antagonists.
  • Bronchodilator drugs dilate the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lungs.
  • Corticosteroid drugs are effective at reducing asthma symptoms by blocking the body's inflammatory response.
  • the leukotriene antagonists have limited efficacy, with only small increases in pulmonary function demonstrated in clinical trials.
  • COPD is a term used to classify two major airflow obstruction disorders: chronic bronchitis and emphysema.
  • Chronic bronchitis is inflammation of the bronchial airways.
  • Emphysema is inflammation of the alveoli, or air sacs in the lungs.
  • Emphysema has a number of causes, including smoking, exposure to environmental pollutants, alpha-one antitrypsin deficiency, and aging.
  • COPD is a disease of the respiratory apparatus, characterized by an irreversible obstruction of the airways, of a degree that varies according to the gravity.
  • Glycopyrronium is a long acting muscarinic antagonist. Its chemical name is 3-(2- cyclopentyl-2-hydroxy-2-phenylacetoxy)-l, 1 -dimethylpyrrolidinium. It has following structure:
  • Glycopyrronium bromide (also known as Glycopyrrolate) is currently approved in the U.S. as Robinul ® (as 0.2mg/ml injection and as tablets of lmg strength); which is indicated for treatment of peptic ulcer and as preoperative anti-muscarinic to reduce salivary, tracheobronchial, and pharyngeal secretions in anesthesia.
  • Glycopyrronium bromide is also approved in Europe as dry powder inhaler Seebri Breezhaler (Novartis) which is indicated for the treatment of COPD. Seebri Breezhaler is presented as an inhalation powder in hard capsules. Each capsule contains 63 meg of glycopyrronium bromide, equivalent to 50 meg of glycopyrronium.
  • SeebriTM Neohaler ® glycopyrrolate inhalation powder 15.6 meg as a stand-alone monotherapy for the same COPD indication.
  • SeebriTM Neohaler and Seebri Breezhaler ® contains lactose and magnesium stearate as inactive ingredients.
  • International Publication No. WO2005/107873 relates to the use of glycopyrronium in treatment of childhood asthma.
  • International Publication No. WO 2005/105043 relates to dry powder compositions which exhibit improved stability over time comprising glycopyrronium, and methods for producing the same.
  • the present invention relates to an inhalable pharmaceutical dry powder composition
  • an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose.
  • an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose, wherein said composition is free from a hydrophobic excipient.
  • an inhalable pharmaceutical dry powder composition consisting of an effective amount of glycopyrronium or its salt and lactose.
  • the present invention relates to an inhalable pharmaceutical dry powder composition
  • an inhalable pharmaceutical dry powder composition comprising (i) a co-micronized premix of glycopyrronium or its salt and one part of lactose in a weight ratio of about 1:5 to about 1:200 and having D90 particle size in the range of about 0.5 ⁇ to about 10 ⁇ , and (ii) another part of lactose having D90 particle size in the range of about 5 ⁇ to about 200 ⁇ ; wherein said composition is free from a hydrophobic excipient.
  • the present invention relates to an inhalable pharmaceutical dry powder composition
  • an inhalable pharmaceutical dry powder composition comprising (i) a co-micronized premix consisting of glycopyrronium or its salt and one part of lactose in a weight ratio of about 1:5 to about 1:200 and having D90 particle size in the range of about 0.5 ⁇ to about 10 ⁇ , and (ii) another part of lactose having D90 particle size in the range of about 5 ⁇ to about 200 ⁇ ; wherein said composition is free from a hydrophobic excipient.
  • the weight ratio of glycopyrronium or its salt to the one part of lactose in the co-micronized premix ranges from about 1: 12 to about 1:75, or from about 1: 14 to about 1:65.
  • the present invention relates an inhalable pharmaceutical dry powder composition
  • a co-micronized premix consisting of
  • the D90 particle size of the co-micronized premix is in the range of about 2 ⁇ to about 7 ⁇ , or about 3 ⁇ to about 5 ⁇ .
  • said inhalable pharmaceutical dry powder composition is free from a hydrophobic excipient.
  • step (b) blending the co-micronized premix of step (a) with another part of lactose having D90 particle size in the range of about 5 ⁇ to about 200 ⁇ .
