EP1778227A1 - Medicament a inhaler contenant des corticosteroides, des beta-mimetiques et un nouvel anticholinergique - Google Patents

Medicament a inhaler contenant des corticosteroides, des beta-mimetiques et un nouvel anticholinergique

Info

Publication number
EP1778227A1
EP1778227A1 EP05771986A EP05771986A EP1778227A1 EP 1778227 A1 EP1778227 A1 EP 1778227A1 EP 05771986 A EP05771986 A EP 05771986A EP 05771986 A EP05771986 A EP 05771986A EP 1778227 A1 EP1778227 A1 EP 1778227A1
Authority
EP
European Patent Office
Prior art keywords
composition according
hydroxy
acid
ethanol
propellant
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Withdrawn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
EP05771986A
Other languages
German (de)
English (en)
Inventor
Michael P. Pieper
Michel Pairet
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
Priority claimed from DE102004038886A external-priority patent/DE102004038886A1/de
Priority claimed from DE102004053023A external-priority patent/DE102004053023A1/de
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Publication of EP1778227A1 publication Critical patent/EP1778227A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—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
    • 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
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids

Definitions

  • the present invention relates to novel drug compositions based on a novel anticholinergic, corticosteroids and betamimetics, processes for their preparation and their use in the treatment of respiratory diseases.
  • the present invention relates to novel drug compositions for inhalation based on a novel anticholinergic, corticosteroids and betamimetics, to processes for their preparation and to their use in the treatment of respiratory diseases.
  • an unexpectedly beneficial therapeutic effect can be demonstrated in the treatment of inflammatory or obstructive airways disease when a novel anticholinergic agent is co-administered with one or more corticosteroids and together with one or more betamimetics.
  • the above-mentioned effects can be observed both in simultaneous application within a single drug formulation and in successive application of the three drug components in separate formulations.
  • the simultaneous administration of the active ingredient components in a single formulation is preferred.
  • the medicaments according to the invention are preferably applied by inhalation according to the invention.
  • X is a singly 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.
  • the salts of the formula ⁇ _ are used, in which
  • X is a singly negatively charged anion selected from the group
  • Chloride bromide, 4-toluenesulfonate and methanesulfonate, preferably bromide.
  • salts of formula 1 are used wherein X "is a singly negatively charged anion selected from the group
  • the salts of formula 1 are known from international patent application WO 03/064419. Reference to the salts of Formula 1 includes reference to their optionally available hydrates and solvates.
  • corticosteroids are understood as meaning compounds which are selected from the group consisting of flunisolides (2J-), beclomethasone (2 ⁇ 2), triamcinolones (2 ⁇ 3), budesonide (2.4), Fluticasone (2y), mometasone (2yy), ciclesonide (27), rofleponide (2y), GW 215864 (2 ⁇ ), KSR 592 (2yo), ST-126 (2y) 1 dexametasone (2y2), etiprednol (2.13). Loteprednol (2J4), EPM 77 (2J5) and PLD-177 (2J6).
  • compound 2 is selected from the group consisting of flunisolides (2J), beclomethasone (2 ⁇ 2), triamcinolones (2JJ), budesonide (2A), fluticasone (2.5), mometasone (2JJ), ciclesonide (27), etiprednol ( 2.13), EPM 77 (2.15) and Dexametasone (2J2).
  • Particularly preferred is the compound 2 selected from budesonide (2A), fluticasone (2Jj), mometasone (2JJ) and ciclesonide (27), wherein mometasone (2JJ) and ciclesonide (27) according to the invention is of particular importance. If appropriate, only the term steroids 2 is used in the context of the present patent application instead of the term corticosteroids 2.
  • Reference to steroids 2 in the context of the present invention includes reference to salts or derivatives T_ that may be formed by the steroids.
  • Examples of possible salts or derivatives are: sodium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
  • the compounds of formula 2 may also be present in the form of their hydrates.
  • betamimetics 3 preferably include compounds selected from the group consisting of albuterol (3J), bambuterol (3.2), bitolterol (3Y), broxaterol (3H4), carbuterol (3Y), clenbuterol (3Y), Fenoterol (37), Formoterol (3Y), Hexoprenaline (3J), Ibuterol (3.10). Isoetharin (3.11). Isoprenaline (3.12), levosalbutamol (3.13), mabuterol (3.14), meluadrin (3.15), metaproterenol (3.16). Orciprenaline (3.17). Pirbuterol (3.18). Procaterol (3.19). Reproterol (3.20).
