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
  • A61K9/00—Medicinal preparations characterised by special physical form
• • 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
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • 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
  • 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
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/10—Anthelmintics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents

Definitions

• the present invention relates to a propellant-free aerosol formulation comprising one or more compounds of general formula 1,
• radicals R 1 , R 2 , R 3 and X may have the meanings given in the claims and in the description, and two further active compounds 2 and 3, for inhalation.
• R 1 is hydrogen, Ci -4 alkyl, OC- ⁇ - 4 alkyl or halogen
• R 2 is hydrogen, Ci -4 alkyl, O-Ci -4 alkyl or halogen
• an agent 2 selected from the group consisting of budesonide, beclomethasone, fluticasone, ciclesonide or a metabolite thereof, optionally in the form of their tautomers, enantiomers, mixtures of enantiomers, racemates, solvates or hydrates
• an agent 3 selected from the group consisting of tiotropium salts, oxitropium salts, flutropium salts,
• Ipratropium salts optionally in the form
• Hydrate at least one pharmacologically acceptable acid, optionally further pharmacologically acceptable excipients, and as a solvent ethanol or a mixture of water and ethanol.
• X- a singly or multiply negatively charged anion, preferably a singly or multiply negatively charged anion selected from the group consisting of chloride,
• toluenesulfonate optionally, in the form of their tautomers, enantiomers, mixtures of enantiomers, racemates, solvates or hydrates.
• R 3 is methoxy, ethoxy, fluorine, chlorine, bromine, 0-CH 2 -COOH, -O-CH 2 or O-CH 2 -COOMethyl -COOEthyl;
• R 1 , R 2 and X may have the abovementioned meanings, if appropriate in the form of their tautomers, enantiomers, mixtures of the enantiomers, racemates, solvates or hydrates.
• the active ingredient 2 is selected from the group of steroids consisting of budesonide, beclomethasone, fluticasone, ciclesonide or a metabolite thereof.
• the aforementioned steroids have chiral carbon centers.
• the medicament combinations according to the invention may contain the steroids in the form of their enantiomers, mixtures of the enantiomers or racemates, steroids with high enantiomeric purity preferably being used.
• the active ingredient 3 is selected from the group of anticholinergics consisting of tiotropium salts (3.1), oxitropium salts (3.2), flutropium salts (3.3), ipratropium salts (3.4), glycopyrronium salts (3.5) and trospium salts (3.6).
• the aforementioned anticholinergics have chiral carbon centers.
• the drug combinations according to the invention the anticholinergics in the form of their enantiomers, mixtures contain the enantiomers or racemates, preferably using anticholinergics with high enantiomeric purity.
• the cations tiotropium, oxitropium, flutropium, ipratropium, glycopyrronium and trospium are the pharmacologically active constituents.
• An explicit reference to the abovementioned cations is made by the designations 3.1 'to 3.6 1 . Any reference to the abovementioned salts 3.1 to 3.6 naturally also includes a reference to the corresponding cations tiotropium (3.1 '), oxitropium (3.2 1), flutropium (3.3 1), ipratropium (3.4 1), glycopyrronium (3.5 1), trospium ( 3.6 1 ) with.
• salts 3.1 to 3.6 those compounds are understood according to the invention, in addition to the cations tiotropium (3.1 1), oxitropium (3.2 1), flutropium (3.3 1), ipratropium (3.4 1), glycopyrronium (3.5 1) and trospium (3.6 1 ) as the counterion (anion) chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulfonate, wherein chloride, bromide, iodide, sulfate, Methanesulfonate or p-toluenesulfonate are preferred as counterions.
• the chlorides, bromides, iodides and methanesulfonates are particularly preferred.
• the abovementioned salts can be present in the medicament combinations according to the invention optionally in the form of their solvates or hydrates, preferably in the form of their hydrates.
• the drug combinations according to the invention preferably contain this in the form of the crystalline tiotropium bromide monohydrate, which is known from WO 02/30928. If the tiotropium bromide is used in the medicament combinations according to the invention in anhydrous form, then preferably the anhydrous crystalline tiotropium bromide is used, which is known from WO 03/000265.
• C 1-4 -alkyl (including those which are part of other groups) is taken to mean branched and unbranched alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, n-propyl, / propyl, n-butyl, / -butyl, sec-butyl or te / f-butyl.
