EP1879571A1 - Combinaison de medicaments a inhaler contenant un betamimetique et un steroide en plus d'un anticholinergique - Google Patents

Combinaison de medicaments a inhaler contenant un betamimetique et un steroide en plus d'un anticholinergique

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Publication number
EP1879571A1
EP1879571A1 EP06763047A EP06763047A EP1879571A1 EP 1879571 A1 EP1879571 A1 EP 1879571A1 EP 06763047 A EP06763047 A EP 06763047A EP 06763047 A EP06763047 A EP 06763047A EP 1879571 A1 EP1879571 A1 EP 1879571A1
Authority
EP
European Patent Office
Prior art keywords
hydroxy
alkyl
methyl
optionally
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06763047A
Other languages
German (de)
English (en)
Inventor
Ingo Konetzki
Thierry Bouyssou
Andreas Schnapp
Michael P. Pieper
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Priority to EP06763047A priority Critical patent/EP1879571A1/fr
Publication of EP1879571A1 publication Critical patent/EP1879571A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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]

Definitions

  • the present invention relates to new medicaments for inhalation containing one or more, preferably an anticholinergic 1 in combination with one or more betamimetics 2 and one or more steroids 3, processes for their preparation and their use in the treatment of respiratory diseases.
  • the present invention relates to medicaments characterized by the content of one or more, preferably an anticholinergic agent l_in combination with one or more betamimetics 2 and one or more steroids 3, optionally in combination with pharmaceutically acceptable excipients, wherein the anticholinergic agent is 1. selected from the group consisting of
  • X ' is a singly negatively charged anion, preferably an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p Toluenesulfonate, optionally in the form of their racemates, enantiomers or hydrates, optionally in the form of their diastereomers, mixtures of their diastereomers or racemates, and optionally in the form of their hydrates and / or solvates; b) compounds of the formula Ib
  • X ⁇ may have the abovementioned meanings, if appropriate in the form of their enantiomers, mixtures of their enantiomers or racemates, and, if appropriate, in the form of their hydrates and / or solvates;
  • A is a dibasic group selected from the groups
  • R, 1 1 J 5 is hydrogen, hydroxy, methyl, ethyl, -CF 3 , CHF 2 or fluorine;
  • R 1 and R 2 are the same or different optionally substituted by C3-C5-cycloalkyl, hydroxy or halogen, or RR 11 uuind R 2 together denote a -C3-C5-Alkylenbrucke,
  • R 13 , R 14 , R ⁇ and R 14 are identical or different, hydrogen, -C 1 -C 4 -alkyl, C 1 -C 6 alkyloxy, hydroxy, -CF 3, -CHF 2, CN, NO 2 or halogen;
  • R 16 is hydrogen, hydroxy, -C 1 -C 4 -alkyl, -Ci-C 4 -alkyloxy, -Ci-C 1 -C 4 -alkylene-halogen, -O-C 1 -C -cycylene-alkylene-halogen,
  • R 1 and R 2 are identical or different, -C 1 -C 5 -alkyl, which may optionally be substituted by -C 3 -C 6 -cycloalkyl, hydroxy or halogen, or
  • R and R together form a -C3-C5-alkylene bridge;
  • R 17 , R 18 , R 17 ' and R 18' are hydrogen, -C 1 -C 4 -alkyl,
  • R x and R x are identical or different, hydrogen, -C 1 -C 4 -alkyl, -C 1 -C 4 -alkyl,
  • R x and R x together represent a single bond or one of the divalent ones
  • a ' is a divalent group selected from
  • R, 1'9 v is hydroxy, methyl, hydroxymethyl, ethyl, -CF3, CHF2 or fluorine;
  • R 1 and R 2 are identical or different, C 1 -C 5 -alkyl, which may optionally be substituted by C 3 -C 6 -cycloalkyl, hydroxy or halogen, or R 1 and R 2 together are a -C 3 -C 5 -alkylene bridge;
  • R 20 , R 21 , R 20 ' and R 21' are identical or different, hydrogen, -C 1 -C 4 -alkyl,
  • oxitropium salts (If), flutropium salts (Ig), ipratropium salts (Ih) and trospium salts (Ii), optionally in combination with pharmaceutically acceptable excipients.
  • betamimetic 2 which may also be referred to as beta-2-agonist, is preferably selected from the group consisting of albuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharines , Isoprenaline, Levosalbutamol, Mabuterol, Meluadrin, Metaproterenol, Orciprenaline, Pirbuterol, Procaterol, Reproterol, Rimiterol, Ritodrine, Salmeterol, Salmefamol, Soterenot, Sulphoneterol, Tiaramide, Terbutaline, Tolubuterol, CHF-1035, HOKU-81, KUL-1248, 3 - (4- ⁇ 6- [2-hydroxy-2- (4-
  • R 1 and R 2 are identical or different and are hydrogen or C 1 -C 4 -alkyl
  • R 3 and R 4 are identical or different and are hydrogen, Ci-C 4 alkyl, -0-C 1 -C 4 -alkyl,
  • R 3 and R 4 together represent one of the bridging groups
  • - C r C 4 alkylene or -OC r C 4 alkylene-O- mean, if appropriate in the form of racemates, enantiomers, diastereomers and optionally in the form of pharmaceutically acceptable acid addition salts and hydrates or solvates.
  • the steroid 3_ is preferably selected from the group consisting of prednisolone (3 ⁇ ), prednisone (3.2), butixocortepionate (33), RPR-106541 (3A), flunisolide QS), beclomethasone (3.6), triamcinolone QJ), budesonide (3.8), fluticasone (3J ) ), mometasone (3.10), ciclesonide (3.11), rofleponide Q ⁇ 2), ST-126 (3 ⁇ 13), dexamethasone (3Ji), 6 ⁇ , 9 ⁇ -difluoro-17 ⁇ - [(2- furanylcarbonyl) oxy] -1,1-hydroxy-16 ⁇ -methyl-3-oxo-androsta-1,4-diene-17 ⁇ -carbothioic acid (S) -fluoromethyl ester (3.15), 6 ⁇ , 9 ⁇ -difluoro-1 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-17 ⁇ -pro
  • salts of the formula Ia in which X "is a singly negatively charged anion, preferably an anion selected from the group consisting of fluorine, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate , Acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate, optionally in the form of their racemates, enantiomers or hydrates, optionally in the form of their diastereomers, mixtures of their diastereomers or racemates, and optionally in the form of their hydrates and / or solvates.
  • anion preferably an anion selected from the group consisting of fluorine, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate , Acetate, citrate, fumarate
  • Preferred drug combinations contain salts of the formula Ia, in which X "is a singly negatively charged anion, preferably an anion selected from the group consisting of fluoride, chlond, bromide, methanesulfonate and p-
  • Toluene sulfonate preferably bromide, optionally in the form of their diastereomers, mixtures of their diastereomers or racemates, and optionally in the form of their hydrates and / or solvates.
  • Preferred drug combinations contain salts of the formula Ia, in which
  • X is a singly negatively charged anion, preferably an anion selected from the group consisting of chlo ⁇ d, bromide and methanesulfonate, preferably bromide, optionally m the form of their diastereomers, mixtures of their diastereomers or racemates, and optionally in the form of their hydrates and / or solvates ,
  • the compound of the formula Ia can be present in the medicament combinations according to the invention particularly preferably in the form of one of its 4 diastereomers, which are listed below:
  • anticholinergic compounds according to the invention are salts of the invention
  • X ' is a singly negatively charged anion, preferably an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate,
  • Succinate, benzoate and p-toluenesulfonate means, optionally in the form of their enantiomers, mixtures of their enantiomers or racemates, and optionally in the form of their hydrates and / or solvates.
  • Preferred drug combinations contain salts of the formula Ib, in which
  • X ⁇ a single negative charged anion, preferably an anion selected from the group consisting of fluoride, chloride, bromide, methanesulphonate and p-toluenesulphonate, preferably bromide, optionally in the form of their enantiomers, mixtures of enantiomers or racemates thereof, and optionally in the form their hydrates and / or solvates.
  • anion selected from the group consisting of fluoride, chloride, bromide, methanesulphonate and p-toluenesulphonate, preferably bromide, optionally in the form of their enantiomers, mixtures of enantiomers or racemates thereof, and optionally in the form their hydrates and / or solvates.
