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WO2005013967A1 - Medicaments comprenant des inhibiteurs de pde iv et un nouvel anticholinergique, et leur utilisation pour le traitement de troubles respiratoires - Google Patents

Medicaments comprenant des inhibiteurs de pde iv et un nouvel anticholinergique, et leur utilisation pour le traitement de troubles respiratoires Download PDF

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Publication number
WO2005013967A1
WO2005013967A1 PCT/EP2004/008003 EP2004008003W WO2005013967A1 WO 2005013967 A1 WO2005013967 A1 WO 2005013967A1 EP 2004008003 W EP2004008003 W EP 2004008003W WO 2005013967 A1 WO2005013967 A1 WO 2005013967A1
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Prior art keywords
methyl
hydroxy
benzyl
benzoylamino
nicotinamide
Prior art date
Application number
PCT/EP2004/008003
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English (en)
Inventor
Sabine Germeyer
Christopher John Montague Meade
Helmut Meissner
Gerd Morschhaeuser
Michel Pairet
Sabine Pestel
Michael P. Pieper
Gerald Pohl
Richard Reichl
Georg Speck
Original Assignee
Boehringer Ingelheim International Gmbh
Boehringer Ingelheim Pharma Gmbh & Co. Kg
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Publication date
Application filed by Boehringer Ingelheim International Gmbh, Boehringer Ingelheim Pharma Gmbh & Co. Kg filed Critical Boehringer Ingelheim International Gmbh
Priority to JP2006521453A priority Critical patent/JP2007500148A/ja
Priority to CA002533786A priority patent/CA2533786A1/fr
Priority to EP04741118A priority patent/EP1651208A1/fr
Publication of WO2005013967A1 publication Critical patent/WO2005013967A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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
    • A61K31/4015—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 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • 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
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to novel pharmaceutical compositions based on PDE IN 5 inhibitors and salts of a new anticholinergic, processes for preparing them and their use in the treatment of respiratory complaints.
  • the present invention relates to novel pharmaceutical compositions based on PDE IV 10 inhibitors and salts of a new anticholinergic 1, processes for preparing them and their use in the treatment of respiratory complaints.
  • the anticholinergic agents used are the Salts of formula 1 15
  • an anion with a single negative charge preferably an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulphate, 20 phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate.
  • the salts of formula 1 are used wherein X " denotes an anion with a single negative charge selected from among the 25 fluoride, chloride, bromide, 4-toluenesulphonate and methanesulphonate, preferably bromide.
  • the salts of formula 1 are used wherein X " denotes an anion with a single negative charge selected from among the chloride, bromide and methanesulphonate, preferably bromide.
  • an unexpectedly beneficial therapeutic effect can be observed in the treatment of inflammatory and/or obstructive diseases of the respiratory tract if the anticholinergic of formula 1 is used with one or more PDE IV inhibitors 2.
  • any reference to the compound V_ is to be regarded as a reference to the pharmacologically active cation of the following formula contained in the salts 1 :
  • the active substances may be combined in a single preparation or contained in two separate formulations.
  • Pharmaceutical compositions which contain the active substances 1 and 2 in a single preparation are preferred according to the invention.
  • PDE IV inhibitors 2 in the combinations according to the invention are selected from the group consisting of enprofylline, theophylline, roflumilast, ariflo (cilomilast), CP-325,366, BY343, D-4396 (Sch-351591), AWD-12-281 (GW-842470), N-(3,5-dichloro-l-oxo-pyridin-4-yl)-4-difluoromethoxy-3- cyclopropylmethoxybenzamide, NCS-613, pumafentine, (-)p-[(4 ⁇ R*J0bS*)-9-ethoxy- 1 ,2,3 ,4,4a, 10b-hexahydro-8-methoxy-2methylbenzo [s] [ 1 ,6]naphthyridin-6-yl]-N,N- diisopropylbenzamide, (R)-(+)-l-(4-bromobenz
  • the PDE IV inhibitors 2 are selected from the group consisting of enprofylline, roflumilast, ariflo (cilomilast), AWD-12-281 (GW-842470), N-(3,5-dichloro-l-oxo-pyridin-4-yl)-4-difluoromethoxy-3- cyclopropylmethoxybenzamide, T-440, T-2585, arofylline, cis[4-cyano-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-carboxylic acid] , 2-carbomethoxy-4- cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l-one, cis[4-cyano- 4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l-one, cis[4
  • the PDE IV inhibitors 2 are selected from the group consisting of roflumilast, ariflo (cilomilast), AWD-12-281 (GW- 842470), arofylline, Z-15370, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4- ( ⁇ fluoromethoxyphenyl)cyclohexan-l-one, cis[4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexan-l-ol], atizoram, 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2-thienyl)-9H-pyrazolo[3,4-c]-l ,2,4-triazolo[4,3-a]pyridine, and 9-cyclopentyl-5,6- dihydro-7-ethyl-3-(tert-butyl)-9H-pyra
  • the PDE TV inhibitors 2 are selected from the group consisting of 2-(4-fluoro-phenoxy)-N- ⁇ 4-[(6-fluoro-2-hydroxy- benzoylamino)-methyl]-benzyl ⁇ nicotinamide, 2-(4-fluoro-phenoxy)-N- ⁇ 4-[(5-fluoro-2- hydroxy-benzoylamino)-methyl]-benzyl ⁇ nicotinamide, 2-(4-fluoro-phenoxy)-N- ⁇ 4-[(3- hydroxy-4-methyl-benzoylamino)methyl]benzyl ⁇ nicotinamide, 2-(4-fluoro-phenoxy)-N- ⁇ 4- [(3hydroxy-benzoylamino)-methyl] -benzyl ⁇ nicotinamide, 2-(4-f_uoro-phenoxy)-N- ⁇ 4- [(2-hydroxy-benzoylamino)methyl]-
  • a suitable salt thereof may be formed by reactmg the compound with an appropriate base to provide the corresponding base addition salt.