• the abbreviations Me, Et, n-Pr, / -Pr, n-Bu, / -Bu, t-Bu, etc. are also used for the abovementioned groups.
• the definitions of propyl and butyl include all conceivable isomeric forms of the respective radicals. For example, propyl includes n-propyl and / propyl, butyl includes / butyl, sec-butyl and te / f-butyl, etc.
• C 1-4 -alkylene (including those which are part of other radicals) are understood as meaning branched and unbranched alkylene groups having 1 to 4 carbon atoms. Examples include: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1, 1-dimethylethylene or 1, 2-dimethylethylene. Unless otherwise stated, the definitions propylene and butylene include all conceivable isomeric forms of the respective radicals of the same carbon number. For example, propylene also includes 1-methylethylene and butylene includes 1-methylpropylene, 1, 1-dimethylethylene, 1, 2-dimethylethylene.
• Halogen in the context of the present invention is fluorine, chlorine, bromine or iodine. Unless otherwise indicated, fluorine, chlorine and bromine are preferred halogens.
• compounds of high enantiomeric purity are meant those compounds which may consist of two or more enantiomers in which one enantiomer is in excess, preferably the excess is more than 90%, more preferably more than 95%, in particular more than 98% of the total mass.
• the preparation of the compounds according to the invention can be carried out in analogy to procedures already known in the prior art. Suitable preparation processes are known, for example, from US Pat. No. 4,460,581, to which reference is made in full at this point.
• the compounds of formula 1 can be present in the pharmaceutical formulations according to the invention optionally in the form of their tautomers. Tautomerism is the appearance of isomeric compounds that are formed by shifting ⁇ or ⁇ bonds and can be in equilibrium. Examples of possible tautomeric forms of the compounds of formula 1 are
• Another aspect of the present invention relates to pharmaceutical formulations which contain the abovementioned compounds of the formula I in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates.
• Particularly preferred are pharmaceutical formulations containing the above-mentioned compounds of formula 1 in the form of compounds with high enantiomeric purity, in which case the R-enantiomers of the compounds of formula 1 according to the invention is of outstanding importance.
• These R-enantiomers can be represented by the general formula I-1
• the above-mentioned use is for the manufacture of a medicament for the treatment of obstructive lung diseases selected from the group consisting of bronchial asthma, pediatric asthma, severe asthma, acute asthma attack, chronic bronchitis, and chronic obstructive pulmonary disease (COPD), wherein the use for the preparation of a medicament for the treatment of asthma bronchial or COPD according to the invention is particularly preferred.
• obstructive lung diseases selected from the group consisting of bronchial asthma, pediatric asthma, severe asthma, acute asthma attack, chronic bronchitis, and chronic obstructive pulmonary disease (COPD)
• COPD chronic obstructive pulmonary disease
• ARDS adult respiratory distress syndrome
• the present invention is concerned with inhalable liquid drug formulations of the above compounds, wherein the liquid formulations of the invention must meet high quality standards.
• the formulations according to the invention can be inhaled orally or pernasally.
• the application of a liquid, dispensing with propellant gases, formulation by means of suitable inhalers offers.
• the inhalative administration of such a formulation can be carried out both orally and nasally.
• Particularly suitable are those inhalers which can nebulise a small amount of a liquid formulation in the therapeutically necessary dosage within a few seconds in a therapeutically inhalation suitable aerosol.
• Such a device for propellant-free administration of a metered amount of a liquid medicament for inhalation use is for example in the International Patent Application WO 91/14468 "Atomizing Device and Methods" as well as in WO 97/12687, there Figures 6a and 6b and the associated description, described in detail.
• a drug solution is transferred by means of high pressure of up to 500 bar in a respirable aerosol and sprayed.
• the pH of the formulation according to the invention is preferably in the range from 2.0 to 6.5, preferably from 2.5 to 5.5, according to the invention preferably between about 3.0 and 5.0, in particular between 2.8 and 4.8.
• the pH is adjusted by adding pharmacologically acceptable acids.
• pharmacologically acceptable inorganic or organic acids can be used.
• preferred inorganic acids are selected from the group consisting of hydrochloric acid, phosphoric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid.
