WO2004004704A1 - Nouvelles compositions medicamenteuses a base de nouveaux anticholinergiques et inhibiteurs de pde-iv - Google Patents

Nouvelles compositions medicamenteuses a base de nouveaux anticholinergiques et inhibiteurs de pde-iv Download PDF

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Publication number
WO2004004704A1
WO2004004704A1 PCT/EP2003/006668 EP0306668W WO2004004704A1 WO 2004004704 A1 WO2004004704 A1 WO 2004004704A1 EP 0306668 W EP0306668 W EP 0306668W WO 2004004704 A1 WO2004004704 A1 WO 2004004704A1
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Prior art keywords
acid
inhalation
group
propellant
optionally
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PCT/EP2003/006668
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German (de)
English (en)
Inventor
Michel Pairet
Christopher John Montague Meade
Michael P. Pieper
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Boehringer Ingelheim Pharma Gmbh & Co. Kg
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Application filed by Boehringer Ingelheim Pharma Gmbh & Co. Kg filed Critical Boehringer Ingelheim Pharma Gmbh & Co. Kg
Priority to AU2003242755A priority Critical patent/AU2003242755A1/en
Priority to EP03762509A priority patent/EP1521576A1/fr
Priority to CA002492026A priority patent/CA2492026A1/fr
Priority to JP2004518566A priority patent/JP2005532379A/ja
Publication of WO2004004704A1 publication Critical patent/WO2004004704A1/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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to novel pharmaceutical compositions based on new anticholinergics and PDE-IV inhibitors, processes for their preparation and their use in the therapy of respiratory diseases.
  • the present invention relates to novel pharmaceutical compositions based on new anticholinergics and PDE-IV inhibitors, processes for their preparation and their use in the therapy of respiratory diseases.
  • an unexpectedly advantageous therapeutic effect in particular a synergistic effect in the treatment of inflammatory and / or obstructive respiratory diseases, can be observed if one or more, preferably a new anticholinergic of formula 1 together with one or more, preferably a PDE-IV inhibitor 2 apply.
  • the pharmaceutical combinations according to the invention can be used in lower doses than is the case with the otherwise customary monotherapy of the individual compounds.
  • undesirable side effects which can occur when PDE IV inhibitors are applied, can thereby be reduced.
  • X _ is a single negatively charged anion, preferably an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate means to use.
  • X ⁇ is a single negatively charged anion selected from the group consisting of chloride, bromide, 4-toluenesulfonate and methanesulfonate, preferably bromide.
  • the salts of the formula ⁇ are particularly preferably used, in which X "denotes a simply negatively charged anion selected from the group consisting of chloride, bromide and methanesulfonate, preferably bromide.
  • the salt of formula 1 in which X "represents bromide is particularly preferred.
  • Compounds 1 naturally include a reference to the cation V.
  • PDE-IV inhibitors are understood to mean compounds which are selected from the group consisting of enprofylline, theophylline, roflumilast, ariflo (cilomilast), Bay-198004, CP-325,366, BY343, D.
