[go: up one dir, main page]

WO2001032166A1 - NEW COMBINATION COMPRISING A β2-ADRENORECEPTOR AGONIST AND A LEUKOTRIENE RECEPTOR ANTAGONIST - Google Patents

NEW COMBINATION COMPRISING A β2-ADRENORECEPTOR AGONIST AND A LEUKOTRIENE RECEPTOR ANTAGONIST Download PDF

Info

Publication number
WO2001032166A1
WO2001032166A1 PCT/SE2000/002116 SE0002116W WO0132166A1 WO 2001032166 A1 WO2001032166 A1 WO 2001032166A1 SE 0002116 W SE0002116 W SE 0002116W WO 0132166 A1 WO0132166 A1 WO 0132166A1
Authority
WO
WIPO (PCT)
Prior art keywords
active ingredient
pharmaceutically acceptable
bambuterol
receptor antagonist
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.)
Ceased
Application number
PCT/SE2000/002116
Other languages
French (fr)
Inventor
Jan Trofast
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 AB
Original Assignee
AstraZeneca AB
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 AB filed Critical AstraZeneca AB
Priority to AU16526/01A priority Critical patent/AU1652601A/en
Publication of WO2001032166A1 publication Critical patent/WO2001032166A1/en
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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to combinations of pharmaceutically active substances for use in the treatment of inflammatory conditions/disorders, especially respiratory diseases.
  • glucocorticosteroid therapy has been found to be highly effective in the management of asthma, glucocorticosteroids have broad and nonspecific actions and, when taken orally, can produce serious side-effects.
  • Inhaled glucocorticosteroids are much less likely to cause serious side-effects but may still be of concern to some patients.
  • glucocorticosteroids there are factors which can mitigate against the use of inhalers and, in terms of patient drug compliance, s oral administration is generally the favoured route in medical practice.
  • a pharmaceutical composition comprising, in admixture, a first active ingredient which is a beta2 ( ⁇ 2) 5 adrenoreceptor agonist selected from bambuterol and pharmaceutically acceptable derivatives thereof, and a second active ingredient which is a leukotriene receptor antagonist.
  • a pharmaceutically o acceptable derivative of bambuterol means a pharmaceutically acceptable salt or solvate of bambuterol (e.g. bambuterol hydrochloride) or a pharmaceutically acceptable solvate of such a salt.
  • Examples of pharmaceutically acceptable salts include acid addition salts derived from inorganic and organic acids such as a chloride, bromide, sulphate, phosphate, maleate, fumarate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulphonate, methanesulphonate, ascorbate, acetate, succinate, lactate, glutarate, gluconate, tricarballylate, hydroxynaphthalene-carboxylate or oleate salt.
  • Examples of pharmaceutically acceptable solvates include hydrates.
  • the invention also provides a pharmaceutical product comprising, in combination, a preparation of a first active ingredient which is a beta2 ( ⁇ 2) adrenoreceptor agonist selected from bambuterol and pharmaceutically acceptable derivatives thereof, and a preparation of a second active ingredient which is a leukotriene receptor antagonist, for simultaneous, sequential or separate use in therapy.
  • a pharmaceutical product comprising, in combination, a preparation of a first active ingredient which is a beta2 ( ⁇ 2) adrenoreceptor agonist selected from bambuterol and pharmaceutically acceptable derivatives thereof, and a preparation of a second active ingredient which is a leukotriene receptor antagonist, for simultaneous, sequential or separate use in therapy.
  • the invention provides a kit comprising a preparation of a first active ingredient which is a beta2 2) adrenoreceptor agonist selected from bambuterol and pharmaceutically acceptable derivatives thereof, a preparation of a second active ingredient which is a leukotriene receptor antagonist, and instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
  • a preparation of a first active ingredient which is a beta2 2) adrenoreceptor agonist selected from bambuterol and pharmaceutically acceptable derivatives thereof
  • a preparation of a second active ingredient which is a leukotriene receptor antagonist and instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
  • 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); rhinitis and rheumatic arthritis.
  • leukotriene receptor antagonists as second active ingredient include: zafirlukast, pranlukast, pobilukast, montelukast (sodium), verlukast, tomelukast, iralukast, L-648,051 (see article by D.J. Tocco et al, Drug Metab. Dispos., 1988, 16(5), 697-700), MK-571 (see article by T.R. Jones et al, Can. J.