• particularly suitable organic acids are selected from the group consisting of ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid, propionic acid, sorbic acid, benzoic acid, methanesulfonic acid and benzenesulfonic acid.
• Preferred inorganic acids are hydrochloric acid, phosphoric acid and sulfuric acid, hydrochloric acid and phosphoric acid being of particular importance in accordance with the invention.
• organic acids ascorbic acid, fumaric acid, methanesulfonic acid and citric acid are preferred, with citric acid being particularly preferred according to the invention.
• mixtures of said acids may also be employed, particularly in the case of acids which, in addition to their acidification properties, also possess other properties, e.g. as flavorants or antioxidants, such as citric acid or ascorbic acid.
• pharmacologically acceptable bases can be used to accurately titrate out the pH. Suitable bases are, for example, alkali metal hydroxides and alkali metal carbonates. Preferred alkali ion is sodium. If such bases are used, care must be taken that the resulting salts, which are then present in the finished pharmaceutical formulation, are also pharmacologically acceptable with the abovementioned acid.
• the adjustment of the pH can also be carried out via a pharmacologically acceptable buffer system.
• pharmacologically acceptable inorganic or organic buffer systems can be used.
• preferred buffer systems are selected from the group consisting of citrate buffer, acetate buffer and phosphate buffer. Particularly preferred here is the phosphate buffer.
• the formulations according to the invention may contain complexing agents as further pharmacologically acceptable auxiliaries.
• complexing agents are understood to mean molecules capable of complexing. Cations, more preferably metallic cations, are preferably to be complexed by these compounds.
• the formulations according to the invention contain as complexing agents preferably editic acid (EDTA) or a known salt thereof, for example sodium EDTA or disodium EDTA.
• EDTA editic acid
• a known salt thereof for example sodium EDTA or disodium EDTA.
• disodium edetate if appropriate in the form of its hydrates, particularly preferably in the form of its dihydrate.
• EDTA may be in the ethanol-containing solution form its ethyl ester, this may be in the form of the mono-, di-, tri- or tetraethyl ester or mixtures thereof.
• disodium edetate or EDTA ethyl ester is used as complexing agent in the formulations according to the invention, its content is preferably in a range from 0.10 to 25 mg per 100 ml, more preferably in a range from 0.15 to 15 mg per 100 ml of inventive formulation.
• the formulations according to the invention contain a complexing agent in an amount of about 0.20 to 8 mg per 100 ml.
• Analogous as stated above for disodium edetate also applies to possible additives which are comparable with EDTA or its salts and which have complex-forming properties and can be used instead, such as, for example, nitrilotriacetic acid and its salts.
• auxiliaries and additives are understood as meaning any pharmacologically acceptable and therapeutically useful substance which is not an active substance but which can be formulated together with the active substance in the pharmacologically suitable solvent in order to improve the qualitative properties of the active ingredient formulation. These substances preferably do not develop any appreciable or at least no undesirable pharmacological effect in the context of the intended therapy.
• the auxiliaries and additives include, for example, stabilizers, antioxidants and / or preservatives, the duration of use extend the finished drug formulation and flavorings, vitamins and / or other additives known in the art.
• the additives also include pharmacologically acceptable salts such as sodium chloride.
• Preferred excipients include antioxidants, such as ascorbic acid, if not already used for pH adjustment, propyl gallate and natural and synthetic phenolic antioxidants.
• the natural phenolic antioxidants include e.g. Vitamin A, tocopherols, such as vitamin E, similar vitamins or provitamins found in the human body.
• Natural antioxidants also include flavonoids found in the plant organism, e.g. Naringenin and resveratrol.
• the synthetic antioxidants include e.g.
• BHA butylhydroxyanisole
• BHT butylhydroxytoluene
• TBHQ tert-butylhydroxyquinone
• BHT or tocopherols more preferably BHT.
• antioxidants are used in the context of the formulations according to the invention, their content is preferably in a range from 0.1 to 200 mg per 100 ml.
• Preferred formulations contain except the solvent water and ethanol, the compounds of formula 1 and active ingredient 2 only an antioxidant and the Adjusting the pH necessary acid.
• Particularly preferred formulations contain, apart from the solvents water and ethanol, the compounds of the formula 1 and the active compounds 2 and 3, only BHT and the acid necessary for adjusting the pH.
