EP1274436A1 - Compositions medicales comprenant du (r,r)-formoterol et du rofleponide - Google Patents

Compositions medicales comprenant du (r,r)-formoterol et du rofleponide

Info

Publication number
EP1274436A1
EP1274436A1 EP01919656A EP01919656A EP1274436A1 EP 1274436 A1 EP1274436 A1 EP 1274436A1 EP 01919656 A EP01919656 A EP 01919656A EP 01919656 A EP01919656 A EP 01919656A EP 1274436 A1 EP1274436 A1 EP 1274436A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical formulation
pharmaceutically acceptable
rofleponide
formoterol
solvate
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.)
Withdrawn
Application number
EP01919656A
Other languages
German (de)
English (en)
Inventor
Brian Charles GlaxoSmithKline GAVIN
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
Publication of EP1274436A1 publication Critical patent/EP1274436A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—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
    • 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
    • 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
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention is concerned with combinations of (R,R)-formoterol and rofleponide, particularly compositions containing a combination of (R,R)- formoterol and rofleponide and the use of such compositions in medicine, particularly in the prophylaxis and treatment of respiratory diseases.
  • Formoterol i.e. 2'-hydroxy-5'-[(RS)-1 -hydroxy-2 ⁇ [(RS)-p-methoxy- ⁇ - methylphenethyl]amino ⁇ ethyl]formanilide, particularly its fumarate salt is a well- known adrenoreceptor agonist which is now used clinically in the treatment of bronchial asthma and related disorders.
  • .Formoterol includes two asymmetric centres and in a particular form exists as the (R,R)- isomer.
  • the (R,R) isomer of formoterol has been described previously, for example, in WO98/21175 and US5795564.
  • WO 92/13872 describes rofleponide i.e. 16 ⁇ ,17 ⁇ -butylidenedioxy-6 ,9 ⁇ - difluoro-11 ⁇ ,21-dihydroxypregn-4-ene-3,20-dione, salts and esters thereof and pharmaceutical formulations thereof.
  • Rofleponide is an antiinflammatory corticosteroid, which is proposed for use in the treatment of bronchial asthma and related disorders.
  • WO 99/00134 describes combinations of formoterol and rofleponide but is silent as to the utility of (R,R)-formoterol.
  • a combination of (R,R)-formoterol or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof and rofleponide or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof may be administered simultaneously, either in the same or different pharmaceutical formulations or sequentially. If there is sequential administration, the delay in administering the second compound should not be such as to lose the beneficial therapeutic effect of the combination.
  • a pharmaceutical formulation comprising (R,R)-formoterol or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof and rofleponide or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and . a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients.
  • a pharmaceutical formulation comprising (R,R)-formoterol fumarate and rofleponide palmitate, and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients.
  • the above pharmaceutical formulations are suitable for administration by inhalation.
  • rofleponide contains several asymmetric centres.
  • the present invention includes each isomer of rofleponide, particularly the (22R) and (22S) isomers, either in substantially pure form or admixed in any proportions.
  • the isomers of rofleponide have been described previously in WO 92/13872.
  • physiologically functional derivative a chemical derivative of (R,R)-formoterol or rofleponide having the same physiological function as the free compound, for example, by being convertible in the body thereto.
  • physiologically functional derivatives include esters.
  • Suitable salts according to the invention include those formed with both organic and inorganic acids.
  • Pharmaceutically acceptable acid addition salts include but are not limited to those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, oxalic, fumaric, maleic, oxaloacetic, methanesulphonic, ethanesulphonic, p- toluenesulphonic, benzenesulphonic, isethionic, and naphthalenecarboxylic, such as 1-hydroxy-2-naphthalenecarboxylic acids.
  • esters of (R,R)-formoterol or rofleponide may have a hydroxyl group converted to a C ⁇ - 6 alkyl, aryl, aryl C ⁇ . 6 alkyl, or amino acid ester.
  • the present invention provides a method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which a selective ⁇ 2 -adrenoreceptor agonist and/or antiinflammatory corticosteroid is indicated, which comprises administration of a therapeutically effective amount of a combination of (R,R)-formoterol or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof and rofleponide or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
  • the present invention further provides a method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which a selective ⁇ 2 -adrenoreceptor agonist and/or antiinflammatory corticosteroid is indicated, which comprises administration of a therapeutically effective amount of a pharmaceutical formulation comprising (R,R)-formoterol or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof and rofleponide or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical formulation comprising (R,R)-formoterol or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof and rofleponide or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier or excipient.
  • a method which comprises administration of a therapeutically effective amount of a pharmaceutical formulation comprising (R,R)-formoterol fumarate and rofleponide palmitate, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical formulation comprising (R,R)-formoterol fumarate and rofleponide palmitate, and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides such methods for the prophylaxis or treatment of a disease associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease.
  • COPD chronic obstructive pulmonary disease
  • a pharmaceutical formulation comprising (R,R)- formoterol or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof (suitably, (R,R)-formoterol fumarate) and rofleponide or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof (suitably, rofleponide palmitate), and a pharmaceutically acceptable carrier or excipient for use in therapy, particularly for use in the prophylaxis or treatment of a clinical condition for which a selective ⁇ 2 - adrenoreceptor agonist and/or antiinflammatory corticosteroid is indicated.
