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WO2002060532A1 - Compositions medicamenteuses contenant des betamimetiques et ayant des effets secondaires limites - Google Patents

Compositions medicamenteuses contenant des betamimetiques et ayant des effets secondaires limites Download PDF

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Publication number
WO2002060532A1
WO2002060532A1 PCT/EP2002/000674 EP0200674W WO02060532A1 WO 2002060532 A1 WO2002060532 A1 WO 2002060532A1 EP 0200674 W EP0200674 W EP 0200674W WO 02060532 A1 WO02060532 A1 WO 02060532A1
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WO
WIPO (PCT)
Prior art keywords
acid
inhalation
contain
betamimetics
salmeterol
Prior art date
Application number
PCT/EP2002/000674
Other languages
German (de)
English (en)
Inventor
Karl-Heinz Bozung
Michel Pairet
Richard Reichl
Alexander Walland
Original Assignee
Boehringer Ingelheim Pharma Gmbh & Co. Kg
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 Boehringer Ingelheim Pharma Gmbh & Co. Kg filed Critical Boehringer Ingelheim Pharma Gmbh & Co. Kg
Priority to EP02712840A priority Critical patent/EP1357975A1/fr
Priority to CA002434872A priority patent/CA2434872A1/fr
Priority to JP2002560721A priority patent/JP2004517942A/ja
Publication of WO2002060532A1 publication Critical patent/WO2002060532A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—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
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • 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
    • 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
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to novel pharmaceutical compositions based on long-acting beta2 agonists and ipratropium salts, processes for their preparation and their use in the therapy of respiratory diseases.
  • beta mimetics can be successfully used to treat obstructive airway diseases.
  • the long-acting betamimetics salmeterol and formoterol are particularly important. These compounds can be used effectively for the therapy of, for example, COPD or asthma.
  • Ipratropium salts 1 have the following chemical structure:
  • ipratropium bromide X stands for bromine.
  • This compound can also by the chemical name (e ⁇ o, syn) - ( ⁇ ) -3- (3-hydroxy-1-oxo-2-phenylpropoxy) - 8-methyl-8- (1-methylethyl) -8-azoniabicyclo [3.2.1] octane bromide.
  • ipratropium is to be understood in the context of the present invention as a reference to the free cation V.
  • ipratropium salts 1 are suitable for effectively counteracting the sometimes extremely threatening side effects caused by beta-mimetics 2. It has also been found that ipratropium salts are suitable for effectively counteracting the side effects caused by betamimetics 2, particularly particularly in the period shortly after their application. It has also been found that ipratropium salts 1 not only contribute to reducing the side effects which occur in particular shortly after the application of the betamimetics, but that they also significantly increase the therapeutic effect desired by the betamimetics 2 in a synergistic manner.
  • the present invention therefore relates to long-acting medicaments containing betamimetics 2, characterized in that they also contain ipratropium salts 1 in order to reduce the side effects caused by the application of the betamimetics.
  • the present invention further relates to long-acting medicaments containing betamimetics 2, characterized in that they further contain ipratropium salts 1 in order to reduce the side effects caused by the betamimetics in the period shortly after the application of the betamimetics 2.
  • the present invention further relates to long-acting drugs containing betamimetics 2, characterized in that they further contain ipratropium salts in a sufficiently high dose to reduce the side effects caused by the application of the betamimetics.
  • the present invention therefore relates to long-acting drugs containing betamimetics 2, characterized in that they also contain ipratropium salts ⁇ in order to reduce the side effects caused by the multiple daily, preferably twice daily application of the betamimetics.
  • the present invention further relates to long-acting pharmaceuticals containing betamimetics 2, characterized in that they further contain ipratropium salts 1 in order to reduce the side effects caused by the betamimetics in Reduce the period shortly after the multiple daily, preferably twice daily application of the betamimetics 2.
  • the present invention further relates to long-acting drugs containing betamimetics 2, characterized in that they also contain ipratropium salts in a sufficiently high dose to reduce the side effects caused by the more daily, preferably twice daily application of the betamimetics.
  • the active compounds can either be contained together in a single dosage form or in two separate dosage forms. According to the invention, preference is given to medicaments which contain the active ingredients 1 and 2 in a single dosage form.
  • salmeterol salts or formoterol salts are preferred as long-acting betamimetics 2.
  • betamimetics 2 includes a reference to the respective enantiomers or mixtures thereof.
  • the salts of salmeterol and formoterol accordingly includes the respective enantiomeric salts of R-salmeterol, S-salmeterol,?, R-formoterol, S, S-formomoterol, R, S-formoterol, S , R-formoterol and mixtures thereof, the enantiomeric salts of f? -Salmeterol and r?, F? -Formoterol being of particular importance.
  • the compounds 2 can also be present in the form of their hydrates or solvates.
  • physiologically acceptable acid addition salts of betamimetics 2 are understood to be pharmaceutically acceptable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, 1-hydroxy-2-acid or naphthalene Are maleic acid. If appropriate, mixtures of the abovementioned acids can also be used to prepare the salts 2.
  • the salts of betamimetics 2 are preferably selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, fumarate methanesulfonate and xinafoate.
  • the salts of 2 in the case of salmeterol are particularly preferably selected from hydrochloride, sulfate and xinafoate, of which the sulfates and xinafoates are particularly preferred.
  • Importance are salmeterol x 1/2 H2SO4 and salmeterol xinafoate.
  • the salts of 2 in the case of formoterol are particularly preferably selected from hydrochloride, sulfate and fumarate, of which the hydrochloride and fumarate are particularly preferred. According to the invention, formoterol fumarate is of outstanding importance.
  • beta mimetics not present in the salt form this can be recognized by a reference to compounds T_.