  • betamimetics ⁇ which are selected from the group consisting of ZJ_, 3 J ⁇ > 3 ⁇ 23, 3 ⁇ 30, 3 ⁇ 33, 3 ⁇ 34, 3 ⁇ 37, 3 ⁇ 38 3 ⁇ 39, ZAQ, ZM_ and 3 ⁇ 45, optionally in Form of their racemates, enantiomers, diastereomers and optionally in the form of physiologically acceptable acid addition salts and hydrates.
  • betamimetics 3 includes reference to the respective enantiomers or mixtures thereof. Particular preference is given in this connection to those compounds which have R-configuration at the C-OH-carbon.
  • the salts of salmeterol and formoterol accordingly includes the respective enantiomeric salts of the ft-salmeterol, S-salmeterol, ft, ft-formoterol, S, S-formoterol, R, S-formoterol , S, ft-formoterols and mixtures thereof, wherein the enantiomeric salts of ft-salmeterol and ft, ft-formoterol is of particular importance.
  • the compounds 3 can furthermore be present in the form of their hydrates or solvates.
  • Physiologically acceptable acid addition salts of betamimetics 3 are pharmaceutically acceptable salts according to the invention selected from the salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, fumaric, succinic, lactic, citric, tartaric, 1-hydroxy-2-naphthalenecarboxylic acid, Cinnamic acid, 4-phenylcinnamic acid, diflunisal or maleic acid.
  • mixtures of the abovementioned acids can also be used for the preparation of the salts 3.
  • the salts of the betamimetics 3 are preferably selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, fumarate, methanesulfonate, 4-phenylcinnamate, diflunisal and xinafoate.
  • Particularly preferred are the salts of 3 in the case of salmeterol selected from those salts having a solubility in water of 0.1 mg / ml or less, preferably 0.05 mg / ml or less, more preferably 0.04 mg / ml or have less.
  • the particularly preferred salts of almeterol are xinafoate, 4-phenylcinnamate and diflunisal.
  • Particularly preferred salts 3 of salmeterol have a solubility in water of 0.035 mg / ml or less, such as 4-phenylcinnamate or diflunisal.
  • Particularly preferred are the salts of 3 in the case of the formoterol selected from hydrochloride, sulfate and fumarate, of which the hydrochloride and fumarate are particularly preferred.
  • formoterol fumarate preferably formoterol fumarate dihydrate or formoterol hemifumarate, preferably in the form of its monohydrate, are of outstanding importance according to the invention.
  • betamimetics 3 are optionally also referred to as sympathomimetics or beta-2 receptor agonists (ß2-agonists). All of these terms are considered equivalent in the context of the present invention.
  • suitable inhalable powders which are filled into suitable capsules (inhalers) by means of appropriate powder inhalers may preferably be used.
  • One aspect of the present invention accordingly relates to a pharmaceutical composition containing a combination of 1, 2 and 3.
  • Another aspect of the present invention relates to a pharmaceutical composition containing one or more salts ⁇ _, one or more compounds 2 and one or more
  • the active ingredients may be present either together in a single administration form, in two or in three separate administration forms.
  • Preferred according to the invention are medicaments which contain the active ingredients ⁇ _, 2 and 3 in a single administration form.
  • the present invention further relates to the use of 1, 2 and 3 for the preparation of a therapeutically effective amount of 1, 2 and 3 containing medicament for the treatment of inflammatory and / or obstructive
  • Respiratory diseases in particular of asthma and / or chronic obstructive pulmonary diseases (COPD) by simultaneous or successive application.
  • COPD chronic obstructive pulmonary diseases
  • the drug combinations according to the invention for the preparation of a medicament for the treatment of fibrotic lung diseases for example cystic fibrosis or allergic alveolitis (Farmers Lung) by simultaneous or successive application find use.
  • An application of the active compound combinations according to the invention does not take place only if a treatment with one of the pharmaceutically active substances is contraindicated.
  • the present invention further aims at the simultaneous or successive use of therapeutically effective doses of the combination of the above medicaments 1, 2 and 3 for the treatment of inflammatory or obstructive airways diseases, in particular asthma and / or chronic obstructive pulmonary diseases (COPD), if treatment with steroids or Betamimetics is not contraindicated from a therapeutic point of view, by simultaneous or successive application.