  • BI-L-284 a compound proprietary to Boehringer Ingelheim
  • pharmaceutically acceptable derivatives in this context is intended to mean a pharmaceutically acceptable ester, salt or solvate or a pharmaceutically acceptable solvate of such an ester or salt.
  • esters examples include lower alkyl (Cj-Cg alkyl) esters.
  • Pharmaceutically acceptable salts include, where applicable, acid addition salts derived from pharmaceutically acceptable inorganic and organic acids such as a chloride, bromide, sulphate, phosphate, maleate, fumarate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulphonate, methanesulphonate, ascorbate, acetate, succinate, lactate, glutarate, gluconate, tricarballylate, hydroxynaphthalene-carboxylate or oleate salt; and salts prepared from pharmaceutically acceptable inorganic and organic bases.
  • acid addition salts derived from pharmaceutically acceptable inorganic and organic acids such as a chloride, bromide, sulphate, phosphate, maleate, fumarate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p-
  • Salts derived from inorganic bases include aluminium, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and bismuth salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, cyclic amines like arginine, betaine, choline and the like.
  • Examples of pharmaceutically acceptable solvates include hydrates.
  • Certain of the active ingredients used in the present invention are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the active ingredients and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
  • Preferred combinations of first and second active ingredients include bambuterol/zafirlukast, bambuterol/montelukast sodium, bambuterol/pranlukast, bambuterol hydrochloride/zafirlukast, bambuterol hydrochloride/montelukast sodium and bambuterol hydrochloride/pranlukast.
  • the pharmaceutical composition of the invention may be prepared by mixing the first active ingredient with the second active ingredient. Therefore, in a further aspect of the present invention, there is provided a process for the preparation of a pharmaceutical composition which comprises mixing a first active ingredient which is a beta2 ( ⁇ 2) adrenoreceptor agonist selected from bambuterol and pharmaceutically acceptable derivatives thereof, with a second active ingredient which is a leukotriene receptor antagonist.
  • a first active ingredient which is a beta2 ( ⁇ 2) adrenoreceptor agonist selected from bambuterol and pharmaceutically acceptable derivatives thereof.
  • the first and second active ingredients may alternatively be administered simultaneously (other than in admixture as described above), sequentially or separately to treat inflammatory conditions.
  • 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 employed, the mode of administration, the treatment desired and the disorder indicated.
  • satisfactory results will be obtained when the total daily oral dosage of first active ingredient(s) is in the range from 1 to 50 mg, particularly from 1, 2, 3, 4 or 5 to 40, preferably to 30, more preferably to 20 mg, and the total daily oral dosage of second active ingredient(s) is in the range from 1 to 200 mg, preferably from 1, 5 or 10 to 150, more preferably to 100, even more preferably to 80 or 50 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 are conveniently administered 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.
  • 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.
  • 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 inflammatory disorder.
  • the present invention provides a method of treating an inflammatory disorder which comprises administering a therapeutically effective amount of a pharmaceutical composition of the invention to a patient in need thereof.
  • the present invention provides a method of treating an inflammatory disorder which comprises simultaneously, sequentially or separately administering: (a) a (therapeutically effective) dose of a first active ingredient which is a beta2 ( ⁇ 2) adrenoreceptor agonist selected from bambuterol and pharmaceutically acceptable derivatives thereof; and
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question.
  • Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Otolaryngology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention provides a pharmaceutical composition, pharmaceutical product or kit comprising a first active ingredient which is a beta2 (β2) adrenoreceptor agonist and a second active ingredient which is a leukotriene receptor antagonist, for use in the treatment of inflammatory disorders.

