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
  • A61K31/535—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
  • A61K31/536—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 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
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • 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
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • 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
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • 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
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • 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

Definitions

• the present invention relates to a propellant-free aerosol formulation containing one or more compounds of general formula 1
• radicals R 1 , R 2 , R 3 and X may have the meanings mentioned in the claims and in the description for the inhalation.
• Betamimetics ( ⁇ -adrenergic agents) are known in the art. For example, reference may be made in this regard to the disclosure of US 4341778 or EP 43940, which suggests betamimetics for the treatment of a wide variety of diseases.
• -1- are characterized by a longer duration of action and thus can be used for the production of medicaments with a longer efficacy.
• the pharmaceutical formulations according to the invention are propellant-free pharmaceutical formulations containing as sole active ingredient one or more compounds of general formula 1
• R 1 and R 2 are identical or different, are hydrogen, halogen, d-4 alkyl or together Ci -6 alkylene and
• R 3 is hydrogen, halogen, OH, Ci -4 -AlkVl or O-Ci.-alkyl;
• X " is one or more hydrogen cations and a singly or multiply negatively charged anion, preferably a singly or multiply negatively charged anion selected from the group consisting of chloride,
• R 1 and R 2 identical or different, represent hydrogen, fluorine, chlorine, methyl, ethyl, propyl, butyl or together -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 - CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -;
• R 3 is hydrogen, fluorine, chlorine, OH, methyl, ethyl, methoxy, or ethoxy
• X " is a singly or multiply negatively charged anion, preferably a singly or multiply negatively charged anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate,
• R 1 and R 2 identical or different, denote hydrogen, methyl, ethyl, propyl or together -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 - or
• R 3 is hydrogen, fluorine, OH, methyl or methoxy.
• X " is a singly or multiply negatively charged anion selected from the group consisting of selected from the group consisting of chloride,
• R 1 and R 2 are identical or different, ethyl, propyl or together -CH 2 -CH 2 -, -CH 2 -
• R 3 is hydrogen, fluorine, OH, methyl or methoxy.
• R 1 and R 2 are ethyl, propyl or together -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - CH 2 - or
• R 3 is hydrogen, fluorine, OH or methoxy.
• compositions containing compounds of general formula 1 which are selected from the group consisting of: 1.1: N- (5- ⁇ 2- [1,1-dimethyl-3- (4-methyl-2-oxo) 4H-benzo [d] [1,3-oxazin-1-yl) propylamino] -1-hydroxy-ethyl ⁇ -2-hydroxyphenyl) -methanesulfonamide 1.2: N- (5- ⁇ 2- [1, 1 -Dimethyl-3- (2-oxo-4H-benzo [d] [1,3] oxazin-1-yl) -propylamino] -1-hydroxy-ethyl ⁇ -2-hydroxyphenyl) -methanesulfonamide 1.3: N- (5- ⁇ 2- [3- (4-Ethyl-2-oxo-4H-benzo [d] [1,3] oxazin-1-yl) -1, 1-dimethyl-propylamino] -
• N - ⁇ . 2-hydroxyphenyl] -methanesulfonamide 1.9: N - ⁇ . 1-hydroxyethyl) -2-hydroxy-phenyl] -methanesulfonamide 1.10: N- (5- ⁇ 2- [3- (4,4-diethyl-2-oxo-4H-benzo [d] [1, 3 ] oxazin-1-yl) -1, 1-dimethyl-propylamino] -1-hydroxy-ethyl ⁇ -2-hydroxyphenyl) -methanesulfonamide: 1.11: N- (5- ⁇ 2- [3- (4.4 -Diethyl-6-fluoro-2-oxo-4H-benzo [d] [1,3] oxazin-1-yl) -1, 1-dimethyl-propylamino] -1-hydroxy-ethyl ⁇ -2-hydroxy-phenyl ) -methanesulfonamide 1.12: N- (5-
• compositions containing compounds of general formula 1 which are selected from the group consisting of: 1.7: N- (5- ⁇ 2- [1, 1-dimethyl-3- (2-oxo-4,4-) dipropyl 4H-benzo [d] [1,3] oxazin-1-yl) propylamino] -1-hydroxyethyl ⁇ -2-hydroxy-phenyl) -methanesulfonamide 1.8: N- [5- (2- ⁇ 1 , 1-Dimethyl-3- [spiro (cyclohexane-1, 4'-2H-3 ', 1'-benzoxazine) -2'-oxo-1-yl] propylamino ⁇ -1-hydroxyethyl) -2- hydroxy-phenyl] -methanesulfonamide
• the pharmaceutical formulations according to the invention contain as solvent pure water, pure ethanol or mixtures of ethanol and water. If ethanol-water mixtures are used, the percentage by weight of ethanol in these mixtures is preferably in the range between 5 and 99% ethanol, particularly preferably in the range from 10 to 96% ethanol. Very particularly preferred pharmaceutical formulations for the purposes of the present invention contain as solvent pure water, pure ethanol or ethanol-water mixtures containing between 50 and 92%, more preferably between 69 and 91% ethanol.