  • the present invention further aims at the simultaneous or successive use of therapeutically effective doses of the combination of the above drugs 1, 2 and 3 for the treatment of, for example, cystic fibrosis or allergic alveolitis (Farmers Lung).
  • the constituents 1, 2 and 3 may be present in the form of their enantiomers, mixtures of the enantiomers or in the form of the racemates.
  • the medicaments of the invention contain the active ingredients ⁇ _, 2 and 3 in such an amount that a single application of a dosage of the active ingredient combination ⁇ _, 2 and 3 from 1 to 10000 ⁇ g, preferably from 10 to 2000 ⁇ g corresponds.
  • the conditions in which the active compounds 1, 2 and 3 can be used in the active compound combinations according to the invention are variable.
  • the active compounds ⁇ _, 2 and 3 may optionally be present 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 various compounds and due to their different potency.
  • the drug combinations according to the invention may contain the compounds Y_ and 2 in weight ratios ranging from 1: 250 to 250: 1, preferably from 1: 150 to 150: 1.
  • the weight ratios of V to 2 are more preferably in a range of about 1:40 to 40: 1, further preferably from 1:30 to 30: 1.
  • preferred combinations of 1 and 2 according to the invention can be the cation V and one the above preferably used steroids 2 in the following weight ratios: 1:40; 1:39; 1: 38, 1: 37; 1:36; 1:35; 1:34; 1:33; 1:32; 1:31; 1:30; 1:29; 1:28; 1:27; 1:26; 1:25; 1: 24; 1:23; 1:22; 1:21; 1:20; 1:19; 1:18; 1:17; 1:16; 1:15; 1:14; 1:13; 1:12; 1: 11; 1:10; 1: 9; 1: 8; 1: 7; 1: 6; 1: 5; 1: 4; 1: 3; 1: 2; 1: 1; 2: 1; 3: 1; 4: 1; 5: 1; 6: 1; 7: 1; 8: 1; 9: 1; 10: 1; 11: 1; 12: 1; 13: 1; 14: 1; 15: 1; 16: 1;
  • the use of the medicaments according to the invention containing the combinations of X and 2 is usually carried out so that V and 2 together in dosages of 5 to 5000 ⁇ g preferably from 10 to 5000 ⁇ g, more preferably from 15 to 4500 ⁇ g, further preferably from 20 to 4000 ⁇ g, preferably according to the invention 30 to 3500 ⁇ g, preferably from 40 to 3000 ⁇ g, preferably from 50 to 2500 ⁇ g, preferably from 40 to 2250 ⁇ g, more preferably from 50 to 2000 ⁇ g are included per single dose.
  • combinations of 1 and 2 according to the invention contain such an amount of V and steroid 2 that the total dosage per single administration is approximately 35 ⁇ g, 45 ⁇ g, 50 ⁇ g, 55 ⁇ g, 60 ⁇ g, 65 ⁇ g, 70 ⁇ g, 75 ⁇ g, 80 ⁇ g, 85 ⁇ g, 90 ⁇ g, 95 ⁇ g, 100 ⁇ g.
  • the combinations according to the invention of 1 and 2 can contain an amount of cation V and steroid 2 such that 2.5 ⁇ g V and 25 ⁇ g 2, 2.5 ⁇ g V and 50 ⁇ g 2 per single dose 2,5 ⁇ g r and 100 ⁇ g 2, 2,5 ⁇ g V and 150 ⁇ g 2, 2,5 ⁇ g V and 200 ⁇ g 2, 2,5 ⁇ g V and 250 ⁇ g 2, 2,5 ⁇ g V and 300 ⁇ g 2 j _2,5 ⁇ g V and 320 ⁇ g 2 j _2, 5 ⁇ g V and 350 ⁇ g 2j 2.5 ⁇ g V and 400 ⁇ g 2j _2,5 ⁇ g V and 500 ⁇ g 2j _2,5 ⁇ g V and 600 ⁇ g 2j _2,5 ⁇ g V and 700 ⁇ g 2 j _2,5 ⁇ g Y_ and 800 ⁇ g 2 j _2,5 ⁇ g V and 1000 ⁇ g 2j _7.5 ⁇ g V and 25 ⁇ g 2, 7.5 ⁇ g V and 50 ⁇ g 2, 7.5 ⁇ g V and 100 ⁇
  • the active compound combinations according to the invention can V and 3 in the case of, for example, formoterol based on free base formoterol in
  • Weight ratios for example, in a range of about 1: 50 to 300: 1, preferably 1: 20 to 200: 1, preferably 1:10 to 150: 1, more preferably from 1: 5 to 100: 1 are.
  • preferred combinations of 1 and 3 according to the invention may contain the pharmacologically active cation V and formoterol 3 in the following ratios by weight: 1: 80, 1:79, 1:78, 1:77, 1: 76, 1: 75, 1: 74, 1: 73, 1:72, 1: 71.1: 70, 1: 69, 1: 68, 1: 67, 1: 66, 1: 65, 1: 64, 1: 63, 1: 62, 1: 61.1: 60, 1: 59, 1:58, 1:57, 1:56, 1:55, 1:54, 1:53, 1:52, 1: 51, 1:50, 1:49, 1:48, 1:47, 1:46, 1:45, 1:44, 1:43, 1:42, 1:41, 1:40, 1: 39, 1: 38, 1: 37, 1:36, 1:35, 1:34, 1:33, 1:32
  • combinations of 1 and 3 according to the invention contain such an amount of cation V and formoterol 3 that the total dosage per single dose is about 0.5 ⁇ g, 1 ⁇ g, 5 ⁇ g, 10 ⁇ g, 15 ⁇ g, 20 ⁇ g, 25 ⁇ g, 30 ⁇ g, 35 ⁇ g, 45 ⁇ g, 50 ⁇ g , 55 ⁇ g, 60 ⁇ g, 65 ⁇ g, 70 ⁇ g, 75 ⁇ g, 80 ⁇ g, 85 ⁇ g, 90 ⁇ g, 95 ⁇ g, 100 ⁇ g, 105 ⁇ g, 110 ⁇ g, 115 ⁇ g, 120 ⁇ g, 125 ⁇ g, 130 ⁇ g, 135 ⁇ g, 140 ⁇ g, 145 ⁇ g, 150 ⁇ g, 155 ⁇ g, 160 ⁇ g, 165 ⁇ g, 170 ⁇ g, 175 ⁇ g , 180 ⁇ g, 185 ⁇ g, 190 ⁇ g, 195 ⁇ g, 200 ⁇ g, 205 ⁇ g, 210 ⁇ g, 215 ⁇ g, 220 ⁇ g, 225 ⁇ g, 230 ⁇ g
