WO2001012191A2 - Compositions pharmaceutiques - Google Patents

Compositions pharmaceutiques Download PDF

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Publication number
WO2001012191A2
WO2001012191A2 PCT/GB2000/003112 GB0003112W WO0112191A2 WO 2001012191 A2 WO2001012191 A2 WO 2001012191A2 GB 0003112 W GB0003112 W GB 0003112W WO 0112191 A2 WO0112191 A2 WO 0112191A2
Authority
WO
WIPO (PCT)
Prior art keywords
active ingredient
hydroxy
propylsulphonyl
phenylethoxy
benzothiazol
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/GB2000/003112
Other languages
English (en)
Other versions
WO2001012191A3 (fr
Inventor
Francis Ince
John Dixon
Philip Holt
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.)
AstraZeneca UK Ltd
Original Assignee
AstraZeneca UK 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 AstraZeneca UK Ltd filed Critical AstraZeneca UK Ltd
Priority to AU64601/00A priority Critical patent/AU6460100A/en
Publication of WO2001012191A2 publication Critical patent/WO2001012191A2/fr
Publication of WO2001012191A3 publication Critical patent/WO2001012191A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • 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

Definitions

  • the present invention relates to combinations of pharmaceutically active substances for use in the treatment of obstructive airways diseases.
  • a pharmaceutical composition comprising, in admixture, a first active ingredient (A) being 4-hydroxy-7-[2- [2-[3-[2-phenylethoxy]propylsulphonyl]ethylamino]ethyl]- 1 ,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof, and a second active ingredient (B) being a glucocorticoid.
  • the invention also provides a pharmaceutical product comprising, in combination, a preparation of a first active ingredient (A) being 4-hydroxy-7-[2-[2-[3-[2-phenylethoxy]- propylsulphonyl]ethylamino]ethyl]-l,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof, and a preparation of a second active ingredient (B) being a glucocorticoid for sequential or separate use in therapy.
  • A a preparation of a first active ingredient (A) being 4-hydroxy-7-[2-[2-[3-[2-phenylethoxy]- propylsulphonyl]ethylamino]ethyl]-l,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof, and a preparation of a second active ingredient (B) being a glucocorticoid for sequential or separate use in therapy.
  • the invention provides a kit comprising a preparation of a first active ingredient (A) being 4-hydroxy-7-[2-[2-[3-[2-phenylethoxy]propylsulphonyl]- ethylamino]ethyl]- 1 ,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof, a preparation of a second active ingredient (B) being a glucocorticoid, and instructions for the sequential or separate administration of the preparations to a patient in need thereof.
  • the combination of active ingredients according to the invention is advantageous because it is beneficial in the treatment of obstructive airways diseases including chronic obstructive pulmonary disease (COPD); and asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness).
  • COPD chronic obstructive pulmonary disease
  • asthma such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness).
  • COPD chronic obstructive pulmonary disease
  • asthma such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness).
  • the active ingredient (A) is most preferably 4-hydroxy-7-[2-[2-[3-[2- phenylethoxy]propylsulphonyl]ethylamino]ethyl]-l,3-benzothiazol-2(3H)-one hydrochloride.
  • Examples of the active ingredient (B) include known glucocorticoids such as:
  • the pharmaceutical composition of the invention may be prepared by mixing the first active ingredient (A) with the second active ingredient (B). Therefore, in another aspect of the present invention, there is provided a process for the preparation of a pharmaceutical composition which comprises mixing a first active ingredient (A) being 4-hydroxy-7-[2-[2- [3-[2-phenylethoxy]propylsulphonyl]ethylamino]ethyl]- 1 ,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof, with a second active ingredient (B) being a glucocorticoid.
  • the pharmaceutical composition of the invention will typically comprise a total amount of first active ingredient (A) and second active ingredient (B) in the range from 0.05 to 99 %w (per cent by weight), more preferably in the range from 0.10 to 70 %w, and even more preferably in the range from 0.10 to 50 %w, all percentages by weight being based on total composition.
  • the first and second active ingredients (A) and (B) may alternatively be administered sequentially or separately in any suitable order to treat obstructive airways diseases.
  • sequential is meant that the first and second active ingredients are administered one immediately after the other. They still have the desired effect if they are administered separately but less than about 4 hours apart, preferably less than about 2 hours apart, more preferably less than about 30 minutes apart.
  • the active ingredients may, and indeed usually will, be used in admixture with one or more pharmaceutically acceptable ingredients which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings and colorants.