• other co-solvents can be used in addition to ethanol and water. According to the invention, however, a further solvent is not used.
• X " is selected from the group consisting of chloride, maleate, salicylate, fumarate or succinate, optionally in the form of their hydrates and solvates.
• Particularly preferred within the scope of the present invention are those formulations which contain the compound of formula 1 in which X "is chloride.
• references to the compound of formula 1 in the context of the present invention always include all possible amorphous and crystalline modifications of this compound. References to the compound of formula 1 in the context of the present invention furthermore include all possible solvates and hydrates which can be formed by this compound.
• radicals R 1 , R 2 and R 3 may have the meanings given above.
• Another aspect of the present invention relates to pharmaceutical formulations comprising as sole active ingredient a free base of formula V wherein the radicals R 1, R 2 and R 3 have the meanings given above may have to mean, optionally in the form of the tautomers, enantiomers, mixtures of enantiomers, Racemates or solvates, at least one pharmacologically acceptable acid, optionally further pharmacologically acceptable excipients and / or complexing agents and as a solvent water, ethanol or a mixture of water and ethanol.
• 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 the enantiomerically pure compounds, in which case the R-enantiomers of the compounds of formula 1 according to the invention of
• d- 4 alkyl (including those which are part of other groups) are meant branched and unbranched alkyl groups with 1 to 4 carbon atoms. Examples include: methyl, ethyl, n-propyl, / so-propyl, n-butyl, iso-butyl, sec-butyl or te / f-butyl. Optionally, the abbreviations Me, Et, n-Pr, / -Pr, n-Bu, / -Bu, t-Bu, etc. are also used for the abovementioned groups. Unless otherwise stated, the definitions of propyl and butyl include all conceivable isomeric forms of the respective radicals. For example, propyl includes n-propyl and / so-propyl, butyl includes / so-butyl, sec-butyl and te / f-butyl, etc.
• C 1-6 -alkylene (including those which are part of other radicals) are to be understood as meaning branched and unbranched alkylene groups having 1 to 6 carbon atoms and branched and unbranched alkylene groups having 1 to 10 by the term “C 1-4 -alkylene” 4 carbon atoms understood.
• alkylene groups having 1 to 4 carbon atoms examples include: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1, 1-dimethylethylene, 1, 2-dimethylethylene, pentylene, 1, 1-dimethylpropylene, 2,2, -dimethylpropylene, 1, 2-dimethylpropylene, 1, 3-dimethylpropylene or hexylene.
• propylene, butylene, pentylene and hexylene include all conceivable isomeric forms of the respective radicals of the same carbon number.
• propylene includes
• -8th- 1-methylethylene and butylene also include 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.
• enantiomerically pure describes in the context of the present invention compounds of the formula 1 which are present in an enantiomeric purity of at least 85% ee, preferably of at least 90% ee, particularly preferably of> 95% ee.
• ee enantiomeric excess
• a further aspect of the present invention relates to the use of the pharmaceutical formulations according to the invention for the preparation of a medicament for the treatment of respiratory diseases selected from the group consisting of obstructive pulmonary diseases of different origin, pulmonary emphysema of different origin, restrictive lung diseases, interstitial lung diseases, cystic fibrosis, bronchitis of different origin , Bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary edema.