  • R 1 is C-
  • R 2 C-
  • R 3 is C 5 -C 5 -alkyl, which is optionally substituted by C-] -C 4 -alkoxy,
  • C ⁇ -Cß-cycloalkyl phenoxy or by a 5- or 6-membered, saturated or unsaturated heterocyclic ring which can contain one or two heteroatoms selected from the group consisting of oxygen and nitrogen,
  • Cs-Cß-cycloalkyl or phenyl or benzyl optionally substituted by C -C4-alkoxy can mean, optionally in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, optionally in the form of their tautomers and, if appropriate, their pharmacologically acceptable
  • R 1 C 1 -C 4 -alkyl, Cs-Cß-cycloalkyl, tetrahydrofuranyi, tetrahydropyranyl,
  • R 3 is C 1 -C 4 -alkyl, which may be by C 1 -C 4 -alkoxy, C- ⁇ -Cß-cycloalkyl, phenoxy, (C-
  • R 1 is ethyl, propyl, butyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl,
  • R 2 is ethyl, propyl, allyl or butenyl
  • R 3 is ethyl, propyl, butyl, cyclopentyl, cyclohexylmethyl, benzyl, phenylethyl,
  • Phenoxy methyl, methoxybenzyl or N-pyrolylmethyl can optionally be in the form of their racemates, their enantiomers, in
  • Particularly preferred components 2 are those of
  • R 1 is ethyl, n-propyl, tert-butyl, cyclopentyl, 3-tetrahydrofuryl, N-morpholinyl or phenyl;
  • R 2 is ethyl or n-propyl
  • R 3 is ethyl, i-propyl, n-propyl, n-butyl, t-butyl, cyclopentyl, cyclohexylmethyl,
  • Benzyl, phenylethyl, phenoxymethyl, 4-methoxybenzyl or N-pyrollylmethyl can optionally be in the form of their racemates, their enantiomers, in the form of their diastereomers and their
  • alkyl groups also insofar as they are part of other radicals
  • branched and unbranched alkyl groups with 1 to 5 carbon atoms are considered, for example the following are mentioned: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. Butyl , tert-butyl, n-pentyl, isopentyl or neopentyl.
  • Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. are also used for the above-mentioned groups.
  • Cycloalkyl radicals with 5 or 6 carbon atoms are called cyclopentyl or cyclohexyl.
  • Examples of 5- or 6-membered, saturated or unsaturated heterocyclic rings which may contain one or two heteroatoms selected from the group consisting of oxygen and nitrogen are: furan, tetrahydrofuran, tetrahydrofuranone, ⁇ -butylrolactone, -pyran, ⁇ -pyran , Dioxolane, tetrahydropyran, dioxane, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, morpholine, oxazole, isoxazole, oxazine, pyrazolidine.
  • Table 1 summarizes those compounds of the general formula 2a which are particularly preferably used in combination with the compounds 1 in the context of the present invention.
  • Compound 2 is furthermore preferably selected from the group consisting of enprofylline, roflumilast, Ariflo and AWD-12-281, N- (3,5-dichloro-1-oxopyridin-4-yl) -4-difluoromethoxy-3- cyclopropylmethoxybenzamide, Ariflo, roflumilast, AWD-12-281 and the above-mentioned compounds of formula 2a being particularly preferred as compound 2 according to the invention.
  • a reference to the abovementioned PDE IV inhibitors 2 includes a reference to their pharmacologically acceptable acid addition salts which may exist.
  • the physiologically compatible acid addition salts which can be formed by 2 are understood to be pharmaceutically compatible 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 or maleic acid ,
  • the pharmaceutical combinations according to the invention from 1_ and 2 are preferably administered by inhalation.
  • Suitable inhalable powders can be filled into suitable capsules (inhalettes) appropriate powder inhalers are applied, are used.
  • inhalative use can also be carried out by applying suitable inhalation aerosols.
  • suitable inhalation aerosols which contain, for example, HFA134a (also called TG134a), HFA227 (also called TG227) or their mixture as propellant.
  • the inhalation application can also take place by means of suitable solutions of the drug combination consisting of 1 and 2.
  • One aspect of the present invention accordingly relates to a medicament which contains a combination of 1 and 2.
  • Another aspect of the present invention relates to a medicament which contains one or more salts 1 and one or more compounds 2, optionally in the form of their solvates or hydrates.
  • the active ingredients can either be used together in a single dosage form or in two separate forms
  • Dosage forms may be included. According to the invention, preference is given to medicaments which contain the active compounds 1 and 2 in a single administration form.
  • the present invention further relates to the use of ⁇ _ and 2 for the production of a therapeutically effective amount of ⁇ and 2 containing medicament for the treatment of inflammatory and / or obstructive respiratory diseases, in particular asthma or chronic obstructive pulmonary disease (COPD), and their complications such as pulmonary Hypertension, also allergic and non-allergic rhinitis.