  • step (b) blending the co-micronized premix of step (a) with another part of lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ .
  • step (b) blending the co-micronized premix of step (a) with another part of lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ .
  • the weight ratio of glycopyrronium or its salt to lactose in the co- micronized premix of the present invention ranges from about 1 :5 to about 1:200, 1 : 10 to about 1 : 100, more preferably from about 1 : 12 to about 1 : 75 or from about 1 : 14 to about 1 :65.
  • the weight ratio of the co-micronized premix to lactose ranges froml : l to 1 :50, preferably, from 1 :5 to 1 :30.
  • an inhalable pharmaceutical dry powder composition comprising from about 0.01 % to about 10% by weight, or preferably from about 0.1 % to about 1 % by weight of glycopyrronium or its salt, wherein the composition has fine particle mass in the range of 20 meg to 30 meg, and wherein said composition is prepared by a method comprising:
  • step (b) blending the co-micronized premix of step (a) with another part of lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ .
  • an inhalable pharmaceutical dry powder composition comprising from about 0.01 % to about 10% by weight, or preferably from about 0.1 % to about 1 % by weight of glycopyrronium or its salt, wherein the composition has fine particle mass in the range of 18 meg to 30 meg, and wherein said composition is prepared by a method comprising:
  • step (b) blending the co-micronized premix of step (a) with another part of lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ .
  • an inhalable pharmaceutical dry powder composition comprising from about 0.1 % to about 1 % by weight of glycopyrronium or its salt, wherein the composition has fine particle mass in the range of 20 meg to 30 meg, and wherein said composition is prepared by a method comprising:
  • an inhalable pharmaceutical dry powder composition comprising from about 0.1% to about 1% by weight of glycopyrronium or its salt, wherein the composition has fine particle mass in the range of 18 meg to 30 meg, and wherein said composition is prepared by a method comprising:
  • step (b) blending the co-micronized premix of step (a) with lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ .
  • an inhalable pharmaceutical dry powder composition comprising from about 0.1% to about 1% by weight of glycopyrronium or its salt, wherein the composition has fine particle mass in the range of 20 meg to 30 meg, and wherein said composition is prepared by a method comprising:
  • step (b) blending the co-micronized premix of step (a) with lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ .
  • an inhalable pharmaceutical dry powder composition comprising from about 0.1% to about 1% by weight of glycopyrronium or its salt, wherein the composition has fine particle mass in the range of 18 meg to 30 meg, and wherein said composition is prepared by a method comprising:
  • step (b) blending the co-micronized premix of step (a) with lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ .
  • an inhalable pharmaceutical dry powder composition comprising a co-micronized premix consisting of glycopyrronium or its salt and lactose in a weight ratio of about 1: 10 to about 1 :200 and lactose wherein said premix has mean particle size of less than about 5 ⁇ , and said composition is free from a hydrophobic excipient and wherein the composition has fine particle mass in the range of 20 meg to 30 meg.
  • an inhalable pharmaceutical dry powder composition comprising a co-micronized premix consisting of glycopyrronium or its salt and lactose in a weight ratio of about 1 : 10 to about 1 :200 and lactose wherein said premix has mean particle size of less than about 5 ⁇ , and said composition is free from a hydrophobic excipient and wherein the composition has fine particle mass in the range of 18 meg to 30 meg.
  • an inhalable pharmaceutical dry powder composition comprising a co-micronized premix of glycopyrronium or its salt and lactose in a weight ratio of about 1: 10 to about 1:200, wherein said premix has mean particle size of less than about 5 ⁇ , and said composition is free from a hydrophobic excipient and wherein the composition has fine particle mass in the range of 20 meg to 30 meg.
  • an inhalable pharmaceutical dry powder composition comprising a co-micronized premix of glycopyrronium or its salt and lactose in a weight ratio of about 1: 10 to about 1:200, wherein said premix has mean particle size of less than about 5 ⁇ , and said composition is free from a hydrophobic excipient and wherein the composition has fine particle mass in the range of 18 meg to 30 meg.
  • an inhalable pharmaceutical dry powder composition comprising (a) glycopyrronium bromide in an amount of 5 meg to 200 meg, and (b) lactose, wherein said composition is free from magnesium stearate.