  • the preferred betamimetics T_ which are not in salt form are understood to mean the free base of formoterol or salmeterol, whereas the compounds 2 which are particularly preferred according to the invention are, for example, salmeterol xinafoate, salmeterol x V ⁇ H2SO4 or formoterol fumarate.
  • betamimetics 2 are also referred to as sympathomimetics or beta-2 agonists ( ⁇ 2 agonists). All of these terms are considered equivalent within the scope of the present invention.
  • ipratropium salts 1 which can be used in the context of the present invention are to be understood as meaning the compounds which, in addition to ipratropium, contain chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate or methyl sulfate as counterion (anion).
  • methanesulfonate, chloride, bromide or iodide are preferred in the context of the present invention, the methanesulfonate or bromide being of particular importance.
  • Ipratropium bromide is of outstanding importance according to the invention.
  • the term ipratropium is to be understood in the context of the present invention as a reference to the free cation V.
  • the medicaments according to the invention can contain 1_ in the form of its enantiomers, mixtures of the enantiomers or in the form of the racemates. If ⁇ is contained in the form of an enantiomer, preferred compounds ⁇ are preferred as enantiomers in which V is in the form of (et.do, syn) - (-) - 3- (3-hydroxy-1-oxo-2-phenylpropoxy ) -8-methyl-8- (1-methylethyl) -8-azoniabicyclo [3.2.1] octane is present.
  • One aspect of the present invention relates to the above-mentioned medicaments which, in addition to therapeutically effective amounts of and 2, contain a pharmaceutically acceptable carrier.
  • One aspect of the present invention relates the aforementioned medicinal products which, in addition to therapeutically effective amounts of and 2, contain no pharmaceutically acceptable carrier.
  • the present invention further relates to the use of therapeutically effective amounts of ipratropium salts I for the production of a long-acting medicament containing betamimetics 2 for the treatment of inflammatory or obstructive respiratory diseases, in particular asthma or COPD with simultaneous reduction in the stimulating effects on the heart caused by betamimetics 2, in particular tachycardia , palpitations, angina-like symptoms and arrhythmias.
  • the present invention preferably relates to the use mentioned above for the manufacture of a medicament for the treatment of inflammatory or obstructive respiratory diseases, in particular asthma or COPD, with a simultaneous reduction in the stimulating effects on the heart, in particular tachycardia, caused by betamimetics 2 in the period shortly after their application Palpitations, angina-like symptoms and arrhythmias.
  • the present invention preferably relates to the use mentioned above for the manufacture of a medicament for the treatment of inflammatory or obstructive respiratory diseases, in particular asthma or COPD, with a simultaneous reduction in the stimulating effects on the heart caused by the multiple daily, preferably twice daily application of the betamimetics 2, in particular the Tachycardia, palpitations, angina-like symptoms and arrhythmias.
  • the present invention preferably relates to the abovementioned uses of ipratropium salts for the production of a medicament for the treatment of inflammatory or obstructive respiratory diseases, in particular asthma or COPD, with a simultaneous reduction in tachycardia.
  • the compounds 1 and 2 can be applied simultaneously or in succession, the simultaneous administration of the compounds 1 and 2 being preferred according to the invention.
  • the present invention further relates to the use of therapeutically effective amounts of ipratropium salts 1 and long-acting betamimetics 2 for the treatment of inflammatory or obstructive respiratory diseases, in particular of Asthma or COPD with simultaneous reduction of the stimulating effects on the heart caused by betamimetics 2, in particular tachycardia, palpitations, angina-like symptoms and arrhythmias.
  • the present invention preferably relates to the use mentioned above for the treatment of inflammatory or obstructive respiratory diseases, in particular of asthma or COPD while simultaneously reducing the stimulating effects on the heart caused by betamimetics 2 in the period shortly after their application, in particular tachycardia, palpitations, and angina -pectoris-like complaints as well as arrhythmias.
  • the present invention preferably relates to the use mentioned above for the treatment of inflammatory or obstructive respiratory diseases, in particular asthma or COPD, with simultaneous reduction of the stimulating effects on the heart, in particular tachycardia, of the heart caused by the multiple daily, preferably twice daily application of betamimetics 2 , the angina-like symptoms and the arrhythmias.
  • the present invention preferably relates to the abovementioned uses of ipratropium salts 1 for the treatment of inflammatory or obstructive respiratory diseases, in particular asthma or COPD, with a simultaneous reduction in tachycardia.
  • the ratios in which the two active ingredients 1 and 2 can be used in the active ingredient combinations according to the invention are variable. Active ingredients 1 and 2 may optionally be in the form of their solvates or hydrates. Depending on the choice of salts or 2, the weight ratios which can be used in the context of the present invention vary on account of the different molecular weights of the various salt forms. The weight ratios given below were therefore based on the ipratropium cation V and the free bases of the betamimetics salmeterol and formoterol preferred according to the invention.
  • the active compound combinations according to the invention can contain V and 2J in weight ratios which, for example, are preferably in a range from about 1: 5 to 300: 1, preferably 1: 4 to 200: 1, preferably 1: 3 to 150: 1 from 1: 2 to 100: 1, preferably from 1: 1 to 65: 1, particularly preferably from 2: 1 to 50: 1.
  • preferred combinations according to the invention of 1 and 2 ipratropium V and formoterol can contain the following weight ratios: 1: 3, 1: 2, 1: 1, 2: 1, 3: 1.4 : 1.5: 1.6: 1.7: 1.8: 1.9: 1, 10: 1, 11: 1.12: 1, 13: 1, 14: 1, 15: 1.16: 1 , 17: 1, 18: 1,
  • compositions according to the invention containing the combinations of 1 and 2 are usually used in such a way that ipratropium V and formoterol _ together in doses of 5 to 5000 ⁇ g, preferably 10 to 2000 ⁇ g, particularly preferably 15 to 1000 ⁇ g, further preferably 20 to 800 ⁇ g , according to the invention preferably from 30 to 600 ⁇ g, preferably from 40 to 500 ⁇ g, preferably from 30 to 400 ⁇ g, preferably from 40 to 300 ⁇ g, particularly preferably from 50 to 250 ⁇ g per single dose.
