[go: up one dir, main page]

WO2010097114A1 - Nouvelle combinaison d'agents thérapeutiques - Google Patents

Nouvelle combinaison d'agents thérapeutiques Download PDF

Info

Publication number
WO2010097114A1
WO2010097114A1 PCT/EP2009/052303 EP2009052303W WO2010097114A1 WO 2010097114 A1 WO2010097114 A1 WO 2010097114A1 EP 2009052303 W EP2009052303 W EP 2009052303W WO 2010097114 A1 WO2010097114 A1 WO 2010097114A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
product
administration
product according
dose
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP2009/052303
Other languages
English (en)
Inventor
Darrell Baker
Mark Bruce
Anthony Cahn
Marian Thomas
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glaxo Group Ltd
Original Assignee
Glaxo Group Ltd
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 Glaxo Group Ltd filed Critical Glaxo Group Ltd
Priority to PCT/EP2009/052303 priority Critical patent/WO2010097114A1/fr
Publication of WO2010097114A1 publication Critical patent/WO2010097114A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
    • 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
    • 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

  • This invention relates to pharmaceutical products and compositions for use in the treatment of chronic obstructive pulmonary disease (COPD), asthma and related disorders.
  • COPD chronic obstructive pulmonary disease
  • this invention relates to the combination of a muscarinic antagonist and a beta-2 adrenoreceptor agonist, and the use of said combination in treating diseases mediated via the M3 muscarinic acetylcholine receptor and/or the beta-2 adrenoreceptor.
  • this invention is concerned with novel medicament combinations comprising a combination of 4- ⁇ (1 R)-2-[(6- ⁇ 2-[(2,6- dichlorobenzyl)oxy]ethoxy ⁇ hexyl)amino]-1 -hydroxyethyl ⁇ -2-(hydroxymethyl)phenol triphenylacetate and (endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia- bicyclo[3.2.1]octane bromide and the use of said combinations in medicine, particularly in treating diseases mediated via the M3 muscarinic acetylcholine receptor and/or the beta-
  • 2 adrenoreceptor for example in the prophylaxis and treatment of respiratory diseases.
  • Beta-2 adrenoreceptor agonists have been used in the prophylaxis and treatment of clinical conditions for which a bronchodilating agent has been indicated.
  • diseases associated with airflow obstruction such as chronic obstructive pulmonary diseases (COPD) (e.g. chronic and whez bronchitis, emphysema), asthma, respiratory tract infection and upper respiratory tract disease (e.g. rhinitis, including seasonal and allergic rhinitis).
  • COPD chronic obstructive pulmonary diseases
  • asthma and other related disorders are typically treated with beta-2 adrenergic receptor agonists (beta-2 agonists) as they provide a bronchodilator effect to the patient, resulting in relief from the symptoms of breathlessness.
  • beta-2 agonist class there are presently available short acting compounds for immediate relief, such as salbutamol, biltolterol, pirbuterol and terbutaline.
  • short acting compounds for immediate relief such as salbutamol, biltolterol, pirbuterol and terbutaline.
  • longer acting compounds such as salmeterol and formoterol.
  • salmeterol and formoterol are effective bronchodilators, in general their duration of action in human subjects is around 12 hours, hence twice daily dosing is generally required.
  • inhaled anticholinergic agents have become well established as well-tolerated and effective bronchodilators for the treatment of COPD.
  • Treatment with anticholinergics significantly improves FE ⁇ , (forced expiratory volume in 1 second) resting and dynamic lung hyperinflation, symptoms and exercise capacity, and reduces COPD exacerbations.
  • FE ⁇ forced expiratory volume in 1 second
  • oxitropium bromide the short-acting ipratropium bromide
  • tiotropium bromide tiotropium; dosed once-daily.
  • WO 03/024439 describes compounds of the general formula:
  • the compound 4- ⁇ (1 R)-2-[(6- ⁇ 2-[(2,6-dichlorobenzyl)oxy]ethoxy ⁇ hexyl)amino]-1 - hydroxyethyl ⁇ -2-(hydroxymethyl)phenol is specifically described in WO03/024439, as are pharmaceutically acceptable salts thereof, in particular the acetate, triphenylacetate, ⁇ -phenylcinnamate, 1 -naphthoate and (R)-mandelate salts.
  • WO2005/037280 describes compounds of the formulae:
  • WO2005/037280 specifically describes the compound (endo)-3-(2-cyano- 2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane bromide.
  • the present invention provides for a novel combination product comprising the therapeutic agents:
  • Compound (II) or a pharmaceutically acceptable salt thereof.
  • Compound (II) may refer to the free base depicted above, and/or one or more salts thereof, as dictated by the context. It will be appreciated that each of the therapeutic agents Compound (I) and Compound (II) may be employed in enantiomerically pure form or as a mixture of isomers eg a racemic mixture.
  • the combination comprises a combination of 4- ⁇ (1 R)-2-[(6- ⁇ 2-[(2,6- dichlorobenzyl)oxy]ethoxy ⁇ hexyl)amino]-1 -hydroxyethyl ⁇ -2-(hydroxymethyl)phenol triphenylacetate and (endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia- bicyclo[3.2.1]octane bromide.
  • combination of Compound (I) and Compound (II) additionally comprises an inhaled corticosteroid.
  • This invention also provides for use of the combination in the manufacture of a medicament for the treatment and/or prophylaxis of conditions for which administration of one or more of the therapeutic compounds is indicated.