• the nebulization of drugs dissolved or suspended in water can be done by compressed air or ultrasound.
• the resulting particle spectrum is superior to propellant gas and powder aerosols in its pulmonary action.
• This type of inhalation is suitable for severe forms of asthma and, due to the simple inhalation technique, is also suitable for children and patients with problems in respiratory coordination.
• the usable dosage forms are limited to microbiologically flawless, aqueous, isotonic and pH-neutral solutions or suspensions.
• Nozzle Nebulizer For a long time, simple devices have been used to break down solutions by passing a powerful stream of air over the opening of a capillary tube through which the solution is aspirated (perfume atomizer principle). In hand atomizers made of glass (nebulizer), the air flow through. Compression of a rubber ball or by pumping (pump sprayer) generated. Newer stationary devices for aerosol therapy are nebulisers working with compressed air, which can generate more than 50% of the optimal size range (1-5 ⁇ m). Compressed air is accelerated through a nozzle and tears drug solution through capillaries with (Bernoulli effect), which is dispersed. A baffle plate located behind the nozzle also serves for shredding.
• Ultrasonic Nebulizer - A piezoelectric crystal is excited by high-frequency alternating voltage to vibrate, which are transmitted via a transfer medium to the drug solution and release the finest liquid droplets, but also heat the liquid.
• the medicament formulations according to the invention are preferably used in an inhaler of the type described above in order to produce therefrom the propellant-free aerosols according to the invention.
• an inhaler of the type described above in order to produce therefrom the propellant-free aerosols according to the invention.
• This nebuliser (Respimat ®) can advantageously be used to produce the inhalable aerosols 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 form inhalable aerosols.
• the preferred atomizer of an upper housing part, a pump housing, a nozzle, a locking mechanism, a spring housing, a spring and a reservoir, characterized by
• One end carries a nozzle body with the nozzle or nozzle arrangement
• 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 disclosed in WO 97/12687 devices. 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 of the abovementioned International Patent Application.
• 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 from 10 to 17.5 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, ie produced by microtechnology.
• Microstructured nozzle bodies are disclosed, for example, in patent application WO 99/16530; 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 of glass and / or silicon, of which at least one plate has one or more microstructured channels which connect 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 beam 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 formulation 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 sizes of the aerosol are up to 20 microns, preferably up to 10 microns.
• the locking mechanism includes a spring, preferably a cylindrical helical compression spring, as a memory for the mechanical energy.
• the spring acts on the output flange as a jump piece whose movement is determined by the position of a locking member.
• the path of the output flange is precisely limited by an upper and a lower stop.
• the spring is preferably transmitted via a force translating gear, e.g. a fferschubgetriebe, stretched by an external torque that is generated when turning the upper housing part against the spring housing in the lower housing part.
• the upper housing part and the output flange contain a single or multi-start wedge gear.
• the locking member with engaging locking surfaces is arranged annularly around the output flange.
• 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 locking member 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 upper housing part When actuating the atomizer, the upper housing 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, for example 180 degrees.
• the driven part Simultaneously with the tensioning of the spring, the driven part is in Housing upper part displaced 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 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.
• FIG. 6 a shows a longitudinal section through the atomizer with the spring tensioned
• FIG. 6 b 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 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 cocked.
• 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 upper housing 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 is within the spring housing.
• 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 nebulizer described above is suitable for nebulizing the aerosol preparations according to the invention to form an aerosol suitable for inhalation.
• the mass expelled in at least 97%, preferably at least 98% of all actuations of the inhaler (puffs) a defined quantity with a tolerance of not more than 25%, preferably from 20 % of this amount.
• a defined quantity with a tolerance of not more than 25%, preferably from 20 % of this amount.
• between 5 and 30 mg of formulation per stroke are applied as a defined mass, more preferably between 5 and 20 mg.
• the formulation according to the invention can also be nebulized by means of inhalers other than those described above, for example jet-stream inhalers or liquid-drop inhalers.
• the present invention further relates to an inhalation kit consisting of one of the above-described pharmaceutical preparations according to the invention and one for Nebulization of this drug formulation suitable inhaler.
• the present invention preferably relates to an inhalation kit consisting of one of the pharmaceutical preparations according to the invention the inhaler described above and the Respimat ® described above.