  • combinations of 1_ and 2 according to the invention contain such an amount of ipratropium V and formoterol 2
  • that the total dosage per single dose is approximately 20 ⁇ g, 25 ⁇ g, 30 ⁇ g, 35 ⁇ g, 45 ⁇ g, 50 ⁇ g, 55 ⁇ g, 60 ⁇ g, 65 ⁇ g, 70 ⁇ g, 75 ⁇ g, 80 ⁇ g, 85 ⁇ g , 90 ⁇ g, 95 ⁇ g, 100 ⁇ g, 105 ⁇ g, 110 ⁇ g, 115 ⁇ g, 120 ⁇ g, 125 ⁇ g, 130 ⁇ g, 135 ⁇ g, 140 ⁇ g, 145 ⁇ g, 150 ⁇ g, 155 ⁇ g, 160 ⁇ g, 165 ⁇ g, 170 ⁇ g, 175 ⁇ g, 180 ⁇ g, 185 ⁇ g, 190 ⁇ g, 195 ⁇ g, 200 ⁇ g, 205 ⁇ g, 205 ⁇ g , 215 ⁇ g, 220 ⁇ g, 225 ⁇ g, 230 ⁇ g, 235 ⁇ g, 240 ⁇ g, 245 ⁇ g, 250 ⁇ g, 255 ⁇ g, 260 ⁇
  • the combinations of ⁇ and 2 according to the invention can contain such an amount of ipratropium V and formoterol 2J that, for example, per single dose 16.1 ⁇ g and 4.9 ⁇ g 2, 16.1 ⁇ g V and 9.8 ⁇ g, 16.1 ⁇ g and 14.7 ⁇ g 2 ;, 16.1 ⁇ g and 19.6 ⁇ g T, 16.1 ⁇ g V and 24.4 ⁇ g 2j, 32.2 ⁇ g V and 4.9 ⁇ g 2J, 32.2 ⁇ g V and 9.8 ⁇ g 2j, 32.2 ⁇ g V and 14.7 ⁇ g 2 ⁇ 32.2 ⁇ g V and 19.6 ⁇ g 2J, 32.2 ⁇ g and 24.4 ⁇ g 2 ⁇ 48.3 ⁇ g V and 4.9 ⁇ g, 48.3 ⁇ g V and 9.8 ⁇ g 2j, 48.3 ⁇ g V and 14.7 ⁇ g 2, 48.3 ⁇ g r and 19.6 ⁇ g _, 48.3 ⁇ g V and 24.4 ⁇ g?, 80.5 ⁇ g V
  • the amounts of active ingredient and and 2J applied per single administration given above correspond to the subsequent amounts of ⁇ and 2: 20 ⁇ g applied per single administration 1 and 5.7 ⁇ g 2, 20 ⁇ g and 11, 5 ⁇ g 2, 20 ⁇ g 1 and 17.2 ⁇ g 2, 20 ⁇ g 1 and 22.9 ⁇ g 2, 20 ⁇ g 1 and 28.5 ⁇ g 2, 40 ⁇ g 1 and 5.7 ⁇ g 2, 40 ⁇ g 1 and 11 , 5 ⁇ g 2, 40 ⁇ g 1 and 17.2 ⁇ g 2, 40 ⁇ g 1 and 22.9 ⁇ g 2, 40 ⁇ g 1 and 28.5 ⁇ g 2, 60 ⁇ g 1 and 5.7 ⁇ g 2, 60 ⁇ g 1 and 11, 5 ⁇ g 2, 60 ⁇ g 1 and 17.2 ⁇ g 2, 60 ⁇ g 1 and 22.9 ⁇ g 2, 60 ⁇ g 1 and 28.5 ⁇ g 2, 100 ⁇ g 1 and 5.7 ⁇ g 2, 100 ⁇ g 1 and 11, 5 ⁇ g 2, 100 ⁇ g l and 17.2
  • the amounts of active ingredient V and 2J administered per single administration given above correspond to the subsequent amounts administered per single administration 1 and 2: 20.8 ⁇ g 1 and 6 ⁇ g 2, 20.8 ⁇ g 1 and 12 ⁇ g 2, 20.8 ⁇ g 1 and 18 ⁇ g 2, 20.8 ⁇ g 1 and 24 ⁇ g 2, 20.8 ⁇ g 1 and 30 ⁇ g 2, 41, 7 ⁇ g 1 and 6 ⁇ g 2, 41, 7 ⁇ g 1 and 12 ⁇ g 2, 41, 7 ⁇ g 1 and 18 ⁇ g 2, 41, 7 ⁇ g 1 and 24 ⁇ g 2, 41, 7 ⁇ g 1 and 30 ⁇ g 2, 62.5 ⁇ g 1 and 6 ⁇ g 2, 62.5 ⁇ g 1 and 12 ⁇ g 2, 62.5 ⁇ g 1 and 18 ⁇ g 2, 62.5 ⁇ g 1 and 24 ⁇ g 2, 62.5 ⁇ g 1 and 30 ⁇ g 2, 104.2 ⁇ g 1 and 6 ⁇ g 2, 104.2 ⁇ g 1 and 6 ⁇ g 2, 104.2 ⁇ g 1 and 6 ⁇ g 1
  • the active compound combinations according to the invention can contain V and T_ in the case of, for example, salmeterol in weight ratios which are, for example, in a range from about 1:30 to 400: 1, preferably 1:25 to 200: 1, preferably 1:20 to 100: 1 from 1:15 to 50: 1, preferably from 1:13 to 20: 1, preferably from 1: 1 to 15: 1.