  • bases include alkali metal hydroxides including potassium hydroxide, sodium hydroxide, and lithium hydroxide; alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal alkoxides, e.g., potassium ethanolate and sodium propanolate; and various organic bases such as piperidine, diethanolamine, and N- methylglutamine.
  • the aluminum salts of the component compounds of the present invention are also included.
  • acid addition salts may be formed by treating said compounds with pharmaceutically acceptable organic and inorganic acids, e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide; other mineral acids and their corresponding salts such as sulfate, nitrate, phosphate, etc.; and alkyl- and mono- arylsulfonates such as ethanesulfonate, toluenesulfonate, and benzenesulfonate; and other organic acids and their corresponding salts such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate, etc.
  • organic and inorganic acids e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide
  • other mineral acids and their corresponding salts such as sulfate, nitrate, phosphate, etc.
  • alkyl- and mono- arylsulfonates such as
  • the pharmaceutically acceptable acid addition salts of the component compounds of the present invention include, but are not limited to: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-
  • Particularly preferred examples of pharmacologically acceptable acid addition salts of the compounds 2 according to the invention are the pharmaceutically acceptable salts which are selected from among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid; l-hydroxy-2-naphthalenecarboxylic acid or maleic acid. If desired, mixtures of the abovementioned acids may also be used to prepare the salts 2.
  • the compounds 2 may be present in the form of their racemates, enantiomers or mixtures thereof.
  • the separation of the enantiomers from the racemates may be carried out using methods known in the art (e.g. by chromatography on chiral phases, etc.).
  • the present invention relates to the abovementioned pharmaceutical compositions which contain, in addition to therapeutically effective quantities of 1 and 2, a pharmaceutically acceptable carrier.
  • the present invention relates to the abovementioned pharmaceutical compositions which do not contain any pharmaceutically acceptable carrier in addition to therapeutically effective quantities of 1 and 2.
  • the present invention also relates to the use of therapeutically effective quantities of the salts 1 for preparing a pharmaceutical composition containing PDE IN inhibitors 2 for treating inflammatory or obstructive diseases of the respiratory tract.
  • the present invention relates to the abovementioned use for preparing a pharmaceutical composition for treating asthma or COPD.
  • the compounds 1 and 2 may be administered simultaneously or successively, while it is preferable according to the invention to administer compounds 1 und 2 simultaneously.
  • the present invention further relates to the use of therapeutically effect amounts of salts 1 and PDEIV inhibitors 2 for treating inflammatory or obstructive respiratory complaints, particularly asthma or COPD.
  • the proportions in which the active substances 1 and 2 may be used in the active substance combinations according to the invention are variable. Active substances 1 and 2 may possibly be present in the form of their solvates or hydrates. Depending on the choice of the compounds 1 and 2, the weight ratios which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various salt forms.
  • the pharmaceutical combinations according to the invention may contain compounds 1 and 2 in ratios by weight ranging from 1:100 to 100:1, preferably from 1:80 to 80:1.
  • the weight ratios of 1 to 2 are most preferably in a range in which T and 2 are present in proportions of about 1:50 to 50:1, more preferably from 1:20 to 20:1.
  • V and PDE-IV inhibitor 2 may be used as for instance ariflo, roflumilast or AWD-12-281.
  • compositions according to the invention containing the combinations of 1 and 2 are normally administered so that 1 and 2 are present together in doses of 0.01 to lOOOO ⁇ g, preferably from 0J to 5000 ⁇ g, more preferably from 1 to 3000 ⁇ g, better still from 10 to 2000 ⁇ g, better still from 20 to 1500 ⁇ g, yet more preferred from 50 to 1200 ⁇ g per single dose.