  • an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose wherein the said composition has Hausner ratio in the range of 1 to 2 or preferably Hausner ratio is in the range of 1.25 to 1.75 or more preferably Hausner ratio is in the range of 1.30 to 1.65.
  • an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose wherein said composition has Carr index in the range of 20% -45% or more preferably the Carr index is in the range of 22%-40%.
  • an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose wherein said composition has bulk density in the range of 0.45 g/mL - 0.65 g/mL or more preferably bulk density in the range of 0.5 g/mL - 0.6 g/mL.
  • an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose wherein said composition has tap density in the range of 0.65 g/mL - 0.95 g/mL or more preferably tap density in the range of 0.7 g/mL - 0.9 g/mL.
  • an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose wherein MMAD of glycopyrronium in said composition is in the range of 1 ⁇ - 4 ⁇ or more preferably MMAD of glycopyrronium in said composition is in the range of 1.5 ⁇ - 3 ⁇ .
  • the present invention relates to a method of treating respiratory disorders in a subject, said method comprising administering by inhalation route to the subject the dry powder composition comprising an effective amount of glycopyrronium bromide and lactose, wherein said composition is free from magnesium stearate.
  • the respiratory disorder in the context of present invention, includes but is not limited to asthma, emphysema, bronchitis, COPD, sinusitis, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), irritant induced asthma, occupational asthma, sensory hyper-reactivity, airway (or pulmonary) inflammation, multiple chemical sensitivity, and aid in smoking cessation therapy.
  • asthma includes acute asthma, chronic asthma, intermittent asthma, mild persistent asthma, moderate persistent asthma, severe persistent asthma, chronic persistent asthma, mild to moderate asthma, mild to moderate persistent asthma, mild to moderate chronic persistent asthma, allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, nocturnal asthma, bronchial asthma, exercise induced asthma, occupational asthma, seasonal asthma, silent asthma, gastroesophageal asthma, idiopathic asthma and cough variant asthma.
  • the present invention relates to a method of treating asthma in a subject, said method comprising administering by inhalation route to the subject the dry powder composition comprising an effective amount of glycopyrronium bromide and lactose, wherein said composition is free from magnesium stearate.
  • the present invention relates to a method of treating COPD in a subject, said method comprising administering by inhalation route to the subject the dry powder composition comprising an effective amount of glycopyrronium bromide and lactose, wherein said composition is free from magnesium stearate.
  • the present invention relates to use of an effective amount of glycopyrronium bromide in the inhalable pharmaceutical dry powder composition of the present invention for the treatment of respiratory disorders in a subject.
  • the present invention relates to an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium bromide for the treatment of respiratory disorders in a subject.
  • an excipient includes a single excipient as well as two or more different excipients, and the like.
  • Glycopyrrolate is a quaternary ammonium salt.
  • Suitable counter ions are pharmaceutically acceptable counter ions including, for example, fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl-acetate or triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, 1- hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate, methane- sulfonate and benzenesulfonate.
  • glycopyrronium bromide is glycopyrronium 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 (3S, 2'S).
  • salts and esters are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use.
  • Representative acid additions salts include the hydrochloride, furoate, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, and lauryl sulphate salts.
  • Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts.
  • an effective amount denotes an amount of an active ingredient that, when administered to a subject for treating respiratory disorders, produces an intended therapeutic benefit in a subject.
  • active ingredient (used interchangeably with “active” or “active substance” or “drug”) as used herein includes Glycopyrronium or a pharmaceutically acceptable salt thereof.
  • treating also covers the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder modulated by the Glycopyrronium or its salt in a mammal.
  • subject includes mammals like human and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
  • domestic animals e.g., household pets including cats and dogs
  • non-domestic animals such as wildlife
  • the subject is a human.
  • pharmaceutically acceptable excipients any of the components of a pharmaceutical composition other than the actives and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.
  • the term "average particle size” refers to the distribution of particles, wherein about 50 volume percent of all the particles measured have a size less than the defined average particle size value and about 50 volume percent of all measurable particles measured have a particle size greater than the defined average particle size value. This can be identified by the term “D50” or “d (0.5)”.