  • the invention is concerned with the prophylaxis or treatment of a disease associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease.
  • COPD chronic obstructive pulmonary disease
  • (R,R)-formoterol and rofleponide or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, and the particular disorder or disease being treated.
  • (R,R)-formoterol fumarate is generally administered to adult humans by aerosol inhalation at a dose of 12mcg or 24mcg twice daily.
  • rofleponide is described in WO 92/13872 as being administered to adult humans by aerosol inhalation at a dose of from 10mcg to lOOOmcg, preferably 20mcg to 250mcg.
  • the active ingredients of the combination While it is possible for the active ingredients of the combination to be administered as the raw chemical, it is preferable to present them as a pharmaceutical formulation.
  • the individual compounds of the combination When the individual compounds of the combination are administered separately, they are generally each presented as a pharmaceutical formulation as described previously in the art.
  • Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient's supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in traditional prescriptions.
  • the inclusion of a package insert has been shown to improve patient compliance with the physician's instructions and, therefore, lead generally to more successful treatment. It will be understood that the administration of the combination of the invention by means of a single patient pack, or patient packs of each component compound, and containing a package insert instructing the patient to the correct use of the invention is a desirable additional feature of the invention.
  • active ingredients means (R,R)-formoterol or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, preferably (R,R)-formoterol fumarate, and rofleponide, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, preferably rofleponide palmitate.
  • the pharmaceutical formulations which are suitable for inhalation according to the invention comprise the active ingredients in amounts such that each actuation provides therapeutically effective dose, for example, a dose of (R,R)-formoterol of 10mcg to 150mcg, preferably 24mcg and a dose of rofleponide of 10mcg to 1.6mg, preferably 20mcg to 250mcg.
  • the pharmaceutical formulations according to the invention may further include other therapeutic agents for example anti-inflammatory agents such as other corticosteroids (e.g.
  • fluticasone propionate beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide or budesonide) or NSAIDs (e.g. sodium cromoglycate, nedocromil sodium, PDE-4 inhibitors, leukotriene antagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine 2a agonists), or other ⁇ 2 -adrenoreceptor agonists (such as salbutamol, salmeterol, fenoterol or terbutaline and salts thereof), or anticholinergic agents (such as ipratropium, or tiotropium).
  • NSAIDs e.g. sodium cromoglycate, nedocromil sodium, PDE-4 inhibitors, leukotriene antagonists, iNOS inhibitors, tryptase and elastas
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), intranasal, inhalation (including fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulisers or insufflators), rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredients 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 ingredients with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations for inhalation include powder compositions which will preferably contain lactose, and spray compositions which may be formulated, for example, as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1 ,1,1,2,3,3,3- heptafluoropropane, 1,1 ,1 ,2-tetrafluoroethane, carbon dioxide or other suitable gas.
  • Suitable aerosol formulations include those described in EP 0372777 and WO93/11743.
  • the active ingredients should be micronised so as to permit inhalation of substantially all of the active ingredients into the lungs upon administration of the aerosol formulation, thus the active ingredients will have a particle size of less than 100 microns, desirably less than 20 microns, and preferably in the range 1 to 10 microns, for example, 1 to 5 microns.
  • 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.
  • agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants.
  • Capsules and cartridges or for example gelatin, or blisters of for example laminated aluminium foil, for,use in an inhaler or insuflator may be formulated containing a powder mix of the active ingredients and a suitable powder base such as lactose or starch.
  • the active ingredients are suitably micronised so as to permit inhalation of substantially all of the active ingredients into the lungs upon administration of the dry powder formulation, thus the active ingredients will have a particle size of less than 100 microns, desirably less than 20 microns, and preferably in the range 1 to 10 microns.
  • Solutions for inhalation by nebulation 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 sterilised by filtration or heating in an autoclave, or presented as a non-sterile product.
  • Preferred unit dosage formulations are those containing a pharmaceutically effective dose, as hereinbefore recited, or an appropriate fraction thereof, of the active ingredient.
  • a pharmaceutically effective dose as hereinbefore recited, or an appropriate fraction thereof, of the active ingredient.
  • one actuation of the aerosol may deliver half of the therapeutically effective amount such that two actuations are necessary to deliver the therapeutically effective dose.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question.
  • claimed formulations include bioequivalents as defined by the US Food and Drugs Agency.
  • micronised active ingredients are weighed into an aluminium can, 1 ,1,1,2- tetrafluoroethane is then added from a vacuum flask and a metering valve is crimped into place.
  • the active ingredients are micronised and bulk blended with the lactose in the proportions given above.
  • the blend is filled into hard gelatin capsules or cartridges or in specifically constructed double foil blister packs to be administered by an inhaler such as a Rotahaler, Diskhaler, or Diskus inhaler (each of these being a Trademark of Glaxo Group Limited).