  • Preferred drug combinations contain salts of the formula Ib in which X "is a singly negatively charged anion, preferably an anion selected from the group consisting of chloride, bromide and methanesulfonate, preferably bromide, optionally in the form of their enantiomers, mixtures of their enantiomers or racemates, and optionally in the form of their hydrates and / or solvates.
  • X is a singly negatively charged anion, preferably an anion selected from the group consisting of chloride, bromide and methanesulfonate, preferably bromide, optionally in the form of their enantiomers, mixtures of their enantiomers or racemates, and optionally in the form of their hydrates and / or solvates.
  • Particularly preferred drug combinations contain the compound of formula Ib in the form of the bromide, optionally in the form of their enantiomers, mixtures of their enantiomers or racemates, and optionally in the form of their hydrates and / or solvates.
  • X - an anion selected from chlo ⁇ d, bromide and methanesulfonate, preferably
  • RI 5 is hydroxy, methyl or fluorine, preferably methyl or hydroxy
  • R 1 and R 2 are identical or different, methyl or ethyl, preferably methyl;
  • R 13 , R 14 , R 13 and R 14 are identical or different and denote hydrogen, -CF 3, -CHF 2 or fluorine, preferably hydrogen or fluorine
  • particularly preferred compounds of formula Ic are those in which A is a divalent group selected from
  • R 15 is hydroxy or methyl, preferably methyl
  • R 1 and R 2 are identical or different, methyl or ethyl, preferably methyl,
  • R n , R 14 , R 1 'and R 14 are identical or different, hydrogen or fluorine Of particular importance are those drug combinations which contain one of the following compounds of the formula Ic:
  • the compounds of the formula Ic can be present in the form of their enantiomers, mixtures of their enantiomers or racemates, and, if appropriate, in the form of their hydrates and / or solvates.
  • the anticholinergics 1 contained in the medicament combinations according to the invention are preferably selected from the compounds of the formula Id, in which X "is chloride, bromide or methanesulfonate, preferably bromide;
  • R 16 is hydrogen, hydroxy, -Ci-C4-alkyl, -Ci -Cz ⁇ alkyloxy, -CF 3, -CHF 2,
  • R 1 and R 2 are identical or different, C 1 -C 4 -alkyl, which may optionally be substituted by hydroxyl, fluorine, chlorine or bromine, or R 1 and R 2 together are a -C 3 -C 4 -alkylene bridge;
  • R 17, R 18, R 17 'and R 18' are hydrogen, C r C 4 alkyl,
  • R x and R x ' together represent a single bond or a divalent group selected from O, S, NH and CH 2.
  • R 1 and R 2 are the same or different, methyl or ethyl
  • R, R, R and R are hydrogen, -CF 3 or fluorine, preferably
  • R x and R x ' are identical or different, hydrogen, -CF 3 or fluorine, preferably hydrogen, or
  • R x and R x together represent a single bond or -O-.
  • R 16 is hydrogen, hydroxy or methyl
  • R 1 and R 2 are methyl
  • R 17 , R 18 , R 17 and R 18 are hydrogen or fluorine, preferably hydrogen;
  • R x and R x are identical or different, hydrogen or fluorine, preferably hydrogen, or R x and R x 'together represent a single bond or the group -O-.
  • the compounds of the formula Id can be present in the form of their enantiomers, mixtures of their enantiomers or racemates, and, if appropriate, in the form of their hydrates and / or solvates.
  • the anticholinergics 1 contained in the drug combinations according to the invention are selected from the compounds of the formula Ie in which A 'is a divalent group selected from
  • ⁇ X is chloride, bromide or Methansulfnat, preferably bromide
  • R 19 is hydroxy or methyl
  • R 1 and R 2 are identical or different, methyl or ethyl, preferably methyl;
  • R 20 , R 21 , R 20 ' and R 21' are identical or different, hydrogen, -CF 3, -CHF 2 or fluorine, preferably hydrogen or fluorine.
  • particularly preferred compounds of formula Ie are those in which A 'is a divalent group selected from
  • R 19 is hydroxy or methyl, preferably methyl
  • R 1 and R 2 are identical or different, methyl or ethyl, preferably methyl; R ⁇ , R4 ; R3 and R ⁇ 'are identical or different, hydrogen or fluorine.
  • the compounds of the formula Ie can be present in the form of their enantiomers, mixtures of their enantiomers or racemates, and, if appropriate, in the form of their hydrates and / or solvates.
  • anticholinergics _T is to be understood as referring to the pharmacologically active cations of the respective salts.
  • the anticholinergics contained in the medicament combinations according to the invention are selected from the group consisting of oxitropium salts (If), flutropium salts (Ig), ipratropium salts (Ih) and trospium salts (Jd).
  • the cations oxitropium, flutropium, ipratropium and trospium are the pharmacologically active ingredients. Explicit reference to the aforementioned cations is made by the designations IT to IT. Any reference to the above salts If to 11 naturally includes a reference to the corresponding cations.
  • the salts If to Ii are understood to mean those compounds which, in addition to the cations oxitropium (IT), flutropium (Ig '), ipratropium (Ih') and trospium (1 lb), as the counterion (anion) chloride, bromide, iodide, sulfate , Phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulfonate, with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate being preferred as counterions.
  • the chlorides, bromides, iodides and methanesulfonates are particularly preferred.
  • the chloride is particularly preferred.
  • the methanesulfonates and bromides are of particular importance.
  • drug combinations containing oxitropium salts (If) or Ipratropiumsalze (Ih) wherein the respective bromides are particularly important according to the invention.
  • the abovementioned salts can be present in the medicament combinations according to the invention optionally in the form of their solvates or hydrates, preferably in the form of their hydrates.
  • the betamimetic 2 which may also be referred to as beta-2-agonist, is preferably selected from the group consisting of bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenalm, ibuterol, pirbuterol, procaterol, reproterol , Salmeterol, sulfonterol, terbutaline, toluubuterol, 3- (4- ⁇ 6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -hexyloxy ⁇ -butyl) -benzenesulfoneamide, 4-hydroxy -7- [2- ⁇ [2- ⁇ [3- (2-phenylethoxy) propyl] sulphonyl ⁇ ethyl] -ammo ⁇ ethyl] -2 (3H) -benzothiazolone, 1- (2-phenylethoxy)
  • Betamimetics 2 which are particularly preferably used according to the invention are preferably selected from the group consisting of fenoterol, formoterol, salmeterol, 3- (4- ⁇ 6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylammo] - hexyloxy ⁇ -butyl) - benzenesulfoneamide, 1- [3- (4-methoxybenzylamino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylammo] ethanol, 1- [ 2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylammo] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4
  • R 1 and R 2 are the same or different and are hydrogen, methyl or ethyl;
  • R 3 and R 4 together represent one of the bridging groups propylene, butylene, -O-ethylene-O- or O-propylene-O-, optionally in the form of the racemates, enantiomers, diastereomers and optionally in the form of the pharmaceutically acceptable acid addition salts and hydrates or solvates.
  • R 1 and R 2 are identical or different and are hydrogen or ethyl, preferably hydrogen;
  • R 3 and R 4 are identical or different and are hydrogen, methyl, ethyl, propyl, butyl or methyoxymethyl or
  • R 3 and R 4 together represent one of the bridging groups butylene or -O-ethylene-O-, optionally in the form of the racemates, enantiomers, diastereomers and optionally in the form of the pharmaceutically acceptable acid addition salts and hydrates or solvates
  • the compounds of the formula 2a are preferably used in the combinations according to the invention, in which
  • R 1 and R 2 are hydrogen and R 3 and R 4 are ethyl (2a.l); or b) R 1 and R 2 are hydrogen and R 3 and R 4 are methyl (2a.2); or c) R 1 and R 2 are ethyl and R 3 and R 4 are hydrogen (2a.3); or d) R 1 and R 2 are hydrogen and R 3 and R 4 together are butylene (2a.4); or e) R 1 and R 2 are hydrogen and R 3 and R 4 together are -O-ethylene-O-QaS); or f) R 1 and R 2 are hydrogen and R 3 and R 4 are tert-butyl Qa ⁇ j); or g) R 1 and R 2 are hydrogen and R 3 and R 4 are iso-propyl (2a.7); or h) R 1 and R 2 are hydrogen and R 3 and R 4 are methoxymethyl (2a.8), optionally in the form of the racemates, enantiomers, diastereomers and optionally in the form of the pharmaceutically
  • Acid addition salts with pharmacologically acceptable acids of the betamimetics 2 are understood as meaning, for example, salts selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,
  • Methanesulfonic acid acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, 1-hydroxy-2-naphthalenecarboxylic acid, 4-phenylcinnamic acid, 5- (2,4-difluorophenyl) salicylic acid or maleic acid.
