Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
  • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • 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
  • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
  • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
  • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • 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
  • A61P11/08—Bronchodilators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to novel pharmaceutical compositions based on anticholinergics and dopamine agonists, processes for their preparation and their use in the therapy of respiratory diseases.
• the present invention relates to novel pharmaceutical compositions based on anticholinergics and dopamine agonists, processes for their preparation and their use in the therapy of respiratory diseases.
• an unexpectedly advantageous therapeutic effect in particular a synergistic effect in the treatment of inflammatory or obstructive respiratory diseases, can be observed if one or more, preferably an anticholinergic, are used together with one or more, preferably a dopamine agonist.
• the pharmaceutical combinations according to the invention can be used at lower doses than is the case with the otherwise customary monotherapy of the individual compounds. This can cause unwanted
• anticholinergics 1 are understood to mean salts which are preferably selected from the group consisting of tiotropium salts, oxitropium salts and ipratropium salts, ipratropium salts and tiotropium salts being particularly preferred.
• the cations tiotropium, oxitropium and ipratropium are the pharmacologically active constituents.
• reference to the above cations can be recognized by using the designation V.
• a reference to compounds 1 naturally includes a reference to the constituents V (tiotropium, oxitropium or ipratropium).
• the salts 1 which can be used in the context of the present invention are taken to mean the compounds which, in addition to tiotropium, oxitropium or ipratropium, contain chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate as the counterion (anion).
• methanesulfonate, chloride, bromide or iodide are preferred for the purposes of the present invention, methanesulfonate or bromide being of particular importance.
• salts 1 which are selected from the group consisting of tiotropium bromide, oxitropium bromide and ipratropium bromide. Ipratropium bromide and tiotropium bromide are particularly preferred.
• dopamine agonists are understood to be compounds which are selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and - (2-Aminoethyl) benzothiazolones of the general formula 3
• X and Y are the same or different -S (O) n - or -O-; n 0, 1 or 2; p, q and r are the same or different 2 or 3;
• R 1 , R 2 and R 3 the same or different, mean hydrogen or Ci-C ⁇ - alkyl.
• dopamine agonists 2 are preferably understood, which are selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexol, terguride and the compound of the formula 3 ⁇
• the dopamine agonist 2 is preferably selected from the group consisting of pramipexole, talipexole and viozan, with pramipexole and viozan, in particular viozan, being of particular importance.
• Drug combinations are those that do not cross the blood-brain barrier 'and are primarily characterized by peripheral activity. >
• peripherally active dopamine agonists 2 selected from the group consisting of dopamine, fenoldopam, dopexamine, CHF 1035, tolnaperisine and RU-40021 are particularly preferred, with dopamine, fenoldopam, dopexamine and CHF 1035, in particular dopamine, fenoldopam and dopexamine being outstanding Importance.
• a reference to the above-mentioned dopamine agonists 2 includes a reference to their pharmacologically acceptable acid addition salts which may exist.
• physiologically acceptable acid addition salts which can be formed by 2 are understood to mean, for example, pharmaceutically acceptable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid ,
• the pharmaceutical combinations of ⁇ and 2 according to the invention are preferably administered by inhalation.
• Suitable inhalable powders which are filled into suitable capsules (inhalettes) and applied by means of appropriate powder inhalers, can be used.
• inhalative use can also be carried out by applying suitable inhalation aerosols.
• suitable inhalation aerosols This also includes inhalation aerosols containing, for example, HFA134a, HFA227 or their mixture as propellant.
• the inhalation application can also take place by means of suitable solutions of the drug combination consisting of ⁇ and 2.
• One aspect of the present invention accordingly relates to a medicament which contains a combination of ⁇ and 2.
• Another aspect of the present invention relates to a medicament which contains one or more salts ⁇ and one or more compounds 2, optionally in the form of their solvates or hydrates.
• the active ingredients can either be contained together in a single dosage form or in two separate dosage forms.
• a further aspect of the present invention relates to a medicament which, in addition to therapeutically effective amounts of 1 and 2, contains a pharmaceutically compatible auxiliary.
• Another aspect of the present invention relates to a medicament which, in addition to therapeutically effective amounts of 1_ and 2, contains no pharmaceutically acceptable auxiliary.