• this atomizer may be provided on the mouthpiece with a cap, which is similar to a cylindrical pyramid, that is of a pyramid with a round or oval cross section or a tapered, round or oval cylinder, is constructed.
• This essay is then hollow inside and has two openings. One of the openings can be placed on the mouthpiece and the other opening on the pointed end can be inserted into a nostril.
• this article preferably has the form of a spout of conventional nasal sprays.
• the attachment may be designed so that it is releasably connected to the mouthpiece or inseparably connected thereto. Such an attachment can also replace the mouthpiece.
• the inhalation solution is contained in a suitable gas- and liquid-tight container whose filling volume is adapted to the intended use, which at a low negative pressure in a predetermined manner plastically and irreversibly collapses and is almost completely emptied.
• a container for a medical liquid which is gas and liquid-tight, and which is characterized by • a foil bag which is closed at both ends, and at a differential pressure between the interior of the container and its surroundings below 300 hPa (300 mbar) is deformable by the external pressure and collapses,
• the collapsible foil bag can already be deformed and collapsed by the external pressure at a differential pressure below 150 hPa (150 mbar) or preferably below 80 hPa (80 mbar).
• the foil bag can be closed at both ends by a weld.
• the dimensionally stable flange on the side of the film bag preferably in the vicinity of one end of the film bag, welded tight.
• the foil bag can also be sealed at one end by a weld and at the other end by the dimensionally stable flange.
• one end of the foil bag is welded to the dimensionally stable flange, preferably on its circumference.
• the dimensionally stable flange can be shaped differently. If it is attached to the end of the film bag as its closure, it can be rotationally symmetrical shaped and adapted to the size of the end of the film bag.
• the dimensionally stable flange may be provided with a guide channel into which the withdrawal nozzle is inserted and in which the withdrawal nozzle is located with attached container. It may be expedient to provide the guide channel with a press fit, which encloses the sampling neck.
• the interference fit may be a portion of the guide channel which consists of a smooth inner wall with an inner diameter which deviates only slightly from the outer diameter of the sampling nozzle.
• a plurality of protrusions may be present in a section of the guide channel on the inner wall thereof.
• the bulges may be, for example, three axially symmetric and elongated bulges.
• a plurality of bulges arranged at an axial distance from each other and extending in the azimuthal direction can be provided, which for example form two rings or which consist of a plurality of ring sections.
• the bulges can be helical; they may consist of several distributed on the inner wall of the guide channel helical sections or of a helical section whose length is greater than the circumference of the guide channel.
• the dimensionally stable flange is made of rubber, metal or plastic, preferably of a thermoplastic material. It may be appropriate to make the dimensionally stable flange of the same plastic, of which the foil bag or the inside of the foil bag consists.
• the weld at one or both ends of the film bag may be U-, V- or T-shaped; it runs essentially transversely to the bag axis. It may extend partially in the direction of the bag axis, whereby the defined deformation of the film bag is promoted when removing liquid.
• the sealing point may consist of a ring in one on the
• the cross section of the ring may be O-shaped or substantially rectangular.
• the ring is optionally provided with a sealing lip.
• the ring may be made of an elastomer, a thermoplastic elastomer or rubber.
• the sealing point seals the filling chamber of the plugged-on the sampling nozzle container against the ambient air gas and liquid-tight. It allows the removal of the empty container from the sampling nozzle. The sealing point is required if the sealing effect of the interference fit is insufficient.
• the removal is preferably designed as a puncture site.
• a puncture site may be provided by a pierceable membrane bare, which is pierced when attaching the container to the sampling nozzle.
• the membrane is preferably arranged between the sealing point and the liquid space in the foil bag.
• the pierceable membrane may be attached to one of the ends or within the guide channel. It is preferably attached directly to the end of the guide channel or in the vicinity of this end, which faces the liquid space. It may be part of the dimensionally stable flange or part of the foil bag. If it is part of the dimensionally stable flange, it can be made simultaneously with the dimensionally stable flange. It can consist of the same plastic as the dimensionally stable flange.
• the By piercing bare membrane acts as an original closure for the filling of the foil bag.
• the removal point can be sealed with a sealing foil which is pulled off before the attachment of the container to the withdrawal nozzle, or which is pierced when attaching the container to the withdrawal nozzle.