  • Preferred according to the invention are the salts of the betamimetics 2 selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, fumarate, methanesulfonate, A-phenylcinnamate, 5- (2,4-difluorophenyl) salicylate, maleate and xinafoate.
  • the betamimetics 2 can be used in the drug combinations according to the invention in the form of their racemates, enantiomers, diastereomers or mixtures thereof.
  • the enantiomeric or di asteromeric separation from the racemates can be carried out by methods known in the art (eg by chromatography on chiral phases, etc.). More preferably, the betamimetics 2 are used in the form of those enantiomers or diastereomers which are R-configured at the C-OH group.
  • the steroid 3 is selected from the group consisting (j 3 5) of flunisolide, beclomethasone (3.6), triamcinolone (3.7), budesonide (3.8), fluticasone (3.9), mometasone (3.10), ciclesonide (3.11) , Rofleponide (3.12), ST-126 (3 ⁇ 3), dexamethasone (3.14), 6 ⁇ , 9 ⁇ -difluoro-17 ⁇ - [(2-furanylcarbonyl) oxy] -1 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta- 1,4-diene-17 ⁇ -carbothionic acid (S) -fluoromethyl ester (3.15), 6 ⁇ , 9 ⁇ -difluoro-11 ⁇ -hydroxy-16oc-methyl-3-oxo-17 ⁇ -propionyloxy-androsta-1,1,4-diene-17 ⁇ -carbamic acid (S) - (2-oxo-tetrahydrofuran-3S-yl
  • the steroid 3 is selected from the group consisting of budesonide (3.8), fluticasone (3.9), mometasone (3.10), ciclesonide (3.11), 6 ⁇ , 9 ⁇ -difluoro-17 ⁇ - [(2-furanylcarbonyl) oxy] -l ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-l, 4-diene-17 ⁇ -carbothioic acid (S) -fluoromethyl ester (3.15) and etiprednol dichloroacetate (3.17), optionally in the form of their racemates, enantiomers or diastereomers, and optionally in the form of their salts and derivatives, their solvates and / or hydrates.
  • Any reference to steroids 3 includes reference to their optionally existing salts or derivatives, hydrates or solvates.
  • Examples of possible salts and derivatives of steroids 3 may be: Alkahsalze, such as Nat ⁇ um- or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
  • alkyl groups are branched and unbranched alkyl groups having 1 to 4 carbon atoms.
  • the abbreviations Me, Et, Prop or Bu are also used to designate the groups methyl, ethyl, propyl or butyl.
  • the definitions of propyl and butyl include all conceivable isomeric forms of the respective radicals.
  • propyl includes n-propyl and iso-propyl
  • butyl includes iso-butyl, sec-butyl and tert-butyl, etc.
  • the alkylene groups are branched and unbranched divalent alkyl bridges having 1 to 4 carbon atoms. Examples include: methylene, ethylene, propylene or butylene.
  • Alkyloxy groups are, unless stated otherwise, branched and unbranched alkyl groups having 1 to 4 carbon atoms, which are linked via an oxygen atom.
  • methylox, ethyloxy, propyloxy or butyloxy are mentioned.
  • the abbreviations MeO, EtO, PropO or BuO are also optionally used to designate the groups methyloxy, ethyloxy, propyloxy or butyloxy.
  • the definitions propoxy and butoxy include all conceivable isomeric forms of the respective radicals.
  • propyloxy includes n-propyloxy and iso-propyloxy, butoxy includes iso-butyloxy, sec-butyloxy and tert.
  • alkyloxy instead of the name alkyloxy, the term alkoxy is also used. Accordingly, the terms methoxy, ethoxy, propoxy or butoxy are also used to designate the groups methyloxy, ethyloxy, propyloxy or butyloxy.
  • alkylene-alkyloxy groups are branched and unbranched divalent alkyl bridges having 1 to 4 carbon atoms which are monosubstituted, disubstituted or trisubstituted, preferably monosubstituted by an alkyloxy group.
  • an unexpectedly advantageous therapeutic effect in the treatment of inflammatory or obstructive respiratory diseases can be observed when one or more, preferably an anticholinergic 1, is used in combination with pharmacologically acceptable salts of a betamimetics 2 and a steroid 3.
  • ⁇ -mimetics include, for example, general agitation, agitation, insomnia, anxiety, finger shaking, sweating and headache.
  • the active compound combinations according to the invention are characterized in part both by a rapid onset of action and by a long-lasting duration of action. This is of great importance for the well-being of the patient, since on the one hand, after application of the combination, he feels a rapid improvement of his condition and, on the other hand, due to the long duration of action, an application once a day is sufficient.
  • One aspect of the present invention relates to a pharmaceutical composition which contains one or more anticholinergics 1, one or more betamimetics 2 and one or more steroids 3.
  • the active ingredients may be contained either together in a single dosage form or in two separate dosage forms.
  • Preferred according to the invention are medicaments which contain the active compounds 1, 2 and 3 in a single administration form.
  • One aspect of the present invention relates to the above
  • Medicament combinations which contain, in addition to therapeutically effective amounts of 1, 2 and 3, a pharmaceutically acceptable carrier.
  • One aspect of the present invention relates to the above-mentioned medicaments which contain, in addition to therapeutically effective amounts of 1, 2 and 3, no pharmaceutically acceptable carrier.
  • the present invention further relates to the use of therapeutically effective amounts of the active ingredients I- for producing a further one or more, preferably an active ingredient 2 and a drug-containing drug for the treatment of inflammatory and obstructive airway diseases, for the prevention of premature onset labor in obstetrics (tocolysis ), for the recovery of sinus rhythm in the heart in atrio-ventricular block, for the correction of bradykaler arrhythmias (antiarrhythmic), for the treatment of circulatory shock (vasodilation and increase in cardiac output) and for the treatment of itching and inflammation of the skin.
  • inflammatory and obstructive airway diseases for the prevention of premature onset labor in obstetrics (tocolysis ), for the recovery of sinus rhythm in the heart in atrio-ventricular block, for the correction of bradykaler arrhythmias (antiarrhythmic), for the treatment of circulatory shock (vasodilation and increase in cardiac output) and for the treatment of itching and inflammation of the skin.
  • a preferred aspect of the present invention relates to the use of therapeutically effective amounts of the active compounds 1 for producing a further one or more, preferably an active ingredient 2 and a drug-containing drug for the treatment of respiratory diseases, which are selected from the group consisting of obstructive pulmonary diseases of different origin , Pulmonary emphysema of various origins, restrictive lung diseases, interstitial lung diseases, cystic fibrosis, bronchitis of various causes, bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary edema.
  • respiratory diseases which are selected from the group consisting of obstructive pulmonary diseases of different origin , Pulmonary emphysema of various origins, restrictive lung diseases, interstitial lung diseases, cystic fibrosis, bronchitis of various causes, bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary edema.
  • obstructive pulmonary diseases which are selected from the group consisting of bronchial asthma, pediatric asthma, severe asthma, acute asthma attack, chronic bronchitis and COPD (chronic obstructive pulmonary disease) , wherein the use for the preparation of a medicament for the treatment of bronchial asthma and COPD according to the invention is particularly preferred.
  • restrictive lung diseases which are selected from the group consisting of allergic alveolitis, restrictive lung diseases caused by occupational noxae, such as asbestosis or silicosis and restriction due to lung tumors such as lymphangiosis carcinomatosa, bronchoalveolar carcinoma and lymphomas.
  • interstitial lung diseases which are selected from the group consisting of infectious pneumonia, such as due to infection with viruses, bacteria, fungi, protozoa, helminths or other agents, pneumonitis due to differential causes such as aspiration and left ventricular failure, radiation-induced pneumonitis or fibrosis, collagenoses such as lupus erythematosus, scleroderma or sarcoidosis, granulomatosis such as Boeck's disease, idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF).