  • preferred combinations according to the invention of 1 and 2 ipratropium V and salmeterol can contain the following weight ratios: 1:15, 1:14, 1:13, 1: 12.1: 11, 1:10, 1: 9.1: 8.1: 7, 1: 6.1: 5.1: 4.1: 3, 1: 2.1: 1.2: 1.3: 1.4: 1.5: 1.6: 1.7: 1, 8: 1, 9: 1, 10: 1, 11: 1, 12: 1, 13: 1, 14: 1, 15: 1, 16: 1, 17: 1, 18: 1, 19: 1.20: 1.
  • the medicaments according to the invention containing the combinations of 1 and 2 are usually used in such a way that ipratropium V and salmeterol together according to the invention in doses of 5 to 5000 ⁇ g, preferably 10 to 2000 ⁇ g, particularly preferably 15 to 1000 ⁇ g, further preferably 20 to 800 ⁇ g preferably from 30 to 700 ⁇ g, preferably from 40 to 600 ⁇ g, preferably from 50 to 550 ⁇ g, preferably from 40 to 500 ⁇ g, particularly preferably from 50 to 400 ⁇ g per single dose.
  • combinations of 1 and 2 according to the invention contain such an amount of ipratropium V and salmeterol that the total dosage per single dose is about 35 ⁇ g, 45 ⁇ g, 50 ⁇ g, 55 ⁇ g, 60 ⁇ g, 65 ⁇ g, 70 ⁇ g, 75 ⁇ g, 80 ⁇ g, 85 ⁇ g, 90 ⁇ g, 95 ⁇ g, 100 ⁇ g, 105 ⁇ g, 110 ⁇ g, 115 ⁇ g, 120 ⁇ g, 125 ⁇ g, 130 ⁇ g, 135 ⁇ g, 140 ⁇ g, 145 ⁇ g, 150 ⁇ g, 155 ⁇ g, 160 ⁇ g, 165 ⁇ g, 170 ⁇ g, 175 ⁇ g, 180 ⁇ g, 185 ⁇ g, 190 ⁇ g, 195 ⁇ g, 200 ⁇ g, 205 ⁇ g, 210 ⁇ g, 215 ⁇ g, 220 ⁇ g, 225 230 ⁇ g, 235 ⁇ g, 240 ⁇ g, 245 ⁇ g, 250 ⁇ g, 255 ⁇ g, 260 ⁇ g, 265 ⁇ g, 270 ⁇ g, 275 ⁇ g, 280 ⁇
  • the combinations of and 2 according to the invention can contain such an amount of ipratropium V and salmeterol that, for example, 16.1 ⁇ g and 25 ⁇ g 2 ⁇ 16.1 ⁇ g V and 50 ⁇ g, 16, 1 ⁇ g V and 75 ⁇ g 2J, 16.1 ⁇ g V and 100 ⁇ g, 16.1 ⁇ g V and 200 ⁇ g 2, 32.2 ⁇ g V and 25 ⁇ g, 32.2 ⁇ g V and 50 ⁇ g, 32.2 ⁇ g V and 75 ⁇ g 2j, 32.2 ⁇ g V and 100 ⁇ g?, 32.2 ⁇ g V and 200 ⁇ g 2j, 48.3 ⁇ g V and 25 ⁇ g, 48.3 ⁇ g V and 50 ⁇ g 2
  • the amounts of active ingredient V and 2J applied per single dose correspond to the subsequent amounts of 1 and 2: 20 ⁇ g 1 and 36.3 ⁇ g 2, 20 ⁇ g 1 and 72.6 ⁇ g 2, 20 ⁇ g 1 and 108.9 ⁇ g 2, 20 ⁇ g 1 and 145.2 ⁇ g 2, 20 ⁇ g 1 and 290.4 ⁇ g 2, 40 ⁇ g 1 and 36.3 ⁇ g 2, 40 ⁇ g 1 and 72.6 ⁇ g 2, 40 ⁇ g 1 and 108.9 ⁇ g 2, 40 ⁇ g ⁇ and 145.2 ⁇ g 2, 40 ⁇ g 1 and 290.4 ⁇ g 2, 60 ⁇ g 1 and 36.3 ⁇ g 2, 60 ⁇ g 1 and 72.6 ⁇ g 2, 60 ⁇ g 1 and 108.9 ⁇ g 2, 60 ⁇ g 1 and 145.2 ⁇ g 2, 60 ⁇ g 1 and 290.4 ⁇ g 2, 100 ⁇ g 1 and 36.3 ⁇ g 2, 100 ⁇ g 1 and 72.6 ⁇ g 2, 100 ⁇ g 1 and 108.
  • the above-mentioned active substance amounts of V and 2j correspond to the following amounts of 1 and 2 applied per single dose: 20.8 ⁇ g 1 and 36.3 ⁇ g 2, 20.8 ⁇ g 1 and 72.6 ⁇ g 2, 20.8 ⁇ g 1 and 108.9 ⁇ g 2, 20.8 ⁇ g 1 and 145.2 ⁇ g 2, 20.8 ⁇ g 1 and 290.4 ⁇ g 2, 41, 7 ⁇ g 1 and 36.3 ⁇ g 2, 41, 7 ⁇ g 1 and 72.6 ⁇ g 2, 41, 7 ⁇ g 1 and 108.9 ⁇ g 2, 41, 7 ⁇ g 1 and 145.2 ⁇ g 2, 41, 7 ⁇ g 1 and 290.4 ⁇ g 2, 62.5 ⁇ g 1 and 36.3 ⁇ g 2, 62.5 ⁇ g 1 and 72.6 ⁇ g 2, 62.5 ⁇ g 1 and 108.9 ⁇ g 2, 62.5 ⁇ g 1 and 145.2 ⁇
  • the amount of active substance applied per single dose of the pharmaceutical combinations according to the invention can be calculated if, instead of the salmeterol xinafoate, the compound 2 according to the invention, the salmeterol 1/2-sulfate is used.