  • combinations of 1 and 2 according to the invention contain a quantity of V_ and PDE-IV inhibitor 2 (as for instance ariflo, roflumilast or AWD-12-281) such that the total dosage per single dose is about lOO ⁇ g, 105 ⁇ g, HO ⁇ 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 ⁇ g, 230 ⁇ g, 235 ⁇ g, 240 ⁇ g, 245 ⁇ g, 250 ⁇ g, 255 ⁇ g, 260 ⁇ g, 265/xg, 270 ⁇ g, 275 ⁇ g, 280 ⁇ g, 285 ⁇ g, 290 ⁇ g, 295 ⁇ g, 300 ⁇
  • the combinations of 1 and 2 according to the invention may contain a quantity of V_ and PDE-IV inhibitor 2 (as for instance ariflo,'roflumilast or AWD-12-281) such that, for each single dose, 16.5 ⁇ g of V and 25 ⁇ g of 2, 16.5 ⁇ g of V and 50 ⁇ g of 2, 16.5 ⁇ g of V and lOO ⁇ g of 2, 16.5 ⁇ g of
  • the quantities of active substance £ and 2 administered per single dose mentioned before by way of example correspond to the following quantities of 1 and 2 administered per single dose: 20 ⁇ g of 1 and 25 ⁇ g of 2, 20 ⁇ g of 1 and 50 ⁇ g of 2, 20 ⁇ g of 1 and lOO ⁇ g of 2, 20 ⁇ g of 1 and 200 ⁇ g of 2, 20 ⁇ g of 1 and 300 ⁇ g of 2, 20 ⁇ g of 1 and 400 ⁇ g of 2, 20 ⁇ g of 1 and 500 ⁇ g of 2, 20 ⁇ g of 1 and 600 ⁇ g of 2, 20 ⁇ g of 1 and 700 ⁇ g of 2, 20 ⁇ g of 1 and 800 ⁇ g of 2, 20 ⁇ g of 1 and 900 ⁇ g of 2, 20 ⁇ g of 1 and lOOO ⁇ g of 2, 20 ⁇ g of 1 and 1250 ⁇ g of 2, 20 ⁇ g of 1 and 1500 ⁇ g of 2, 20 ⁇ g of 1 and 1750 ⁇ g of 2, 20 ⁇ g of 1 and 2000 ⁇ g of 2, 40 ⁇ g of 1 and 25 ⁇ g
  • the aforementioned examples of possible doses applicable for the combinations according to the invention are to be understood as referring to doses per single application. However, these examples are not be understood as excluding the possibility of administering the combinations according to the invention multiple times. Depending on the medical need patients may receive also multiple inhalative applications. As an example patients may receive the combinations according to the invention for instance two or three times (e.g. two or three puffs with a powder inhaler, an MDI etc) in the morning of each treatment day. As the aforementioned dose examples are only to be understood as dose examples per single application (i.e. per puff) multiple application of the combinations according to the invention leads to multiple doses of the aforementioned examples.
  • the application of the combositions according to the invention can be for instance once a day, or depending on the duration of action of the anticholinergic agent twice a day, or once every 2 or 3 days.
  • the aforementioned dose examples are to be understood as examples of metered doses only. In other terms, the aforementioned dose examples are not to be understood as the effective doses of the combinations according to the invention that do in fact reach the lung. It is clear for the person of ordinary skill in the art that the delivered dose to the lung is generally lower than the metered dose of the administered active ingredients.
  • the active substance combinations of 1 and 2 according to the invention are preferably administered by inhalation.
  • ingredients 1 and 2 have to be made available in forms suitable for inhalation.
  • Inhalable preparations according to the invention include inhalable powders, propellant-containing metered dose aerosols or propellant-free inhalable solutions.
  • Inhalable powders according to the invention containing the combination of active substances 1 and 2 may consist of the active substances on their own or of a mixture of the active substances with physiologically acceptable excipients.
  • the term carrier may optionally be used instead of the term excipient.
  • propellant-free inhalable solutions also includes concentrates or sterile inhalable solutions ready for use.
  • the preparations according to the invention may contain the combination of active substances 1 and 2 either together in one formulation or in two separate formulations. These formulations which may be used within the scope of the present invention are described in more detail in the next part of the specification.
  • the inhalable powders according to the invention may contain 1 and 2 either on their own or in admixture with suitable physiologically acceptable excipients.
  • physiologically acceptable excipients may be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose, trehalose), oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol, xylitol), cyclodextrines (e.g.
  • monosaccharides e.g. glucose or arabinose
  • disaccharides e.g. lactose, saccharose, maltose, trehalose
  • oligo- and polysaccharides e.g. dextran
  • polyalcohols e.g. sorbitol, mannitol, xylitol
  • cyclodextrines e.g.