  • inflammatory and / or obstructive respiratory diseases in particular asthma or chronic obstructive pulmonary disease (COPD)
  • COPD chronic obstructive pulmonary disease
  • the present invention further aims at the simultaneous or successive use of therapeutically effective doses of the combination of the above medicinal products 1 and 2 for the treatment of inflammatory and / or obstructive respiratory diseases, in particular asthma or chronic obstructive pulmonary disease (COPD), and their complications such as, for example, pulmonary hypertension, also allergic and non-allergic rhinitis, through simultaneous or successive application.
  • inflammatory and / or obstructive respiratory diseases in particular asthma or chronic obstructive pulmonary disease (COPD)
  • COPD chronic obstructive pulmonary disease
  • constituents 1 and 2 can be present in the form of their enantiomers, mixtures of the enantiomers or in the form of the racemates.
  • the ratios in which the two active substances ⁇ and 2 can be used in the active substance combinations according to the invention are variable.
  • the active ingredients 1 and 2 may optionally be in the form of their solvates or hydrates.
  • the weight ratios which can be used in the context of the present invention vary on account of the different molecular weight of the different compounds and on the basis of their different potency.
  • the pharmaceutical combinations according to the invention can contain the compounds 1 and 2 in weight ratios which are in a range from 1: 100 to 100: 1, preferably from 1:80 to 80: 1.
  • the weight ratios of 1 to 2 are particularly preferably in a range in which V and 2 are contained in ratios of 1:50 to 50: 1, further preferably 1:20 to 20: 1.
  • preferred combinations according to the invention of V and PDE-IV inhibitor 2 can contain the following weight ratios:
  • compositions according to the invention containing the combinations of 1 and 2 are usually used in such a way that 1 and 2 together in doses of from 0.01 to 10,000 / g, preferably from 0.1 to 2000 / g, particularly preferably from 1 to 1500 g , further preferably from 50 to 1200 ⁇ g per single dose are included.
  • doses of from 0.01 to 10,000 / g preferably from 0.1 to 2000 / g, particularly preferably from 1 to 1500 g , further preferably from 50 to 1200 ⁇ g per single dose are included.
  • V and PDE-IV inhibitor 2 contain such an amount of V and PDE-IV inhibitor 2 that the total dosage per single dose is 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 / g, 230 // g, 235 // g, 240yg, 245 g, 250yi / g, 255 g, 260 g, 265 / yg, 270 g, 275 / g, 280 g, 285y / g, 290 g, 295 // g, 300
  • the combinations according to the invention from 1 and 2 can contain such an amount of V and PDE-IV inhibitor 2 that 16.5 / yg V and 25 / yg 2, 16, 5 / yg V and 50 / yg 2, 16.5 / y g and 100 / yg 2, 16.5 / yg V and 200 / yg 2, 16.5 / yg V and 300 / yg 2, 16.5 / yg r and 400 / y g 2, 16.5 / yg r and 500 // g 2, 16.5 / tg and 600 / g 2, 16.5 / yg V and 700 / g 2, 16.5 / y g V and 800 / g 2, 16.5 / tg and 900 // g 2, 16.5 / yg V and 1000 / yg 2, 33.1 / yg and 25 / y g 2, 33.1 / yg r and 50 //
  • the amounts of active ingredient V and 2 applied per single administration given above correspond to the subsequent amounts of 1 and 2: 20 / yg 1 and administered per single administration 25 // g 2, 20 / yg 1 and 50 / yg 2, 20 / yg 1 and 100 / yg 2, 20 / yg 1 and 200 / yg 2, 20 yg 1 and 300 yg 2, 20 / yg I and 400 / yg 2, 20 / yg 1 and 500 / yg 2, 20 yg 1 and 600 / yg 2, 20 // g 1 and 700 / yg 2, 20 / yg 1 and 800 yg 2, 20 / yg 1 and 900 / yg 2, 20 / yg 1 and 1000 // g 2, 40 / yg 1 and 25 / g 2, 40 / yg I and 50 / yg 2, 40
  • inhalable dosage forms inhalation powders containing propellant gas or propellant-free inhalation solutions come into consideration.