  • pharmaceutically acceptable ingredients which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings and colorants.
  • the dosages administered will, of course, vary with the first and second active ingredients (A) and (B) employed, the mode of administration, the treatment desired and the disorder indicated. If the active ingredients are administered by inhalation, then the total daily dosage of first active ingredient (A) and second active ingredient (B) together is preferably in the range from 5 to 1500 ⁇ g, e.g. from 10 to 1450 ⁇ g or from 20 to 1400 ⁇ g. Alternatively, if the first active ingredient (A) is administered by inhalation, the total daily dosage of first active ingredient (A) is preferably in the range from 5 to 1500 ⁇ g, e.g.
  • the total daily dosage of second active ingredient (B) is preferably in the range from 1 to 50 mg, particularly from 1, 2, 3, 4 or 5 to 40, preferably to 30 mg.
  • the pharmaceutical composition, pharmaceutical product or kit according to the invention may be administered as divided doses from 1 to 4 times a day, and preferably once or twice a day.
  • the first and second active ingredients (A) and (B) may be administered topically (to the lung and/or airways) in the form of solutions, suspensions, aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions.
  • metered dose inhaler devices may be used to administer the active ingredient(s), dispersed in a suitable propellant and with or without additional excipients such as ethanol, surfactants, lubricants or stabilising agents.
  • Suitable propellants include hydrocarbon, chlorofluorocarbon and hydrofluoroalkane
  • propellants e.g. heptafluoroalkane
  • propellants e.g. HFA-134a and HFA-227, each of which may be used alone or in combination with other propellants and/or surfactants and/or other excipients.
  • Nebulised aqueous suspensions or, preferably, solutions may also be employed, with or without a suitable pH and/or tonicity adjustment, either as a unit-dose or multi-dose formulations.
  • Dry powder inhalers may be used to administer the active ingredient(s), alone or in combination with a pharmaceutically-acceptable carrier, in the latter case either as a finely divided powder or as an ordered mixture.
  • the dry powder inhaler may be single dose or multi-dose and may utilise a dry powder or a powder-containing capsule.
  • Metered dose inhaler, nebuliser and dry powder inhaler devices are well known and a variety of such devices are available.
  • Tablets and gelatin capsules, which may be coated if desired, containing the active ingredient(s) may, for example, also include one or more diluents, carriers, binders, lubricants or stabilising agents.
  • Injectable solutions of the active ingredient(s) may also contain, for example, one or more preservatives, stabilising agents, viscosity-regulating agents, emulsifying agents or buffering agents.
  • the present invention further provides the use of a pharmaceutical composition, pharmaceutical product or kit according to the invention in the manufacture of a medicament for the treatment of an obstructive airways disease.
  • the present invention provides a method of treating, or reducing the risk of, an obstructive airways disease in a patient suffering from, or at risk of, the disease, which comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition of the invention.
  • the present invention provides a method of treating, or reducing the risk of, an obstructive airways disease which comprises sequentially or separately administering (in any suitable order) to a patient suffering from, or at risk of, the disease (a) a (therapeutically effective) dose of a first active ingredient (A) being 4-hydroxy-7-[2- [2-[3-[2-phenylethoxy]propylsulphonyl]ethylamino]ethyl]-l ,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof; and (b) a (therapeutically effective) dose of a second active ingredient (B) being a glucocorticoid.
  • a first active ingredient (A) being 4-hydroxy-7-[2- [2-[3-[2-phenylethoxy]propylsulphonyl]ethylamino]ethyl]-l ,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof; and
  • CR/CD rats weighing 250-300g were dosed orally at lml.kg "1 with either distilled water (DIH 0) or dexamethasone (active ingredient (B)) (see table 1). Sixty (60) minutes later they were placed into open fronted holding cones that were attached to a cylindrical metal aerosol chamber.
  • DIH 0 distilled water
  • B dexamethasone
  • the lavages were centrifuged at 1800 rpm for 10 min at 4°C.
  • the supernatant from tube A was kept for future mediator analysis, and the remaining supernatant poured away into Trigene.
  • the cell pellets from the remaining two tubes were resuspended in a total of lml HBSS.
  • a 1 in 10 dilution of the lavage suspension was made in Kimura's stain and using an improved Neubauer counting chamber, the number of neutrophils counted.
  • Glucocorticoids such as dexamethasone are known to have anti-inflammatory properties and as the above data clearly demonstrate, such compounds in combination with the active ingredient (A) show an advantageous synergistic improvement in these properties.