  • the active substance combinations from and 2 according to the invention are preferably administered by inhalation.
  • components 1 and 2 must be provided in inhalable dosage forms.
  • Inhalable dosage forms include inhalable powders, metered-dose aerosols containing propellants or propellant-free inhalation solutions.
  • Inhalable powder according to the invention containing the active ingredient combination of and
  • propellant-free inhalation solutions also includes concentrates or sterile, ready-to-use inhalation solutions.
  • the dosage forms according to the invention can contain the combination of active substances from and 2 either together in one or in two separate dosage forms. These dosage forms which can be used in the context of the present invention are described in detail in the following part of the description.
  • A) Inhalation powder containing the active compound combinations according to the invention from 1 and 2 can contain 1_ and 2 either alone or in a mixture with suitable physiologically acceptable auxiliaries. If the active ingredients 1 and 2 are contained in a mixture with physiologically acceptable auxiliaries, the following physiologically acceptable auxiliaries can be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose), oligo- and Polysaccharides (e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these auxiliaries with one another. Mono- or disaccharides are preferably used, the use of lactose or glucose being preferred, particularly but not exclusively in the form of their hydrates.
  • monosaccharides e.g. glucose or arabinose
  • the auxiliaries have a maximum average particle size of up to 250 ⁇ m, preferably between 10 and 150 ⁇ m, particularly preferably between 15 and 80 ⁇ m. If appropriate, it may appear sensible to add finer excipient fractions with an average particle size of 1 to 9 ⁇ m to the excipients mentioned above. The latter finer excipients are also selected from the group of excipients that can be used.
  • micronized active ingredient 1 and 2 preferably with an average particle size of 0.5 to 10 ⁇ m, particularly preferably from 1 to 6 ⁇ m, are admixed with the excipient mixture.
  • inhalable powders according to the invention Processes for producing the inhalable powders according to the invention by grinding and micronizing and by finally mixing the constituents are known from the prior art.
  • the inhalable powders according to the invention can be provided and applied either in the form of a single powder mixture which contains both 1 and 2 or in the form of separate inhalable powders which contain only 1 and 2.
  • the inhalable powders according to the invention can be applied using inhalers known from the prior art.
  • Inhalation powders according to the invention which in addition to and 2 also contain a physiologically acceptable auxiliary, can be applied, for example, by means of inhalers which take a single dose from a supply by means of a measuring chamber, as described in US 4570630A, or via other apparatus as described in DE 36 25 685 A are described, meter.
  • the inhalable powders according to the invention which contain and 2 optionally in combination with a physiologically compatible auxiliary, can be used, for example, using the inhaler known under the name Turbuhaler ® or with inhalers as disclosed, for example, in EP 237507 A.
  • inhalable powders according to the invention which in addition to 1 and 2 contain physiologically acceptable excipients, are preferably filled into capsules (for so-called inhalers), which are used in inhalers as described, for example, in WO 94/28958.
  • FIG. 1 An inhaler which is particularly preferred for use of the pharmaceutical combination according to the invention in inhalettes can be seen in FIG. 1.
  • This inhaler for the inhalation of powdered pharmaceuticals from capsules is characterized by a housing 1, containing two windows 2, a deck 3, in which there are air inlet openings and which is provided with a sieve 5 fastened via a sieve housing 4, one with a deck 3 connected inhalation chamber 6, on which a pusher 8 provided with two ground needles 7 and movable against a spring 8 is provided, as well as a mouthpiece 12 which is hinged to the housing 1, the deck 3 and a cap 11 via an axis 10.
  • inhalable powders according to the invention are to be filled into capsules (inhalettes) in the sense of the preferred application mentioned above, fill quantities of 1 to 30 mg per capsule are appropriate. According to the invention, these contain either together or in each case the doses per single dose already mentioned above for V and 2 and T_.
  • Inhalation aerosols containing propellant gas according to the invention can contain 1 and 2 dissolved in the propellant gas or in dispersed form.
  • 1 and 2 can be contained in separate dosage forms or in a common dosage form, where 1 and 2 can either be both dissolved, both dispersed or in each case only one component dissolved and the other dispersed.
  • the propellant gases which can be used to produce the inhalation aerosols according to the invention are known from the prior art.
  • Suitable propellants are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halogenated hydrocarbons such as preferably chlorinated and fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • hydrocarbons such as n-propane, n-butane or isobutane
  • halogenated hydrocarbons such as preferably chlorinated and fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • the above-mentioned propellant gases can be used alone or in mixtures thereof.
  • Particularly preferred propellants are halogenated alkane derivatives selected from TG11, TG12, TG134a (1, 1, 1, 2- Tetrafluoroethane), TG227 (1, 1, 1, 2,3,3,3-heptafluoropropane) and mixtures thereof, the propellant gases TG 134a, TG227 and mixtures thereof being preferred.
  • the inhalation aerosols containing propellant gas according to the invention can furthermore contain further constituents such as cosolvents, stabilizers, surfactants, antioxidants, lubricants and agents for adjusting the pH. All of these components are known in the art.
  • the inhalation aerosols containing propellant gas according to the invention can contain up to 5% by weight of active ingredient 1 and / or 2. Aerosols according to the invention contain, for example, 0.002 to 5% by weight, 0.01 to 3% by weight, 0.015 to 2% by weight, 0.1 to 2% by weight, 0.5 to 2% by weight or 0.5 to 1 % By weight of active ingredient 1 and / or 2.