  • infectious pneumonia such as due to infection with viruses, bacteria, fungi, protozoa, helminths or other agents
  • pneumonitis due to differential causes such as aspiration and left ventricular failure
  • radiation-induced pneumonitis or fibrosis such as lupus erythematosus, scleroderma or sarcoidosis
  • granulomatosis such as Boeck's disease
  • bronchitis such as for example bronchitis caused by bacterial or viral infection gOische, Aller 1 bronchitis and toxic bronchitis.
  • ARDS adult respiratory distress syndrome
  • the above-mentioned use of the drug combinations according to the invention for the manufacture of a medicament for the treatment of asthma or COPD is also important.
  • the present invention further relates to the use of therapeutically effective amounts of an active ingredient of the formula 1 in combination with therapeutically effective amounts of an active ingredient 2 and in combination with therapeutically effective amounts of an active ingredient 3 for the preparation of a medicament for the treatment of one of the abovementioned disorders
  • the present invention further relates to a method for the treatment of one of the abovementioned disorders, which is characterized in that therapeutically effective amounts of an active substance 1 in combination with therapeutically effective amounts of an active substance 2 and in combination with therapeutically effective amounts of an active substance areapplied.
  • the conditions in which the two active compounds 1, 2 and 3 can be used in the active compound combinations according to the invention are vanabel.
  • the active compounds 1, 2 and 3 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 due to the different molecular weight of the different salt forms. The weight ratios indicated below were therefore based on the cations Y_ and the free bases T_.
  • Examples of erfmdungsgespecialized preferred drug combinations are combinations containing the compounds Ia and 2A_ and 3 ⁇ 9; A ⁇ and 22_ and 3J ) ; _la and 23 and 3.9; Ia and 2a.1 and 3 ⁇ 9; Ia and 2a.2 and 3 ⁇ 9; ⁇ ⁇ and 2a.3 and 3 j 9; Ia and 2a.4 and 3J ) ; Ia and 2a.5 and 3J); Ia and 2a.6 and 3J>; Ia and 2a.7 and 3J ) ; Ia and 2a.8 and 3J ) ; Ia and 2 ⁇ and 3.10; _la and 22 and 3.10; _la and 23 and 3JO; Ia and 2a.1 and 3.10; Ia and 2a.2 and 3.10; Ia and 2a.3 and 3.10; Ia and 2a.4 and 3.10; Ia and 2a.5 and 3.10; Ia and 2a.6 and 3.10; Ia and
  • the (3R, 2'R) -enantiomer of the compound Ia is particularly preferably used according to the invention.
  • Examples of preferred drug combinations according to the invention are combinations containing the compounds JJ) and 2J. and 3J ) ; JJ) and 2; 2 and 3 j 9; JJ) and 23 and 3J ) ; Ib and 2a.1 and X9, Jb and 2a2 and 3J ) ; Jb and 2a.3 and 33 ;, Vo and 2a.4 and 3.9; Ib and 2a.5 and 3J); Jb and 2a.6 and 3J); Jb and 2a.7 and 3J>; JJb and 2a.8 and 3J>; Jl) and 21 and 3JO; J ⁇ and 2 j 2 and 3JO; J ⁇ b and 23 and 3JO; Jb and 2aJ.
  • Examples of preferred combinations of medicaments according to the invention are combinations comprising the compounds Ic.l and 2J and 3J ) ; lc.l and 2, 2 and 3J ) ; lc.l and 2; 3 and 3.9; lc.l and 2aJ. and 3.9; lc.l and 2 ⁇ 2 and 3.9; lc.l and 2a3 and 3.9; lc.l and 2 ⁇ 4 and 3.9; lc.l and 2aJ5 and 3.9; lc.l and 2a ⁇ > and 3.9; lc.l and 2aJ7 and 3.9; lc.l and 2a.8 and 3 ⁇ 9; JXJ. and 2y. and 3JO; JCJ.
  • Examples of preferred drug combinations according to the invention are combinations containing the compounds ld.l and 2J. and 3 ⁇ 9; Id.l and 2, 2 and 3j9; Id.l and 23 and 3.9; Id.l and 2a.l and 3.9; Id.l and 2a.2 and 3.9; Id.l and 2a.3 and 3.9; Id.l and 2a.4 and 3.9; ld.l and 2 ⁇ 5 and 3.9; Id.l and 2a.6 and 3.9; ld.l and 2a, and 3.9; ld.l and 2aJ $ and 3.9; ld.l and 2J_ and 3JJ); Id.l and 22 and 3JO; Id.l and 23 and 3.10; IDJ.
  • Examples of preferred drug combinations according to the invention are combinations containing the compounds le.l and 2 ⁇ and 3J); le.l and 2; 2 and 3 ⁇ 9; le.l and 23 and 3.9; le.l and 2a.l and 3.9; le.l and 2a.2 and 3.9; le.l and 2a.3 and 3.9; le.l and 2a.4 and 3.9; le.l and 2a.5 and 3.9; le.l and 2a.6 and 3.9; le.l and 2a.7 and 3.9; le.l and 2a.8 and 3J>; JeJ. and 2 ⁇ and 3JO; JeJ and 2 ⁇ 2 and 3JO; JEj.
  • le.3 and2a.2 and3.9 le.3 and 2a.3 and 3.9; le.3 and 2a.4 and 3.9; le.3 and 2a.5 and 3.9; le.3 and 2au6 and 3.9; le.3 and 2a / 7 and 3.9; le.3 and 2aJ $ and 3.9; le.3 and 2 ⁇ and 3.10; le.3 and 23 and 3 ⁇ 0; le.3 and 23 and 3.10; le.3 and 2a ⁇ and 3.10; le.3 and 2 ⁇ 2 and 3.10; le.3 and 2a.3 and 3.10; le.3 and 2aA and 3.10; le.3 and 2a.5 and 3.10; le.3 and 2a.6 and 3.10; le.3 and 2a.7 and 3.10; le.3 and 2a.8 and 3.10; le.3 and 2 ⁇ and 3.11; le.3 and 2 ⁇ 2 and 3.11; le.3 and 23 and 3.11; le.3 and 2a.1 and 3.11;
  • le.3 and 2 and 317 le.3 and 2, 2 and 3.17; le.3 and 23 and 3.17; le.3 and 2a.1 and 3.17; le.3 and 2a.2 and 3.17; le.3 and 2aJ and 3.17; le.3 and 2 ⁇ 4 and 3.17; le.3 and 2 ⁇ 5 and 3.17; le.3 and 2a.6 and 3.17; le.3 and 2a.7 and 3.17; le.3 and2 ⁇ 8 and 3.17; lc.4 and 2 ⁇ and 3J9, le.4 and 23 and 3J); le.4 and 23 and 3.9; le.4 and 2aJ.
  • le.4 and 2a.2 and 3.9 le.4 and 2a.3 and 3.9; le.4 and 2a.4 and 3.9; le.4 and 2a.5 and 3.9; le.4 and 2a.6 and 3.9; le.4 and 2a.7 and 3.9; le.4 and 2a.8 and 3.9; le.4 and 2 ⁇ and 3.10; le.4 and 2 ⁇ 2 and 3.10; le.4 and 23 and 3.10; le.4 and 2a ⁇ and 3.10; le.4 and 2a3 and 3.10; le.4 and 2a.3 and 3.10; le.4 and 2a.4 and 3.10; le.4 and 2a.5 and 3.10; le.4 and 2a.6 and 3.10; le.4 and 2a.7 and 3.10; le.4 and 2a.8 and 3.10; le.4 and 2 ⁇ and 3.11; le.4 and 23 and 3.11; le.4 and 23 and3.11; le.4 and 2aJ and3.11; le.4 and 4 and 2
  • le.5 and 2a2 and 3.9 le.5 and 2a3 and 3.9; le.5 and 2a.4 and 3.9; le.5 and 2a.5 and 3.9; le.5 and 2a.6 and 3.9; le.5 and 2a.7 and 3.9; le.5 and 2a.8 and 3.9; le.5 and 21.