• the present invention further relates to the use of i and 2 for the preparation of a therapeutically effective amount of medicament containing 1 and 2 for the treatment of inflammatory or obstructive respiratory diseases, in particular asthma or chronic obstructive pulmonary diseases (COPD), and their complications such as, for example, pulmonary hypertension , also allergic and non-allergic rhinitis, provided treatment with dopamine agonists is not contraindicated from a therapeutic point of view, through simultaneous or successive application.
• inflammatory or obstructive respiratory diseases in particular asthma or chronic obstructive pulmonary diseases (COPD)
• COPD chronic obstructive pulmonary diseases
• Drug combinations from 1 and 2 can also be used for the production of a medicament for the treatment of cystic fibrosis by simultaneous or successive application of and 2.
• the present invention further aims at the simultaneous or successive use of therapeutically effective doses of the combination of the above medicinal products ⁇ and 2 for the treatment of inflammatory or obstructive respiratory diseases, in particular asthma or chronic obstructive pulmonary diseases (COPD), as well as their complications such as, for example, pulmonary hypertension also allergic and non-allergic rhinitis, if treatment with dopamine agonists is not contraindicated from a therapeutic point of view, by simultaneous or successive application.
• the present invention further relates to the use of therapeutically effective doses of the combination of the above medicinal products and 2 for the treatment of cystic fibrosis by simultaneous or successive application of and 2.
• the constituents _ and 2 can be contained in the form of their enantiomers, mixtures of the enantiomers or in the form of the racemates.
• the ratios in which the two active substances and 2 can be used in the active substance combinations according to the invention are variable. Active ingredients 1 and 2 may optionally be in the form of their solvates or hydrates. Depending on the choice of the compounds ⁇ or 2, the weight ratios which can be used in the context of the present invention vary on account of the different molecular weight of the different compounds and on account of their different potency. As a rule, the pharmaceutical combinations of the invention may contain in weight ratios of the compounds 1 and 2, in a range of 1: 1, '.- 300 to 50: 1, preferably from 1: 250 to 40 wt. For the particularly preferred drug combinations that
• the weight ratios of 1 to 2 are particularly preferably in a range in which ipratropium or tiotropium V and 2 in ratios from 1: 150 to 30: 1, further preferably from 1:50 to 20: 1.
• preferred combinations according to the invention of 1 and 2 ipratropium or tiotropium V and dopamine agonists 2 can contain the following weight ratios: 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; 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: 3; 1: 2; 1: 1;
• the medicaments according to the invention containing the combinations of 1 and 2 are usually used in such a way that and 2 together in doses of 0.01 to 10000 ⁇ g, preferably 0.1 to 2000 ⁇ g, particularly preferably 1 to 1000 ⁇ g, further preferably 5 to 600 ⁇ g are included per single dose.
• combinations of and 2 according to the invention contain such an amount of 1 ⁇ and dopamine agonist 2 that the total dosage per single dose is about 20 ⁇ g, 25 ⁇ g, 30 ⁇ g, 35 ⁇ g, 45 ⁇ g, 50 ⁇ g, 55 ⁇ g, 60 ⁇ g, 65 ⁇ g, 70 ⁇ g, 75 ⁇ g, 80 ⁇ g, 85 ⁇ g , 90 ⁇ g, 95 ⁇ g, 100 ⁇ g, 105 ⁇ g, 110 ⁇ g, 115 ⁇ g, 120 ⁇ g, 125 ⁇ g, 130 ⁇ g, 135 ⁇ g, 140 ⁇ g, 145 ⁇ g, 150 ⁇ g, 155 ⁇ g, 160 ⁇ g, 165 ⁇ g, 170 ⁇ g, 175 ⁇ g, 180 ⁇ g, 185 ⁇ g, 190 ⁇ g, 195 ⁇ g, 200 ⁇ g, 205 ⁇ g, 205 ⁇ g , 215 ⁇ g, 220 ⁇ g, 225 ⁇ g, 230 ⁇ g, 235 ⁇ g, 240 ⁇ g, 245 ⁇ g, 250 ⁇ g, 255 ⁇ g, 260 ⁇ g, 265 ⁇
• the combinations of 1 and 2 according to the invention may contain such an amount of V and dopamine agonist 2 that 5 ⁇ g Y and 25 ⁇ g 2, 5 ⁇ g V and 45 ⁇ g 2, 5 ⁇ g Y and ⁇ O ⁇ g 2, 5 ⁇ g Y and 100 ⁇ g 2, 5 ⁇ g
• the combination of active ingredients in which 1 is tiotropium bromide corresponds the amounts of Y and 2 of active substances applied as examples per single dose and the following quantities of 1 and 2 applied per single dose: 6 ⁇ g 1 and 25 ⁇ g 2, 6 ⁇ g ⁇ and 45 ⁇ g 2, 6 ⁇ g 1 and 50 ⁇ g 2, 6 ⁇ g ⁇ and 100 ⁇ g 2, 6 ⁇ g ⁇ and 200 ⁇ g 2, 6 ⁇ g 1 and 250 ⁇ g 2, 6 ⁇ g 1 and 270 ⁇ g 2, 6 ⁇ g 1 and 400 ⁇ g 2, 6 ⁇ g 1 and 495 ⁇ g 2, 12 ⁇ g i and 25 ⁇ g 2, 12 ⁇ g 1 and 45 ⁇ g 2, 12 ⁇ g 1 and 50 ⁇ g 2, 12 ⁇ g 1 and 100 ⁇ g 2, 12 ⁇ g 1 and 200 ⁇ g 2, 12 ⁇ g and 250 ⁇ g 2, 12 ⁇ g 1 and 270 ⁇ g 2, 12 ⁇ g 1 and 400 ⁇ g 2, 12 ⁇ g 1 and 495 ⁇ g 2, 21, 7 ⁇ g 1 and 25 ⁇ g 2, 21, 7 ⁇ g 1 and 45 ⁇ g 2, 21,
• the amounts of active ingredient of Y and 2 applied per single dose above correspond to the following amounts of 1 and 2 applied per single dose: 6.2 ⁇ g 1 and 25 ⁇ g 2 , 6.2 ⁇ g ⁇ and 45 ⁇ g 2, 6.2 ⁇ g 1 and 50 ⁇ g 2, 6.2 ⁇ g ⁇ and 10O ⁇ g 2, 6.2 ⁇ g 1 and 200 ⁇ g 2, 6.2 ⁇ g I and 250 ⁇ g 2, 6.2 ⁇ g 1 and 270 ⁇ g 2, 6 , 2 ⁇ g 1 and 400 ⁇ g 2, 6.2 ⁇ g 1 and 495 ⁇ g 2, 12.5 ⁇ g 1 and 25 ⁇ g 2, 12.5 ⁇ g 1 and 45 ⁇ g 2, 12.5 ⁇ g 1 and 50 ⁇ g 2, 12.5 ⁇ g 1 and 100 ⁇ g 2, 12.5 ⁇ g 1 and 200 ⁇ g 2, 12.5 ⁇ g 1 and 250 ⁇ g 2, 12.5 ⁇ g 1 and 270 ⁇ g 2, 12.5 ⁇ g 1 and 400 ⁇ g 2, 12.5 ⁇ g 1 and 495
• the active compound combinations according to the invention from 1 and 2 are preferably administered by inhalation.
• the components and 2 must be provided in inhalable dosage forms.
• Inhalable dosage forms include inhalable powders, metered-dose aerosols containing propellants or propellant-free inhalation solutions.
• Inhalable powders according to the invention containing the combination of active substances 1_ and 2 can consist solely of the active substances mentioned or of a mixture of the active substances mentioned with physiologically compatible auxiliaries.
• propellant-free inhalation solutions also include concentrates or sterile, ready-to-use
• the dosage forms according to the invention can contain the active ingredient combination from 1 and 2 either together in one or in two separate dosage forms. These dosage forms which can be used in the context of the present invention are described in detail in the following part of the description.
• the inhalable powders according to the invention can and 2 contain either, alone or in a mixture with suitable physiologically acceptable excipients.
• physiologically safe auxiliary substances can be used to prepare these inhalable powders according to the invention: monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, sucrose, maltose), oligosaccharides and polysaccharides (for example dextrans), polyalcohols (for example sorbitol, mannitol, xylitol), salts (for example sodium chloride, calcium carbonate) or mixtures of these auxiliaries with one another.
• monosaccharides eg glucose or arabinose
• disaccharides eg lactose, sucrose, maltose
• oligosaccharides and polysaccharides for example dextrans
• polyalcohols for example sorbitol, mannitol, xylitol
• salts for example sodium chloride, calcium carbonate
• the auxiliaries have a maximum average particle size of up to 250 ⁇ m, preferably between 10 and 150 ⁇ m, particularly preferably between 15 and 80 ⁇ m. If appropriate, it may appear sensible to add finer excipient fractions with an average particle size of 1 to 9 ⁇ m to the excipients mentioned above. The latter finer excipients are also selected from the above mentioned group of excipients that can be used.
• micronized active ingredient and 2 preferably with an average particle size of 0.5 to 10 ⁇ m, particularly preferably 1 to 6 ⁇ m, are admixed with the excipient mixture.
• inhalable powders according to the invention Processes for producing the inhalable powders according to the invention by grinding and micronizing and by finally mixing the constituents are known from the prior art.
• the inhalable powders according to the invention can be provided and applied either in the form of a single powder mixture which contains both ⁇ and 2 or in the form of separate inhalable powders which contain only ⁇ and 2.
• Inhalation powders according to the invention which in addition to 1 and 2 also contain a physiologically acceptable auxiliary, can be applied, for example, by means of inhalers which take a single dose from a supply by means of an h
• the inhalable powders according to the invention which contain ⁇ _ and 2 optionally in conjunction with a physiologically compatible auxiliary, can be applied, for example, by means of the inhaler known under the name Turbuhaler ® or with inhalers as disclosed, for example, in EP 237507 A.
• the inhalable powders according to the invention which in addition to and contain 2 physiologically acceptable excipients, are preferably filled into capsules (for so-called inhalers), which are contained in
• FIG. 1 An inhaler which is particularly preferred for use of the pharmaceutical combination according to the invention in inhalettes can be seen in FIG. 1.
• This inhaler for the inhalation of powdered pharmaceuticals from capsules is characterized by a housing 1, containing two windows 2, a deck 3, in which there are air inlet openings and which is provided with a sieve 5 attached via a sieve housing 4, one with a deck 3 connected inhalation chamber 6, on which a pusher 8 provided with two ground needles 7 and movable against a spring 8 is provided, as well as a mouthpiece 12 which is hinged to the housing 1, the deck 3 and a cap 11 via an axis 10.
• a housing 1 containing two windows 2, a deck 3, in which there are air inlet openings and which is provided with a sieve 5 attached via a sieve housing 4, one with a deck 3 connected inhalation chamber 6, on which a pusher 8 provided with two ground needles 7 and movable against a spring 8 is provided, as well as a mouthpiece 12 which is hinged to the housing 1, the deck 3 and a cap 11 via an axis 10.
• inhalable powders according to the invention are to be filled into capsules (inhalettes) in the sense of the preferred use mentioned above, fill quantities of 1 to 30 mg, preferably 3 to 20 mg, preferably 5 to 10 mg inhalable powder per capsule are appropriate. According to the invention, these contain either together or in each case the doses per single dose already mentioned above for Y and 2.
• propellant gas inhalation aerosols containing the active ingredient combinations according to the invention from 1 and 2 propellant gas inhalation aerosols according to the invention can and 2 dissolved in the propellant gas or contain in dispersed form. 1. and 2 may be contained in separate dosage forms or in a common dosage form, 1_ and 2 either being both dissolved, both dispersed or in each case only one component being dissolved and the other being dispersed.
• the propellant gases which can be used to produce the inhalation aerosols according to the invention are known from the prior art.
• Suitable propellants are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halogenated hydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
• the above-mentioned propellant gases can be used alone or in mixtures thereof.
• Particularly preferred propellants are halogenated alkane derivatives selected from TG134a (1, 1, 1, 2-tefrafluoroethane), TG227 (1, 1, 1, 2,3,3,3-heptafluoropropane) and mixtures thereof.
• the inhalation aerosols containing propellant gas according to the invention can furthermore contain further constituents such as cosolvents, stabilizers, surfactants, antioxidants, lubricants and agents for adjusting the pH. All of these components are known in the art.
• the inhalation aerosols containing propellant gas according to the invention can contain up to 5% by weight of active ingredient 1 and / or 2. Aerosols according to the invention contain, for example, 0.002 to 5% by weight, 0.01 to 3% by weight, 0.015 to 2% by weight, 0.1 to 2% by weight, 0.5 to 2% by weight or 0.5 to 1 % By weight of active ingredient 1 and / or 2.
• 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.
• a further aspect of the present invention relates to medicaments in the form of propellant-containing aerosols as described above in connection with one or more inhalers suitable for the administration of these aerosols.
• the present invention further relates to inhalers, characterized in that they contain propellant-containing aerosols according to the invention described above.
• the present invention further relates to cartridges which can be used with a suitable valve in a suitable inhaler and which contain one of the above-mentioned inhalation aerosols containing propellant gas according to the invention.
• Suitable cartridges and methods for filling these cartridges with the inhalation aerosols containing propellant gas according to the invention are known from the prior art.
• the active compound combination according to the invention is particularly preferably applied in the form of propellant-free inhalation solutions and inhalation suspensions.
• Suitable solvents for this purpose are aqueous or alcoholic, preferably ethanolic, solutions.
• the solvent can only be water or it is a mixture of water and ethanol.
• the relative proportion of ethanol to water is not limited, but the maximum limit is preferably up to 70 volume percent, in particular up to 60 volume percent and particularly preferably up to 30 volume percent.
• the remaining volume percentages are filled up with water.
• Solutions and suspensions containing 2 and 2, separately or together, are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. Acids selected from inorganic or organic acids can be used to adjust this pH.
• inorganic acids examples include 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 ingredients. Ascorbic acid, fumaric acid and citric acid are preferred among the organic acids. If appropriate, mixtures of the acids mentioned can also be used, particularly in cases of acids which, in addition to their acidifying properties, also have other properties, for example as flavorings, antioxidants or complexing agents, such as, for example, citric acid or ascorbic acid. According to the invention, hydrochloric acid is particularly preferably used to adjust the pH.
• the addition of editic acid (EDTA) or one of the known salts thereof, sodium edetate, as a stabilizer or complexing agent can be dispensed with in the present formulation.
• Other embodiments include this connection (s).
• the content based on sodium edetate is less than 100 mg / 100 ml, preferably less than 50 mg / 100 ml, particularly preferably less than 20 mg / 100 ml.
• Co-solvents and / or further auxiliaries can be added to the propellant-free inhalation solutions according to the invention.
• Preferred co-solvents are those which contain hydroxyl groups or other polar * groups, for example alcohols - in particular isopropyl alcohol, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
• auxiliaries and additives are understood to mean any pharmacologically acceptable substance which is not an active substance, but which can be formulated together with the active substance (s) in the pharmacologically suitable solvent in order to improve the qualitative properties of the
• auxiliaries and additives include e.g. surfactants such as Soy lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents,
• Antioxidants and / or preservatives that ensure or extend the useful life of the finished pharmaceutical formulation, flavors, vitamins and / or other additives known in the art.
• the additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.
• the preferred auxiliaries include antioxidants, such as, for example, ascorbic acid, unless already used for adjusting the pH.
• antioxidants such as, for example, ascorbic acid, unless already used for adjusting the pH.
• Preservatives can be used to protect the formulation from contamination with germs. Suitable preservatives are those known from the prior art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art.
• the above-mentioned preservatives are preferably contained in concentrations of up to 50 mg / 100 ml, particularly preferably between 5 and 20 mg / 100 ml.
• preferred formulations only contain benzalkonium chloride and sodium edetate. In another preferred embodiment, sodium edetate is dispensed with.
• those inhalers are particularly small. Can atomize the amount of a liquid formulation in the therapeutically necessary dosage within a few seconds into a therapeutically inhalable aerosol.
• those nebulisers are preferred in which one
• Amount of less than 100 .mu.L, preferably less than 50 .mu.L, particularly preferably between 10 and 30 .mu.L of active ingredient solution with preferably one stroke to an aerosol with an average particle size of less than 20 .mu.m, preferably less than 10 .mu.m, can be atomized that the inhalable portion of the aerosol already corresponds to the therapeutically effective amount.
• Such a device for propellant-free administration of a metered amount of a liquid medicament for inhalation use is described in detail, for example, in international patent application WO 91/14468 and also in WO 97/12687 (there in particular FIGS. 6a and 6b).
• the 30 nebulizers (devices) described there are also known under the name Respimat ® .
• This nebuliser may be advantageous to produce the inhalable aerosols according to the invention containing the combination of active substances and are used. 2 Due to its cylinder-like shape and a handy size of less than 9 to 15 cm in length and 2 to 4 cm in width, this device can be carried by the patient at any time. The nebulizer sprays a defined volume of the drug formulation using high pressures through small nozzles, so that inhalable aerosols are produced.
• the preferred atomizer consists of an upper housing part, a pump housing, a nozzle, a locking mechanism, a spring housing, a spring and a storage container, characterized by a pump housing which is fastened in the upper housing part and which has a nozzle body with the nozzle at one end or nozzle arrangement carries, a hollow piston with valve body, an output flange in which the hollow piston is fastened, and which is in the
• Upper housing part is - a locking mechanism, which is located in the upper housing part, a spring housing with the spring therein, which is rotatably mounted on the upper housing part by means of a rotary bearing, a lower housing part which is attached to the spring housing in the axial direction.
• the hollow piston with valve body corresponds to a device disclosed in WO 97/12687. It projects partially into the cylinder of the pump housing and is arranged axially displaceably in the cylinder. In particular, reference is made to FIGS. 1-4 - in particular FIG. 3 - and the associated parts of the description.
• the hollow piston with valve body exerts a pressure of 5 to 60 Mpa (about 50 to 600 bar), preferably 10 to 60 Mpa (about 100 to 600 bar) on the fluid, the measured active ingredient solution on its high pressure side at the time the spring is triggered. Volumes of 10 to 50 microliters are preferred, volumes of 10 to 20 microliters are particularly preferred, and a volume of 15 microliters per stroke is very particularly preferred.
• the valve body is preferably attached to the end of the hollow piston which faces the nozzle body.
• the nozzle in the nozzle body is preferably microstructured, that is to say manufactured by micro technology.
• Microstructured nozzle bodies are disclosed, for example, in WO-94/07607; reference is hereby made to this document, in particular to FIG. 1 and its description disclosed therein.
• the nozzle body consists, for example, of two plates of glass and / or silicon which are firmly connected to one another, of which at least one plate has one or more microstructured channels which connect the nozzle inlet side to the nozzle outlet side.
• On the nozzle outlet side there is at least one round or non-round opening of 2 to 10 micrometers deep and 5 to 15 micrometers Width, the depth being preferably 4.5 to 6.5 micrometers and the length being 7 to 9 micrometers.
• the jet directions of the nozzles in the nozzle body can run parallel to one another or they are inclined towards one another in the direction of the nozzle opening.
• the jet directions can be inclined at an angle of 20 degrees to 160 degrees, an angle of 60 to 150 degrees is preferred, particularly preferably 80 to 100 °.
• the nozzle openings are preferably arranged at a distance of 10 to 200 micrometers, more preferably at a distance of 10 to 100 micrometers, particularly preferably 30 to 70 micrometers. Most preferred are 50 microns.
• the jet directions meet in the vicinity of the nozzle openings.
• the liquid pharmaceutical preparation hits the nozzle body with an inlet pressure of up to 600 bar, preferably 200 to 300 bar, and is atomized into an inhalable aerosol via the nozzle openings.
• the preferred particles Droplet sizes of the aerosol are up to 20 micrometers, preferably 3 to 10 micrometers.
• the locking mechanism contains a spring, preferably a cylindrical helical compression spring, as a store for the mechanical energy.
• the spring acts on the output flange as a jumping piece, the movement of which is determined by the position of a locking element.
• the path of the output flange is precisely limited by an upper and a lower stop.
• the spring is preferably via a force-transmitting gear, e.g. a screw-type thrust gear, tensioned by an external torque which is generated when the upper housing part is turned against the spring housing in the lower housing part.
• the upper part of the housing and the output flange contain a single or multi-speed wedge gear.
• the locking member with engaging locking surfaces is arranged in a ring around the output flange. It consists, for example, of a radially elastically deformable ring made of plastic or metal. The ring is arranged in a plane perpendicular to the atomizer axis. After tensioning the spring, the locking surfaces of the locking member slide into the path of the output flange and prevent the spring from relaxing.
• the locking element is triggered by a button.
• the trigger button is connected or coupled to the locking member. To release the locking mechanism, the release button parallel to the ring plane is preferred into the atomizer, shifted; the deformable ring is deformed in the ring plane. Constructive details of the locking mechanism are described in WO 97/20590.
• the lower part of the housing is pushed in the axial direction over the spring housing and covers the bearing, the drive of the spindle and the reservoir for the fluid.
• the upper housing part When the atomizer is actuated, the upper housing part is rotated against the lower housing part, the lower housing part taking the spring housing with it.
• the spring is compressed and tensioned via the screw-type thrust gear, and the locking mechanism engages automatically.
• the angle of rotation is preferably an integer fraction of 360 degrees, for example 180 degrees.
• the driven part in the upper part of the housing Simultaneously with the tensioning of the spring, the driven part in the upper part of the housing is displaced by a predetermined distance, the hollow piston is withdrawn within the cylinder in the pump housing, as a result of which a partial quantity of the fluid is sucked out of the reservoir 1 into the high-pressure space in front of the nozzle.
• the storage container contains the aqueous aerosol preparation according to the invention.
• the atomization process is initiated by gently pressing the trigger button.
• the barrage clears the way for the stripping section.
• the tensioned spring pushes the piston into the cylinder of the pump housing.
• the components of the atomizer are made of a material that is suitable for their function.
• the housing of the atomizer and - as far as the function allows - other parts are preferably made of plastic, e.g. manufactured by injection molding. Physiologically harmless materials are used for medical purposes.
• Figure 2a shows a longitudinal section through the atomizer with the spring under tension
• Figure 2b shows a longitudinal section through the atomizer with the spring relaxed.
• the upper housing part (51) contains the pump housing (52), at the end of which the holder (53) for the atomizer nozzle is attached.
• the nozzle body (54) and a filter (55) are located in the holder.
• the hollow piston (57) fastened in the output flange (56) of the locking tensioning mechanism partially protrudes into the cylinder of the pump housing.
• the hollow piston carries the valve body (58) at its end.
• the hollow piston is sealed by means of the seal (59).
• Inside the upper part of the housing is the stop (60), against which the output flange rests when the spring is relaxed.
• the stop (61) is located on the output flange, against which the output flange rests when the spring is tensioned.
• the locking member (62) slides between the stop (61) and a support (63) in the upper part of the housing.
• the release button (64) is connected to the locking member.
• the upper housing part ends in the mouthpiece (65) and is closed with the clip-on protective cap (66).
• the spring housing (67) with compression spring (68) is rotatably mounted on the upper part of the housing by means of the snap lugs (69) and rotary bearings.
• the lower housing part (70) is pushed over the spring housing.
• the replaceable reservoir (71) for the fluid (72) to be atomized is located within the spring housing.
• the storage container is closed with the stopper (73) through which the hollow piston protrudes into the storage container and with its end is immersed in the fluid (supply of active substance solution).
• the spindle (74) for the mechanical counter is mounted in the outer surface of the spring housing.
• the drive pinion (75) is located at the end of the spindle which faces the upper housing part.
• the rider (76) sits on the spindle.
• the nebuliser described above is suitable for nebulizing the aerosol preparations according to the invention into an aerosol suitable for inhalation.
• the mass expelled in at least 97%, preferably at least 98% of all actuations of the inhaler (spray) a defined quantity with a tolerance of not more than 25%, preferably 20% of these quantity correspond.
• a defined quantity with a tolerance of not more than 25%, preferably 20% of these quantity correspond.
• Between 5 and 30 mg of formulation are preferably applied as a defined mass per stroke, particularly preferably between 5 and 20 mg.
• the formulation according to the invention can also be nebulized using inhalers other than those described above, for example jet stream inhalers or other stationary nebulizers.