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

Abstract

L'invention concerne des formulations pharmaceutiques comprenant une combinaison de (R,R)-formotérol et de rofléponide, ainsi que leur utilisation en médecine, notamment en matière de prophylaxie et de traitement de troubles respiratoires.
EP01919656A 2000-04-18 2001-04-11 Compositions medicales comprenant du (r,r)-formoterol et du rofleponide Withdrawn EP1274436A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB0009607.3A GB0009607D0 (en) 2000-04-18 2000-04-18 Medical compositions
GB0009607 2000-04-18
PCT/GB2001/001629 WO2001078738A1 (fr) 2000-04-18 2001-04-11 Compositions medicales comprenant du (r,r)-formoterol et du rofleponide

Publications (1)

Publication Number Publication Date
EP1274436A1 true EP1274436A1 (fr) 2003-01-15

Family

ID=9890187

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01919656A Withdrawn EP1274436A1 (fr) 2000-04-18 2001-04-11 Compositions medicales comprenant du (r,r)-formoterol et du rofleponide

Country Status (5)

Country Link
EP (1) EP1274436A1 (fr)
JP (1) JP2004500431A (fr)
AU (1) AU4671701A (fr)
GB (1) GB0009607D0 (fr)
WO (1) WO2001078738A1 (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0012260D0 (en) * 2000-05-19 2000-07-12 Astrazeneca Ab Novel composition
FI20002216A0 (fi) * 2000-10-06 2000-10-06 Orion Yhtymae Oyj Yhdistelmäpartikkelit astman hoitoon
DE10130371A1 (de) * 2001-06-23 2003-01-02 Boehringer Ingelheim Pharma Neue Arzneimittelkompositionen auf der Basis von Anticholinergika, Corticosteroiden und Betamimetika
WO2004052374A1 (fr) 2002-12-12 2004-06-24 Altana Pharma Ag Medicament combine
AU2004246819A1 (en) * 2003-06-13 2004-12-23 Nycomed Gmbh Formoterol and ciclesonide combination
WO2005025578A1 (fr) 2003-09-16 2005-03-24 Altana Pharma Ag Utilisation de ciclesonide dans le traitement de maladies respiratoires
CA2580019A1 (fr) * 2004-09-09 2006-03-16 Cipla Limited Composition pharmaceutique comportant un isomere d'un agent betamimetique et un agent anticholinergique

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9100341D0 (sv) * 1991-02-04 1991-02-04 Astra Ab Novel steroids
US5795564A (en) * 1991-04-05 1998-08-18 Sepracor, Inc. Methods and compositions for treating pulmonary disorders using optically pure (R,R)-formoterol
CA2271004C (fr) * 1996-11-11 2007-05-01 Sepracor Inc. Procede de preparation d'isomeres de formoterol optiquement purs
CA2295076A1 (fr) * 1997-06-27 1999-01-07 Astra Aktiebolag Nouvelle combinaison de medicaments antiasthmatiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0178738A1 *

Also Published As

Publication number Publication date
JP2004500431A (ja) 2004-01-08
AU4671701A (en) 2001-10-30
GB0009607D0 (en) 2000-06-07
WO2001078738A1 (fr) 2001-10-25

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