  • le.5 and 2j2 and 3.10 le.5 and 23 and 3.10; le.5 and 2al and 3.10; le.5 and 2 ⁇ 2 and 3.10; le.5 and 2 ⁇ 3 and 3.10; le.5 and 2a.4 and 3.10; le.5 and 2a.5 and 3.10; le.5 and 2a.6 and 3.10; le.5 and 2a.7 and 3.10; le.5 and 2 ⁇ & and 3.10; le.5 and 21 and 3Jl; le.5 and 22 and 3Jl; le.5 and 2.3 and 3.11; le.5 and 2al and 3.11; le.5 and 2 ⁇ 2 and 3.11; le.5 and 2 ⁇ 3 and 3.11; le.5 and 2a.4 and 3.11; le.5 and 2a.5 and3.11; le.5 and 2a.6 and 3.11; le.5 and 2a.7 and 3.11; le.5 and 2a.8 and 3.11; le.5 and 21 and 3.15; le.5 and 22_ and 3. 3.
  • Examples of medicament combinations which are preferred according to the invention are combinations comprising the compounds_lf and 2J. and 3 ⁇ ; _lf and 2 j 2 and 3 ⁇ ; _lf and 23 and 3.9; If and 2aJ. Jf and 2a.5 and 3.9; Jf and 2a, 6 and 3.9; Jf and 2a, 7 and 3.9; Jf and 2 ⁇ 8 and 3 ⁇ 9; Jf and 2J and 3JO; Jf and 22 and 3JO; Jf and 23 and 3JO; Jf and 2aJ and 3JO; Jf and 23 ⁇ 2 and 3.10; If and 2a3 and 3JO; Jf and 2aA and 3JO; Jf and 2a ⁇ 5 and 3JO; Jf and 2au6 and 3.10; If and 2a / 7 and 3JO; Jf and 2a ⁇ 8 and 3JO; Jf and 2J and 3JJ; Jf and 2, 2 and 3.11; Jf and 23 and 3Jl; Jf and 2aJ and 3Jl;
  • Examples of preferred drug combinations according to the invention are combinations containing the compounds Jg and 2J and X9; Jg and 22 and 3j9; Jg and 23 and 3J); Ig and 2a.l and 3J); Jg and 2a.2 and 3J); Jg and 2a.3 and 3J); Jg and 2a.4 and 3.9; Ig and 2a.5 and 3J ) ; Jg and 2a.6 and 3J); Jg and 2a.7 and 3J); Jg and 2a.8 and 3J ) ; Jg and 2J and 3JO; Jg and 22 and 3JO; Jg and 23 and 3JO; Jg and 2aJ and 3JO; Jg and 2a.2 and 3JO; Jg and 2a3 and 3JO; Jg and 2a, 4 and 3JO; Jg and 2 ⁇ 5 and 3JO; Jg and 2a.6 and 3JO; Jg and 2a.7 and 3.10; Ig and 2a.8 and 3.10; Ig and 2J and 3.
  • Examples of preferred combinations of medicaments according to the invention are combinations containing the compounds Jh and 2J and 3; 9; Jh and 2 ⁇ 2 and 3j9; Jh and 23 and 3.9; Ih and 2aJ and 3.9; Jh and 2 ⁇ 2 and 3J ⁇ Jh and 2a3 and 3 ⁇ 9; Jh and 2a4 and 3.9; Ih and 2a ; 5 and 3 ⁇ 9; Jh and 2a.6 and 3 j 9; Jh and 2aJ and 3J); Jh and 2a.8 and 3 ⁇ 9; Jh and 2J and 3JO; Jh and 2, 2 and 3JO; Jh and 23 and 3JO; Jh and 2aJ and 3JO; Jh and 2a.2 and 3.10; Ih and 2a.3 and 3.10; Ih and 2aJ and 3.10; Ih and 2a.5 and 3.10; Ih and 2a.6 and 3JO; Jh and 2aJ_ and 3JO; Jh and 2 ⁇ 8 and 3JO; J
  • Examples of preferred according to the invention drug combinations are combinations containing the compounds Ji and 2 ⁇ and 3J); Ji and 2 j 2 and 3 J ); Ji and 23 and 3.9; Ii and 2a.1 and 3J ) ; Ji and 2a.2 and 2k9; Ji and 2a.3 and 3J ) ; Ji and 2a.4 and 3J ) ; Ji and 2a.5 and 3J ) ; Ji and 2a.6 and 3J ) ; Ji and 2a.7 and 3J>; Ji and 2a.8 and 3J ) ; Ji and 2y. and 3.10, Ji and 2J. and 3JO; Ji and 23 and 3JO; Ji and 2aJ.
  • the application of the inventive medicament containing the combinations of I 1 2_und 3 are normally administered so that the cation 1 /, the compound 2 (based on free base) and the compound 3 present together in doses of 0.01 to lOOOO ⁇ g, preferably 0, 1 to 5000 .mu.g, preferably from 25 to 2000 .mu.g, particularly preferably from 50 to 100 .mu.g per single dose are included.
  • inventive combinations of 1, 2 and 3 contain such an amount of active ingredient that the total dosage per single dose about 15 ⁇ g, 20 ⁇ g, 25 ⁇ g, 30 ⁇ g, 35 ⁇ g, 40 ⁇ g, 45 ⁇ g, 50 ⁇ g, 55 ⁇ g, 60 ⁇ g, 65 ⁇ g, 70 ⁇ g, 75 ⁇ g, 80 ⁇ g, 85 ⁇ g, 90 ⁇ g, 95 ⁇ g, 100 ⁇ g, 105 ⁇ g, 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 ⁇ g,
  • 0.1-100 ⁇ g of a compound of the formula 1 can be administered per single administration.
  • 1 to 500 ⁇ g, particularly preferably 3 to 100 ⁇ g of the compound of the formula 1 are administered per single administration, a dosage range of 5 to 75 ⁇ g, preferably of 7 to 50 ⁇ g being preferred according to the invention.
  • the medicaments according to the invention are administered in such an amount that 9 to 40 ⁇ g, more preferably 1 to 30 ⁇ g, more preferably 12 to 25 ⁇ g of the compound of formula 1 are administered per amount become.
  • 5 ⁇ g, 7.5 ⁇ g, 10 ⁇ g, 12.5 ⁇ g, 15 ⁇ g, 17.5 ⁇ g, 20 ⁇ g, 22.5 ⁇ g, 25 ⁇ g, 27.5 ⁇ g, 30 ⁇ g, 32.5 ⁇ g may be used per single dose , 35 ⁇ g, 37.5 ⁇ g, 40 ⁇ g, 42.5 ⁇ g, 45 ⁇ g, 47.5 ⁇ g, 50 ⁇ g, 52.5 ⁇ g, 55 ⁇ g, 57.5 ⁇ g, 60 ⁇ g, 62.5 ⁇ g, 65 ⁇ g, 67.5 ⁇ g, 70 ⁇ g, 72.5 ⁇ g or 75 ⁇ g a compound of formula 1 are applied.
  • the particular appropriate amount of salt used Ia or possibly used for reaching hydrates or solvates are readily calculable for the skilled person depending on the choice of anion.
  • the administration of the abovementioned dosages is preferably carried out one to four times daily, the application two to three times a day being particularly preferred according to the invention. If the diastereomer (3R, 2'R) -la preferred according to the invention is used, the application of the above-mentioned If appropriate, active substance quantities can also be administered once a day.
  • such amounts of anticholinergic agent are administered that 50 to 100 ⁇ g, preferably 100 to 800 ⁇ g, more preferably 200 to 700 ⁇ g, more preferably 300 to 600 ⁇ g of Ib are contained per single dose.
  • the respective corresponding amount of the salt used Ib or optionally used for reaching hydrates or solvates are readily calculable for the skilled person depending on the choice of anion.
  • the administration of the abovementioned dosages is preferably one to three times a day, the one to twice, particularly preferably the once daily application in particular in the case of application of the enantiomerically pure compounds Ib-en is particularly preferred according to the invention.
  • such amounts of anticholinergic (lc ', _ ld' or _le ') are applied that for each single dose of 1 - 500 ⁇ g, preferably 5 - 300 micrograms, particularly preferred 10-200 ⁇ g lc ', _ ld' or Ie 'are included.