  • D90 value relates to about 90 volume percent of all the particles measured have a size less than the defined particle size value (also referred to as "D90 particle size').
  • the particle size can be measured using various techniques like laser diffraction, photon correlation spectroscopy (PCS) and Coulter's principle.
  • co-micronisation refers to milling or micronisation of the active ingredient and lactose together in suitable mill to obtain micronised mixture of active ingredient and lactose.
  • the mixture of active ingredient and lactose after co-micronisation process can be called as co-micronised premix of active ingredient and lactose.
  • Jet mill, Air jet mill, Ball mill and the like can be used for the milling purpose.
  • Air Jet Mill may be used for co-micronisation.
  • the fine particle mass test is normally conducted using a validated multistage impactor or impinger method, or a suitably validated alternative. It is normally considered acceptable to set upper and lower limits on the results of pooled stages corresponding to a particle size distribution of less than 5 micrometer, although alternative limits may be found acceptable with adequate justification.
  • the drug mass should be reported rather than the percentage of emitted dose (or other derived parameter).
  • the Mass Median Aerodynamic Diameter is defined as the diameter at which 50% of the particles by mass are larger and 50% are smaller.
  • the Carr index and Hausner ratio are frequently used in as an indication of the flowability of a powder.
  • the Carr index and Hausner ratio can be determined using Tap Density Apparatus.
  • the bulk density and tap density of the powder composition can be determined by Tap density apparatus.
  • the therapeutically effective amount of Glycopyrronium bromide to be administered per day ranges from about 5 meg to about 400 meg.
  • the pharmaceutical composition in the above embodiments may optionally comprise one or more pharmaceutically acceptable excipients.
  • the inhalable pharmaceutical dry powder composition of the present invention may contain one or more pharmaceutically acceptable excipients. Examples of such excipients include but are not limited to diluents, solvents, and the like.
  • the pharmaceutically acceptable diluent suitable for use in the invention is selected from lactose, mannitol, sucrose, trehalose, cyclodextrin, or mixtures thereof.
  • the pharmaceutically acceptable diluent is lactose.
  • Various grade of lactose are available for use in dry powder compositions are selected from Respitose ® SV010, Respitose ® SV003, Respitose ® ML006, Lactose Monohydrate Inhalation 40M, Lactose Anhydrous 120M, Lactohale ® 300, and the like.
  • solvents examples include water; propylene glycol; ether; petroleum ether; alcohols, e.g., methanol, ethanol, isopropyl alcohol and higher alcohols; alkanes, e.g., pentane, hexane and heptane; ketones, e.g., acetone and methyl ethyl ketone; and the like and mixtures thereof.
  • step (b) blending the co-micronized premix of step (a) with another part of lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ .
  • the powder composition may be further be filled into a capsule for inhalation or may be processed into a lightly compressed tablet or powder agglomeration which can be easily crushed to obtain a powder for inhalation.
  • the composition can be filled, either as discrete dosage units, in a blister or a sachet or in a reservoir for multiple use.
  • an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose, wherein said composition is free from a hydrophobic excipient.
  • an inhalable pharmaceutical dry powder composition consisting of an effective amount of glycopyrronium or its salt and lactose.
  • the present invention relates to an inhalable pharmaceutical dry powder composition
  • an inhalable pharmaceutical dry powder composition comprising (i) a co-micronized premix of glycopyrronium or its salt and one part of lactose in a weight ratio of about 1:5 to about 1:200 and having D90 particle size in the range of about 0.5 ⁇ to about 10 ⁇ , and (ii) another part of lactose having D90 particle size in the range of about 5 ⁇ to about 200 ⁇ ; wherein said composition is free from a hydrophobic excipient.
  • the present invention relates to an inhalable pharmaceutical dry powder composition
  • an inhalable pharmaceutical dry powder composition comprising (i) a co-micronized premix consisting of glycopyrronium or its salt and one part of lactose in a weight ratio of about 1:5 to about 1:200 and having D90 particle size in the range of about 0.5 ⁇ to about 10 ⁇ , and (ii) another part of lactose having D90 particle size in the range of about 5 ⁇ to about 200 ⁇ ; wherein said composition is free from a hydrophobic excipient.