  • the active ingredient particles preferably have an average particle size of up to 10 ⁇ m, preferably from 0.1 to 5 ⁇ m, particularly preferably from 1 to 5 ⁇ m.
  • the present invention further relates to inhalers, characterized in that they contain propellant-containing aerosols according to the invention described above.
  • the present invention further relates to cartridges which can be used with a suitable valve in a suitable inhaler and which contain one of the above-mentioned inhalation aerosols containing propellant gas according to the invention. Suitable cartridges and methods for filling these cartridges with the inhalation aerosols containing propellant gas according to the invention are known from the prior art.
  • the active compound combination according to the invention is particularly preferably applied in the form of propellant-free inhalation solutions and inhalation suspensions if salmeterol 1/2-sulfate is used as betamimetic 2 in the pharmaceutical combinations according to the invention becomes.
  • Suitable solvents for this purpose are aqueous or alcoholic, preferably ethanolic, solutions.
  • the solvent can only be water or it is a mixture of water and ethanol.
  • the relative proportion of ethanol to water is not limited, but the maximum limit is preferably up to 70 volume percent, in particular up to 60 volume percent and particularly preferably up to 30 volume percent.
  • the remaining volume percentages are filled up with water.
  • the solutions and suspensions containing oder and 2, separately or together, are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids.
  • Acids selected from inorganic or organic acids can be used to adjust this pH.
  • inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid.
  • organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others.
  • Preferred inorganic acids are hydrochloric acid, sulfuric acid. It is also possible to use the acids which already form an acid addition salt with one of the active ingredients. Ascorbic acid, fumaric acid and citric acid are preferred among the organic acids.
  • mixtures of the acids mentioned can also be used, in particular in the case of acids which, in addition to their acidifying properties, also have other properties, for example as flavorings, antioxidants or complexing agents, such as, for example, citric acid or ascorbic acid.
  • hydrochloric acid is particularly preferably used to adjust the pH.
  • Stabilizer or complexing agent can be dispensed with.
  • the content is based on
  • Sodium edetate is 0 to 10mg / 100ml.
  • Co-solvents and / or further auxiliaries can be added to the propellant-free inhalation solutions according to the invention.
  • Preferred co-solvents are those which contain hydroxyl groups or other polar groups, for example alcohols - in particular isopropyl alcohol, glycols - In particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
  • auxiliary substances and additives are understood to mean any pharmacologically acceptable substance which is not an active substance, but which can be formulated together with the active substance (s) in the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation.
  • These substances preferably have no or no significant or at least no undesirable pharmacological effect in the context of the desired therapy.
  • the auxiliaries and additives include, for example, surface-active substances, such as, for example, soy lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or preservatives which guarantee or extend the useful life of the finished pharmaceutical formulation, flavors, vitamins and / or other additives known in the prior art.
  • the additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.
  • the preferred auxiliaries include antioxidants, such as, for example, ascorbic acid, unless already used for adjusting the pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human organism.
  • Preservatives can be used to protect the formulation from contamination with germs. Suitable preservatives are those known from the prior art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art.
  • the above-mentioned preservatives are preferably contained in concentrations of up to 50 mg / 100 ml, particularly preferably between 5 and 20 mg / 100 ml.
  • preferred formulations only contain benzalkonium chloride and sodium edetate. In another preferred embodiment, sodium edetate is dispensed with.
  • nebulizers are preferred in which an amount of less than 100 ⁇ L, preferably less than 50 ⁇ L, is particularly preferred between 10 and 30 ⁇ L of active ingredient solution, preferably with a stroke to an aerosol with an average particle size of less than 20 ⁇ m, preferably less than 10 ⁇ m, can be atomized so that the inhalable portion of the aerosol already corresponds to the therapeutically effective amount.
  • Such a device for propellant-free administration of a metered amount of a liquid medicament for inhalation use is described in detail, for example, in international patent application WO 91/14468 and also in WO 97/12687 (there in particular FIGS. 6a and 6b).
  • the nebulizers described there are also known under the name Respimat ® .
  • This nebuliser may be advantageous to produce the inhalable aerosols according to the invention containing the combination of active substances and are used. 2 Due to its cylinder-like shape and a handy size of less than 9 to 15 cm in length and 2 to 4 cm in width, this device can be carried by the patient at any time. The nebulizer sprays a defined volume of the drug formulation using high pressures through small nozzles, so that inhalable aerosols are produced.
  • the preferred atomizer consists of an upper housing part, a pump housing, a nozzle, a locking mechanism, a spring housing, a spring and a storage container, characterized by a pump housing which is fastened in the upper housing part and which has a nozzle body with the nozzle at one end or nozzle arrangement carries, a hollow piston with valve body, an output flange in which the hollow piston is fastened, and which is in the
  • Upper housing part is, a locking mechanism, which is located in the upper housing part, a spring housing with the spring therein, which is rotatably mounted on the upper housing part by means of a rotary bearing, a lower housing part which is attached to the spring housing in the axial direction.
  • the hollow piston with valve body corresponds to a device disclosed in WO 97/12687. It projects partially into the cylinder of the pump housing and is arranged axially displaceably in the cylinder. In particular, reference is made to FIGS. 1-4 - in particular FIG. 3 - and the associated parts of the description.
  • the hollow piston with valve body exercises on its high pressure side When the spring is released, a pressure of 5 to 60 Mpa (approximately 50 to 600 bar), preferably 10 to 60 Mpa (approximately 100 to 600 bar), is exerted on the fluid, the measured active ingredient solution. Volumes of 10 to 50 microliters are preferred, volumes of 10 to 20 microliters are particularly preferred, and a volume of 15 microliters per stroke is very particularly preferred.