Description

NEW COMBINAΗON COMPRISING A βj- ADRENORECEPTOR AGONIST AND A LEUKOTRIENE RECEPTOR
ANTAGONIST
The present invention relates to combinations of pharmaceutically active substances for use in the treatment of inflammatory conditions/disorders, especially respiratory diseases.
There are many different inflammatory mediators implicated in the pathogenesis of respiratory diseases such as asthma. However, drugs that are used to treat respiratory diseases are not always very selective for the pathological features of these diseases. Thus, whilst glucocorticosteroid therapy has been found to be highly effective in the management of asthma, glucocorticosteroids have broad and nonspecific actions and, when taken orally, can produce serious side-effects. Inhaled glucocorticosteroids, on the other hand, are much less likely to cause serious side-effects but may still be of concern to some patients. Despite the advantages of inhaled (versus oral) glucocorticosteroids, there are factors which can mitigate against the use of inhalers and, in terms of patient drug compliance, s oral administration is generally the favoured route in medical practice.
In view of the complexity of respiratory diseases like asthma, it is unlikely that any one mediator can satisfactorily treat the disease alone.
o Thus, it would be desirable to develop new pharmaceuticals which can provide a more effective treatment of inflammatory conditions.
In accordance with the present invention, there is therefore provided a pharmaceutical composition comprising, in admixture, a first active ingredient which is a beta2 (β2) 5 adrenoreceptor agonist selected from bambuterol and pharmaceutically acceptable derivatives thereof, and a second active ingredient which is a leukotriene receptor antagonist.
In the context of the present specification, unless otherwise stated, a pharmaceutically o acceptable derivative of bambuterol means a pharmaceutically acceptable salt or solvate of bambuterol (e.g. bambuterol hydrochloride) or a pharmaceutically acceptable solvate of such a salt. Examples of pharmaceutically acceptable salts include acid addition salts derived from inorganic and organic acids such as a chloride, bromide, sulphate, phosphate, maleate, fumarate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulphonate, methanesulphonate, ascorbate, acetate, succinate, lactate, glutarate, gluconate, tricarballylate, hydroxynaphthalene-carboxylate or oleate salt. Examples of pharmaceutically acceptable solvates include hydrates.
The invention also provides a pharmaceutical product comprising, in combination, a preparation of a first active ingredient which is a beta2 (β2) adrenoreceptor agonist selected from bambuterol and pharmaceutically acceptable derivatives thereof, and a preparation of a second active ingredient which is a leukotriene receptor antagonist, for simultaneous, sequential or separate use in therapy.
In another aspect, the invention provides a kit comprising a preparation of a first active ingredient which is a beta2 2) adrenoreceptor agonist selected from bambuterol and pharmaceutically acceptable derivatives thereof, a preparation of a second active ingredient which is a leukotriene receptor antagonist, and instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
It has been found that the choice of active ingredients according to the invention is advantageous because it results in a beneficial anti-inflammatory and bronchodilator effect and, accordingly, can be used to treat various acute and chronic inflammatory conditions/disorders such as chronic obstructive pulmonary disease (COPD); asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness); rhinitis and rheumatic arthritis.
Another advantage is that the active ingredients may be conveniently formulated for oral administration thereby facilitating patient drug compliance. Examples of leukotriene receptor antagonists as second active ingredient include: zafirlukast, pranlukast, pobilukast, montelukast (sodium), verlukast, tomelukast, iralukast, L-648,051 (see article by D.J. Tocco et al, Drug Metab. Dispos., 1988, 16(5), 697-700), MK-571 (see article by T.R. Jones et al, Can. J. Physiol Pharmacol, 1991, 69(12), 1847-1854), BI-L-284 (a compound proprietary to Boehringer Ingelheim) and their pharmaceutically acceptable derivatives. The term 'pharmaceutically acceptable derivative' in this context is intended to mean a pharmaceutically acceptable ester, salt or solvate or a pharmaceutically acceptable solvate of such an ester or salt.
Examples of suitable esters include lower alkyl (Cj-Cg alkyl) esters.
Pharmaceutically acceptable salts include, where applicable, acid addition salts derived from pharmaceutically acceptable inorganic and organic acids such as a chloride, bromide, sulphate, phosphate, maleate, fumarate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulphonate, methanesulphonate, ascorbate, acetate, succinate, lactate, glutarate, gluconate, tricarballylate, hydroxynaphthalene-carboxylate or oleate salt; and salts prepared from pharmaceutically acceptable inorganic and organic bases. Salts derived from inorganic bases include aluminium, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and bismuth salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, cyclic amines like arginine, betaine, choline and the like.