  • the use is for the manufacture of a medicament for the treatment and/or prophylaxis of inflammatory or respiratory tract diseases, by simultaneous or successive administration of Compound (I) and Compound (II).
  • the use is for the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease (COPD) and/or asthma, by simultaneous or successive administration of Compound (I) and Compound (II).
  • COPD chronic obstructive pulmonary disease
  • the invention also provides said combination for use in the treatment and/or prophylaxis of inflammatory or respiratory tract diseases, such as chronic obstructive pulmonary disease (COPD) and/or asthma.
  • Another embodiment of the invention is a method for the treatment and/or prophylaxis of inflammatory or respiratory tract diseases, comprising administering either sequentially or simultaneously, to a patient in need thereof, a pharmaceutical product comprising Compound (I) and Compound (II).
  • the inflammatory or respiratory tract disease is selected from the group consisting of chronic obstructive pulmonary disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, allergic rhinitis, small airways disease, bronchiectasis and cystic fibrosis.
  • the pharmaceutical product may be used for the treatment of the inflammatory or respiratory tract disease, and more specifically the treatment of chronic obstructive pulmonary disease (COPD) and/or asthma by simultaneous or successive administration of Compound (I) and Compound (II).
  • COPD chronic obstructive pulmonary disease
  • the present invention is directed to a pharmaceutical product comprising
  • the pharmaceutically acceptable anion depicted by R 1" may be selected from chloride, bromide, iodide, sulfate, benzene sulfonate or toluene sulfonate.
  • the structural formula for the quaternary moiety (cation) of Compound (I) is also referred to as (endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8- dimethyl-8-azonia-bicyclo[3.2.1]octane.
  • Compound (I) is (endo)-3-(2-cyano-2,2-diphenyl- ethylj- ⁇ . ⁇ -dimethyl- ⁇ -azonia-bicyclo ⁇ .ijoctane bromide (also referred to herein as the bromide compound).
  • Pharmaceutically acceptable acid addition salts of Compound (II) include those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, thfluoroacetic, triphenylacetic, phenylacetic, substituted phenyl acetic eg.
  • the pharmaceutically acceptable salt of Compound (II) is selected from the acetate, 1 -naphthoate and (R)-mandelate salts.
  • the pharmaceutically acceptable salt of Compound (II) is the ⁇ -phenylcinnamate salt.
  • the pharmaceutically acceptable salt of Compound (II) is the triphenylacetate salt.
  • the structural formula shown above for Compound (II) may be named as 4- ⁇ (1 R)-2-
  • Compound (II) is 4- ⁇ (1 R)-2-[(6- ⁇ 2-[(2,6- dichlorobenzyl)oxy]ethoxy ⁇ hexyl)amino]-1 -hydroxyethyl ⁇ -2-(hydroxymethyl)phenol triphenylacetate.
  • the combination of the invention comprises (endo)-3-(2-cyano- 2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane bromide and 4- ⁇ (1 R)- 2-[(6- ⁇ 2-[(2,6-dichlorobenzyl)oxy]ethoxy ⁇ hexyl)amino]-1 -hydroxyethyl ⁇ -2- (hydroxymethyl)phenol triphenylacetate.
  • the combination of Compound (I) and Compound (II) additionally comprises an inhaled corticosteroid, e.g, , fluticasone prophonate, mometasone furoate, budesonide or 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3- oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester (fluticasone furoate).
  • an inhaled corticosteroid e.g, fluticasone prophonate, mometasone furoate, budesonide or 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3- oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester (fluticasone furoate).
  • said combination comprises (endo)-3-(2-cyano-2,2-diphenyl- ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane bromide, 4- ⁇ (1 R)-2-[(6- ⁇ 2-[(2,6- dichlorobenzyl)oxy]ethoxy ⁇ hexyl)amino]-1 -hydroxyethyl ⁇ -2-(hydroxymethyl)phenol triphenylacetate and 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ - methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester (fluticasone furoate).
  • the combination of the invention comprises (endo)-3-(2-cyano- 2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane bromide and 4- ⁇ (1 R)- 2-[(6- ⁇ 2-[(2,6-dichlorobenzyl)oxy]ethoxy ⁇ hexyl)amino]-1 -hydroxyethyl ⁇ -2- (hydroxymethyl)phenol triphenylacetate as the sole active ingredients.
  • Compound (I) specifically (endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8- azonia-bicyclo[3.2.1]octane bromide has been the subject of extensive studies in animal models and humans and has been found to be a long acting high-affinity pan- active muscarinic receptor antagonist which has potential for once-daily administration.
  • the bromide compound has been found to be dose dependent.
  • the bromide compound has been shown to have a slow "off-rate" at the muscarinic acetylcholine (ACh) receptor. This is known to be predictive of a long duration of action.
  • the bromide compound has been found to have a 10-fold selectivity for the M1 and M3 receptors over the M2 receptors, and the bromide compound has also been found to be a partially reversible antagonist.
  • Compound (II) specifically 4- ⁇ (1 R)-2-[(6- ⁇ 2-[(2,6- dichlorobenzyl)oxy]ethoxy ⁇ hexyl)amino]-1 -hydroxyethyl ⁇ -2-(hydroxymethyl)phenol and its salts has been extensively tested in animal and human studies and has been found to demonstrate sustained bronchodilation over a 24 hour period in conjunction with a favourable safety profile and thus has the potential for once-daily administration.
  • Said compounds have also been administered to humans in combination.