  • -cyclodextrine ⁇ -cyclodextrine, ⁇ -cyclodextrine, methyl- ⁇ - cyclodextrine, hydroxypropyl- ⁇ -cyclodextrine
  • salts e.g. sodium chloride, calcium carbonate
  • mono- or disaccharides are used, while the use of lactose, trehalose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates.
  • the excipients have a maximum average particle size of up to 250 ⁇ m, preferably between 10 and 150 ⁇ m, most preferably between 15 and 80 ⁇ m. It may sometimes seem appropriate to add finer excipient fractions with an average particle size of 1 to 9 ⁇ m to the excipient mentioned above. These finer excipients are also selected from the group of possible excipients listed hereinbefore. Finally, in order to prepare the inhalable powders according to the invention, micronised active substance 1 and 2, preferably with an average particle size of 0.5 to lO ⁇ m, more preferably from 1 to 6 ⁇ m, is added to the excipient mixture.
  • inhalable powders according to the invention may be prepared and administered 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 or 2.
  • the inhalable powders according to the invention may be administered using inhalers known from the prior art.
  • Inhalable powders according to the invention which contain one or more physiologically acceptable excipients in addition to 1 and 2 may be administered, for example, by means of inhalers which deliver a single dose from a supply using a measuring chamber as described in US 4570630A, or by other means as described in DE 36 25 685 A.
  • the inhalable powders according to the invention which contain 1 and 2 optionally in conjunction with a physiologically acceptable excipient may be administered, for example, using the inhaler known by the name Turbuhaler ® or using inhalers as disclosed for example in EP 237507 A.
  • the inhalable powders according to the invention which contain physiologically acceptable excipient in addition to 1 and 2 are packed into capsules (to produce so-called inhalettes) which are used in inhalers as described, for example, in WO 94/28958.
  • FIG. 1 A particularly preferred inhaler for using the pharmaceutical combination according to the invention in inhalettes is shown in Figure 1.
  • This inhaler for inhaling powdered pharmaceutical compositions from capsules is characterised by a housing 1 containing two windows 2, a deck 3 in which there are air inlet ports and which is provided with a screen 5 secured via a screen housing 4, an inhalation chamber 6 connected to the deck 3 on which there is a push button 9 provided with two sharpened pins 7 and movable counter to a spring 8, and a mouthpiece 12 which is connected to the housing 1, the deck 3 and a cover 11 via a spindle 10 to enable it to be flipped open or shut, as well as airholes 13 for adjusting the flow resistance.
  • a housing 1 containing two windows 2, a deck 3 in which there are air inlet ports and which is provided with a screen 5 secured via a screen housing 4, an inhalation chamber 6 connected to the deck 3 on which there is a push button 9 provided with two sharpened pins 7 and movable counter to a spring 8, and a mouthpiece 12 which is connected to the housing 1, the deck 3 and a cover 11 via a spindle 10
  • the quantities packed into each capsule should be 1 to 30mg per capsule.
  • These capsules contain, according to the invention, either together or separately, the doses of 1 or £ and 2 mentioned hereinbefore for each single dose.
  • Inhalation aerosols containing propellant gas according to the invention may contain substances 1 and 2 dissolved in the propellant gas or in dispersed form. 1 and 2 may be present in separate formulations or in a single preparation, in which 1 and 2 are either both dissolved, both dispersed or only one component is dissolved and the other is dispersed.
  • the propellant gases which may be used to prepare the inhalation aerosols according to the invention are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • propellant gases mentioned above may be used on their own or in mixtures thereof.
  • Particularly preferred propellant gases are halogenated alkane derivatives selected from TGI 1, TG12, TG134a (lJJ,2Jetrafluoroethane) and TG227 (1,1,1,2,3,3,3- heptafluoropropane) and mixtures thereof, of which the propellant gases TG134a, TG227 and mixtures thereof are preferred.
  • the propellant-driven inhalation aerosols according to the invention may also contain other ingredients such as co-solvents, stabilisers, surfactants, antioxidants, lubricants and pH adjusters. All these ingredients are known in the art.
  • the inhalation aerosols containing propellant gas according to the invention may contain up to 5 wt.-% of active substance 1 and/or 2. Aerosols according to the invention contain, for example, 0.002 to 5 wt.-%, 0.01 to 3 wt.-%, 0.015 to 2 wt.-%, 0.1 to 2 wt.- , 0.5 to 2 wt.-% or 0.5 to 1 wt.-% of active substance 1 and/or 2.
  • the particles of active substance preferably have an average particle size of up to lO ⁇ m, preferably from 0J to 6 ⁇ m, more preferably from 1 to 5 ⁇ m.