Examples of pharmaceutically acceptable solvates include hydrates.
Methods of assaying compounds for leukotriene receptor antagonist activity are known in the art, for example, as described in European Patent No. 199 543 and in the articles by M.S. Malamas et al, J. Med. Chem., 1996, 39, 237-245, by S. Charleson et al, Mol Pharmacol, 1992, 41.(5), 873-879, and by F J. Sweeney et al, Prostaglandins Leukot. Med., 1987, 28(1), 73-93.
Certain of the active ingredients used in the present invention are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the active ingredients and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
Preferred combinations of first and second active ingredients include bambuterol/zafirlukast, bambuterol/montelukast sodium, bambuterol/pranlukast, bambuterol hydrochloride/zafirlukast, bambuterol hydrochloride/montelukast sodium and bambuterol hydrochloride/pranlukast.
The pharmaceutical composition of the invention may be prepared by mixing the first active ingredient with the second active ingredient. Therefore, in a further aspect of the present invention, there is provided a process for the preparation of a pharmaceutical composition which comprises mixing a first active ingredient which is a beta2 (β2) adrenoreceptor agonist selected from bambuterol and pharmaceutically acceptable derivatives thereof, with a second active ingredient which is a leukotriene receptor antagonist.
The first and second active ingredients may alternatively be administered simultaneously (other than in admixture as described above), sequentially or separately to treat inflammatory conditions. By 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.
For the above-mentioned therapeutic uses the dosages administered will, of course, vary with the first and second active ingredients employed, the mode of administration, the treatment desired and the disorder indicated. However, in general, satisfactory results will be obtained when the total daily oral dosage of first active ingredient(s) is in the range from 1 to 50 mg, particularly from 1, 2, 3, 4 or 5 to 40, preferably to 30, more preferably to 20 mg, and the total daily oral dosage of second active ingredient(s) is in the range from 1 to 200 mg, preferably from 1, 5 or 10 to 150, more preferably to 100, even more preferably to 80 or 50 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 are conveniently administered 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.
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.
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 inflammatory disorder.
Also, the present invention provides a method of treating an inflammatory disorder which comprises administering a therapeutically effective amount of a pharmaceutical composition of the invention to a patient in need thereof.
Still further, the present invention provides a method of treating an inflammatory disorder which comprises simultaneously, sequentially or separately administering: (a) a (therapeutically effective) dose of a first active ingredient which is a beta2 (β2) adrenoreceptor agonist selected from bambuterol and pharmaceutically acceptable derivatives thereof; and
(b) a (therapeutically effective) dose of a second active ingredient which is a leukotriene receptor antagonist, to a patient in need thereof.
In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.
Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
The present invention will now be further understood by reference to the following illustrative examples. The examples describe how certain pharmaceutical compositions can be prepared in tablet form for oral administration.
Example 1
Bambuterol hydrochloride 10 mg
Zafirlukast 10 mg
Lactose monohydrate 125 mg
Maize starch 78 mg
Polyvinylpyrrolidone 6.7 mg
("Polyvidone K25")
Microcrystalline cellulose 13 mg
Magnesium stearate 0.8 mg
Example 2
Bambuterol hydrochloride 20 mg
Zafirlukast 10 mg
Lactose monohydrate 125 mg
Maize starch 78 mg
Polyvinylpyrrolidone 6.7 mg
("Polyvidone K25")
Microcrystalline cellulose 13 mg
Magnesium stearate 0.8 mg Example 3
Bambuterol hydrochloride 10 mg
Montelukast sodium 5.2 mg
Lactose monohydrate 63 mg
Maize starch 39 mg
Polyvinylpyrrolidone 3.3 mg
("Polyvidone K25")
Microcrystalline cellulose 6.7 mg
Magnesium stearate 0.4 mg
Example 4
Bambuterol hydrochloride 20 mg
Montelukast sodium 5.2 mg
Lactose monohydrate 125 mg
Maize starch 78 mg
Polyvinylpyrrolidone 6.7 mg
("Polyvidone K25")
Microcrystalline cellulose 13 mg
Magnesium stearate 0.8 mg
Example 5
Bambuterol hydrochloride 10 mg
Montelukast sodium 10.4 mg
Lactose monohydrate 125 mg
Maize starch 78 mg
Polyvinylpyrrolidone 6.7 mg
("Polyvidone K25")
Microcrystalline cellulose 13 mg
Magnesium stearate 0.8 mg