  • the respective appropriate amount of the salt used Ic, Id or _le or optionally used for reaching hydrates or solvates are easily calculable for the skilled person depending on the choice of anion in the case of cations Ic, Id or Ie, the application of the above doses is preferably one to three times a day, wherein the one to twice, particularly preferably once daily application according to the invention is particularly preferred
  • such amounts of anticholinergic (If) can be administered that 1 to 500 .mu.g, preferably 5 to 300 .mu.g, particularly preferably 15 to 200 .mu.g, are contained per single administration.
  • the respective appropriate amount of the reaching If salt or possibly used reaching hydrates or solvates are easily calculable for the skilled person depending on the choice of anion in the case of Oxitropiums If the application of the above dosages is preferably one to four times daily, the two to three times daily administration according to the invention is particularly preferred.
  • such amounts of anticholinergic can be applied that per single dose 1 - 500 ⁇ g, preferably 5 - 300 micrograms, more preferably 15-200 micrograms Ij ⁇ are included ,
  • the particular appropriate amount of salt used Ig or optionally used reaching hydrates or solvates are easily calculable for the skilled person depending on the choice of anion.
  • the administration of the abovementioned dosages is preferably carried out one to four times a day, the application two to three times a day being particularly preferred according to the invention.
  • Ih / amounts of anticholinergic (Ih ') can be applied such that 1-150 ⁇ g, preferably 5-300 ⁇ g, more preferably 20-200 ⁇ g IhV are contained per single dose.
  • the administration of the abovementioned dosages is preferably carried out one to four times daily, with the application of two to three times, particularly preferably three times a day, being particularly preferred according to the invention.
  • 1T such amounts of anticholinergic (Ii ') can be applied that for each single dose 1000-6500 ⁇ g, preferably 2000-6000 ⁇ g, more preferably 3000-5500 ⁇ g, more preferably 4000-5000 ⁇ g IT are included.
  • 3500 .mu.g, 3750 .mu.g, 4000 .mu.g, 4250 .mu.g, 4500 .mu.g, 4750 .mu.g, or 5000 .mu.g IT can be administered per single administration.
  • the particular appropriate amount of used salt 2 or optionally used for reaching hydrates or solvates are easily calculable for the skilled person depending on the choice of anion.
  • the application of the dosages mentioned above is preferably carried out once to three times daily, wherein the application once to twice daily according to the invention is particularly preferred.
  • Compounds 3 such amounts are administered, that for each single dose about 1 - 1500 micrograms are administered. Preferably, such amounts are applied to 3 that 5 - lOOO ⁇ g 3 are included per single dose.
  • the application of the active compound combinations according to the invention is preferably carried out by inhalation.
  • the ingredients 1, 2 and 3 must be provided in inhaled dosage forms.
  • inhalable dosage forms in particular inhalable powders are considered.
  • Inventive inhalable powders containing the active ingredient combination of X, 2 and 3 may consist solely of the active substances mentioned or of a mixture of the active substances mentioned with physiologically acceptable excipients.
  • the dosage forms according to the invention may contain the active ingredient combination of .1, 2 and 3 either together in one or in two separate administration forms. This in the
  • the inhalable powders according to the invention may contain 1., _2_und_3_entrepreneur either alone or in admixture with suitable physiologically acceptable excipients.
  • physiologically acceptable excipients can be used to prepare these inhalable powders according to the invention:
  • Monosaccharides eg glucose or arabinose
  • disaccharides eg lactose, sucrose, maltose, trehalose
  • oligo- and polysaccharides eg dextrans
  • polyalcohols eg sorbitol, mannitol, xylitol
  • salts eg sodium chloride, calcium carbonate
  • mono- or disaccharides are used, wherein the use of lactose or glucose, in particular, but not exclusively in the form of their hydrates, is preferred.
  • Lactose most preferably lactose monohydrate, is used as adjuvant for the purposes of the invention.
  • the auxiliaries have a maximum mean particle size of up to 250 ⁇ m, preferably between 10 and 150 ⁇ m, especially preferably between 15 and 80 ⁇ m. If appropriate, it may appear appropriate to add finer excipient fractions having a mean particle size of 1 to 9 ⁇ m to the auxiliaries mentioned above. The latter finer excipients are also selected from the aforementioned group of usable excipients. In particularly preferred inhalable powders, the excipient is a middle one
  • average particle size refers to the 50% value from the volume distribution measured by a laser diffractometer according to the dry dispersion method. Analogously, the 10% fine fraction in the sense used here is to be understood as meaning the 10% value from the volume distribution measured with a laser diffractometer.
  • Auxiliaries of high crystallinity are preferably used for the powder formulations according to the invention. This crystallinity can be judged from the enthalpy (solution enthalpy) released upon dissolution of the excipient.
  • lactose monohydrate adjuvant used particularly preferably according to the invention, it is preferable to use lactose which is replaced by a
  • Solution enthalpy of> 45 J / g, preferably of> 50 J / g, more preferably of> 52 J / g is characterized.
  • micronized active ingredient 1, 2_ and 3 preferably having an average particle size of 0.5 to lO ⁇ m, more preferably from 1 to 5 .mu.m, the excipient mixture admixed.
  • the inhalable powders according to the invention may be provided either in the form of a single powder mixture containing both 1, 2 and 3 or in the form of separate inhalable powders which are only 1, 2 or 3 and applied.
  • the inhalable powders according to the invention can be applied by means of inhalers known from the prior art.
  • Inhalable powders according to the invention which besides 1., 2_ and 3_ also contain a physiologically acceptable excipient, can be administered, for example, by means of inhalers comprising a single dose from a supply by means of a measuring chamber as described in US 4570630A or by other apparatuses such as they are described in DE 36 25 685 A, metering.
  • the inhalable powders according to the invention which contain, in addition to 1, 2_ and 3_physiologically harmless excipient, however, filled into capsules (called inhalers), which are used in inhalers such as described in WO 94/28958, for example.
  • FIG. 1 A particularly preferred inhaler for use of the medicament combination according to the invention in capsules is shown in FIG.
  • This inhaler for the inhalation of powdered medicines from capsules is characterized by a housing 1, comprising two windows 2, a deck 3, in which there are air inlet openings and which is provided with a sieve 5 fastened via a screen housing 4, one with deck 3 connected inhalation chamber 6, on which a provided with two ground needles 7, is provided against a spring 8 movable pusher 8, and a hinged via an axis 10 to the housing 1, the deck 3 and a cap 11 mouthpiece 12, and air passage holes 13 for the Strömun ⁇ G6S ° resistance setting.
  • the inhalable powders according to the invention comprising 1, 2_ and 3 by means of powder-containing capsules
  • those capsules whose material is selected from the group of synthetic plastics, more preferably selected from the group consisting of polyethylene, polycarbonate, polyester, polypropylene and polyethylene terephthalate.
  • Polyethylene, polycarbonate or polyethylene terephthalate are particularly preferred synthetic synthetic materials. If polyethylene is used as one of the capsule materials which are particularly preferred according to the invention, preference is given to polyethylene having a density between 900 and 1000 kg / m 3 , preferably from 940 to 980 kg / m 3 , particularly preferably from about 960 to 970 kg / m 3 (high molecular weight).
  • the synthetic plastics in the context of the invention can be processed in a versatile manner by means of the manufacturing process known in the prior art.
  • Preferred in the context of the invention is the injection molding processing of plastics.
  • Particularly preferred is the injection molding technique waiving the use of mold release agents. This production process is well-defined and characterized by a particularly good reproducibility.
  • Another aspect of the present invention relates to the aforementioned capsules containing the above-mentioned inhalable powders according to the invention with 1, 2_ and ⁇ .
  • the inhalable powders according to the invention are to be filled into capsules (inhalettes) in the sense of the preferred application mentioned above, fillages of from 1 to 30 mg, preferably from 3 to 20 mg, preferably from 5 to 10 mg of inhalable powder per capsule are suitable.
  • the present invention further comprises a kit consisting of two capsules, each containing one of the active ingredients 1, 2_ and 3_, optionally in combination with one of the physiologically compatible auxiliaries mentioned above.
  • the present invention relates to an inhalation kit consisting of one or more of the above-described capsules containing 1, 2_ and 3_ inhalable powders according to the invention in combination with the inhaler according to FIG. 1.