  • the present invention relates to pharmaceutical compositions in the form of propellant-driven aerosols as hereinbefore described combined with one or more inhalers suitable for administering these aerosols.
  • the present invention relates to inhalers which are characterised in that they contain the propellant gas- containing aerosols described above according to the invention.
  • the present invention also relates to cartridges fitted with a suitable valve which can be used in a suitable inhaler and which contain one of the above-mentioned propellant gas-containing inhalation aerosols according to the invention. Suitable cartridges and methods of filling these cartridges with the inhalable aerosols containing propellant gas according to the invention are known from the prior art.
  • Propellant-free inhalable solutions and suspensions according to the invention contain, for example, aqueous or alcoholic, preferably ethanolic solvents, optionally ethanolic solvents mixed with aqueous solvents. If aqueous/ethanolic solvent mixtures are used the relative proportion of ethanol compared with water is not limited but preferably the maximum is up to 70 percent by volume, more particularly up to 60 percent by volume of ethanol. The remainder of the volume is made up of water.
  • the solutions or suspensions containing 1 and 2, separately or together, are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjusted using acids selected from inorganic or organic acids.
  • Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid.
  • Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid etc.
  • Preferred inorganic acids are hydrochloric and sulphuric acids. It is also possible to use the acids which have already formed an acid addition salt with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred.
  • mixtures of the above acids may be used, particularly in the case of acids which have other properties in addition to their acidifying qualities, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example.
  • the addition of editic acid (EDTA) or one of the known salts thereof, sodium editate, as stabiliser or complexing agent is unnecessary in the present formulation.
  • Other embodiments may contain this compound or these compounds.
  • the content based on sodium editate is less than lOOmg lOOml, preferably less than 50mg/100 ml, more preferably less than 20mg/100 ml.
  • inhalable solutions ' in which the content of sodium editate is from 0 to lOmg/lOOml are preferred.
  • Co-solvents and/or other excipients may be added to the propellant-free inhalable solutions according to the invention.
  • Preferred co-solvents are those which contain hydroxyl groups or other polar groups, e.g. alcohols - particularly isopropyl alcohol, glycols - particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
  • excipients and additives in this context denote any pharmacologically acceptable substance which is not an active substance but which can be formulated with the active substance or substances in the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation.
  • these substances have no pharmacological effect or, in connection with the desired therapy, no appreciable or at least no undesirable pharmacological effect.
  • the excipients and additives include, for example, surfactants such as soya lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art.
  • the additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.
  • the preferred excipients include antioxidants such as ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins and provitamins occurring in the human body.
  • Preservatives may be used to protect the formulation from contamination with pathogens. Suitable preservatives are those which are known in the art, particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art.
  • the preservatives mentioned above are preferably present in concentrations of up to 50mg/100ml, more preferably between 5 and 20mg/100ml.
  • Preferred formulations contain, in addition to the solvent water and the combination of active substances 1 and 2, only benzalkonium chloride and sodium editate. In another preferred embodiment, no sodium editate is present.
  • the propellant-free inhalable solutions according to the invention are administered in particular using inhalers of the kind which are capable of nebulising a small amount of a liquid formulation in the therapeutic dose within a few seconds to produce an aerosol suitable for therapeutic inhalation.
  • preferred inhalers are those in which a quantity of less than lOO ⁇ L, preferably less than 50 ⁇ L, more preferably between 20 and 30 ⁇ L of active substance solution can be nebulised in preferably one spray action to form an aerosol with an average particle size of less than 20 ⁇ m, preferably less than lO ⁇ m, in such a way that the inhalable part of the aerosol corresponds to the therapeutically effective quantity.
  • nebulisers devices described therein are known by the name Respimat®.
  • This nebuliser can advantageously be used to produce the inhalable aerosols according to the invention containing the combination of active substances 1 and 2. Because of its cylindrical shape and handy size of less than 9 to 15 cm long and 2 to 4 cm wide, this device can be carried at all times by the patient.
  • the nebuliser sprays a defined volume of pharmaceutical formulation using high pressures through small nozzles so as to produce inhalable aerosols.
  • the preferred atomiser essentially consists of an upper housing part, a pump housing, a nozzle, a locking mechanism, a spring housing, a spring and a storage container, characterised by - a pump housing which is secured in the upper housing part and which comprises at one end a nozzle body with the nozzle or nozzle arrangement, - a hollow plunger with valve body, - a power takeoff flange in which the hollow plunger is secured and which is located in the upper housing part, a locking mechanism situated in the upper housing part, - a spring housing with the spring contained therein, which is rotatably mounted on the upper housing part by means of a rotary bearing, - a lower housing part which is fitted onto the spring housing in the axial direction.
  • the hollow plunger with valve body corresponds to a device disclosed in WO 97/12687. It projects partially into the cylinder of the pump housing and is axially movable within the cylinder. Reference is made in particular to Figures 1 to 4, especially Figure 3, and the relevant parts of the description.