  • the combinations of 1 and 3 according to the invention may contain such an amount of cation V and formoterol 3 (based on free base) that, for example, 2.5 ⁇ g V and 2.5 ⁇ g 3 , 2.5 ⁇ g V and 4.9 ⁇ g 3, 2.5 ⁇ g V and 9.8 ⁇ g 3, 2.5 ⁇ g V and 14.7 ⁇ g 3, 2.5 ⁇ g Y_ and 19.6 ⁇ g 3, 2.5 ⁇ g V and 24.4 ⁇ g 3 , 7.5 ⁇ g V and 2.5 ⁇ g 3, 7.5 ⁇ g V and 4.9 ⁇ g 3, 7.5 ⁇ g V and 9.8 ⁇ g 3, 7.5 ⁇ g V and 14.7 ⁇ g 3, 7.5 ⁇ g V and 19.6 ⁇ g 3 , 7.5 ⁇ g r and 24.4 ⁇ g 3, 15.0 ⁇ g V and 2.5 ⁇ g 3, 15.0 ⁇ g V and 4.9 ⁇ g 3, 15.0 ⁇ g V and 9.8 ⁇ g 3, 15.0 ⁇ g V and 9.8 ⁇ g 3, 15.0 ⁇ g V and 9.8 ⁇ g 3, 15.0 ⁇ g V and 9.8 ⁇ g 3, 15.0 ⁇ g V and 9.8 ⁇ g 3, 15.0 ⁇ g V and
  • the active compound combinations according to the invention can contain V and 3 in the case of, for example, salmeterol (based on free base) in weight ratios which, for example, in a range from about 1:30 to 400: 1, preferably 1:25 to 200: 1, preferably 1:20 to 100: 1, more preferably from 1:15 to 50: 1.
  • preferred combinations of 1 and 3 according to the invention may contain the cation V and salmeterol 3 (based on free base) in the following weight ratios: 1:15, 1:14, 1:13, 1 : 12, 1:11, 1:10, 1: 9, 1: 8, 1: 7, 1: 6, 1: 5, 1: 4, 1: 3, 1: 2, 1: 1, 2: 1 , 3: 1.4: 1.5: 1.6: 1.7: 1.8: 1.9: 1, 10: 1.11: 1, 12: 1, 13: 1, 14: 1, 15 : 1, 16: 1, 17: 1, 18: 1.19: 1, 20: 1, 21: 1, 22: 1, 23: 1, 24: 1, 25: 1, 26: 1, 27: 1 , 28: 1, 29: 1, 30: 1, 31: 1, 32: 1, 33: 1.34: 1.35: 1.
  • the use of the medicaments according to the invention containing the combinations of 1 and 3 is usually carried out so that the cation V and salmeterol 3 (based on free base) together in dosages of 5 to 5000 ⁇ g, preferably from 10 to 2000 ⁇ g, more preferably from 15 to 1000 ⁇ g, furthermore preferably from 20 to 800 .mu.g, according to the invention preferably from 30 to 750 .mu.g, preferably from 40 to 700 .mu.g are contained.
  • combinations of 1 and 3 according to the invention contain such an amount of V and salmeterol 3 (based on free base) that the total dosage per single dose is approximately 15 ⁇ g, 20 ⁇ g, 25 ⁇ g, 30 ⁇ g, 35 ⁇ g, 45 ⁇ g, 50 ⁇ g, 55 ⁇ g, 60 ⁇ g, 65 ⁇ g, 70 ⁇ g , 75 ⁇ g, 80 ⁇ g, 85 ⁇ g, 90 ⁇ g, 95 ⁇ g, 10 ⁇ 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, 240 ⁇ g, 245 ⁇
  • the inventive combinations of 1 and 3 may contain such an amount of cation V and salmeterol 3 (based on free base) that, for example, 2.5 ⁇ g V and 12.5 ⁇ g 3 per single dose , 2.5 ⁇ g V and 25 ⁇ g 3, 2.5 ⁇ g V and 50 ⁇ g 3, 2.5 ⁇ g V and 75 ⁇ g 3, 2.5 ⁇ g V and 10O ⁇ g 3, 2.5 ⁇ g V and 200 ⁇ g 3, 7.5 ⁇ g V and 12.5 ⁇ g 3 , 7,5 ⁇ g V and 25 ⁇ g 3, 7,5 ⁇ g V and 50 ⁇ g 3, 7,5 ⁇ g V and 75 ⁇ g 3, 7,5 ⁇ g V and 10O ⁇ g 3, 7,5 ⁇ g V and 200 ⁇ g 3, 15,0 ⁇ g V and 12,5 ⁇ g 3 , 15.0 ⁇ g V and 25 ⁇ g 3, 15.0 ⁇ g V and 50 ⁇ g 3, 15.0 ⁇ g V and 75 ⁇ g 3, 15.0 ⁇ g V and 100 ⁇ g 3, 15.0 ⁇ g V and 200 ⁇ g 3, 30.0 ⁇ g Y_ and 12.5 ⁇ g 3 , 30.0 ⁇
  • Preferred drug combinations according to the invention are selected from the group consisting of: 1,2 ⁇ _ and 37; 1,2 ⁇ _ and 3JJ; 1,2 ⁇ _ and 3,23; 1,2 ⁇ _ and 3:30; 1,2J and 3,33; 1,2J and 3J34; 1,2J and 3J37; 1,2J and 3J38; 1 , 2J. and 3.39: 1,2J. and 340; 1,2J. and 341; 1,2J. and 3 ⁇ 45; 1, Z2 and 37; 1, Z2 and Z &, 1, g2 and 3 ⁇ 23; 1g2 and 3 ⁇ 30; 1g2 and 3 ⁇ 33 ; 1g2 and3 ⁇ 34; 1g2 and3 ⁇ 37; 1 22. and3 ⁇ 38; 122.
  • Suitable inhalable dosage forms according to the invention are inhalable powders, propellant-containing metered dose inhalers or propellant-free inhalable solutions.
  • Inventive inhalable powders comprising the active ingredient combination of 1, 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 term carrier is used in the context of the present invention instead of the term excipient.
  • propellant-free inhalable solutions also includes concentrates or sterile, ready-to-use inhalable solutions.
  • the administration forms according to the invention may contain the active ingredient combination of 1, 2 and 3 either together in one, in two or in three separate administration forms. These administration forms which can be used in the context of the present invention are described in detail in the following part of the description.
  • the inhalable powders according to the invention may contain 1, 2 and 3 either alone or in admixture with suitable physiologically acceptable auxiliaries.
  • 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), oligo and polysaccharides (eg dextrans),
  • monosaccharides eg glucose or arabinose
  • disaccharides eg lactose, sucrose, maltose
  • 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 average particle size of up to 250 ⁇ m, preferably between 10 and 150 ⁇ m, particularly preferably between 15 and 80 ⁇ m. If appropriate, it may appear 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.