  • Compound (I) and Compound (II) and the combination thereof are considered to have potential in the treatment of respiratory tract disease such as chronic obstructive pulmonary disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, allergic rhinitis, small airways disease, bronchiectasis and cystic fibrosis. Said compounds and the combination thereof are also considered to have the potential for once-daily administration in conjunction with a favourable safety profile.
  • COPD is a chronic disease characterised by airways obstruction and reduced maximum expiratory flow from the lungs that manifests as persistent daily symptoms, such as shortness of breath (dyspnoea), and limitation of the ability to perform daily activities or exertion.
  • Bronchodilator treatment in COPD includes but is not necessarily limited to reducing symptoms, particularly dyspnoea, to allow a patient to undertake more daily activities and other activities that require exertion, and preventing exacerbations.
  • Asthma is a chronic condition, which is characterised by widespread, variable and reversible airflow obstruction. Symptoms include coughing, wheezing, breathlessness and/or a tight feeling in the chest. Asthma attacks are generally caused by exposure to a trigger, such as pollen, dust or other allergens, which causes constriction of the airways (bronchoconstriction). It will be appreciated that a subject suffering from a condition such as asthma, may variously from time to time display no overt symptoms of the conditions, or may suffer from periodic attacks during which symptoms are displayed or may experience exacerbations or worsening of the condition. In this context the term 'treatment' is intended to encompass prevention of such periodic attacks or exacerbations of the existing condition. Such treatment may be referred to as 'maintenance treatment' or 'maintenance therapy'.
  • Compound (I) and specifically (endo)-3-(2-cyano-2,2-diphenyl- ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane bromide may be administered by inhalation at a dose of from about 10mcg to about 200mcg/daily, e.g. 12.5, 25, 50, 100 or 200mcg per day. In general Compound (I) will be administered as a once-daily dose.
  • Compound (II) may for example be administered by inhalation at a dose of from about 1 meg to about 400mcg/day (calculated as the free base).
  • Compound (II), and specifically 4- ⁇ (1 R)-2-[(6- ⁇ 2-[(2,6- dichlorobenzyl)oxy]ethoxy ⁇ hexyl)amino]-1 -hydroxyethyl ⁇ -2-(hydroxymethyl)phenol triphenylacetate may be administered by inhalation at a dose of from about 1 mcg to 100 meg/day, for example 3, 6.25, 12.5, 25, 50 or 100 meg/day (calculated as the free base).
  • Compound (II) will be administered as a once-daily dose.
  • Compound (II) may be administered by inhalation at a dose of 12.5mcg/day. In another embodiment Compound (II) may be administered by inhalation at a dose of 25 meg/day. In another embodiment Compound (II) may be administered by inhalation at a dose of 50 meg/day.
  • the combination additionally includes an inhaled corticosteroid
  • this may be used at doses known in the art.
  • the inhaled corticosteroid is fluticasone furoate this may be administered by inhalation at a dose of from about 25mcg to about 800mcg daily, and if necessary in divided doses.
  • the daily dose of fluticasone furoate may be for example 25, 50, 100, 200, 300, 400, 600 or 800 meg, in general as a once-daily dose.
  • the individual compounds of the pharmaceutical product as described herein may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations or compositions.
  • Compound (I) and Compound (II) may for example, be formulated separately and presented in separate packs or devices for sequential administration, or said individually formulated components may be presented in a single pack or device.
  • the individual therapeutic agents may also be admixed within the same formulation and presented as a fixed pharmaceutical combination.
  • such individual or admixed formulations of the compounds will include pharmaceutical carriers or excipients as described hereinafter, but combinations of the compounds free of excipients or carriers are also within the ambit of this invention.
  • the individual compounds may be administered simultaneously in a combined pharmaceutical formulation or presentation.
  • the combination additionally includes an inhaled corticosteroid, eg 6 ⁇ ,9 ⁇ - difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4- diene-17 ⁇ -carbothioic acid S-fluoromethyl ester (fluticasone furoate)
  • an inhaled corticosteroid eg 6 ⁇ ,9 ⁇ - difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4- diene-17 ⁇ -carbothioic acid S-fluoromethyl ester (fluticasone furoate)
  • this may likewise be formulated separately, either with or without one or more pharmaceutical carriers or excipients, and presented for either sequential or concurrent administration, or the inhaled corticosteroid may be admixed with either Compound (I) or Compound (II).
  • the invention therefore provides: A pharmaceutical product comprising Compound (I) and Compound (II) presented separately for sequential or simultaneous administration; A pharmaceutical product comprising Compound (I) and Compound (II) formulated separately but held in the same pack or device, for sequential or simultaneous administration; and
  • a pharmaceutical product comprising Compound (I) and Compound (II) in a blended formulation for simultaneous administration.
  • each of Compound (I) and/or Compound (II) may be formulated with or without excipients.