  • the hollow plunger with valve body exerts a pressure of 5 to 60 Mpa (about 50 to 600 bar), preferably 10 to 60 Mpa (about 100 to 600 bar) on the fluid, the measured amount of active substance solution, at its high pressure end at the moment when the spring is actuated. Volumes of 10 to 50 microlitres are preferred, while volumes of 10 to 20 microlitres are particularly preferred and a volume of 15 microlitres per spray is most particularly preferred.
  • the valve body is preferably mounted at the end of the hollow plunger facing the valve body.
  • the nozzle in the nozzle body is preferably microstructured, i.e. produced by microtechnology. Microstructured nozzle bodies are disclosed for example in WO 94/07607; reference is hereby made to the contents of this specification, particularly Figure 1 therein and the associated description.
  • the nozzle body consists for example of two sheets of glass and/or silicon firmly joined together, at least one of which has one or more microstructured channels which connect the nozzle inlet end to the nozzle outlet end.
  • the directions of spraying of the nozzles in the nozzle body may extend parallel to one another or may be inclined relative to one another in the direction of the nozzle opening.
  • the directions of spraying may be at an angle of 20 to 160° to one another, preferably 60 to 150°, most preferably 80 to 100°.
  • the nozzle openings are preferably arranged at a spacing of 10 to 200 microns, more preferably at a spacing of 10 to 100 microns, most preferably 30 to 70 microns. Spacings of 50 microns are most preferred.
  • the directions of spraying will therefore meet in the vicinity of the nozzle openings.
  • the liquid pharmaceutical preparation strikes the nozzle body with an entry pressure of up to 600 bar, preferably 200 to 300 bar, and is atomised into an inhalable aerosol through the nozzle openings.
  • the preferred particle or droplet sizes of the aerosol are up to 20 microns, preferably 3 to 10 microns.
  • the locking mechanism contains a spring, preferably a cylindrical helical compression spring, as a store for the mechanical energy.
  • the spring acts on the power takeoff flange as an actuating member the movement of which is determined by the position of a locking member.
  • the travel of the power takeoff flange is precisely limited by an upper and lower stop.
  • the spring is preferably biased, via a power step-up gear, e.g. a helical thrust gear, by an external torque which is produced when the upper housing part is rotated counter to the spring housing in the lower housing part.
  • the upper housing part and the power takeoff flange have a single or multiple V-shaped gear.
  • the locking member with engaging locking surfaces is arranged in a ring around the power takeoff flange.
  • the locking member consists, for example, of a ring of plastic or metal which is inherently radially elastically deformable.
  • the ring is arranged in a plane at right angles to the atomiser axis. After the biasing of the spring, the locking surfaces of the locking member move into the path of the power takeoff flange and prevent the spring from relaxing.
  • the locking member is actuated by means of a button.
  • the actuating button is connected or coupled to the locking member. In order to actuate the locking mechanism, the actuating button is moved parallel to the annular plane, preferably into the atomiser; this causes the deformable ring to deform in the annular plane. Details of the construction of the locking mechanism are given in WO 97/20590.
  • the lower housing part is pushed axially over the spring housing and covers the mounting, the drive of the spindle and the storage container for the fluid.
  • the upper housing part When the atomiser is actuated the upper housing part is rotated relative to the lower housing part, the lower housing part taking the spring housing with it.
  • the spring is thereby compressed and biased by means of the helical thrust gear and the locking mechanism engages automatically.
  • the angle of rotation is preferably a whole-number fraction of 360 degrees, e.g. 180 degrees.
  • the power takeoff part in the upper housing part is moved along by a given distance, the hollow plunger is withdrawn inside the cylinder in the pump housing, as a result of which some of the fluid is sucked out of the storage container and into the high pressure chamber in front of the nozzle.
  • a number of exchangeable storage containers which contain the fluid to be atomised may be p ' ushed into the atomiser one after another and used in succession.
  • the storage container contains the aqueous aerosol preparation according to the invention.
  • the atomising process is initiated by pressing gently on the actuating button.
  • the locking mechanism opens up the path for the power takeoff member.
  • the biased spring pushes the plunger into the cylinder of the pump housing.
  • the fluid leaves the nozzle of the atomiser in atomised form.
  • the components of the atomiser are made of a material which is suitable for its purpose.
  • the housing of the atomiser and, if its operation permits, other parts as well, are preferably made of plastics, e.g. by injection moulding.
  • physiologically safe materials are used.
  • Figures 6a/b of WO 97/12687 show the nebuliser (Respimat®) which can advantageously be used for inhaling the aqueous aerosol preparations according to the invention.