Claims

C L A I M S
1. A pharmaceutical composition comprising, in admixture, a first active ingredient which is a beta2 (β2) adrenoreceptor agonist selected from bambuterol and pharmaceutically acceptable derivatives thereof, and a second active ingredient which is a leukotriene receptor antagonist.
2. A composition according to claim 1 , wherein the first or second active ingredient is in the form of a pharmaceutically acceptable salt, solvate or solvate of a salt.
3. A composition according to claim 1 or claim 2, wherein the first active ingredient is bambuterol hydrochloride.
4. A composition according to claim 1, wherein the second active ingredient is zafirlukast.
5. A composition according to claim 1, wherein the second active ingredient is montelukast sodium.
6. A composition according to any one of claims 1 to 5 which is formulated for oral administration.
7. Use of a composition according to claim 1 in the manufacture of a medicament for the treatment of an inflammatory disorder.
8. A process for the preparation of a pharmaceutical composition as defined in claim 1 which comprises mixing the first active ingredient with the second active ingredient.
9. A method of treating an inflammatory disorder which comprises administering a therapeutically effective amount of a pharmaceutical composition as defined in claim 1 to a patient in need thereof.
10. A method according to claim 9, wherein the inflammatory disorder is asthma or chronic obstructive pulmonary disease.
11. A pharmaceutical product comprising, in combination, a preparation of a first active ingredient which is a beta2 (β2) adrenoreceptor agonist selected from bambuterol and pharmaceutically acceptable derivatives thereof, and a preparation of a second active ingredient which is a leukotriene receptor antagonist, for simultaneous, sequential or separate use in therapy.
12. A product according to claim 11, wherein the first or second active ingredient is in the form of a pharmaceutically acceptable salt, solvate or solvate of a salt.
13. A product according to claim 11 or claim 12, wherein the first active ingredient is bambuterol hydrochloride.
14. A product according to claim 11, wherein the second active ingredient is zafirlukast.
15. A product according to claim 11, wherein the second active ingredient is montelukast sodium.
16. Use of a product according to claim 11 in the manufacture of a medicament for the treatment of an inflammatory disorder.
17. A kit comprising a preparation of a first active ingredient which is a beta2 ( _) adrenoreceptor agonist selected from bambuterol and pharmaceutically acceptable derivatives thereof, a preparation of a second active ingredient which is a leukotriene receptor antagonist, and instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
18. A kit according to claim 17, wherein the first or second active ingredient is in the form of a pharmaceutically acceptable salt, solvate or solvate of a salt.
19. A kit according to claim 17 or claim 18, wherein the first active ingredient is bambuterol hydrochloride.
20. A kit according to claim 17, wherein the second active ingredient is zafirlukast.
21. A kit according to claim 17, wherein the second active ingredient is montelukast sodium.
22. Use of a kit according to claim 17 in the manufacture of a medicament for the treatment of an inflammatory disorder.
23. A method of treating an inflammatory disorder which comprises simultaneously, sequentially or separately administering: (a) a dose of a first active ingredient which is a beta2 (β_) adrenoreceptor agonist selected from bambuterol and pharmaceutically acceptable derivatives thereof; and (b) a dose of a second active ingredient which is a leukotriene receptor antagonist, to a patient in need thereof.
PCT/SE2000/002116 1999-11-03 2000-10-27 NEW COMBINATION COMPRISING A β2-ADRENORECEPTOR AGONIST AND A LEUKOTRIENE RECEPTOR ANTAGONIST Ceased WO2001032166A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU16526/01A AU1652601A (en) 1999-11-03 2000-10-27 New combination comprising a beta2-adrenoreceptor agonist and a leukotriene receptor antagonist

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9903995A SE9903995D0 (en) 1999-11-03 1999-11-03 New combination
SE9903995-0 1999-11-03