  • the weight ratio of glycopyrronium or its salt to the one part of lactose in the co-micronized premix ranges from about 1: 12 to about 1:75, or from aboutl : 14 to about 1:65.
  • the present invention relates an inhalable pharmaceutical dry powder composition
  • a co-micronized premix consisting of glycopyrronium or its salt and one part of lactose in a weight ratio of about 1 : 10 to about 1: 100 and having D90 particle size in the range of about 1 ⁇ to about 8 ⁇ , and (ii) another part of lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ ; wherein said composition is free from a hydrophobic excipient.
  • the D90 particle size of the co-micronized premix is in the range of about 2 ⁇ to about 7 ⁇ , or about 3 ⁇ to about 5 ⁇ .
  • said inhalable pharmaceutical dry powder composition is free from a hydrophobic excipient.
  • step (b) blending the co-micronized premix of step (a) with another part of lactose having D90 particle size in the range of about 5 ⁇ to about 200 ⁇ .
  • a process for preparing an inhalable pharmaceutical dry powder composition comprising glycopyrronium or its salt, wherein said process comprises:
  • step (b) blending the co-micronized premix of step (a) with another part of lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ .
  • step (b) blending the co-micronized premix of step (a) with another part of lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ .
  • the weight ratio of glycopyrronium or its salt to lactose in the co- micronized premix of the present invention ranges from about 1 :5 to about 1 :200, 1 : 10 to about 1 : 100, more preferably from about 1 : 12 to about 1 : 75 or from about 1 : 14 to about 1 :65.
  • the weight ratio of the co-micronized premix to lactose ranges froml : l to 1 :50, preferably, from 1 :5 to 1 :30.
  • an inhalable pharmaceutical dry powder composition comprising from about 0.01 % to about 10% by weight, or preferably from about 0.1 % to about 1 % by weight of glycopyrronium or its salt, wherein the composition has fine particle mass in the range of 20 meg to 30 meg, and wherein said composition is prepared by a method comprising:
  • an inhalable pharmaceutical dry powder composition comprising from about 0.1% to about 1% by weight of glycopyrronium or its salt, wherein the composition has fine particle mass in the range of 20 meg to 30 meg, and wherein said composition is prepared by a method comprising:
  • step (b) blending the co-micronized premix of step (a) with lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ .
  • an inhalable pharmaceutical dry powder composition comprising from about 0.1% to about 1% by weight of glycopyrronium or its salt, wherein the composition has fine particle mass in the range of 20 meg to 30 meg, and wherein said composition is prepared by a method comprising:
  • step (b) blending the co-micronized premix of step (a) with lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ .
  • an inhalable pharmaceutical dry powder composition comprising a co-micronized premix consisting of glycopyrronium or its salt and lactose in a weight ratio of about 1: 10 to about 1 :200 and lactose wherein said premix has mean particle size of less than about 5 ⁇ , and said composition is free from a hydrophobic excipient and wherein the composition has fine particle mass in the range of 20 meg to 30 meg.
  • an inhalable pharmaceutical dry powder composition comprising a co-micronized premix of glycopyrronium or its salt and lactose in a weight ratio of about 1: 10 to about 1:200, wherein said premix has mean particle size of less than about 5 ⁇ , and said composition is free from a hydrophobic excipient and wherein the composition has fine particle mass in the range of 20 meg to 30 meg.
  • an inhalable pharmaceutical dry powder composition comprising (a) glycopyrronium bromide in an amount of 5 meg to 200 meg, and (b) lactose, wherein said composition is free from magnesium stearate.
  • the present invention relates to a method of treating respiratory disorders in a subject, said method comprising administering by inhalation route to the subject the dry powder composition comprising an effective amount of glycopyrronium bromide and lactose, wherein said composition is free from magnesium stearate.
  • an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose wherein the said composition has Hausner ratio in the range of 1 to 2 or preferably Hausner ratio is in the range of 1.25 to 1.75 or more preferably Hausner ratio is in the range of 1.30 to 1.65.
  • an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose wherein said composition has Carr index in the range of 20% -45% or more preferably the compressibility index is in the range of 22%-40%.