  • Figure 6a of WO 97/12687 shows a longitudinal section through the atomiser with the spring biased while Figure 6b of WO 97/12687 shows a longitudinal section through the atomiser with the spring relaxed.
  • the upper housing part (51) contains the pump housing (52) on the end of which is mounted the holder (53) for the atomiser nozzle. In the holder is the nozzle body (54) and a filter (55).
  • the hollow plunger (57) fixed in the power takeoff flange (56) of the locking mechanism projects partially into the cylinder of the pump housing. At its end the hollow plunger carries the valve body " (58). The hollow plunger is sealed off by means of the seal (59).
  • the stop (60) Inside the upper housing part is the stop (60) on which the power takeoff flange abuts when the spring is relaxed.
  • the stop (61) On the power takeoff flange is the stop (61) on which the power takeoff flange abuts when the spring is biased.
  • the locking member (62) moves between the stop (61) and a support (63) in the upper housing part.
  • the actuating button (64) is connected to the locking member.
  • the upper housing part ends in the mouthpiece (65) and is sealed off by means of the protective cover (66) which can be placed thereon.
  • the spring housing (67) with compression spring (68) is rotatably mounted on the upper housing part by means of the snap-in lugs (69) and rotary bearing.
  • the lower housing part (70) is pushed over the spring housing.
  • Inside the spring housing is the exchangeable storage container (71) for the fluid (72) which is to be atomised.
  • the storage container is sealed off by the stopper (73) through which the hollow plunger projects into the storage container and is immersed at its end in the fluid (supply of active substance solution).
  • the spindle (74) for the mechanical counter is mounted in the covering of the spring housing.
  • the drive pinion (75) At the end of the spindle facing the upper housing part.
  • the slider (76) sits on the spindle.
  • the nebuliser described above is suitable for nebulising the aerosol preparations according to the invention to produce an aerosol suitable for inhalation.
  • the quantity delivered should correspond to a defined quantity with a tolerance of not more than 25%, preferably 20% of this amount in at least 97%, preferably at least 98% of all operations of the inhaler (spray actuations).
  • the quantity delivered should correspond to a defined quantity with a tolerance of not more than 25%, preferably 20% of this amount in at least 97%, preferably at least 98% of all operations of the inhaler (spray actuations).
  • Preferably, between 5 and 30 mg of formulation, most preferably between 5 and 20 mg of formulation are delivered as a defined mass on each actuation.
  • formulation according to the invention may also be nebulised by means of inhalers other than those described above, e.g. jet stream inhalers or other stationary nebulisers.
  • the invention relates to pharmaceutical formulations in the form of propellant-free inhalable solutions or suspensions as described above combined with a device suitable for administering these formulations, preferably in conjunction with the Respimat®.
  • the invention relates to propellant-free inhalable solutions or suspensions characterised by the combination of active substances 1 and 2 according to the invention in conjunction with the device known by the name Respimat®.
  • the present invention relates to the above-mentioned devices for inhalation, preferably the Respimat®, characterised in that they contain the propellant-free inhalable solutions or suspensions according to the invention as described hereinbefore.
  • inhalable solutions which contain the active substances 1 and 2 in a single preparation are preferred.
  • single preparation also includes preparations which contain the two ingredients 1 and 2 in two-chamber cartridges, as disclosed for example in WO 00/23037. Reference is hereby made to this publication in its entirety.
  • the propellant-free inhalable solutions or suspensions according to the invention may take the form of concentrates or sterile inhalable solutions or suspensions ready for use, as well as the above-mentioned solutions and suspensions designed for use in a Respimat®.
  • Formulations ready for use may be produced from the concentrates, for example, by the addition of isotonic saline solutions.
  • Sterile formulations ready for use may be administered using energy-operated free-standing or portable nebulisers which produce inhalable aerosols by means of ultrasound or compressed air by the Venturi principle or other principles.
  • the present invention relates to pharmaceutical compositions in the form of propellant-free inhalable solutions or suspensions as described hereinbefore which take the form of concentrates or sterile formulations ready for use, combined with a device suitable for administering these solutions, characterised in that the device is an energy-operated free-standing or portable nebuliser which produces inhalable aerosols by means of ultrasound or compressed air by the Venturi principle or other methods.
  • 9-methyl-fluorene-9-carboxylic acid a) methyl 9-methyl-fluorene-9-carboxylate: From 7.6 g (0.33 mol) of sodium and 300 ml of ethanol a sodium ethoxide solution is prepared, to which 69.6 g (0.33 mol) of 9-fluorenecarboxylic acid are added batchwise. After the addition has ended the mixture is stirred for 2.5 hours at ambient temperature. Then it is evaporated to dryness, the residue is suspended in 600 ml of dimethylformamide and 93.96 g (0.662 mol) of methyl iodide are added dropwise. The mixture is stirred for 3 hours at constant temperature.