  • micronized active ingredient ⁇ _, 2 and 3 preferably having an average particle size of 0.5 to 10 ⁇ m, particularly preferably 1 to 5 ⁇ m, is added to the excipient mixture. Process for the preparation of the inhalable powders according to the invention by grinding and micronizing as well as by final mixing of the constituents are known from the prior art
  • the inhalable powders according to the invention may be provided and applied either in the form of a single powder mixture containing both ⁇ _ and 2 and 3 or in the form of separate inhalable powders containing only 1, 2 or 3, respectively.
  • 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 in addition to!, 2 and 3 also contain one or more physiologically acceptable auxiliaries, can be administered, for example, by means of inhalers which deliver a single dose from a supply by means of a measuring chamber as described in US 4570630A or via other apparatus Devices, as described in DE 36 25 685 A, dose.
  • the inhalable powders according to the invention which contain, in addition to!, 2 and 3, physiologically acceptable auxiliaries, are, however, filled into capsules (known as inhalers) which are used in inhalers, for example as described in WO 94/28958.
  • FIG. 1 A particularly preferred inhaler for use of the medicament combination according to the invention in inhalants is shown in FIG.
  • This inhaler (handihaler) 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, at the one provided with two ground needles 7, against a spring 8 movable pusher 9 is provided, and a hinged via an axis 10 with the housing 1, the deck 3 and a cap 11 connected mouthpiece 12 and air passage holes 13 for adjusting the flow resistance.
  • inhalable powders according to the invention are to be filled into capsules (inhalettes) for the purposes of the abovementioned preferred application, 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. According to the invention, these contain either together or in each case the dosages already mentioned above for 1_, 2 and 3 per single dose.
  • Propellant gas-containing inhalation aerosols according to the invention may contain 1, 2 and 3 dissolved in the propellant gas or in dispersed form.
  • 1_, 2 and 3 may be contained in separate administration forms or in a common administration form, where 1., 2_ and 3 either dissolved in each case, in each case dispersed or optionally dissolved only one or two of the components and the other or the other components may be dispersed .
  • the 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 halogenated hydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • hydrocarbons such as n-propane, n-butane or isobutane
  • halogenated hydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • the abovementioned propellant gases can be used alone or in mixtures thereof.
  • Particularly preferred propellants are halogenated alkane derivatives selected from TG134a and TG227 and mixtures thereof.
  • the propellant-containing inhalation aerosols of the present invention may further contain other ingredients such as co-solvents, stabilizers, surfactants, antioxidants, lubricants, preservatives, 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 ⁇ _, 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 ⁇ , 2 and / or 3. If the active compounds 1, 2 and / or 3 are present in dispersed form, 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 that can be equipped with a suitable valve in a suitable inhaler used and one of the abovementioned propellant gas-containing invention
  • 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. To adjust this pH, acids selected from inorganic or organic acids can find use.
  • 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 already with one the active ingredients form an acid addition salt.
  • Ascorbic acid, fumaric acid and citric acid are preferable.
  • mixtures of the abovementioned acids in particular in the case of acids which, in addition to their acidification properties, also possess other properties, for example as flavorings, antioxidants or complexing agents, for example citric acid or ascorbic acid.
  • Hydrochloric acid is particularly preferably used according to the invention for adjusting the pH.
  • Stabilizer or complexing agent can be omitted.
  • the content is based on
  • 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 ones
  • Groups include, for example, alcohols - especially isopropyl alcohol, glycols
  • propylene glycol polyethylene glycol, polypropylene glycol, glycol ethers,
  • Glycerol polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