  • the present invention further provides a pharmaceutical formulation comprising a combination of Compound (I) and Compound (II) wherein at least one of Compound (I) and Compound (II) is formulated with a pharmaceutically acceptable carrier or excipient.
  • the present invention further provides a pharmaceutical formulation comprising a combination of Compound (I) and Compound (II) wherein each of Compound (I) and Compound (II) is formulated with a pharmaceutically acceptable carrier or excipient.
  • formulations of Compounds (I) and (II) include those suitable for inhalation, including fine particle powders, or mists which may be generated and administered by means of various types of inhalers for example, reservoir dry powder inhalers, unit-dose dry powder inhalers, pre-metered multi-dose dry powder inhalers, nasal inhalers or pressurized metered dose inhalers, nebulisers or insufflators.
  • the compounds may also be formulated as a solution for intravenous administration.
  • the formulations may be prepared by any of the methods well known in the art of pharmacy. In general, said methods include the step of bringing the active ingredient(s) into association with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Powder blend formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier/diluent/excipient substance) such as mono-, di or poly-saccharides (e.g. lactose or starch). Use of lactose is preferred.
  • the lactose may be for example anhydrous lactose or lactose monohydrate.
  • Dry powder compositions may also include, in addition to the drug and carrier, a further excipient (eg a ternary agent) such as a sugar ester, calcium stearate or magnesium stearate.
  • a further excipient eg a ternary agent
  • the compound of the invention may be presented without excipients.
  • the term 'composition' herein refers to the therapeutic compounds either with or without excipients or carriers.
  • the present invention further provides a pharmaceutical formulation comprising a combination of Compound (I) and Compound (II) wherein at least one of Compound (I) and Compound (II) is formulated with a pharmaceutically acceptable carrier and a ternary agent.
  • the present invention further provides a pharmaceutical formulation comprising a combination of Compound (I) and Compound (II) wherein Compound (II) is formulated with a pharmaceutically acceptable carrier and a ternary agent.
  • said ternary agent is magnesium stearate.
  • the formulations may be presented in unit dosage form.
  • Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine, or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator.
  • Each capsule or cartridge may generally contain between 10mcg-200mcg of Compound (I) and/or between 1 mcg-400mcg, e.g 1 to 100 meg of Compound (II).
  • Packaging of the formulation may be suitable for unit dose or multi-dose delivery.
  • Compound (I) and Compound (II) may be formulated independently or in admixture. Said compounds may thus be incorporated in separate unit doses or may be combined in a single unit dose with or without additional excipients as deemed necessary.
  • a composition suitable for inhaled administration may be incorporated into a plurality of sealed dose containers provided on medicament pack(s) mounted inside a suitable inhalation device.
  • the containers may be rupturable, peelable or otherwise openable one-at-a-time and the doses of the dry powder composition administered by inhalation on a mouthpiece of the inhalation device, as known in the art.
  • the medicament pack may take a number of different forms, for instance a disk-shape or an elongate strip.
  • Representative inhalation devices are the DISKHALERTM and DISKUSTM devices, marketed by GlaxoSmithKline. The DISKUSTM inhalation device is, for example, described in GB 2242134A.
  • a dry powder inhalable composition may also be provided as a bulk reservoir in an inhalation device, the device then being provided with a metering mechanism for metering a dose of the composition from the reservoir to an inhalation channel where the metered dose is able to be inhaled by a patient inhaling at a mouthpiece of the device.
  • exemplary marketed devices of this type are TURBUHALERTM of AstraZeneca, TWISTHALERTM of Schering and CLICKHALERTM of Innovata.
  • a further delivery method for a dry powder inhalable composition is for metered doses of the composition to be provided in capsules (one dose per capsule) which are then loaded into an inhalation device, typically by the patient on demand.
  • the device has means to rupture, pierce or otherwise open the capsule so that the dose is able to be entrained into the patient's lung when they inhale at the device mouthpiece.
  • ROTAHALERTM of GlaxoSmithKline
  • HANDIHALERTM of Boehringer Ingelheim.
  • a dry powder composition may also be presented in a delivery device which permits separate containment of Compound (I) and Compound (II) optionally in admixture with one or more excipients.
  • the individual compounds of the combination are administrable simultaneously but are stored separately, e.g. in separate pharmaceutical compositions, for example as described in WO 2003/061743 A1 , WO 2007/012871 A1 and/or WO2007/068896.
  • a delivery device permitting separate containment of actives is an inhaler device having two medicament packs in peelable blister strip form, each pack containing pre- metered doses in blister pockets arranged along its length.