• the dimensionally stable flange can be in one piece or in several parts.
• the multi-part flange may preferably be in two parts.
• the outer part of the flange is tightly connected to the foil bag.
• the outer part contains an opening that is sealed to the inner part. Both parts can be screwed together by means of a thread, or be connected to each other by means of a snap connection or by ultrasonic welding.
• the one-piece flange is designed analogously to the two-part flange, but it contains no fasteners.
• the dimensionally stable flange can be manufactured simultaneously with interference fit, groove for the sealing point and pierceable membrane.
• the foil bag can consist of a tube which has no weld running in the axial direction of the foil bag. Further, it can be made of a foil and have one or two longitudinal welds. It can be designed as a flat bag or as a bag with gussets. A bag having a longitudinally extending weld is preferred.
• the welds on the foil bag can be from 0.7 mm to 3 mm wide; their width is chosen according to the demands made on tightness and durability of the seam. Wide longitudinal seams on the film bag can be bent after welding, so that they rest on the outside of the film bag approximately and the film bag is only slightly wider than its width in the unwelded part between the welds.
• the foil bag may consist of a foil of metal or metal alloy - preferably of aluminum, gold or copper - or of plastic - preferably a thermoplastic - exist.
• the film bag may consist of a composite film of plastic and metal.
• the composite foil preferably consists of two or three interconnected slides.
• the film bag can consist of a plastic film onto which a layer of metal, glass or ceramic, for example by vapor deposition, is applied.
• the plastic or metal foils are several microns thick. The thickness of the vapor-deposited layers of metal, glass or ceramic is in the submicrometer range.
• the composite film of two films may consist of a metal foil and a plastic film, which are interconnected.
• the metal foil forms the inside or outside of the composite foil.
• the composite film consists of two different plastics.
• the composite foil of three foils preferably consists of two plastic foils, between which a foil of metal lies. All three slides are connected.
• the metal foil may be present a layer of glass or ceramic, for example of silicon oxide (SiO x ) which is vapor-deposited on a plastic film.
• the inner film of the composite film consists of a copolymer, for example a polyethylene copolymer of ethylene-acrylic acid.
• a plastic is preferably used, for example polyethylene terephthalate whose melting temperature is greater than the melting temperature of the plastic of the inner film.
• an adhesion promoter layer may optionally be present between two films.
• the film bag may consist of a plastic film having a thickness of 20 microns to 100 microns. Further, it may consist of a composite film with an inner plastic film with a thickness of 20 .mu.m to 100 .mu.m and an outer metal film with a thickness of 8 .mu.m to 20 .mu.m. Furthermore, it can consist of a composite foil with an inner foil of plastic with a thickness of 20 ⁇ m to 100 ⁇ m, a middle foil of metal with a thickness of 8 ⁇ m to 20 ⁇ m and an outer foil made of plastic with a thickness of 10 ⁇ m to 40 ⁇ m.
• the welds on the film bag and the weld between film bag and dimensionally stable flange are made by known methods; like thermal Welding, ultrasonic welding or induction welding in metal-foil composite films, wherein the welds are preferably compressed in a heated state.
• thermal Welding like thermal Welding, ultrasonic welding or induction welding in metal-foil composite films, wherein the welds are preferably compressed in a heated state.
• Such processes are given, for example, in EP-0,111,131 and EP-0,130,239.
• a dimensionally stable rubber or metal flange can be bonded to the film bag by gluing or optionally by vulcanization.
• the container may be in a dimensionally stable sleeve made of metal or plastic, one end of which is detachably or non-detachably connected to the dimensionally stable flange, and the other end of which is optionally closed by a bottom.
• the sleeve can be substantially completely closed. However, it contains at least one opening, or at the junction with the flange there is a gap. Further, the sleeve may be formed as a dimensionally stable basket with many openings.
• the container may be in place of the sleeve in a dimensionally stable U-shaped bracket, wherein the end of each leg of the bracket is attached to the rigid flange and the legs are longer than the foil bag.
• the container located in a sleeve is connected only on the dimensionally stable flange with the sleeve.
• the end closed with a weld seam or the two ends of the foil pouch closed with a weld seam are not connected to the sleeve.
• the film bag is diffusion-tight for the medical fluid and its components as well as for gases.