  • auxiliaries and additives are understood as meaning any physiologically compatible substance which is not an active ingredient, but together with the substance (s).
  • Active ingredient (s) can be formulated in the physiologically suitable solvent to improve the qualitative properties of the active ingredient formulation.
  • auxiliaries and additives include e.g. surfactants, e.g. Soya lecithin, oleic acid, sorbitan esters such as polysorbates, polyvinylpyrrolidone other stabilizers, complexing agents, antioxidants and / or
  • Additives also include physiologically 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 provitamins found in the human organism. Preservatives can be used to prepare the formulation
  • 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 abovementioned preservatives are preferably present in concentrations of up to 50 mg / 100 ml, more preferably between 5 and 20 mg / 100 ml.
  • preferred formulations contain 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 inhalant 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 comprising the active ingredient combination of I 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 form inhalable aerosols.
  • 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 fixed in the upper housing part, and at its one end a nozzle body with the nozzle or nozzle arrangement carries, - a hollow piston with valve body, a driven flange, in which the hollow piston is fixed, and located in the
  • Upper housing part is located, a locking body, which is located in the upper housing part, a spring housing with the spring therein, which is rotatably mounted on the upper housing part by means of a rotary bearing, a lower housing part, which is mounted on the spring housing in the axial direction.
  • the hollow piston with valve body corresponds to a device disclosed in WO 97/12687. It partially protrudes 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 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 drug solution. Volumes of from 10 to 50 microliters are preferred, volumes from 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. produced by microtechnology.
  • Microstructured nozzle bodies are disclosed, for example, in WO-94/07607; This document is hereby incorporated by reference, in particular to the figure 1 and its description disclosed therein.
  • the nozzle body consists for example of two firmly interconnected plates made of glass and / or silicon, of which at least one plate has one or more microstructured channels, the nozzle inlet side with the Connect the nozzle outlet side.
  • At the nozzle outlet side at least one round or non-round aperture is 2 to 10 microns deep and 5 to 15 microns wide, with the depth preferably being 4.5 to 6.5 microns and the length being 7 to 9 microns. In the case of several nozzle openings, two are preferred, the
  • 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 Ambichen ⁇ or droplet sizes of the aerosol are up to 20 micrometers, preferably 3 to 10 micrometers.
  • 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 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 push in the path of the output flange and prevent the relaxation of the spring.
  • the Sprerrglied is triggered by a button.
  • the Shutter button is connected or coupled to the locking member. To trigger the locking mechanism, 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 lower housing part is pushed in the axial direction over the spring housing and covers the storage, the drive of the spindle and the reservoir for the fluid.
  • the housing upper part When actuating the atomizer, the housing upper part is rotated against the lower housing part, wherein the lower housing part entrains the spring housing.
  • the spring is compressed and tensioned via the screw slide, and the lock engages automatically.
  • the angle of rotation is preferably an integer fraction of 360 degrees, e.g. 180 degrees.
  • the driven part Simultaneously with the tensioning of the spring, the driven part is displaced in the upper housing part by a predetermined path, the hollow piston is withdrawn within the cylinder in the pump housing, whereby a subset of the fluid from the reservoir is sucked into the high-pressure chamber in front of the nozzle.
  • the storage container contains the aqueous aerosol preparation according to the invention.
  • the sputtering process is initiated by lightly pressing the shutter button.
  • the blocking mechanism clears the way for the stripping section.
  • the tensioned spring pushes the piston into the cylinder of the pump housing.
  • the fluid exits the nozzle of the atomizer in atomized form.