  • an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose wherein said composition has bulk density in the range of 0.45 g/mL - 0.65 g/mL or more preferably bulk density in the range of 0.5 g/mL - 0.6 g/mL.
  • an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose wherein said composition has tap density in the range of 0.65 g/mL - 0.95 g/mL or more preferably tap density in the range of 0.7 g/mL - 0.9 g/mL.
  • an inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium or its salt and lactose wherein MMAD of glycopyrronium in said composition is in the range of 1 ⁇ - 4 ⁇ or more preferably MMAD of glycopyrronium in said composition is in the range of 1.5 ⁇ - 3 ⁇ .
  • the respiratory disorder in the context of present invention, includes but is not limited to asthma, emphysema, bronchitis, COPD, sinusitis, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), irritant induced asthma, occupational asthma, sensory hyper-reactivity, airway (or pulmonary) inflammation, multiple chemical sensitivity, and aid in smoking cessation therapy.
  • asthma includes acute asthma, chronic asthma, intermittent asthma, mild persistent asthma, moderate persistent asthma, severe persistent asthma, chronic persistent asthma, mild to moderate asthma, mild to moderate persistent asthma, mild to moderate chronic persistent asthma, allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, nocturnal asthma, bronchial asthma, exercise induced asthma, occupational asthma, seasonal asthma, silent asthma, gastroesophageal asthma, idiopathic asthma and cough variant asthma.
  • the present invention relates to a method of treating asthma in a subject, said method comprising administering by inhalation route to the subject the dry powder composition comprising an effective amount of glycopyrronium bromide and lactose, wherein said composition is free from magnesium stearate.
  • the present invention relates to a method of treating COPD in a subject, said method comprising administering by inhalation route to the subject the dry powder composition comprising an effective amount of glycopyrronium bromide and lactose, wherein said composition is free from magnesium stearate.
  • the present invention relates to use of an effective amount of glycopyrronium bromide in the inhalable pharmaceutical dry powder composition of the present invention for the treatment of respiratory disorders in a subject.
  • the present invention relates to an inhalable dry powder composition comprising an effective amount of glycopyrronium bromide for the treatment of respiratory disorders in a subject.
  • Glycopyrrolate micronised Premix from Example 1 and fine grade Lactose were sifted and then mixed in a suitable blender. 2. The blend of step 1 was sifted with a part of coarse grade lactose monohydrate and then mixed in a suitable blender.
  • step 2 The blend of step 2 was sifted with remaining part of lactose and then mixed in a suitable blender.
  • step 3 The blend of step 3 was filled in a capsule or dose packet or blister. Fine Particle Mass Determination:
  • the Fine Particle Mass was determined using Andersen Cascade Impactor.
  • the Cascade Impactor was connected to the flow system.
  • the mouth piece of inhaler device having capsule or dose packet or blister containing pharmaceutical composition was attached to mouthpiece adaptor of Cascade Impactor.
  • the inhaler device was actuated and the powder was discharged into the Cascade Impactor by opening of the valves for specific time.
  • the content from each stage of Cascade Impactor was collected and analysed for Fine Particle Mass content.
  • Lactose monohydrate ⁇ 10 ⁇ 3.000 (Lactohale ® 300)
  • step 2 The blend of step 1 was sifted with a part of coarse grade lactose monohydrate and then mixed in a suitable blender.
  • step 2 The blend of step 2 was sifted with remaining part of lactose and then mixed in a suitable blender.
  • step 3 The blend of step 3 was filled in a capsule or dose packet or blister.
  • Lactose monohydrate ⁇ 10 ⁇ 1.000 (Lactohale ® 300)
  • step 2 The blend of step 1 was sifted with a part of coarse grade lactose monohydrate and then mixed in a suitable blender.
  • step 2 The blend of step 2 was sifted with remaining part of lactose and then mixed in a suitable blender.
  • step 3 The blend of step 3 was filled in a capsule or dose packet or blister.
  • step 2 The blend of step 1 was sifted with a part of coarse grade lactose monohydrate and then mixed in a suitable blender.
  • step 2 The blend of step 2 was sifted with remaining part of lactose and then mixed suitable blender.