  • the valve body is preferably attached to the end of the hollow piston which faces the nozzle body.
  • the nozzle in the nozzle body is preferably microstructured, i.e. made by microtechnology.
  • Microstructured nozzle bodies are disclosed, for example, in WO-94/07607; reference is hereby made to this document, in particular to FIG. 1 and its description disclosed therein.
  • the nozzle body is e.g. from two firmly connected plates
  • At least one plate has one or more microstructured channels, which the nozzle inlet side with the
  • Width the depth being preferably 4.5 to 6.5 micrometers and the length being 7 to 9 micrometers.
  • Jet directions of the nozzles in the nozzle body run parallel to one another or they are inclined towards one another in the direction of the nozzle opening.
  • the jet directions can be inclined at an angle of 20 degrees to 160 degrees, an angle of 60 to 150 degrees is preferred, particularly preferably 80 to 100 °.
  • the nozzle openings are preferably arranged at a distance of 10 to 200 micrometers, more preferably at a distance of 10 to 100 micrometers, particularly preferably 30 to 70 micrometers. Most preferred are 50
  • the beam directions meet in the vicinity of the
  • the liquid pharmaceutical preparation hits the nozzle body with an inlet pressure of up to 600 bar, preferably 200 to 300 bar, and is atomized into an inhalable aerosol via the nozzle openings.
  • the preferred particles Droplet sizes of the aerosol are up to 20 micrometers, preferably 3 to 10 micrometers.
  • the locking mechanism contains a spring, preferably a cylindrical helical compression spring, as a store for the mechanical energy.
  • the spring acts on the output flange as a jumping piece, the movement of which is determined by the position of a locking element.
  • the path of the output flange is precisely limited by an upper and a lower stop.
  • the spring is preferably tensioned via a force-transmitting gear, for example a screw-push gear, by an external torque which is generated when the upper housing part is rotated against the spring housing in the lower housing part.
  • a force-transmitting gear for example a screw-push gear
  • the upper part of the housing and the output flange contain a single or multi-speed wedge gear.
  • the locking member with engaging locking surfaces is arranged in a ring around the output flange.
  • the ring is arranged in a plane perpendicular to the atomizer axis. After tensioning the spring, the locking surfaces of the locking member slide into the path of the output flange and prevent the spring from relaxing.
  • the locking element is triggered by a button.
  • the trigger button is connected or coupled to the locking member.
  • the release button is moved parallel to the ring plane, preferably into the atomizer; the deformable ring is deformed in the ring plane. Constructive details of the locking mechanism are described in WO 97/20590.
  • the lower part of the housing is pushed in the axial direction over the spring housing and covers the bearing, the drive of the spindle and the reservoir for the fluid.
  • the upper housing part When the atomizer is actuated, the upper housing part is rotated against the lower housing part, the lower housing part taking the spring housing with it.
  • the spring is compressed and tensioned via the screw-type thrust gear, and the locking mechanism engages automatically.
  • the angle of rotation is preferably an integer fraction of 360 degrees, e.g. 180 degrees.
  • the driven part in the upper part of the housing is shifted by a predetermined distance, the hollow piston is withdrawn inside the cylinder in the pump housing, whereby a part of the fluid is sucked out of the reservoir into the high-pressure space in front of the nozzle.
  • a plurality of interchangeable storage containers containing the fluid to be atomized can be inserted into the atomizer one after the other to be used.
  • the storage container contains the aqueous aerosol preparation according to the invention.
  • the atomization process is initiated by gently pressing the trigger button.
  • the barrage clears the way for the stripping section.
  • the tensioned spring pushes the piston into the cylinder of the pump housing.
  • the components of the atomizer are made of a material that is suitable for their function.
  • the housing of the atomizer and - as far as the function allows - other parts are preferably made of plastic, e.g. manufactured by injection molding. Physiologically harmless materials are used for medical purposes.
  • Figures 2a / b attached to this patent application which are identical to Figures 6a / b of WO 97/12687, describe the nebulizer (Respimat®) with which the aqueous aerosol preparations according to the invention can advantageously be inhaled.
  • Respimat® nebulizer
  • Figure 2a shows a longitudinal section through the atomizer with the spring under tension
  • Figure 2b shows a longitudinal section through the atomizer with the spring relaxed.
  • the upper housing part (51) contains the pump housing (52), at the end of which the holder (53) for the atomizing nozzle is attached.
  • the nozzle body (54) and a filter (55) are located in the holder.
  • the hollow piston (57) fastened in the output flange (56) of the locking tensioning mechanism partially protrudes into the cylinder of the pump housing.
  • the hollow piston carries the valve body (58) at its end.
  • the hollow piston is sealed by means of the seal (59).
  • Inside the upper part of the housing is the stop (60), against which the output flange rests when the spring is relaxed.
  • the stop (61) is located on the output flange, against which the output flange rests when the spring is tensioned.
  • the locking member (62) is pushed between the stop (61) and a support (63) in the upper part of the housing.
  • the release button (64) is connected to the locking member.
  • the upper housing part ends in the mouthpiece (65) and is closed with the clip-on protective cap (66).
  • the spring housing (67) with compression spring (68) is rotatably mounted on the upper part of the housing by means of the snap lugs (69) and rotary bearings.
  • the lower housing part (70) is pushed over the spring housing.
  • the replaceable reservoir (71) for the fluid (72) to be atomized is located within the spring housing.
  • the storage container is closed with the stopper (73) through which the hollow piston protrudes into the storage container and with its end is immersed in the fluid (supply of active substance solution).
  • the spindle (74) for the mechanical counter is mounted in the outer surface of the spring housing.
  • the drive pinion (75) is located at the end of the spindle which faces the upper housing part.