• the material for the film bag and optionally the structure of the composite film are chosen accordingly.
• Diffusion-proof in the sense of the present invention means a loss of liquid (measured with ethanol at room temperature) of the container by diffusion of less than 0.6 mg per day, preferably less than 0.4 mg per day, especially before less than 0.2 mg per day, especially less than 0.1 mg per day.
• the inner foil or the inside of the foil bag is in contact with the filled liquid.
• a material is selected that is not attacked by the liquid and by which the liquid is not affected.
• This film is preferably designed as a weldable film.
• One of the films or a vapor-deposited layer is the diffusion barrier, which prevents the diffusion of the liquid or its components and the diffusion of gases from or into the film bag. It may be expedient to protect the diffusion barrier against mechanical damage and against tearing of the diffusion barrier when bending the film by a further applied to the diffusion barrier plastic film, so that the diffusion of liquid or gases remains permanently prevented.
• the film bag Since the film bag is diffusion-tight against gases, the negative pressure in the film bag resulting from the liquid removal can not be compensated by diffusing gas, and the film bag reliably collapses even with very slow removal of liquid from your container.
• the liquid can also be removed from the foil pouch in many subsets, for example 200 doses, distributed over a longer period of time, for example three months.
• the container located in a substantially closed sleeve is inaccessible from the outside and can not be damaged during storage and when attaching to the withdrawal nozzle.
• the substantially closed sleeve or provided as a basket with many openings sleeve or the dimensionally stable strap facilitate storage of the container with the thin-walled foil bag and its handling when plugging on the sampling nozzle and when removing the empty container from the sampling nozzle.
• the sampling nozzle is for example the hollow piston of a nebulizer for medical fluids.
• a nebulizer for medical fluids.
• Such an atomizer is described in DE-195 36 902.5 and in WO-97/12687 (especially in the figures 6a and 6b there).
• the hollow piston This atomizer is designed as a withdrawal nozzle for the medical liquid contained in the container according to the invention.
• the container is attached to the preferably in the axis of the atomizer mounted hollow piston, wherein the end of the hollow piston pierces the sampling point and thus immersed in the medical fluid.
• the sealing point in the dimensionally stable flange seals the interior of the container tight against the outer wall of the hollow piston.
• the interference fit can mechanically hold the container on the hollow piston.
• a detachable, positive connection between the dimensionally stable flange of the container and the removal device for example an atomizer.
• Such a connection can be made as a plug-in snap connection of several snap hooks, which are mounted in a connector in the removal device.
• the snap lugs are preferably formed round or beveled in both directions of movement of the container to remove an empty container with moderate force and plug a full container into the sampling device can.
• the container according to the invention is particularly suitable as a replaceable cartridge for inhalable drug solutions in propellant-free atomizers.
• the filling volume of the container may be from 0.5 ml to 5 ml, preferably from 1 ml to 4 ml and more preferably from 1 ml to 3 ml or from 2 ml to 4 ml. These solutions are taken in portions at a dose of 10 microliters to 5 microliters, preferably from 15 ul to 20 ul.
• the core diameter may be from 10 mm to 30 mm, preferably from 12 mm to 17 mm.
• the length of the container including the protruding from the sleeve portion of the dimensionally stable flange may be from 20 mm to 60 mm, preferably from 30 mm to 50 mm.