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

Abstract

L'invention concerne une composition pharmaceutique, un produit pharmaceutique ou une trousse comprenant un premier ingrédient actif (A), à savoir 4-hydroxy-7-[2-[2-[3-[2-phényléthoxy]propylsulfonyl]éthylamino]éthyl]-1,3-benzothiazol-2(3H)-one ou un de ses sels acceptables sur le plan pharmaceutique, et un deuxième ingrédient actif (B), à savoir un glucocorticoïde, afin de traiter les maladies obstructives des voies respiratoires.
PCT/GB2000/003112 1999-08-18 2000-08-14 Compositions pharmaceutiques Ceased WO2001012191A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU64601/00A AU6460100A (en) 1999-08-18 2000-08-14 Pharmaceutical compositions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9902936A SE9902936D0 (sv) 1999-08-18 1999-08-18 Pharmaceutical compositions
SE9902936-5 1999-08-18

Publications (2)

Publication Number Publication Date
WO2001012191A2 true WO2001012191A2 (fr) 2001-02-22
WO2001012191A3 WO2001012191A3 (fr) 2001-09-07

Family

ID=20416694

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2000/003112 Ceased WO2001012191A2 (fr) 1999-08-18 2000-08-14 Compositions pharmaceutiques

Country Status (4)

Country Link
AR (1) AR025340A1 (fr)
AU (1) AU6460100A (fr)
SE (1) SE9902936D0 (fr)
WO (1) WO2001012191A2 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7345060B2 (en) 2003-11-21 2008-03-18 Theravance, Inc. Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity
US7700782B2 (en) 2006-12-20 2010-04-20 Astrazeneca Ab Compounds 569
US7709511B2 (en) 2005-08-09 2010-05-04 Astrazeneca Ab Benzothiazolone derivatives
US7951954B2 (en) 2006-03-14 2011-05-31 Astrazeneca Ab Bezothiazol derivatives as Beta2 adrenoreceptor agonists
US8017602B2 (en) 2008-06-18 2011-09-13 Astrazeneca Ab N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethylamino)ethyl)-3-(phenethoxy)propanamide derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy
US8058294B2 (en) 2007-02-08 2011-11-15 Astrazeneca Ab Pharmaceutical salts of N-[2-(diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-3-[2-(1-napthyl)ethoxy]propanamide

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9211172D0 (en) * 1992-05-27 1992-07-08 Fisons Plc Compounds

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7345060B2 (en) 2003-11-21 2008-03-18 Theravance, Inc. Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity
US7838535B2 (en) 2003-11-21 2010-11-23 Theravance, Inc. Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity
US7842704B2 (en) 2003-11-21 2010-11-30 Theravance, Inc. Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity
US8247564B2 (en) 2003-11-21 2012-08-21 Theravance, Inc. Compounds having BETA2 adrenergic receptor agonist and muscarinic receptor antagonist activity
US7709511B2 (en) 2005-08-09 2010-05-04 Astrazeneca Ab Benzothiazolone derivatives
US7951954B2 (en) 2006-03-14 2011-05-31 Astrazeneca Ab Bezothiazol derivatives as Beta2 adrenoreceptor agonists
US7700782B2 (en) 2006-12-20 2010-04-20 Astrazeneca Ab Compounds 569
US8058294B2 (en) 2007-02-08 2011-11-15 Astrazeneca Ab Pharmaceutical salts of N-[2-(diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-3-[2-(1-napthyl)ethoxy]propanamide
US8017602B2 (en) 2008-06-18 2011-09-13 Astrazeneca Ab N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethylamino)ethyl)-3-(phenethoxy)propanamide derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy

Also Published As

Publication number Publication date
AU6460100A (en) 2001-03-13
AR025340A1 (es) 2002-11-20
SE9902936D0 (sv) 1999-08-18
WO2001012191A3 (fr) 2001-09-07

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