  • Inhalable powders according to the invention containing the combination of active substances 1 and 2 can consist solely of the active substances mentioned or of a mixture of the active substances mentioned with physiologically compatible auxiliaries.
  • propellant-free inhalation solutions also includes concentrates or sterile, ready-to-use inhalation solutions.
  • the dosage forms according to the invention can contain the active ingredient combination from 1 and 2 either together in one or in two separate dosage forms.
  • A) Inhalable powder containing the active ingredient combinations according to the invention from 1 and 2 The inhalable powders according to the invention can contain 1 and 2 either alone or in a mixture with suitable physiologically acceptable excipients.
  • 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, trehalose
  • oligo- and polysaccharides e.g. dextrans
  • polyalcohols e.g. sorbitol, mannitol, xylitol
  • salts e.g. sodium chloride, calcium carbonate
  • Mono- or disaccharides are preferably used, the use of lactose or glucose being preferred, in particular, but not exclusively, in the form of their hydrates.
  • Lactose most preferably lactose monohydrate, is used as an auxiliary as particularly preferred in the sense of the invention.
  • the auxiliaries have a maximum average particle size of up to 250 / ym, preferably between 10 and 150 / ym, particularly preferably between 15 and 80 / ym. If appropriate, it may appear sensible to add finer excipient fractions with an average particle size of 1 to 9 / ym to the excipients mentioned above. The latter finer excipients are also selected from the group of excipients that can be used.
  • micronized active ingredients I and 2 preferably with an average particle size of 0.5 to 10 / ym, particularly preferably 1 to 5 / ym, 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 1 and 2, furthermore 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, such as those are described in DE 36 25 685 A, meter.
  • the 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 (Handihaier) 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 attached via a sieve housing 4, one with a deck 3 connected
  • Inhalation chamber 6, on which a pusher 9, 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, and air passage holes 13 for adjustment the flow resistance.
  • inhalable powders according to the invention are to be filled into capsules (inhalettes) in the sense of the preferred use mentioned above, fill quantities of 1 to 30 mg, preferably from 3 to 20 mg, preferably 5 to 10 mg inhalation powder per capsule. According to the invention, these contain either together or in each case the doses per single dose already mentioned above for V and 2.
  • 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 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 TG 134a and TG227 and mixtures thereof.
  • 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 applied in the form of propellant-free inhalation solutions and inhalation suspensions.
  • 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 percent by volume, in particular up to 60 percent by volume and particularly preferably up to 30 percent by volume.
  • the remaining volume percentages are filled up with water.
  • the solutions and suspensions containing 1 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.
  • Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid.
  • Examples of particularly suitable 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 cases 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.
  • the addition of editic acid (EDTA) or one of the known salts thereof, sodium edetate, as a stabilizer or complexing agent can be dispensed with in the present formulation.
  • Other embodiments include this connection (s).
  • the content based on sodium edetate is below 100 mg / 100 ml, preferably below 50 mg / 100 ml, particularly preferably below 20 mg / 100 ml.
  • Co-solvents and / or other 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.
  • auxiliaries and additives are understood to mean any pharmacologically compatible 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
  • auxiliaries and additives include e.g. surfactants such as Soy lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents,
  • Antioxidants and / or preservatives that guarantee or extend the useful life of the finished pharmaceutical formulation, flavors, 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 auxiliary substances 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 concentration known from the prior art.
  • the preservatives mentioned above are preferably present 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.
  • those inhalers which can nebulize a small amount of a liquid formulation in the therapeutically necessary dosage within a few seconds into an aerosol suitable for therapeutic inhalation.
  • those nebulizers are preferred in which an amount of less than 100 / yL, preferably less than 50 ⁇ L, particularly preferably between 20 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 nebulizer can advantageously be used to produce the inhalable aerosols according to the invention containing the combination of active substances 1 and 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 formed.
  • the preferred atomizer consists of an upper housing part, a pump housing, a nozzle, a locking mechanism, a spring housing, a spring and a reservoir, 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 carries the nozzle arrangement, a hollow piston with valve body, an output flange in which the hollow piston is fastened and which is located in the upper housing part, a locking mechanism which is located in the upper housing part, - a spring housing with the spring located 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 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 active ingredient solution on its high pressure side at the time the spring is triggered. 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 disclosed there and its description.