  • step 3 The blend of step 3 was filled in a HPMC capsule.
  • Comparative Examples A1-A8 DPI compositions of Glycopyrronium bromide prepared by conventional mixing process.
  • Micronized Glycopyrrolate, fine grade Lactose and Magnesium stearate (Al or A8) were sifted and then mixed in a suitable blender.
  • step 2 The blend of step 1 was sifted with a part of coarse grade lactose monohydrate and then mixed in a suitable blender.
  • step 2 The blend of step 2 was sifted with remaining part of lactose and then mixed in a suitable blender.
  • step3 was filled in in dose packet or blister.

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Abstract

La présente invention concerne une composition pharmaceutique inhalable comportant du glycopyrronium ou son sel. De préférence, la présente concerne une composition pharmaceutique inhalable comportant une quantité efficace de glycopyrronium ou son sel et du lactose; un procédé de préparation d'une telle composition et son utilisation dans le traitement de troubles respiratoires.
PCT/IB2015/058550 2014-11-05 2015-11-05 Composition pharmaceutique inhalable comportant du glycopyrronium WO2016071862A1 (fr)

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BR112017009315A BR112017009315A2 (pt) 2014-11-05 2015-11-05 composição de pó seco farmacêutico inalável, processo para preparar uma composição de pó seco farmacêutico inalável, e, método para tratar transtornos respiratórios.

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IN3493/MUM/2014 2014-11-05
IN3493MU2014 2014-11-05

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019060604A1 (fr) * 2017-09-20 2019-03-28 Teva Branded Pharmaceutical Products R&D, Inc. Médicament inhalable
WO2019060595A1 (fr) * 2017-09-20 2019-03-28 Teva Branded Pharmaceutical Products R&D, Inc. Médicament inhalable en poudre sèche comprenant du glycopyrronium
JP2019521974A (ja) * 2016-06-08 2019-08-08 ホビオネ サイエンティア リミテッド ラクトースと臭化グリコピロニウムの結晶性医薬品共結晶
WO2024133905A1 (fr) * 2022-12-22 2024-06-27 Stada Arzneimittel Ag Composition pharmaceutique pour le traitement de la bpco

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CN101325945A (zh) * 2005-12-12 2008-12-17 雅戈泰克股份公司 用于吸入的粉末组合物
CN101484134A (zh) * 2006-06-30 2009-07-15 诺瓦提斯公司 用于吸入的格隆铵盐组合物
WO2013009271A1 (fr) * 2011-06-02 2013-01-17 Mahmut Bilgic Nouvelle formulation améliorée de poudre sèche
CN103501781A (zh) * 2011-03-04 2014-01-08 索塞R&D有限公司 吡咯糖用于治疗心动过速的用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101325945A (zh) * 2005-12-12 2008-12-17 雅戈泰克股份公司 用于吸入的粉末组合物
CN101484134A (zh) * 2006-06-30 2009-07-15 诺瓦提斯公司 用于吸入的格隆铵盐组合物
CN103501781A (zh) * 2011-03-04 2014-01-08 索塞R&D有限公司 吡咯糖用于治疗心动过速的用途
WO2013009271A1 (fr) * 2011-06-02 2013-01-17 Mahmut Bilgic Nouvelle formulation améliorée de poudre sèche

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019521974A (ja) * 2016-06-08 2019-08-08 ホビオネ サイエンティア リミテッド ラクトースと臭化グリコピロニウムの結晶性医薬品共結晶
JP7049270B2 (ja) 2016-06-08 2022-04-06 ホビオネ サイエンティア リミテッド ラクトースと臭化グリコピロニウムの結晶性医薬品共結晶
WO2019060604A1 (fr) * 2017-09-20 2019-03-28 Teva Branded Pharmaceutical Products R&D, Inc. Médicament inhalable
WO2019060595A1 (fr) * 2017-09-20 2019-03-28 Teva Branded Pharmaceutical Products R&D, Inc. Médicament inhalable en poudre sèche comprenant du glycopyrronium
WO2024133905A1 (fr) * 2022-12-22 2024-06-27 Stada Arzneimittel Ag Composition pharmaceutique pour le traitement de la bpco

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