  • the components of the atomizer are made of a functionally suitable material.
  • the housing of the atomizer and - as far as the function allows - other parts are preferably made of plastic, for example by injection molding.
  • Physiologically harmless materials are used for medical purposes.
  • FIGS. 6 a / b of WO 97/12687 to which reference is made in full to this specification in addition to the associated descriptive components, the nebuliser (Respimat®) is described, with which the aqueous aerosol preparations according to the invention can advantageously be inhaled.
  • Figure 6a shows a longitudinal section through the atomizer with the spring tensioned
  • Figure 6b shows a longitudinal section through the atomizer with a relaxed spring.
  • the upper housing part (51) contains the pump housing (52), at the end of which the holder (53) for the atomizer nozzle is mounted. In the holder is the nozzle body (54) and a filter (55).
  • the hollow piston (57) fastened in the output 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 output flange rests with a relaxed spring.
  • the stop (61) On 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 housing part.
  • the release button (64) is in communication with the locking member.
  • the housing upper part ends in the mouthpiece (65) and is closed with the attachable protective cap (66).
  • the spring housing (67) with compression spring (68) is rotatably supported by means of the snap lugs (69) and pivot bearing on the upper housing part.
  • the lower housing part (70) is pushed.
  • the replaceable reservoir (71) for the fluid (72) to be atomized Within the spring housing is the replaceable reservoir (71) for the fluid (72) to be atomized.
  • the reservoir is closed with the stopper (73) through which the hollow piston protrudes into the reservoir and with its end immersed in the fluid (stock of drug solution).
  • the spindle (74) for the mechanical counter is mounted in the lateral surface of the spring housing.
  • the drive pinion (75) At the end of the spindle, which faces the upper housing part, there is the drive pinion (75). The rider (76) sits on the spindle.
  • nebulizer described above is suitable for the invention
  • Aerosol preparations to nebulise a suitable for inhalation aerosol.
  • the mass applied should be at least 97%, preferably at least 98% of all operations of the inhaler (Hube) of a defined amount with a maximum tolerance of 25%, preferably 20% of this amount correspond.
  • the mass applied should be at least 97%, preferably at least 98% of all operations of the inhaler (Hube) of a defined amount with a maximum tolerance of 25%, preferably 20% of this amount correspond.
  • the inhaler Hube
  • 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 can 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 aims at propellant-free inhalable solutions or suspensions characterized by the combination of active substances 1, 2 and 3 according to the invention in combination 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.
  • the device 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.
  • the following embodiments are inhalation powders containing lactose as an excipient.
  • the embodiments given by way of example contain the amounts of ⁇ _ (in the form of the bromide), 2 and 3 indicated in the table below.
  • the amounts indicated for components 3 relate to free bases. From this, the respective amounts of corresponding acid addition salts can easily be calculated by the person skilled in the art.
  • Analogous formulations to the abovementioned embodiments are obtained, for example, with the auxiliaries trehalose or glucose.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Pulmonology (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne de nouvelles compositions médicamenteuses à base d'un nouvel anticholinergique, de corticostéroïdes et de bêta-mimétiques, leur procédé de production et leur utilisation dans la thérapie de maladies des voies respiratoires.
EP05771986A 2004-08-10 2005-08-04 Medicament a inhaler contenant des corticosteroides, des beta-mimetiques et un nouvel anticholinergique Withdrawn EP1778227A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE102004038886A DE102004038886A1 (de) 2004-08-10 2004-08-10 Inhalative Arzneimittel enthaltend Corticosteroide, Betamimetika sowie ein neues Anticholinergikum
DE102004053023A DE102004053023A1 (de) 2004-11-03 2004-11-03 Inhalative Arzneimittel enthaltend Corticosteroide, Betamimetika sowie ein neues Anticholinergikum
PCT/EP2005/053840 WO2006018391A1 (fr) 2004-08-10 2005-08-04 Medicament a inhaler contenant des corticosteroides, des beta-mimetiques et un nouvel anticholinergique