  • the nozzle body is e.g. of two firmly connected plates made of glass and / or silicon, of which at least one plate has one or more microstructured channels, which the nozzle inlet side with the
  • the nozzle outlet side On the nozzle outlet side there is at least one round or non-round opening of 2 to 10 micrometers deep and 5 to 15 micrometers wide, the depth preferably being 4.5 to 6.5 micrometers and the length being 7 to 9 micrometers. In the case of several nozzle openings, preferably two, the
  • 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 changed be inclined towards one another at an angle of 20 degrees to 160 degrees, an angle of 60 to 150 degrees is preferred, particularly preferably 80 to 100 degrees.
  • 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 microns.
  • the jet directions meet in the vicinity of the nozzle openings.
  • the liquid pharmaceutical preparation hits the nozzle body at 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 via a force-transmitting gear, e.g. a screw-type thrust gear, tensioned by an external torque generated when the upper housing part is turned against the spring housing in the lower housing part.
  • 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. It consists, for example, of a radially elastically deformable ring made of plastic or metal. 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, and preferably into the atomizer; the deformable ring is deformed in the plane of the ring. Structural 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.
  • Lower housing part rotated, 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.
  • 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.
  • FIGS. 6 a / b of WO 97/12687 describe the nebulizer (Respimat®) with which the aqueous aerosol preparations according to the invention can advantageously be inhaled.
  • FIG 6a of WO 97/12687 shows a longitudinal section through the atomizer with the spring under tension.
  • Figure 6b 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 atomizer 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 tension mechanism partially projects 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).
  • the stop (60) 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) slides 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 exchangeable storage container (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 nebulizer described above is suitable for nebulizing the aerosol preparations according to the invention into an aerosol suitable for inhalation.
  • the mass applied should be at least 97%, preferably at least 98%, of all actuations of the inhaler (hub) of a defined amount with a tolerance range of at most 25%, preferably 20% Amount. Between 5 and 30 mg of formulation are preferably applied as 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.
  • a further aspect of the present invention relates to medicaments in the form of propellant-free inhalable solutions or suspensions as described above in connection with a device suitable for the administration of these formulations, preferably in connection with the Respimat®.
  • the present invention preferably aims at propellant-free inhalation solutions or suspensions characterized by the combination of active substances according to the invention and 2 in conjunction with the device known under the name Respimat®.
  • the present invention relates to the above-mentioned devices for inhalation, preferably the Respimat®, characterized in that they contain propellant-free inhalable solutions or suspensions according to the invention described above.
  • 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 conjunction with a
  • suitable device characterized in that it is an energy-operated standing or portable nebulizer that generates inhalable aerosols by means of ultrasound or compressed air according to the Venturi principle or other principles.

Abstract

L'invention concerne de nouvelles compositions médicamenteuses à base de nouveaux anticholinergiques et inhibiteurs de PDE-IV, des procédés permettant de les produire, ainsi que leur utilisation dans le traitement de maladies de voies respiratoires.