  • the present invention further relates to the use of the abovementioned capsules, which are characterized by a content of inhalable powder according to the invention with 1, 2_ and 3_, for the production of a medicament for the treatment of respiratory diseases, in particular for the treatment of COPD and / or asthma.
  • the presentation of filled capsules containing the inhalable powders according to the invention is carried out by methods known in the art by filling the empty capsules with the inhalable powders according to the invention.
  • Propellant gas-containing inhalation aerosols according to the invention can be dissolved in propellant gas or contained in dispersed form in the 1st, 2nd and 3rd stages. This can be 1., 2_ and 3_in separate Dosage forms or in a common dosage form may be included, wherein 1, 2_und 3 either all dissolved, all dispersed or dissolved in each case only one component and the other may be dispersed.
  • propellant gases which can be used for the preparation of the inhalation aerosols according to the invention are known from the prior art.
  • Suitable propellant gases are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • the abovementioned propellant gases may be used alone or in mixtures thereof.
  • Particularly preferred propellants are halogenated alkane derivatives selected from TGI 34a and TG227 and mixtures thereof.
  • the propellant-containing inhalation aerosols according to the invention may also contain further constituents such as co-solvents, stabilizers, surfactants, antioxidants, lubricants and pH adjusters. All of these ingredients are known in the art.
  • the propellant gas-containing inhalation aerosols according to the invention may contain up to 5% by weight of active ingredient 1, 2_ and / or 3_. 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, 2_and / or 3.
  • the active substance 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.
  • MDIs metered dose inhalers
  • another aspect of the present invention relates to pharmaceutical compositions in the form of propellant-containing aerosols as described above in association with one or more inhalers suitable for administering these aerosols.
  • the present invention relates to inhalers, characterized in that they contain the propellant-containing aerosols according to the invention described above.
  • the present invention further relates to cartridges which can be equipped with a suitable valve in a suitable inhaler and which contain one of the abovementioned propellant-containing inhalation aerosols according to the invention. Suitable cartridges and processes for filling these cartridges with the propellant-containing inhalable inhalable aerosols according to the invention are known from the prior art.
  • propellant-free inhalable solutions or suspensions Particular preference is given to the application of the active ingredient combination according to the invention in the form of propellant-free inhalable solutions and
  • Suitable solvents for this purpose are aqueous or alcoholic, preferably ethanolic solutions.
  • the solvent may be water only or it may be 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% by volume, in particular up to 60% by volume and more preferably up to 30% by volume.
  • the remaining volume percentages are filled up with water.
  • the 1, 2_ and 3, separately or together containing solutions or suspensions are adjusted with suitable acids to a pH of 2 to 7, preferably from 2 to 5.
  • acids selected from inorganic or organic acids can be used. Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid.
  • organic acids examples include: 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 substances.
  • organic acids ascorbic acid, fumaric acid and citric acid are preferable.
  • mixtures of said acids may also be employed, particularly in the case of acids which, in addition to their acidification properties, also possess other properties, e.g. as flavorants, antioxidants or complexing agents, such as citric acid or ascorbic acid.
  • Hydrochloric acid is particularly preferably used according to the invention for adjusting the pH.
  • the addition of editic acid (EDTA) or one of the known salts thereof, sodium edetate, as a stabilizer or Complexing agents are dispensed with.
  • Other embodiments include this compound (s).
  • the content based on sodium edetate is below 100 mg / 100 ml, preferably below 50 mg / 100 ml, more preferably below 20 mg / 100 ml.
  • those inhalable solutions in which the content of sodium edetate is 0 to 10 mg / 100 ml are preferred.
  • Co-solvents and / or further auxiliaries can 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, for example alcohols - in particular isopropyl alcohol, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
  • auxiliaries and additives is meant in this context any pharmacologically acceptable substance which is not an active substance but which can be formulated together with the active ingredient (s) in the pharmacologically suitable solvent in order to improve the qualitative properties of the active ingredient formulation. These substances preferably do not develop any appreciable or at least no undesirable pharmacological effect in the context of the intended therapy.
  • the auxiliaries and additives include e.g.
  • surfactants e.g. Soya lecithin, oleic acid, sorbitan esters such as polysorbates, polyvinylpyrrolidone other stabilizers, chelating agents, antioxidants and / or preservatives which assure or prolong the useful life of the finished drug formulation, flavoring agents, vitamins and / or other additives known in the art.
  • Additives also include pharmacologically acceptable salts such as sodium chloride as isotonants.
  • Preferred excipients include antioxidants, such as ascorbic acid, if not already used for pH adjustment, vitamin A, vitamin E, tocopherols, and similar vitamins or pro-vitamins found in the human organism.
  • Preservatives may be used to protect the formulation from contamination by germs. Suitable preservatives are those known in the art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art.
  • the above-mentioned preservatives are preferably in Concentrations of up to 50mg / 100ml, more preferably between 5 and 20 mg / 100ml.
  • Preferred formulations contain, in addition to the solvent, water and the active ingredient combination of 1, 2_ and 3_ only benzalkonium chloride and sodium edetate. In another preferred embodiment, sodium edetate is dispensed with.
  • propellant-free inhalable solutions are particularly those inhalers that can nebulise a small amount of a liquid formulation in the therapeutically necessary dosage within a few seconds in a therapeutically inhalation suitable aerosol.
  • Such a device for the 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 as well as in WO 97/12687 (there in particular Figures 6a and 6b).
  • the nebulizers (devices) described there are also known as Respimat®.
  • This nebulizer can advantageously be used to produce the inhalable aerosols according to the invention containing the combination of active substances from 1, 2_ and 3_. Due to its cylindrical shape and a handy size of less than 9 to 15 cm in length and 2 to 4 cm in width, this device can always be carried by the patient.
  • the nebulizer sprays a defined volume of the drug formulation using high pressures through small nozzles to produce inhalable aerosols.
  • the preferred atomizer of an upper housing part, a pump housing, a nozzle, a locking mechanism, a spring housing, a spring and a reservoir characterized by a Pumpengehause, which is fixed in the housing upper part, and which carries at one end a Dusenkorper with the nozzle or Dusenanssen, a hollow piston with Ventilkorper, a Abtriebsflansch in which the hollow piston is fixed, and which is located in the housing upper part, a locking work, the located in the housing upper part, a spring housing with the spring then located, which is rotatably mounted on the housing upper part by means of a rotary bearing, a housing base, 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 protrudes partially into the cylinder of the pump housing and is arranged axially displaceable in the cylinder. Particular reference is made to FIGS. 1-4, in particular FIG. 3, and the associated parts of the description Hollow piston with valve body exerts on its high pressure side at the time of release of the spring 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 Wirkstofflosung from doing Volumes of 10 to 50 microliters are preferred, more preferred are volumes of 10 to 20 microliters, most preferably a volume of 15 microliters per stroke
  • valve body is preferably attached to the end of the hollow piston, which faces the Dusenkorper
  • the nozzle in the nozzle body is preferably microstructured, ie produced by microtechnology.
  • Microstructured nozzle bodies are disclosed, for example, in WO-94/07607, the contents of which are hereby incorporated by reference, in particular to FIG. 1 disclosed therein and the description thereof
  • the Dusenkorper z consists of two firmly interconnected plates made of glass and / or silicon, of which at least one plate has one or more microstructured channels that connect the Duseneinlhouseite with the Dusenauslouseite On the
  • Dusenauslanketti is at least one round or non-round opening from 2 to 10
  • Micrometer depth and 5 to 15 micrometers wide the depth preferably at 4, 5 to
  • the directions of the nozzles in the nozzle body can run parallel to one another or they are in the direction of Nozzle opening inclined to each other.
  • the jet directions may be inclined at an angle of 20 degrees to 160 degrees to each other, preferably an angle of 60 to 150 degrees, particularly preferably 80 to 100 °.
  • the nozzle orifices are preferably located at a distance of 10 to 200 microns, more preferably at a distance of 10 to 100 microns, more preferably 30 to 70 microns. Most preferred are 50 microns.
  • the jet directions accordingly meet in the vicinity of the nozzle openings.
  • the liquid pharmaceutical preparation meets the nozzle body with an inlet pressure of up to 600 bar, preferably 200 to 300 bar, and is atomized via the nozzle openings into an inhalable aerosol.