• the compounds of the formula 1 can be prepared in a manner known per se. Exemplified and preferred in the context of the invention compounds are listed below. Thus, preferred are pharmaceutical formulations containing both active compounds 2 and 3 and compounds of general formula 1 which are selected from the group consisting of:
• Example 1 6-Hydroxy-8- ⁇ 1-hydroxy-2- [2- (4-hydroxy-2,6-dimethylphenyl) -1, 1-dimethyl-ethylamino] -ethyl ⁇ -4 H -benzo [ 1,4-oxazin-3-one-methanesulfonate •
• Example 2 8- ⁇ 2- [2- (4-fluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy 4H-benzo [1,4] oxazin-3-one acid addition salt
• Example 6 8- ⁇ 2- [1,1-Dimethyl-2- (2,4,6-trimethylphenyl) ethylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1, 4] oxazin-3-one hydrochloride •
• Example 7 6-Hydroxy-8- ⁇ 1-hydroxy-2- [2- (4-hydroxyphenyl) -1, 1-dimethyl-ethylamino] -ethyl ⁇ -4H-benzo [1, 4] oxazin-3-one hydrochloride
• Example 10 8- ⁇ 2- [2- (4-fluoro-3-methylphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxyethyl ⁇ -6-hydroxy-4H-benzo [1, 4] oxazin-3-one hydrochloride
• Example 11 8- ⁇ 2- [2- (4-Fluoro-2-methylphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxyethyl ⁇ -6-hydroxy-4H-benzo [1, 4] oxazin-3-one hydrochloride
• Example 12 8- ⁇ 2- [2- (2,4-Difluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1, 4] oxazin-3-one hydrochloride •
• Example 13 8- ⁇ 2- [2- (3,5-Difluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H benzo [1,4] oxazin-3-one hydrochloride
• Example 14 8- ⁇ 2- [2- (4-Ethoxy-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1,4-oxazine] 3-one hydrochloride
• Example 15 8- ⁇ 2- [2- (3,5-Dimethylphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1, 4] oxazin-3-one hydrochloride
• Example 16 4- (4- ⁇ 2- [2-Hydroxy-2- (6-hydroxy-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -ethylamino ] -2-methyl-propyl ⁇ -phenoxy) -butyric acid addition salt
• Example 17 8- ⁇ 2- [2- (3,4-Difluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1, 4] oxazin-3-one trifluoroacetate •
• Example 18 8- ⁇ 2- [2- (2-Chloro-4-fluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxyethyl ⁇ -6-hydroxy -4H-benzo [1,4] oxazin-3-one trifluoroacetate
• Example 19 8- ⁇ 2- [2- (4-Chloro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1,4-oxazine] 3-one acid addition salt
• Example 21 8- ⁇ 2- [2- (3-Methylphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxyethyl ⁇ -6-hydroxy-4H-benzo [1,4-oxazine] 3-one acid-addition salt;
• Example 22 8- ⁇ 2- [2- (4-Fluoro-3-methoxy-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1, 4] oxazin-3-one acid addition salt;
• Example 23 8- ⁇ 2- [2- (4-Fluoro-2,6-dimethylphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxyethyl ⁇ -6-hydroxy-4H-benzo 1,4-oxazin-3-one acid addition salt;
• Example 24 8- ⁇ 2- [2- (4-Chloro-2-methylphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxyethyl ⁇ -6-hydroxy-4H-benzo [1, 4] oxazin-3-one acid addition salt;
• Example 28 8- ⁇ 2- [2- (2,6-Difluoro-4-methoxy-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo 1,4-oxazin-3-one acid addition salt;
• Example 29 8- ⁇ 2- [2- (2,5-Difluoro-4-methoxy-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo 1,4-oxazin-3-one acid addition salt;
• Example 30 8- ⁇ 2- [2- (4-Fluoro-3,5-dimethylphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxyethyl ⁇ -6-hydroxy-4H-benzo 1,4-oxazin-3-one acid addition salt;
• Example 31 8- ⁇ 2- [2- (3,5-dichloro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1, 4] oxazin-3-one acid addition salt;
• Example 32 8- ⁇ 2- [2- (4-Chloro-3-methylphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxyethyl ⁇ -6-hydroxy-4H-benzo [1, 4] oxazin-3-one acid addition salt;
• Example 33 8- ⁇ 2- [2- (3,4,5-trifluorophenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1, 4] oxazin-3-one acid addition salt;
• Example 34 8- ⁇ 2- [2- (3,4-dichloro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1, 4] oxazin-3-one acid addition salt.
• EDTA disodium edetate dihydrate, BHA butylated hydroxyanisole and BHT butylhydroxytoluene.
• the active compounds 1, 2 and 3.1 mentioned are optionally used in the form of salts and / or hydrates, but here are given based on the mass of the free base of 1 and the free cation of 3.1.
• Compound 1 is used in the examples below as hydrochloride, hydrotetrafluoroacetate or hydromethanesulfonate, compound 3 as a monohydrate of the bromide.
• A) The table below summarizes inventive formulation examples of the R enantiomer of the compound Example 1, the active ingredient 2 and the active compound 3.1 in the form of base and cation. 100 ml of pharmaceutical preparation contain:

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