Publications (1)

Publication Number Publication Date
WO2001032166A1 true WO2001032166A1 (en) 2001-05-10

Family

ID=20417605

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/SE2000/002116 Ceased WO2001032166A1 (en) 1999-11-03 2000-10-27 NEW COMBINATION COMPRISING A β2-ADRENORECEPTOR AGONIST AND A LEUKOTRIENE RECEPTOR ANTAGONIST
PCT/SE2000/002115 Ceased WO2001032163A1 (en) 1999-11-03 2000-10-27 NEW COMBINATION COMPRISING A BETA 2 (β)2 ADRENO RECEPTOR AGONIST AND A LENKOTRIENE RECEPTOR ANTAGONIST

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/SE2000/002115 Ceased WO2001032163A1 (en) 1999-11-03 2000-10-27 NEW COMBINATION COMPRISING A BETA 2 (β)2 ADRENO RECEPTOR AGONIST AND A LENKOTRIENE RECEPTOR ANTAGONIST

Country Status (13)

Country Link
EP (1) EP1242065A1 (en)
JP (1) JP2003513037A (en)
KR (1) KR20020050254A (en)
CN (1) CN1387431A (en)
AU (2) AU1321401A (en)
BR (1) BR0015172A (en)
CA (1) CA2388657A1 (en)
IL (1) IL149365A0 (en)
MX (1) MXPA02004334A (en)
NO (1) NO20022103D0 (en)
SE (1) SE9903995D0 (en)
WO (2) WO2001032166A1 (en)
ZA (1) ZA200203178B (en)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030055026A1 (en) 2001-04-17 2003-03-20 Dey L.P. Formoterol/steroid bronchodilating compositions and methods of use thereof
US6667344B2 (en) 2001-04-17 2003-12-23 Dey, L.P. Bronchodilating compositions and methods
AR040962A1 (en) * 2002-08-09 2005-04-27 Novartis Ag COMPOUNDS DERIVED FROM TIAZOL 1,3-2-ONA, PHARMACEUTICAL COMPOSITION AND COMPOSITE PREPARATION PROCESS
GB0312148D0 (en) 2003-05-28 2003-07-02 Aventis Pharma Ltd Stabilized pharmaceutical products
GB0315889D0 (en) 2003-07-08 2003-08-13 Aventis Pharma Ltd Stable pharmaceutical products
TWI359675B (en) 2003-07-10 2012-03-11 Dey L P Bronchodilating β-agonist compositions
JP2007531743A (en) * 2004-04-05 2007-11-08 セプラコア インコーポレーテッド (R, R) -formoterol in combination with other drugs
ES2245612B1 (en) * 2004-06-29 2007-08-16 Universidad De Barcelona NEW THERAPEUTIC USE OF FORMOTEROL.
CN101128196B (en) * 2005-03-16 2013-01-02 Meda制药有限及两合公司 Combination of anticholinergics and leukotriene receptor antagonists for the treatment of respiratory diseases
JP2014518203A (en) * 2011-06-06 2014-07-28 キエスィ ファルマチェウティチ エス．ピー．エー． 1-Phenyl-2-pyridinylalkyl alcohol derivatives as phosphodiesterase inhibitors
AR093796A1 (en) * 2012-12-05 2015-06-24 Chiesi Farm Spa ALCOHOL DERIVATIVES 1-PHENYL-2-PIRIDINIL ALQUILICO AS INHIBITORS OF PHOSPHODIESTERASE
JP5846185B2 (en) 2013-11-21 2016-01-20 大日本印刷株式会社 Through electrode substrate and semiconductor device using the through electrode substrate
PT109030B (en) * 2015-12-15 2019-09-25 Hovione Farmaciência, S.A. PREPARATION OF ZAFIRLUCAST INHALABLE PARTICULES

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998027981A1 (en) * 1996-12-20 1998-07-02 Astra Aktiebolag (Publ) An aqueous formulation comprising bambuterol and the use thereof
WO1998039970A1 (en) * 1997-03-13 1998-09-17 Merck & Co., Inc. Quinoline leukotriene antagonists