  • the cloudy solution is stirred into 500 ml of water and 300 ml of diethyl ether with cooling and extracted, the organic phase is washed with water and 10% sodium carbonate solution, dried and evaporated to dryness.
  • tropenol 9-methyl-fluorene-9-carboxylate 6.73 g (0.03 mol) of 9-methyl-fluorene-9-carboxylic acid are suspended in 60 ml dichloromethane, combined with 5.0 g of oxalyl chloride and 1 drop of dimethylformamide, then stirred for one hour at ambient temperature and finally the solvent is distilled off. The acid chloride remaining is used in the next step without any further purification.
  • scopine 9-methyl-fluorene-9-carboxylate methobromide 1.8 g (0.005 mol) of scopine 9-methyl-fluorene-9-carboxylate are taken up in 30 ml acetonitrile and reacted with 2.848 g (0.015 mol) of 50% methyl bromide solution in acetonitrile. The reaction mixture is left to stand for 3 days at ambient temperature, during which time the product crystallises. The crystals precipitated are separated off and recrystallised from diethyl ether to purify them.

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Abstract

La présente invention concerne de nouvelles compositions pharmaceutiques à base d'inhibiteurs de PDE IV et de sels d'un nouvel anticholinergique, des procédés de préparation de ces compositions et leur utilisation dans le traitement de troubles respiratoires.
PCT/EP2004/008003 2003-07-28 2004-07-23 Medicaments comprenant des inhibiteurs de pde iv et un nouvel anticholinergique, et leur utilisation pour le traitement de troubles respiratoires WO2005013967A1 (fr)

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JP2006521453A JP2007500148A (ja) 2003-07-28 2004-07-23 Ｐｄｅｉｖ阻害薬と新規な抗コリン作用薬とを含有する医薬品ならびに呼吸器疾患治療のための該医薬品の使用
CA002533786A CA2533786A1 (fr) 2003-07-28 2004-07-23 Medicaments comprenant des inhibiteurs de pde iv et un nouvel anticholinergique, et leur utilisation pour le traitement de troubles respiratoires
EP04741118A EP1651208A1 (fr) 2003-07-28 2004-07-23 Medicaments comprenant des inhibiteurs de pde iv et un nouvel anticholinergique, et leur utilisation pour le traitement de troubles respiratoires

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WO2005067929A1 (fr) * 2004-01-09 2005-07-28 Boehringer Ingelheim International Gmbh Nouvelles compositions pharmaceutiques a base de derives de scopineester et de nicotinamide
WO2006018392A1 (fr) * 2004-08-10 2006-02-23 Boehringer Ingelheim International Gmbh Formulation d'aerosol a inhaler contenant un anticholinergique
JP2009513203A (ja) * 2005-10-28 2009-04-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 微生物学的保護機能を有するマウスピースを備えた吸入器
JP2009515624A (ja) * 2005-11-15 2009-04-16 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 吸入用粉末カプセルを穿刺するためのニードル
JP2009517148A (ja) * 2005-12-02 2009-04-30 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 計量投与器具
JP2011521938A (ja) * 2008-05-27 2011-07-28 アストラゼネカ・アクチエボラーグ フェノキシピリジニルアミド誘導体およびｐｄｅ４仲介疾患状態におけるその使用
WO2011163469A1 (fr) * 2010-06-23 2011-12-29 Teva Pharmaceutical Industries Ltd. Forme hydratée du roflumilast-n-oxyde anti-inflammatoire

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WO2002069945A2 (fr) * 2001-03-07 2002-09-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles preparations de medicaments a base d'anticholinergiques et d'inhibiteurs pde-iv
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WO2005067929A1 (fr) * 2004-01-09 2005-07-28 Boehringer Ingelheim International Gmbh Nouvelles compositions pharmaceutiques a base de derives de scopineester et de nicotinamide
WO2006018392A1 (fr) * 2004-08-10 2006-02-23 Boehringer Ingelheim International Gmbh Formulation d'aerosol a inhaler contenant un anticholinergique
JP2009513203A (ja) * 2005-10-28 2009-04-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 微生物学的保護機能を有するマウスピースを備えた吸入器
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JP2009515624A (ja) * 2005-11-15 2009-04-16 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 吸入用粉末カプセルを穿刺するためのニードル
JP2009517148A (ja) * 2005-12-02 2009-04-30 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 計量投与器具
JP2011521938A (ja) * 2008-05-27 2011-07-28 アストラゼネカ・アクチエボラーグ フェノキシピリジニルアミド誘導体およびｐｄｅ４仲介疾患状態におけるその使用
WO2011163469A1 (fr) * 2010-06-23 2011-12-29 Teva Pharmaceutical Industries Ltd. Forme hydratée du roflumilast-n-oxyde anti-inflammatoire

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