PCT/EP2003/006668 2002-07-09 2003-06-25 Nouvelles compositions medicamenteuses a base de nouveaux anticholinergiques et inhibiteurs de pde-iv WO2004004704A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU2003242755A AU2003242755A1 (en) 2002-07-09 2003-06-25 Novel pharmaceutical compositions comprising novel anticholinergic agents and pde-iv inhibitors
EP03762509A EP1521576A1 (fr) 2002-07-09 2003-06-25 Nouvelles compositions pharmaceutiques comprenant de nouveaux agents anticholinergiques et des inhibiteurs de la pde-iv
CA002492026A CA2492026A1 (fr) 2002-07-09 2003-06-25 Nouvelles compositions medicamenteuses a base de nouveaux anticholinergiques et inhibiteurs de pde-iv
JP2004518566A JP2005532379A (ja) 2002-07-09 2003-06-25 新規な抗コリン作動薬およびｐｄｅ−ｉｖ阻害剤を基本とする新規な医薬組成物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10230769.5 2002-07-09
DE10230769A DE10230769A1 (de) 2002-07-09 2002-07-09 Neue Arzneimittelkompositionen auf der Basis neuer Anticholinergika und PDE-IV-Inhibitoren

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WO2004004704A1 true WO2004004704A1 (fr) 2004-01-15

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JP (1) JP2005532379A (fr)
AU (1) AU2003242755A1 (fr)
CA (1) CA2492026A1 (fr)
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WO (1) WO2004004704A1 (fr)

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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
US7071333B2 (en) 2003-07-30 2006-07-04 Bristol-Myers Squibb Company Triazolopurine-based tricyclic compounds and pharmaceutical compositions comprising same
WO2006105401A2 (fr) * 2005-03-30 2006-10-05 Schering Corporation Medicaments et procedes de combinaison d'un anticholinergique, un corticosteroide, et un agoniste beta a action prolongee
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JP2008513416A (ja) * 2004-09-22 2008-05-01 ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング ロフルミラストを含有する水性医薬調剤
US8877164B2 (en) 2005-02-25 2014-11-04 Chiesi Farmaceutici S.P.A. Pharmaceutical aerosol formulations for pressurized metered dose inhalers comprising a sequestering agent

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WO2005013967A1 (fr) * 2003-07-28 2005-02-17 Boehringer Ingelheim International Gmbh Medicaments comprenant des inhibiteurs de pde iv et un nouvel anticholinergique, et leur utilisation pour le traitement de troubles respiratoires
US7071333B2 (en) 2003-07-30 2006-07-04 Bristol-Myers Squibb Company Triazolopurine-based tricyclic compounds and pharmaceutical compositions comprising same
WO2005013994A1 (fr) * 2003-07-31 2005-02-17 Boehringer Ingelheim International Gmbh Medicaments pour inhalation comportant un agent a activite anticholinergique et betamimetique
WO2005067929A1 (fr) * 2004-01-09 2005-07-28 Boehringer Ingelheim International Gmbh Nouvelles compositions pharmaceutiques a base de derives de scopineester et de nicotinamide
JP2007520507A (ja) * 2004-02-06 2007-07-26 メダ ファーマ 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 呼吸器系疾患の治療用の抗コリン作用薬及び４型ホスホジエステラーゼの組合せ剤
JP4700014B2 (ja) * 2004-02-06 2011-06-15 メダ ファーマ 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 呼吸器系疾患の治療用の抗コリン作用薬及び４型ホスホジエステラーゼの組合せ剤
JP2008513416A (ja) * 2004-09-22 2008-05-01 ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング ロフルミラストを含有する水性医薬調剤
US8877164B2 (en) 2005-02-25 2014-11-04 Chiesi Farmaceutici S.P.A. Pharmaceutical aerosol formulations for pressurized metered dose inhalers comprising a sequestering agent
WO2006105401A2 (fr) * 2005-03-30 2006-10-05 Schering Corporation Medicaments et procedes de combinaison d'un anticholinergique, un corticosteroide, et un agoniste beta a action prolongee
WO2006105401A3 (fr) * 2005-03-30 2007-06-21 Schering Corp Medicaments et procedes de combinaison d'un anticholinergique, un corticosteroide, et un agoniste beta a action prolongee
JP2008534611A (ja) * 2005-03-30 2008-08-28 シェーリング コーポレイション 抗コリン作用薬、コルチコステロイドおよび長時間作用性βアゴニストを合わせる薬物および方法
EP2484382A1 (fr) * 2005-03-30 2012-08-08 Schering Corporation Médicament à base d'un inhibiteur de la phosphodiestérase IV sous une forme adaptée à l'inhalation

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DE10230769A1 (de) 2004-01-22
JP2005532379A (ja) 2005-10-27
CA2492026A1 (fr) 2004-01-15
AU2003242755A1 (en) 2004-01-23

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