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9704644D0 (en) * 1997-12-12 1997-12-12 Astra Ab New use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998027981A1 (en) * 1996-12-20 1998-07-02 Astra Aktiebolag (Publ) An aqueous formulation comprising bambuterol and the use thereof
WO1998039970A1 (en) * 1997-03-13 1998-09-17 Merck & Co., Inc. Quinoline leukotriene antagonists

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BRIAN J. LIPWORTH ET AL.: "Effects of adding a leukotriene antagonist or a long-acting beta2-agonist in asthmatic patients with the glycine-16 beta2-adrenoceptor genotype", AM. J. MED., vol. 109, 2000, pages 114 - 121 *
JEAN-FRANCOIS DESSANGES ET AL.: "The effect of zafirlukast on repetitive exercise-induced bronchoconstriction: The possible role of leukotrienes in exercise-induced refractoriness", J. ALLERGY CLIN. IMMUNOL., vol. 104, no. 6, 1999, pages 1155 - 1161 *
JONATHAN A. LEFF ET AL.: "Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction", N. ENGL. J. MED., vol. 339, no. 3, 1998, pages 147 - 152 *
OWEN J. DEMPSEY ET AL.: "Additive bronchoprotective and bronchodilator effects with single doses of salmeterol and montelukast in asthmatic patients receiving inhaled corticosteroids", CHEST, vol. 117, 2000, pages 950 - 953 *

Also Published As

Publication number Publication date
NO20022103L (en) 2002-05-02
BR0015172A (en) 2002-06-18
AU1321401A (en) 2001-05-14
MXPA02004334A (en) 2002-11-07
SE9903995D0 (en) 1999-11-03
ZA200203178B (en) 2003-07-22
KR20020050254A (en) 2002-06-26
AU1652601A (en) 2001-05-14
JP2003513037A (en) 2003-04-08
EP1242065A1 (en) 2002-09-25
NO20022103D0 (en) 2002-05-02
CN1387431A (en) 2002-12-25
WO2001032163A1 (en) 2001-05-10
IL149365A0 (en) 2002-11-10
CA2388657A1 (en) 2001-05-10

Similar Documents

Publication Publication Date Title
EP1603565B1 (en) Medicament comprising a highly potent long-lasting beta2-agonist in combination with other active ingredients
AU673660B2 (en) New combination of formoterol and budesonide
WO2001032166A1 (en) NEW COMBINATION COMPRISING A β2-ADRENORECEPTOR AGONIST AND A LEUKOTRIENE RECEPTOR ANTAGONIST
JP2002534380A (en) Treatment of asthma with MEK inhibitors
JP5208473B2 (en) Pharmaceutical composition containing azelastine and anticholinergic agent
EP1078629A2 (en) Use of Salmeterol and salts for the treatment of inflammation and allergy
JP2008509143A5 (en)
CA2575932A1 (en) Pharmaceutical formulations comprising pleconaril for the treatment of airway diseases
US5290815A (en) Treatment of inflammation and allergy
AU2005240404A1 (en) Treating respiratory diseases with gycopyrrolate and analogues
US20060110449A1 (en) Pharmaceutical composition
US20060189642A1 (en) Synergistic combination comprising roflumilast and an anticholinergic agent selected from ipratropium, oxitropium and tiotropium salts for the treatment of respiratory diseases
WO2004047829A1 (en) New synergistic combination comprising roflumilast and formoterol
JP5091474B2 (en) Pharmaceutical composition containing fudosteine and anticholinergic agent
KR20130140672A (en) Carbonate derivatives for the treatment of cough
WO2010071581A1 (en) Pharmaceutical product comprising a muscarinic receptor antagonist and a b2-adrenoceptor agonist
JP2016504358A (en) Methods and compositions for administering oxybutynin
JPH04226916A (en) Novel pharmaceutical uses of benzocycloheptathiophenecarboxylic acid derivatives
WO2007008157A1 (en) New combination 2
Boothe Plugs, bugs and drugs: treating the respiratory tract.
JP2007126441A (en) Pharmaceutical composition for inhibiting goblet cell hyperplasia
EP0526638A1 (en) Remedy for obstructive pulmonary disease

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP