EP1827432A1 - Medicaments administres par inhalation contenant un nouvel anticholinergique, du formoterol et un steroide - Google Patents

Medicaments administres par inhalation contenant un nouvel anticholinergique, du formoterol et un steroide

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Publication number
EP1827432A1
EP1827432A1 EP05803012A EP05803012A EP1827432A1 EP 1827432 A1 EP1827432 A1 EP 1827432A1 EP 05803012 A EP05803012 A EP 05803012A EP 05803012 A EP05803012 A EP 05803012A EP 1827432 A1 EP1827432 A1 EP 1827432A1
Authority
EP
European Patent Office
Prior art keywords
propellant
formoterol
steroid
inhalable
medicament
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Withdrawn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
EP05803012A
Other languages
German (de)
English (en)
Inventor
Michael P. Pieper
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Publication of EP1827432A1 publication Critical patent/EP1827432A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K31/16—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
    • A61K31/58—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]

Definitions

  • the present invention relates to novel drug compositions based on a novel anticholinergic, formoterol salts and a corticosteroid, processes for their preparation and their use in the treatment of respiratory diseases.
  • the present invention relates to novel drug compositions containing an anticholinergic of the formula I
  • X is an anion selected from the group consisting of chloride, bromide and methanesulfonate, preferably bromide,
  • a formoterol salt selected from formoterol fumarate and formoterol hemifumarate, optionally in the form of its hydrates and / or solvates, and optionally in the form of one of its respective enantiomers or mixtures of the enantiomers,
  • a steroid selected from the group consisting of ciclesonide, budesonide and mometasone furoate, each optionally in the form of their solvates and / or hydrates.
  • the salts of formula 1 are known from international patent application WO 02/32899. Reference to the salts of Formula 1 includes reference to their optionally available hydrates and solvates.
  • Reference to the steroids ciclesonide, budesonide and mometasone furoate in the context of the present invention includes reference to salts or derivatives which 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 said steroids may also be present in the form of their hydrates, in the case of mometasone furoate, the mometasone furoate monohydrate is of particular importance.
  • the formoterol salt may optionally be present in enantiomerically pure form.
  • Enantiomers which can be used according to the invention are selected from the group consisting of salts of R, R-formoterol, S, S-formoterol, R, S-formoterol and S, R-formoterol, the enantiomeric salts of the R, R-formomer being of particular importance
  • the formoterol salt may optionally be used in the form of its hydrates and / or solvates. Of particular importance according to the invention are formoterol fumarate dihydrate and formoterol hemifumarate monohydrate.
  • suitable inhalable powders which are filled into suitable capsules (inhalers) by means of appropriate powder inhalers may preferably be used.
  • 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, formoterol salt and one of the steroids ciclesonide, budesonide or mometasone furoate.
  • Another aspect of the present invention relates to a drug kit containing the above-mentioned ingredients in separate drug formulations.
  • Another aspect of the present invention relates to a pharmaceutical composition which contains in addition to therapeutically effective amounts of I, formoerol salt and ciclesonide, budesonide or mometasone furoate a pharmaceutically acceptable carrier.
  • Particularly preferred drugs contain the following drug combinations in addition to a pharmaceutically acceptable excipient or carrier:
  • V-bromide formoterol hemifumarate monohydrate and ciclesonide
  • Ij bromide formoterol hemifumarate monohydrate and budesonide
  • T-bromide formoterol fumarate dihydrate and ciclesonide
  • V-bromide formoterol fumarate dihydrate and budesonide
  • Ij bromide formoterol fumarate dihydrate and mometasone furoate monohydrate
  • the formoterol salt is contained in the form of the formoterol hemifumarate, preferably in the form of the fomroterol hemifumarate monohydrate.
  • the present invention further relates to the use of the above-mentioned.
  • the medicament combinations according to the invention can be used for the production of a medicament for the treatment of, for example, cystic fibrosis or allergic alveolitis (Farmers Lung) by simultaneous or successive application.
  • 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 seeks to provide the simultaneous or successive use of therapeutically effective doses of the combination of the above drugs for the treatment of inflammatory or obstructive airways diseases, in particular asthma and / or chronic obstructive pulmonary disease (COPD), if treatment with steroids or betamimetics is not considered therapeutically Contraindicated 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 medicaments for the treatment of, for example, cystic fibrosis or allergic alveolitis (Farmers Lung).
  • preferred drug combinations containing ciclesonides as steroid are preferably applied such that once or twice daily 15-800 ⁇ g, preferably 50-400 ⁇ g, in particular 50-200 ⁇ g of the active ingredient 1, preferably in the form of its bromide, 3-20 ⁇ g, preferably 4 to 10 ⁇ g of formoterol salt and 50-400 ⁇ g, preferably 100-400 ⁇ g of ciclesonide are administered.
  • preferred drug combinations containing budesonides as steroid are preferably applied such that once or twice daily 15-800 ⁇ g, preferably 50-400 ⁇ g, in particular 50-200 ⁇ g of the active ingredient 1, preferably in the form of its bromide, 3 - 20 ⁇ g, preferably 4 to 10 ⁇ g
  • preferred drug combinations which contain mometasone furoate as steroid are preferably applied in such a way that once or twice daily 15-800 ⁇ g, preferably 50-400 ⁇ g, in particular 50-200 ⁇ g of the active ingredient 1, preferably in the form of its bromide, 3-20 ⁇ g , Preferably 4 to 10 micrograms of formoterol salt and 200-800 micrograms, preferably 300-500 micrograms of mometasone furoate are administered.
  • Suitable inhalable dosage forms according to the invention are inhalable powders, propellant-containing metered-dose aerosols or propellant-free inhalable solutions.
  • Inventive inhalable powders which contain the abovementioned active ingredient combinations may consist solely of the abovementioned active substances or of a mixture of the abovementioned active compounds 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 either together in one, in two or in three separate administration forms. This in the context of Present dosage forms are described in detail in the following part of the description.
  • the inhalable powders according to the invention may contain the active ingredients mentioned 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, trehalose), oligosaccharides and polysaccharides (eg dextrans), polyalcohols (eg sorbitol, mannitol, xylitol), salts (eg sodium chloride, calcium carbonate) or mixtures of these auxiliaries.
  • monosaccharides eg glucose or arabinose
  • disaccharides eg lactose, sucrose, maltose, trehalose
  • oligosaccharides and polysaccharides eg dextrans
  • polyalcohols eg sorbitol, mannitol, xylitol
  • salts eg sodium chloride, calcium carbonate
  • mono- or disaccharides are used, wherein the use of lacto
  • 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.
  • the micronized active ingredients preferably having an average particle size of 0.5 to 10 .mu.m, particularly preferably from 1 to 5 .mu.m, of the excipient mixture are mixed to prepare the inhalable powder according to the invention.
  • inhalable powders according to the invention Methods for producing 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 can be provided and applied either in the form of a single powder mixture containing all three active substances or in the form of separate inhalable powders containing only 2 or in each case only one of the active substances mentioned.
  • the inhalable powders according to the invention can be applied by means of inhalers known from the prior art.
  • Inhalable powders according to the invention which in addition to the abovementioned active substances also contain one or more physiologically acceptable auxiliaries, can be administered, for example, by means of inhalers comprising a single dose from a supply by means of a measuring chamber as described in US 4570630A or by other apparatus , as described in DE 36 25 685 A, dose.
  • the inhalable powders according to the invention which contain physiologically acceptable auxiliaries in addition to the abovementioned active ingredients, are, however, preferably 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 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 which a provided with two ground needles 7, is provided against a spring 8 movable pusher 9, and a hinged via an axis 10 with the housing 1, the deck 3 and a cap 11 mouthpiece 12 and air passage holes thirteenth for setting the flow resistance.
  • inhalable powders according to the invention are to be filled into capsules (inhalettes) in the sense of the preferred application mentioned above, fillages of from 1 to 30 mg, preferably from 3 to 20 mg, preferably from 5 to 10 mg of inhalable powder per capsule are suitable.
  • 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.
  • These contain, according to the invention, either together or in each case the dosages already mentioned above for the abovementioned active substances per single administration.
  • Propellant gas-containing inhalation aerosols can dissolve the abovementioned active substances in the propellant gas or contain them in dispersed form.
  • the above-mentioned active ingredients may be contained in separate dosage forms or in a common dosage form, the above-mentioned
  • 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. The abovementioned propellant gases may 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-containing inhalable inhalation aerosols according to the invention may contain up to 5% by weight of o. Contain active ingredients. 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 on one or more of the above Agents.
  • the active substance particles preferably have an average particle size of up to 10 ⁇ m, preferably from 0.1 to 5 ⁇ m, particularly preferably from 1 to 5 ⁇ m.
  • MDIs metered dose inhalers
  • another aspect of the present invention relates to pharmaceutical compositions in the form of propellant-containing aerosols as described above in association with one or more inhalers suitable for administering these aerosols.
  • the present invention relates to inhalers, characterized in that they contain the propellant-containing aerosols according to the invention described above.
  • the present invention further relates to cartridges which can be equipped with a suitable valve in a suitable inhaler and which contain one of the abovementioned propellant-containing inhalation aerosols according to the invention. Suitable cartridges and processes for filling these cartridges with the propellant-containing inhalable inhalable aerosols according to the invention are known from the prior art.
  • Propellant-free inhalable solutions or suspensions The application of the active ingredient combination according to the invention is particularly preferably carried out in the form of propellant-free inhalable solutions and suspension suspensions.
  • 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 solutions or suspensions containing the abovementioned active substances separately or together are adjusted to a pH of from 2 to 7, preferably from 2 to 5, using suitable acids.
  • acids selected from inorganic or organic acids can find use.
  • inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid.
  • organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others.
  • Preferred inorganic acids are hydrochloric acid, sulfuric acid. It is also possible to use the acids which already form an acid addition salt with one of the active substances.
  • organic acids 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 groups, for example alcohols - in particular isopropyl alcohol, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
  • auxiliaries and additives is meant in this context any physiologically acceptable substance that is not an active ingredient but can be formulated together with the active ingredient (s) in the physiologically suitable solvent in order to improve the qualitative properties of the active ingredient formulation.
  • these substances do not develop any appreciable or at least no undesirable pharmacological in the context of the desired therapy
  • the auxiliaries and additives include e.g. surfactants, e.g. Soya lecithin, oleic acid, sorbitan esters such as polysorbates, polyvinylpyrrolidone other stabilizers, chelating agents, antioxidants and / or preservatives which assure or prolong the useful life of the finished drug formulation, flavoring agents, vitamins and / or other additives known in the art.
  • the additives also include physiologically acceptable salts such as sodium chloride as isotonic agents.
  • Preferred excipients include antioxidants, such as
  • Ascorbic acid if not already used for the adjustment of pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins found in the human body.
  • Preservatives may be used to protect the formulation from contamination by germs. Suitable preservatives are those known in the art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art.
  • the above-mentioned preservatives are preferably contained 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.
  • 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 which contain the active compound combinations according to the invention. Due to its cylindrical shape and a handy size of less than 9 to 15 cm in length and 2 to 4 cm in width, this device can always be carried by the patient.
  • the nebulizer sprays a defined volume of the drug formulation using high pressures through small nozzles to produce inhalable aerosols.
  • the preferred atomizer 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, - an output 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 pivot 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. He partially protrudes into the cylinder of the pump housing and is in Cylinder arranged axially displaceable. 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 e.g. of two fixed plates of glass and / or silicon, at least one plate of which has one or more microstructured channels connecting the nozzle inlet side to 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.
  • the jet directions of the nozzles in the nozzle body can be parallel to one another or they are inclined towards one another in the direction of the nozzle opening.
  • the jet directions may be inclined at an angle of 20 degrees to 160 degrees to each other, preferably an angle of 60 to 150 degrees, particularly preferably 80 to 100 °.
  • the nozzle orifices are preferably located at a distance of 10 to 200 microns, more preferably at a distance of 10 to 100 microns, more preferably 30 to 70 microns. Most preferred are 50 microns.
  • the jet directions accordingly meet in the vicinity of the nozzle openings.
  • the liquid pharmaceutical preparation meets the nozzle body with an inlet pressure of up to 600 bar, preferably 200 to 300 bar, and is atomized via the nozzle openings into an inhalable aerosol.
  • the preferred particle or droplet sizes of the aerosol are up to 20 microns, preferably 3 to 10 microns.
  • the locking work contains 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.
  • the ring is arranged in a plane perpendicular to the atomizer axis. After tensioning the spring, the locking surfaces of the locking member push in the path of the output flange and prevent the relaxation of the spring.
  • the Sprerrglied is triggered by a button.
  • the release button is connected or coupled to the locking member.
  • the shutter button is parallel to the ring plane, and preferably in the atomizer, moved; while the deformable ring is deformed in the ring plane. Constructive details of the locking mechanism are described in WO 97/20590.
  • the 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 lower housing part takes 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, for example 180 degrees.
  • 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.
  • a plurality of interchangeable reservoirs containing the fluid to be atomized can be inserted and used successively in the atomizer.
  • 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 permits, other parts are preferably made of plastic, e.g. by injection molding. Physiologically harmless materials are used for medical purposes.
  • FIGS. 6 a / b of WO 97/12687 describe the nebuliser (Respimat®) with which the aqueous aerosol preparations according to the invention can advantageously be inhaled.
  • FIG. 6a of WO 97/12687 shows a longitudinal section through the atomizer with the spring tensioned
  • FIG. 6b of WO 97/12687 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 connected to the locking member in connection.
  • 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.
  • the nebulizer described above is suitable for nebulizing the aerosol preparations according to the invention to form an aerosol suitable for inhalation.
  • the applied mass should contain at least 97%, preferably at least 98%, of all actuations of the inhaler (Hube) of a defined amount with a maximum tolerance of 25%, preferably 20% Amount correspond.
  • the inhaler Hube
  • a maximum tolerance of 25% preferably 20% Amount correspond.
  • between 5 and 30 mg of formulation per stroke are applied as a defined mass, more preferably between 5 and 20 mg.
  • formulation according to the invention may also be aerosolized by means of inhalers other than those described above, for example jet-stream inhalers.
  • a further aspect of the present invention relates to pharmaceuticals in the form of propellant-free inhalable solutions or suspensions as described above in conjunction with a device suitable for administering these formulations, preferably in conjunction with the Respimat®.
  • the present invention aims at propellant-free inhalable solutions or suspensions characterized by the combination of active substances according to the invention in conjunction with the device known under the name Respimat®.
  • the present invention relates to the aforementioned inhalation devices, preferably the Respimat®, characterized in that they are 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.
  • inhalable powders according to the invention which contain V-bromide, formoterol hemifumarate monohydrate, budesonide and, as adjuvant, lactose monohydrate.
  • inhalable powders according to the invention which contain jT bromide, formoterol hemifumarate monohydrate, ciclesonides and, as excipient, lactose monohydrate.

Abstract

L'invention concerne de nouvelles compositions médicamenteuses à base d'un nouveau anticholinergique, de sels de formotérol et d'un corticostéroïde. L'invention concerne également des procédés permettant de produire lesdites compostions, ainsi que leur utilisation dans le traitement d'affections des voies respiratoires.
EP05803012A 2004-11-23 2005-11-07 Medicaments administres par inhalation contenant un nouvel anticholinergique, du formoterol et un steroide Withdrawn EP1827432A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004056578A DE102004056578A1 (de) 2004-11-23 2004-11-23 Inhalative Arzneimittel enthaltend ein neues Anticholinergikum, Formoterol und ein Steroid
PCT/EP2005/055782 WO2006056526A1 (fr) 2004-11-23 2005-11-07 Medicaments administres par inhalation contenant un nouvel anticholinergique, du formoterol et un steroide

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EP1827432A1 true EP1827432A1 (fr) 2007-09-05

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US (1) US20060110330A1 (fr)
EP (1) EP1827432A1 (fr)
JP (1) JP2008520621A (fr)
CA (1) CA2582153A1 (fr)
DE (1) DE102004056578A1 (fr)
WO (1) WO2006056526A1 (fr)

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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
US20040166065A1 (en) * 2002-08-14 2004-08-26 Boehringer Ingelheim Pharma Gmbh & Co. Kg Aerosol formulation for inhalation comprising an anticholinergic
PE20081788A1 (es) * 2007-02-19 2008-12-18 Cipla Ltd Combinaciones farmaceuticas
BR112013008974A2 (pt) 2010-10-12 2023-12-19 Cipla Ltd Composição farmacêutica, processo para fabricar uma composição farmacêutica e uso de uma composição farmacêutica

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Publication number Priority date Publication date Assignee Title
US5434304A (en) * 1990-09-26 1995-07-18 Aktiebolaget Astra Process for preparing formoterol and related compounds
DE10050994A1 (de) * 2000-10-14 2002-04-18 Boehringer Ingelheim Pharma Neue als Arneimittel einsetzbare Anticholinergika sowie Verfahren zu deren Herstellung
US6706726B2 (en) * 2000-10-14 2004-03-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg Anticholinergics which may be used as medicaments as well as processes for preparing them
DE10130371A1 (de) * 2001-06-23 2003-01-02 Boehringer Ingelheim Pharma Neue Arzneimittelkompositionen auf der Basis von Anticholinergika, Corticosteroiden und Betamimetika
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
US7244742B2 (en) * 2002-08-17 2007-07-17 Boehringer Ingelheim Pharma Gmbh & Co Kg Pharmaceutical compositions for inhalation containing an anticholinergic, corticosteroid and betamimetic
WO2004019985A1 (fr) * 2002-08-29 2004-03-11 Cipla Ltd Produits et compositions pharmaceutiques comprenant des agents anticholinergiques specifiques, des agonistes beta-2 et des corticosteroides

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Title
See references of WO2006056526A1 *

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DE102004056578A1 (de) 2006-05-24
CA2582153A1 (fr) 2006-06-01
WO2006056526A1 (fr) 2006-06-01
US20060110330A1 (en) 2006-05-25
JP2008520621A (ja) 2008-06-19

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