• a further aspect of the present invention relates to medicaments in the form of above-described propellant-free inhalable solutions or suspensions in combination with a suitable device for administering these formulations, preferably in conjunction with the Respimat ®.
• a suitable device for administering these formulations preferably in conjunction with the Respimat ®.
• the present invention to propellant-free inhalable solutions or suspensions characterized by aiming the inventive active ingredient combination of ⁇ and 2 in connection with the known under the name Respimat ® device.
• the present invention relates to the abovementioned devices for inhalation preferred Respimat ®, in the fact that they contain according to the invention the propellant-free inhalable solutions or suspensions as described above.
• a dosage form is also understood to be dosage forms which contain the two components 1 and 2 in two-chamber cartridges, as are disclosed, for example, by WO 00/23037. At this point, full reference is made to these.
• the propellant-free inhalation solutions or suspensions according to the invention can, in addition to the solutions and suspensions intended for application in the Respimat, also be present as concentrates or sterile, ready-to-use inhalation solutions or suspensions.
• Ready-to-use formulations can be generated from the concentrates, for example, by adding isotonic saline solutions.
• Sterile, ready-to-use formulations can be applied using energy-operated stand-up or portable nebulisers that generate inhalable aerosols using ultrasound or compressed air according to the Venturi principle or other principles.
• a further aspect of the present invention relates to medicaments in the form of propellant-free inhalable solutions or suspensions as described above, which are present as concentrates or sterile, ready-to-use formulations, in conjunction with a Administration of these solutions suitable device, characterized in that this device is an energy-operated standing or portable nebulizer that generates inhalable aerosols by means of ultrasound or compressed air according to the Venturi principle or other principles.
• this device is an energy-operated standing or portable nebulizer that generates inhalable aerosols by means of ultrasound or compressed air according to the Venturi principle or other principles.
• tiotropium bromide used in the formulation examples below can be obtained as described in European patent application EP 418 716 A1. Crystalline tiotropium bromide monohydrate can also be used to produce the inhalable powders according to the invention. This crystalline
• Tiotropium bromide monohydrate is as described below. , - '•' Available by far. '• . • ' .' • •
• tiotropium bromide 15.0 kg are introduced into 25.7 kg of water in a suitable reaction vessel. The mixture is heated to 80-90 ° C and stirred at a constant temperature until a clear solution is formed. Activated carbon (0.8 kg), water-moist, is slurried in 4.4 kg of water, this. Mix the mixture into the tiotropium bromide-containing solution and rinse with 4.3 kg of water. The mixture thus obtained is stirred at 80-90 ° C. for at least 15 minutes and then filtered through a heated filter into an apparatus preheated to a jacket temperature of 70 ° C. The filter is rinsed with 8.6 kg of water.
• the contents of the apparatus are cooled to 3-5 ° C per 20 minutes to a temperature of 20-25 ° C. With cold water cooling, the apparatus is cooled further to 10-15 ° C and the crystallization is completed by stirring for at least one hour.
• the crystals are isolated using a suction filter, the isolated crystal slurry is washed with 9 L of cold water (10-15 ° C) and cold acetone (10-15 ° C).
• the crystals obtained are dried at 25 ° C. for 2 hours in a stream of nitrogen. Yield: 13.4 kg tiotropium bromide monohydrate (86% of theory)
• the crystalline tiotropium bromide monohydrate thus obtained is micronized by known methods to provide the active ingredient in the form of the average particle size which corresponds to the specifications according to the invention.

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• 2000
  • 2000-12-20 DE DE10063957A patent/DE10063957A1/de not_active Withdrawn
• 2001
  • 2001-12-12 JP JP2002550966A patent/JP2004516264A/ja active Pending
  • 2001-12-12 WO PCT/EP2001/014568 patent/WO2002049624A2/de active Application Filing
  • 2001-12-12 MX MXPA03005585A patent/MXPA03005585A/es not_active Application Discontinuation
  • 2001-12-12 EP EP01985868A patent/EP1345626A2/de not_active Withdrawn
  • 2001-12-12 AU AU2002235767A patent/AU2002235767A1/en not_active Abandoned
  • 2001-12-12 CA CA002430592A patent/CA2430592C/en not_active Expired - Fee Related

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