  • the rider (76) sits on the spindle.
  • the nebuliser described above is suitable for nebulizing the aerosol preparations according to the invention into an aerosol suitable for inhalation.
  • the mass expelled in at least 97%, preferably at least 98% of all actuations of the inhaler (spray) a defined quantity with a tolerance of not more than 25%, preferably 20% of these Amount.
  • a defined mass per stroke particularly preferably between 5 and 20 mg.
  • the formulation according to the invention can also be nebulized using inhalers other than those described above, for example jet stream inhalers or other stationary nebulizers.
  • a further aspect of the present invention relates to medicaments in the form of above-described propellant-free inhalable solutions or suspensions in combination with a suitable device for administering these formulations, preferably in conjunction with the Respimat ®.
  • the present invention to propellant-free inhalable solutions or suspensions characterized by the aims of the invention combination of active substances 1 and 2 in connection with the known under the name Respimat ® device.
  • the present invention relates to the abovementioned devices for inhalation preferred Respimat ®, in the fact that they contain according to the invention the propellant-free inhalable solutions or suspensions as described above.
  • Inhalation solutions which contain the active ingredients 1 and 2 in a single administration form are preferred according to the invention.
  • dosage forms are also understood that contain the two components ⁇ and 2 in two-chamber cartridges, as are disclosed, for example, by WO 00/23037. At this point, full reference is made to these.
  • the propellant-free inhalation solutions or suspensions according to the invention can, in addition to the solutions and suspensions intended for application in the Respimat, also be present as concentrates or sterile, ready-to-use inhalation solutions or suspensions.
  • Ready-to-use formulations can be generated from the concentrates, for example, by adding isotonic saline solutions.
  • Sterile, ready-to-use formulations can be applied using energy-operated stand-up or portable nebulisers that generate inhalable aerosols using ultrasound or compressed air according to the Venturi principle or other principles.
  • a further aspect of the present invention relates to medicaments in the form of propellant-free inhalable solutions or suspensions as described above, which are present as concentrates or sterile, ready-to-use formulations, in connection with a device suitable for administering these solutions, characterized in that this device is is an energy-operated standing or portable nebuliser that generates inhalable aerosols using ultrasound or compressed air according to the Venturi principle or other principles.

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Abstract

L'invention concerne de nouvelles compositions médicamenteuses à base d'agonistes bêta2 actifs à long terme et de sels d'ipratropium. L'invention concerne également des procédés pour leur production et leur utilisation pour traiter des affections des voies respiratoires.
PCT/EP2002/000674 2001-02-01 2002-01-24 Compositions medicamenteuses contenant des betamimetiques et ayant des effets secondaires limites WO2002060532A1 (fr)

Priority Applications (3)

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EP02712840A EP1357975A1 (fr) 2001-02-01 2002-01-24 Compositions medicamenteuses contenant des betamimetiques et ayant des effets secondaires limites
CA002434872A CA2434872A1 (fr) 2001-02-01 2002-01-24 Compositions medicamenteuses contenant des betamimetiques et ayant des effets secondaires limites
JP2002560721A JP2004517942A (ja) 2001-02-01 2002-01-24 ほとんど副作用を伴わないβ様物質を含む医薬組成物

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DE10104367.8 2001-02-01
DE10104367A DE10104367A1 (de) 2001-02-01 2001-02-01 Betamimetika enthaltende Arzneimittelkompositionen mit geringeren Nebenwirkungen

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US8129405B2 (en) 1999-07-14 2012-03-06 Almirall Prodesfarma S.A. Quinuclidine derivatives and medicinal compositions containing the same
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WO2003013633A1 (fr) * 2001-08-09 2003-02-20 Glaxo Group Limited Dispositif d'inhalation a composition pharmaceutique
WO2004058233A1 (fr) * 2002-12-20 2004-07-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Medicament pulverulent pour l'inhalation, contenant un sel de tiotropium et du xinafoate de salmeterol
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JP2006516135A (ja) * 2002-12-20 2006-06-22 ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト チオトロピウム塩とキシナホ酸サルメテロールとを含む吸入用粉末医薬品
FR2848849A1 (fr) * 2002-12-20 2004-06-25 Boehringer Ingelheim Pharma Poudre pour inhalation, capsule et trousse la contenant et son utilisation pour la preparation d'un medicament
EP2281813A1 (fr) 2005-08-08 2011-02-09 Pulmagen Therapeutics (Synergy) Limited Dérivés de bicyclo[2.2.1]hept-7-ylamine et leurs utilisations
EP2280006A1 (fr) 2005-08-08 2011-02-02 Pulmagen Therapeutics (Synergy) Limited Composition pharmaceutique pour inhalation comprenant un oxazole ou thiazole antagoniste du récepteur m3 muscarinique
US7994211B2 (en) 2005-08-08 2011-08-09 Argenta Discovery Limited Bicyclo[2.2.1]hept-7-ylamine derivatives and their uses
US8044205B2 (en) 2006-07-21 2011-10-25 Laboratorios Almirall, S.A. Process for manufacturing 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide
US9254262B2 (en) 2008-03-13 2016-02-09 Almirall, S.A. Dosage and formulation
US10085974B2 (en) 2008-03-13 2018-10-02 Almirall, S.A. Dosage and formulation
US11000517B2 (en) 2008-03-13 2021-05-11 Almirall, S.A. Dosage and formulation
US9737520B2 (en) 2011-04-15 2017-08-22 Almirall, S.A. Aclidinium for use in improving the quality of sleep in respiratory patients

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EP1357975A1 (fr) 2003-11-05
DE10104367A1 (de) 2002-08-08
JP2004517942A (ja) 2004-06-17
CA2434872A1 (fr) 2002-08-08

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