  • Said device has an internal indexing mechanism which, each time the device is actuated, peels opens a pocket of each strip and positions the packs so that each newly exposed dose of each pack is adjacent a manifold which communicates with a mouthpiece of the device. When the patient inhales at the mouthpiece, each dose is simultaneously drawn out of its associated pocket into the manifold and entrained via the mouthpiece into the patient's respiratory tract. Thus, each time the device is used, the patient is administered a combination therapy consisting of a dose from each medicament pack.
  • a further device that permits separate containment of different compounds is DUOHALERTM of Innovata.
  • Spray compositions for inhalation may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant.
  • Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain the pharmaceutical product and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, especially 1 ,1 ,1 ,2-tetrafluoroethane, 1 ,1 ,1 ,2,3,3,3- heptafluoro-n-propane or a mixture thereof.
  • the aerosol composition may optionally contain additional formulation excipients well known in the art such as surfactants e.g. oleic acid, lecithin or an oligolactic acid derivative e.g. as described in WO94/21229 and WO98/34596 and/or cosolvents e.g. ethanol.
  • additional formulation excipients well known in the art such as surfactants e.g. oleic acid, lecithin or an oligolactic acid derivative e.g. as described in WO94/21229 and WO98/34596 and/or cosolvents e.g. ethanol.
  • Pressurised formulations will generally be retained in a canister (e.g. an aluminium canister) closed with a valve (e.g. a metering valve) and fitted into an actuator provided with a mouthpiece.
  • a pharmaceutical aerosol formulation product comprising Compound (I) and Compound (II) formulated individually or in admixture, with a fluorocarbon or hydrogen-containing chlorofluorocarbon as propellant, optionally in combination with a surfactant and/or a co-solvent.
  • the propellant is selected from 1 ,1 ,1 ,2- tetrafluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoro-n-propane and mixtures thereof.
  • Another aspect of the invention is the aerosol formulation consisting of Compound (I) and Compound (II) formulated individually or in admixture, with a fluorocarbon or hydrogen-containing chlorofluorocarbon as propellant, optionally in combination with a surfactant and/or a cosolvent.
  • the propellant is selected from 1 ,1 ,1 ,2-tetrafluoroethane, or 1 ,1 ,1 ,2,3,3,3-heptafluoro-n- propane and mixtures thereof.
  • Medicaments for administration by inhalation desirably have a controlled particle size.
  • the optimum particle size for inhalation into the bronchial system is usually 1 -1 O ⁇ m, preferably 2-5 ⁇ m. Particles having a size above 20 ⁇ m are generally too large when inhaled to reach the small airways.
  • the particles of the active ingredient as produced may be size reduced by conventional means e.g. by micron ization.
  • the desired fraction may be separated out by air classification or sieving.
  • the particles will be crystalline.
  • the carrier or excipient when it is lactose may form from about 94 to about 99%, e.g. 97.7 - 99.0% by weight of the formulation.
  • the particle size of the carrier for example lactose, will be much greater than the inhaled medicament within the present invention.
  • the carrier is lactose it will typically be present as milled lactose, wherein not more than 85% of lactose particles will have a MMD (mass median diameter) of 60-90 ⁇ m and not more than 15% will have a MMD of less than 15 ⁇ m.
  • Magnesium stearate if present in the formulation, is generally used in an amount of about 0.2 to 2%, e.g. 0.6 to 2%, e.g. 0.75%, 1 %, 1.25% or 1.5%.
  • the magnesium stearate will typically have a particle size in the range 1 to 50 ⁇ m, and more particularly 1 - 20 ⁇ m, e.g.1 -10 ⁇ m.
  • stearic acid may comprise a mixture of stearic and palmitic acids; small amounts of other acids, e.g. lauric acid, myristic acid and/or arachic acid may also be present.
  • magnesium stearate similarly may comprise a mixture of salts formed with said acids.
  • the proportion of stearic acid present is 40.0 to 100%.
  • the proportion of stearic acid is present in an amount from 60 to 75% with the total proportion of stearic and palmitic acids in an amount from 90-100% e.g. 96-100%.
  • Intranasal sprays may be formulated with aqueous or non-aqueous vehicles with the addition of agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants.
  • Solutions for inhalation by nebulization may be formulated with an aqueous vehicle with the addition of agents such as acid or alkali, buffer salts, isotonicity adjusting agents or antimicrobials. They may be sterilized by filtration or heating in an autoclave, or presented as a non-sterile product.
  • the invention also provides a method of preparing a pharmaceutical product as defined herein, the method comprising either:
  • 4- ⁇ (1 R)-2-[(6- ⁇ 2-[(2,6-dichlorobenzyl)oxy]ethoxy ⁇ hexyl)amino]-1 -hydroxyethyl ⁇ -2- (hydroxymethyl)phenol, and its salts, including 4- ⁇ (1 R)-2-[(6- ⁇ 2-[(2,6- dichlorobenzyl)oxy]ethoxy ⁇ hexyl)amino]-1 -hydroxyethyl ⁇ -2-(hydroxymethyl)phenol triphenylacetate may be prepared as described in WO03/024439.
  • Example 1 3-((Endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl- propionitrile, TFA salt a) Preparation of ((endoJ- ⁇ -methyl- ⁇ -aza-bicyclo ⁇ .iloct-S-yO-methanol A mixture of 1 ,1 -dimethylethyl (endo)-3-(hydroxymethyl)-8-azabicyclo[3.2.1] octane-8- carboxylate (0.50 g, 2.05 mmol) and LiAIH 4 (6.16 ml_, 1.0 M in THF, 6.16 mmol) was heated at 8O 0 C with a microwave reactor for 60 min.
  • Compound (I) is a high-affinity, pan-active, competitive and reversible long-acting muscarinic receptor demonstrating in vitro, the onset half times to 50% inhibition of carbachol-induced contraction of isolated human bronchial strips for the bromide compound of 25 min, as compared with ipratropium (10 min) and tiotropium (10 min) when compared at single concentration of 1 OnM. At the same concentration, the offset half time for the bromide compound of 195 min was longer than that of ipratropium (24 min) and shorter than that of tiotropium (314 min).
  • Compound (I) was found to be an effective long-acting anti- muscahnic bronchodilator having an unexpectedly faster onset of action than tiotropium. This demonstration of improved onset of action and the dose dependent nature of Compound (I) provides the potential for once daily (qd) dosing.
  • Compound (I) has been tested in 8 clinical studies to date, variously formulated with lactose and either cellobiose octaacetate or magnesium stearate, or as an infusion.
  • Compound (II) as the ⁇ -phenylcinnamate salt and the triphenylacetate salt has been studied in a number of clinical pharmacology studies, including single- and repeat- dose studies. In addition, these studies have evaluated Compound (II) formulated with lactose and either cellobiose octaacetate or magnesium stearate. In asthmatic patients, a statistically and clinically significant improvement in trough (24-hour) FEV1 was observed for all doses of Compound (II) tested, compared to placebo.
  • Dosing Subjects received a single dose, per dose period, of all 4 possible treatments in randomised order:
  • each subject was provided with two inhalers for each of the specified treatments as shown in Table 1. A single inhalation was taken from each inhaler supplied for a treatment.
  • Dry powder inhaler is an inhaler device having two medicament packs in peelable blister strip form, each pack containing pre-metered doses in blister pockets arranged along its length.
  • Compound (II) administered as single inhaled doses and in combination in healthy subjects are Compound (II) administered as single inhaled doses and in combination in healthy subjects.
  • ECG 12- lead ECG (QTcB, QTcF), and lung function (FEV1 ) at 2 hours and clinical laboratory safety tests.
  • FEV1 lung function
  • Pharmacodynamic endpoints included: Endpoints derived for blood potassium. Weighted mean and minimum blood potassium concentrations (0 - 4h post-dose).
  • Plasma and urine concentrations of Compound (I) and derived pharmacokinetic parameters Plasma and urine concentrations of Compound (I) and derived pharmacokinetic parameters.
  • Plasma and urine concentrations of Compound (II) and derived pharmacokinetic parameters Plasma and urine concentrations of Compound (II) and derived pharmacokinetic parameters.
  • Ph.Eur/USNF was used. Before use, the Lactose Monohydrate was sieved through a coarse screen (mesh size 800 microns) to deaggregate the material. Compound (I) bromide was micronised before use in an APTM microniser to give a mass median diameter of 2 to 5 microns.
  • Compound (I) bromide was combined with lactose monohydrate and blended using a high shear TRV series mixer.
  • the final concentration of compound (I) bromide in the blends was typically in the range 0.1 % w/w - 1.6% w/w (calculated as the quaternary moiety)
  • the blended composition was transferred into blister strips (typical nominal mean quantity of blend per blister is 12.5-13.5mg) of the type generally used for the supply of dry powder for inhalation and the blister strips were sealed in the customary fashion.
  • the quantity of compound (I) bromide used is based on a base-salt conversion factor of 1.23.
  • Ph.Eur/USNF was used. Before use, the Lactose Monohydrate was sieved through a coarse screen (typical mesh size 500 microns) to deaggregate the material. Compound (I) thphenylacetate was micronised before use in an APTM microniser to give a MMD (mass median diameter) of from 2 to 5 microns.
  • Magnesium stearate complying with the requirements of Ph.Eur/NF was used as supplied with a mass median particle size ⁇ 10 microns.
  • the magnesium stearate (typically 13Og) was combined with lactose monohydrate and blended using either a high shear mixer (a QMM, PMA or TRV series mixer) or a low shear tumbling blender (a Turbula mixer) to provide a magnesium stearate/lactose premix, hereinafter referred to as blend A.
  • a high shear mixer a QMM, PMA or TRV series mixer
  • a Turbula mixer a low shear tumbling blender
  • Final blend B was obtained by first pre-mixing an appropriate quantity of blend A with compound (II) thphenylacetate (typically 5-165g) using either a high shear mixer (a QMM, PMA or TRV series mixer) or a low shear tumbling blender (a Turbula mixer) and then blending that blend A/compound (I) thphenylacetate premix with further blend A in a weight ratio appropriate to provide blend B containing the magnesium stearate in the required quantity.
  • the final concentration of compound (II) triphenylacetate was combined with lactose monohydrate and blended using a high shear TRV series mixer.
  • the final concentration of compound (I) triphenylacetate in the blends was typically in the range 0.02 % w/w - 0.8% w/w free base equivalent.
  • the blended composition was transferred into blister strips (typical nominal mean quantity of blend B per blister is 12.5-13.5mg) or the type generally used for the supply of dry powder for inhalation and the blister strips were sealed in the customary fashion.
  • the quantity of compound (I) triphenylacetate used is based on a base to salt conversion factor of 1.59

Landscapes

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

Abstract

L'invention concerne de nouvelles combinaisons d'un antagoniste des récepteurs muscariniques de l'acétylcholine et d'un bêta-2-agoniste destinées à être administrées par inhalation par le nez ou la bouche. Elle concerne des méthodes d'utilisation de ces combinaisons.
PCT/EP2009/052303 2009-02-26 2009-02-26 Nouvelle combinaison d'agents thérapeutiques Ceased WO2010097114A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/EP2009/052303 WO2010097114A1 (fr) 2009-02-26 2009-02-26 Nouvelle combinaison d'agents thérapeutiques

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2009/052303 WO2010097114A1 (fr) 2009-02-26 2009-02-26 Nouvelle combinaison d'agents thérapeutiques

Publications (1)

Publication Number Publication Date
WO2010097114A1 true WO2010097114A1 (fr) 2010-09-02

Family

ID=40959539

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2009/052303 Ceased WO2010097114A1 (fr) 2009-02-26 2009-02-26 Nouvelle combinaison d'agents thérapeutiques

Country Status (1)

Country Link
WO (1) WO2010097114A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011067212A1 (fr) * 2009-12-01 2011-06-09 Glaxo Group Limited Combinaisons d'un antagoniste de récepteur muscarinique et d'un agoniste du récepteur bêta-2 adrénergique
EP2762133A1 (fr) * 2010-04-01 2014-08-06 CHIESI FARMACEUTICI S.p.A. PROCÉDÉ DE PRÉPARATION DE PARTICULES de véhicule POUR POUDRES SÈCHES À INHALER
US9763965B2 (en) 2012-04-13 2017-09-19 Glaxosmithkline Intellectual Property Development Limited Aggregate particles
US9795561B2 (en) 2012-12-17 2017-10-24 Glaxo Group Limited Combination of umeclidinium, fluticasone propionate and salmeterol xinafoate for use in the treatment of inflammatory or respiratory tract diseases
US11116721B2 (en) 2009-02-26 2021-09-14 Glaxo Group Limited Pharmaceutical formulations comprising 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl) phenol

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003024439A1 (fr) * 2001-09-14 2003-03-27 Glaxo Group Limited Derives de phenethanolamine destines au traitement de maladies respiratoires
WO2005037280A1 (fr) * 2003-10-14 2005-04-28 Glaxo Group Limited Antagonistes du recepteur muscarinique de l'acetylcholine
WO2005115463A1 (fr) * 2004-05-31 2005-12-08 Almirall Prodesfarma S.A. Combinaisons d'agents antimuscariniques et d'agonistes beta-adrenergique
WO2007107828A2 (fr) * 2006-03-20 2007-09-27 Pfizer Limited Dérivés amine
WO2008000483A2 (fr) * 2006-06-30 2008-01-03 Novartis Ag Composés organiques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003024439A1 (fr) * 2001-09-14 2003-03-27 Glaxo Group Limited Derives de phenethanolamine destines au traitement de maladies respiratoires
WO2005037280A1 (fr) * 2003-10-14 2005-04-28 Glaxo Group Limited Antagonistes du recepteur muscarinique de l'acetylcholine
WO2005115463A1 (fr) * 2004-05-31 2005-12-08 Almirall Prodesfarma S.A. Combinaisons d'agents antimuscariniques et d'agonistes beta-adrenergique
WO2007107828A2 (fr) * 2006-03-20 2007-09-27 Pfizer Limited Dérivés amine
WO2008000483A2 (fr) * 2006-06-30 2008-01-03 Novartis Ag Composés organiques

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11116721B2 (en) 2009-02-26 2021-09-14 Glaxo Group Limited Pharmaceutical formulations comprising 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl) phenol
US9750726B2 (en) 2009-12-01 2017-09-05 Glaxo Group Limited Combinations of a muscarinic receptor antagonist and a beta-2 adrenoreceptor agonist
EA023839B1 (ru) * 2009-12-01 2016-07-29 Глаксо Груп Лимитед Комбинации антагониста мускариновых рецепторов и агониста бета-2-адренорецепторов
WO2011067212A1 (fr) * 2009-12-01 2011-06-09 Glaxo Group Limited Combinaisons d'un antagoniste de récepteur muscarinique et d'un agoniste du récepteur bêta-2 adrénergique
EP2506844B1 (fr) 2009-12-01 2017-12-20 Glaxo Group Limited Combinaisons d'un antagoniste de récepteur muscarinique et d'un agoniste du récepteur bêta-2 adrénergique
EP3335707A1 (fr) * 2009-12-01 2018-06-20 Glaxo Group Limited Combinaisons d'un antagoniste de récepteur muscarinique et d'un agoniste du récepteur bêta-2 adrénergique
US11090294B2 (en) 2009-12-01 2021-08-17 Glaxo Group Limited Combinations of a muscarinic receptor antagonist and a beta-2 adrenoreceptor agonist
EP3335707B1 (fr) 2009-12-01 2024-04-17 Glaxo Group Limited Combinaisons d'un antagoniste de récepteur muscarinique et d'un agoniste du récepteur bêta-2 adrénergique
EP4454645A1 (fr) * 2009-12-01 2024-10-30 Glaxo Group Limited Combinaisons d'un antagoniste de récepteur muscarinique et d'un agoniste du récepteur bêta-2 adrénergique
US12396986B2 (en) 2009-12-01 2025-08-26 Glaxo Group Limited Combinations of a muscarinic receptor antagonist and a β-2 adrenoreceptor agonist
EP2762133A1 (fr) * 2010-04-01 2014-08-06 CHIESI FARMACEUTICI S.p.A. PROCÉDÉ DE PRÉPARATION DE PARTICULES de véhicule POUR POUDRES SÈCHES À INHALER
US9763965B2 (en) 2012-04-13 2017-09-19 Glaxosmithkline Intellectual Property Development Limited Aggregate particles
US9795561B2 (en) 2012-12-17 2017-10-24 Glaxo Group Limited Combination of umeclidinium, fluticasone propionate and salmeterol xinafoate for use in the treatment of inflammatory or respiratory tract diseases

Similar Documents

Publication Publication Date Title
US12396986B2 (en) Combinations of a muscarinic receptor antagonist and a β-2 adrenoreceptor agonist
US20100329996A1 (en) Novel Combination of Therapeutic Agents
EP2400950A1 (fr) Préparations pharmaceutiques comprenant 4-{(1r)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]éthoxy}hexyl)amino]-1-hydroxyéthyl}-2-(hydroxyméthyl)-phénol
WO2012168160A1 (fr) Composition pour inhalateur de poudre sèche comprenant de l'uméclidinium
WO2010097114A1 (fr) Nouvelle combinaison d'agents thérapeutiques
HK40112155A (en) Combinations of a muscarinic receptor antagonist and a beta-2 adrenoreceptor agonist
HK1249407B (en) Combinations of a muscarinic receptor antagonist and a beta-2 adrenoreceptor agonist
HK1174249A (en) Combinations of a muscarinic receptor antagonist and a beta-2 adrenoreceptor agonist
HK1174249B (en) Combinations of a muscarinic receptor antagonist and a beta-2 adrenoreceptor agonist

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09779095

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09779095

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 03/11/2011)