Publications (1)

Publication Number Publication Date
EP1778227A1 true EP1778227A1 (fr) 2007-05-02

Family

ID=35056854

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05771986A Withdrawn EP1778227A1 (fr) 2004-08-10 2005-08-04 Medicament a inhaler contenant des corticosteroides, des beta-mimetiques et un nouvel anticholinergique

Country Status (5)

Country Link
US (1) US20060034776A1 (fr)
EP (1) EP1778227A1 (fr)
JP (1) JP2008509196A (fr)
CA (1) CA2573370A1 (fr)
WO (1) WO2006018391A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040048887A1 (en) * 2002-07-09 2004-03-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmaceutical compositions based on anticholinergics and EGFR kinase inhibitors
CA2650813A1 (fr) * 2006-05-24 2007-11-29 Boehringer Ingelheim International Gmbh Combinaisons nouvelles de medicaments a longue duree d'action pour le traitement de maladies respiratoires
US20110135580A1 (en) * 2006-05-24 2011-06-09 Boehringer Ingelheim International Gmbh Novel Medicament Combinations for the Treatment of Respiratory Diseases
EP2011534A1 (fr) * 2007-07-03 2009-01-07 CHIESI FARMACEUTICI S.p.A. Actionneur d'inhalateur à dosage mesuré
GB201113662D0 (en) 2011-08-08 2011-09-21 Prosonix Ltd Pharmaceutical compositions
CN108455095B (zh) * 2017-02-21 2023-07-14 李和伟 一种旋转式给药器

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10130371A1 (de) * 2001-06-23 2003-01-02 Boehringer Ingelheim Pharma Neue Arzneimittelkompositionen auf der Basis von Anticholinergika, Corticosteroiden und Betamimetika
DE10203741A1 (de) * 2002-01-31 2003-08-14 Boehringer Ingelheim Pharma Neue Fluorencarbonsäureester, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel
US6790856B2 (en) * 2002-01-31 2004-09-14 Boehringer Ingelheim Pharma Kg Fluorenecarboxylic acid esters, process for the manufacture thereof, and use thereof as medicaments
DE10237739A1 (de) * 2002-08-17 2004-02-26 Boehringer Ingelheim Pharma Gmbh & Co. Kg Inhalative Arzneimittel enthaltend ein neues Anticholinergikum in Kombination mit Corticosteroiden und Betamimetika

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006018391A1 *

Also Published As

Publication number Publication date
WO2006018391A1 (fr) 2006-02-23
US20060034776A1 (en) 2006-02-16
JP2008509196A (ja) 2008-03-27
CA2573370A1 (fr) 2006-02-23

Similar Documents

Publication Publication Date Title
EP1408967B1 (fr) COMPOSITIONS DE MEDICAMENT A BASE de tiotropium, DE ciclesonide ET D'un AGENT BETA-MIMETIQUE POUR LE TRAITEMENT DES MALADIES RESPIRATOIRES ET/OU OBSTRUCTIVES
EP1530471B1 (fr) Medicament a inhaler contenant un nouvel anticholinergique en combinaison avec des corticosteroides et de betamimetiques
EP1349549B1 (fr) Nouvelles compositions medicamenteuses a base des sels de tiotropium et de ciclesonide
EP1497289B1 (fr) Medicament contenant des betamimetiques et un nouvel anticholinergique
EP1808174A1 (fr) Compositions de médicaments à base de sels de tiotropium et de sels de salmeterol
WO2002060532A1 (fr) Compositions medicamenteuses contenant des betamimetiques et ayant des effets secondaires limites
WO2002072095A2 (fr) Composes destines au traitement de maladies inflammatoires
EP1333830A2 (fr) Nouvelle composition medicamenteuse a base d'anticholinergiques et de corticosteroides
WO2006056527A1 (fr) Medicaments administres par inhalation contenant un anticholinergique, du salmeterol et un steroide du groupe ciclesonide ou mometasone furoate
WO2006018391A1 (fr) Medicament a inhaler contenant des corticosteroides, des beta-mimetiques et un nouvel anticholinergique
EP1496902B1 (fr) Medicament contenant des steroides et un nouvel anticholinergique
EP1879571A1 (fr) Combinaison de medicaments a inhaler contenant un betamimetique et un steroide en plus d'un anticholinergique
WO2002060533A2 (fr) Compositions medicamenteuses a faibles effets secondaires
WO2006056526A1 (fr) Medicaments administres par inhalation contenant un nouvel anticholinergique, du formoterol et un steroide
WO2004105759A2 (fr) Nouvelles combinaisons medicamenteuses a action prolongee utilisees pour traiter des maladies des voies respiratoires
DE102004038886A1 (de) Inhalative Arzneimittel enthaltend Corticosteroide, Betamimetika sowie ein neues Anticholinergikum
DE102004053023A1 (de) Inhalative Arzneimittel enthaltend Corticosteroide, Betamimetika sowie ein neues Anticholinergikum
EP1345626A2 (fr) Nouvelles compositions medicamenteuses a base d'anticholinergiques et d'agonistes de la dopamine

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20070312

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20090327

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20121106