  • the preferred particle or droplet sizes of the aerosol are up to 20 microns, preferably 3 to 10 microns.
  • the locking mechanism includes a spring, preferably a cylindrical helical compression spring, as a memory for the mechanical energy.
  • the spring acts on the output flange as a jump piece whose movement is determined by the position of a locking member.
  • the path of the output flange is precisely limited by an upper and a lower stop.
  • the spring is preferably transmitted via a force translating gear, e.g. a fferschubgetriebe, stretched by an external torque that is generated when turning the upper housing part against the spring housing in the lower housing part.
  • the upper housing part and the output flange contain a single or multi-start wedge gear.
  • the locking member with engaging locking surfaces is arranged annularly around the output flange. It consists for example of a radially elastically deformable Rmg 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 push in the path of the output flange and prevent the relaxation of the spring.
  • the Sprerrglied is triggered by a button.
  • the release button is connected or coupled to the locking member.
  • the shutter button is parallel to the ring plane, and preferably in the atomizer, moved; while the deformable ring is deformed in the ring plane. Constructive details of the locking mechanism are described in WO 97/20590.
  • the housing base is pushed in the axial direction over the spring housing and covers the storage, the Ant ⁇ eb the spindle and the Vorratsbehalter for the fluid
  • Betatigen atomizer Gehauseobereil When Betatigen atomizer Gehauseobereil is rotated against the housing base, the Gehauseunterteil entrains the spring housing.
  • the spring is pressed together by the fferschubget ⁇ ebe and stretched, and the locking mechanism automatically locks the angle of rotation is preferably em integer fraction of 360 degrees, eg 180 degrees
  • the hollow piston is withdrawn within the cylinder in the pump housing, whereby a subset of the fluid is sucked from the storage container in the high-pressure chamber in front of the nozzle.
  • the storage container contains the aqueous aerosol preparation according to the invention
  • the atomization process is initiated by lightly impressing the release button.
  • the blocking mechanism clears the way for the Abt'ebsteil.
  • the tensioned spring pushes the piston into the cylinder of the pump housing.
  • the fluid is expelled from the nebulizer nozzle in atomized form
  • the components of the nebulizer are made of a functionally suitable material
  • the housing of the nebulizer and - as far as the function allows - other parts are preferably made of plastic, for example by Sp ⁇ tzg screen process, prepared for medical purposes are physiologically harmless Materials used
  • FIGS. 6 a / b of WO 97/12687 to which reference is made in full at this juncture, the nebuliser (Respimat®) with which the aqueous aerosol preparations according to the invention can advantageously be inhaled is obtained
  • FIG. 6a of WO 97/12687 shows a longitudinal section through the atomizer with the spring tensioned
  • FIG. 6b of WO 97/12687 shows a longitudinal section through the atomizer with a relaxed spring.
  • the housing upper part (51) contains the pump housing (52), at the end of which the holder (53) for the atomizer nozzle is attached. In the holder is the nozzle body (54) and a filter (55).
  • the hollow piston (57) fastened in the discharge flange (56) of the locking mechanism projects partially into the cylinder of the pump housing. At its end, the hollow piston carries the valve body (58).
  • the hollow piston is sealed by means of the seal (59).
  • the stop (60) on which the Abt ⁇ ebsflansch rests with a relaxed spring. At the Abt ⁇ ebsflansch is the stop (61) on which abuts the Abtbeebsflansch with cocked spring.
  • the locking member (62) slides between the stop (61) and a Abstutzung (63) in the upper housing part.
  • the shutter button (64) is in communication with the lock gear.
  • the Gehauseobereil ends in the mouthpiece (65) and is closed with the attachable cap (66).
  • the spring housing (67) with compression spring (68) is rotatably mounted by means of the snap lugs (69) and pivot bearing on the upper housing part.
  • Within the spring housing is the replaceable Vorratsbeh age (71) for the fluid to be atomized (72).
  • the Vorratsbehalter is closed with the stopper (73) through which the hollow piston protrudes into the Vorratsbehalter and immersed with its end in the fluid (stock of Wirkstoffl ⁇ sung).
  • the spindle (74) for the mechanical counter is mounted in the lateral surface of the spring housing.
  • the Ant ⁇ ebs ⁇ tzel (75) At the end of the spindle, which faces the upper housing part, there is the Ant ⁇ ebs ⁇ tzel (75). The rider (76) sits on the spindle.
  • the nebulizer described above is suitable for nebulising the aerosol preparations according to the invention to form an aerosol suitable for inhalation.
  • the applied mass should be at least 97%, preferably at least 98% of all actuations of the inhaler (Hube) of a defined amount with a maximum tolerance of 25%, preferably 20% Amount correspond
  • between 5 and 30 mg of formulation per stroke are applied as a defined mass, more preferably between 5 and 20 mg.
  • formulation according to the invention may also be aerosolized by means of inhalers other than those described above, for example jet-stream inhalers.
  • a further aspect of the present invention relates to pharmaceuticals in the form of propellant-free inhalable solutions or suspensions as described above in conjunction with a device suitable for administering these formulations, preferably in conjunction with the Respimat®.
  • the present invention is directed to propellant-free inhalable solutions or suspensions characterized by the combination of active substances 1, 2, and 3 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®, characterized in that they contain above-described propellant-free inhalable solutions or suspensions according to the invention.
  • the propellant-free inhalable solutions or suspensions according to the invention can also be present as concentrates or sterile ready-to-use inhalable solutions or suspensions in addition to the solutions and suspensions provided above for application in the Respimat.
  • ready-to-use formulations can be generated from the concentrates by adding isotonic saline solutions.
  • Sterile ready-to-use formulations can be applied by means of energy-powered, stand-alone or portable nebulizers which generate inhalable aerosols by means of ultrasound or compressed air according to the Venturi principle or other principles.
  • a further aspect of the present invention relates to pharmaceuticals in the form of propellant-free inhalable solutions or suspensions, described above as concentrates or sterile ready-to-use formulations, in combination with a device suitable for administering these solutions, characterized in that the device is is an energy-powered stand-alone or portable nebulizer that generates inhalable aerosols by means of ultrasound or compressed air according to the Venturi principle or other principles.

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Abstract

L'invention concerne de nouveaux médicaments à inhaler contenant un ou plusieurs, de préférence un anticholinergique 1 combiné à un ou plusieurs bêtamimétiques 2 et un ou plusieurs stéroïdes 3. L'invention concerne également des procédés de fabrication de ces médicaments et leur utilisation dans la thérapie de maladies des voies respiratoires.
EP06763047A 2005-04-23 2006-04-19 Combinaison de medicaments a inhaler contenant un betamimetique et un steroide en plus d'un anticholinergique Withdrawn EP1879571A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP06763047A EP1879571A1 (fr) 2005-04-23 2006-04-19 Combinaison de medicaments a inhaler contenant un betamimetique et un steroide en plus d'un anticholinergique

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP05008956 2005-04-23
PCT/EP2006/061679 WO2006114379A1 (fr) 2005-04-23 2006-04-19 Combinaison de medicaments a inhaler contenant un betamimetique et un steroide en plus d'un anticholinergique
EP06763047A EP1879571A1 (fr) 2005-04-23 2006-04-19 Combinaison de medicaments a inhaler contenant un betamimetique et un steroide en plus d'un anticholinergique

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EP1879571A1 true EP1879571A1 (fr) 2008-01-23

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JP2009537585A (ja) * 2006-05-24 2009-10-29 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 呼吸器疾患の治療のための新規医薬組成物
US8815258B2 (en) 2009-05-29 2014-08-26 Pearl Therapeutics, Inc. Compositions, methods and systems for respiratory delivery of two or more active agents
CN107412212B (zh) 2009-05-29 2021-01-22 珍珠治疗公司 经肺递送长效毒蕈碱拮抗剂及长效β2肾上腺素能受体激动剂的组合物及相关方法与系统
CA2905542C (fr) 2013-03-15 2022-05-03 Pearl Therapeutics, Inc. Procedes et systemes de conditionnement de matieres cristallines particulaires
CN115989032A (zh) 2020-07-31 2023-04-18 化学研究有限公司 用于吸入施用的组合疗法

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CA2607391A1 (fr) 2006-11-02
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US20060239908A1 (en) 2006-10-26

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