• respiratory diseases selected from the group consisting of obstructive pulmonary diseases of different origin, pulmonary emphysema of different origin, restrictive lung diseases, interstitial lung diseases, cystic fibrosis, bronchitis of different origin , Bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary edema.
• 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
• restrictive lung diseases selected from the group consisting of allergic alveolitis, restrictive pulmonary diseases induced by occupational noxae, such as asbestosis or silicosis and restriction due to lung tumors such as lymphangiosis carcinomatosa. brochoalveolar carcinoma and lymphomas.
• interstitial lung diseases which are selected from the group consisting of infectious pneumonias, such as due to infection with viruses, bacteria, fungi, protozoa, helminths or other pathogens, pneumonitis due to differential causes such as aspiration and left ventricular failure, radiation-induced pneumonitis or fibrosis, collagenoses such as lupus erythematosus, systemic scleroderma or sarcoidosis, granulomatosis such as Boeck's disease, idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF).
• infectious pneumonias such as due to infection with viruses, bacteria, fungi, protozoa, helminths or other pathogens
• pneumonitis due to differential causes such as aspiration and left ventricular failure
• radiation-induced pneumonitis or fibrosis such as lupus erythematosus, systemic scleroderma or sarcoidosis
• compositions according to the invention for the production of a medicament for the treatment of cystic fibrosis or cystic fibrosis.
• bronchitis such as, for example, bronchitis due to bacterial or viral infection, allergic bronchitis and toxic bronchitis.
• ARDS adult respiratory distress syndrome
• the pharmaceutical formulations according to the invention for the manufacture of a medicament for the treatment of pulmonary edema, for example toxic pulmonary edema after aspiration or inhalation of toxic substances and foreign substances.
• the present invention relates to the use of the pharmaceutical formulations of the invention for the manufacture of a medicament for the treatment of asthma or COPD.
• the manufacture of a medicament for once-daily treatment of inflammatory and obstructive airway diseases particularly preferably for the once-daily treatment of asthma or COPD.
• the present invention relates to a method for the treatment of the abovementioned disorders, characterized in that one or more of the abovementioned pharmaceutical formulations according to the invention are administered in therapeutically effective amounts.
• the present invention is concerned with inhalable liquid drug formulations of these 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 inhalable aerosol.
• those nebulizers are preferred in which already an amount of less than 100 microliters, preferably less than 50 microliters, particularly preferably less than 35 microliters of active substance solution with preferably one stroke or two strokes to an aerosol with an average particle size (or particle diameter) of less than 20 micrometers, preferably less than 10 micrometers, can be so atomized that the inhalable fraction of the aerosol corresponds to the therapeutically effective amount.
• Such a device for the propellant-free administration of a metered amount of a liquid medicament for inhalation use, for example, in International Patent Application WO 91/14468 "Atomizing Device and Methods" and in WO 97/12687, there Figures 6a and 6b and the accompanying 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 solution formulations are stored in a reservoir.
• the active substance formulations used have a sufficient storage stability and at the same time are such that they can be applied directly for the medical purpose as far as possible without further manipulation.
• they must not contain components that may interact with the inhaler in such a way that the inhaler or the pharmaceutical grade of the solution or the aerosol produced could be damaged.
• a special nozzle is used, as described, for example, WO 94/07607 or WO 99/16530. Both are hereby incorporated by reference.
• Drug formulations must also have sufficient pharmaceutical grade, i. they should be pharmaceutically stable over a shelf life of a few years, preferably at least one year, more preferably two years.
• propellant-free solution formulations must also be able to be atomized under pressure by means of an inhaler, wherein the mass discharged in the generated aerosol is reproducibly within a defined range.
• the formulation preferably contains only one compound of the formula 1.
• the formulation may also contain a mixture of different salts of the formula 1. If the pharmaceutical formulations according to the invention contain various salts of the formula 1, those formulations are preferred according to the invention in which the different salts represent different salts of the same free base of the formula V. Formulations containing active ingredients other than those of formula 1 are not the subject of the invention.
• the concentration of the compound of the formula 1, based on the proportion of pharmacologically active free base V in the medicament formulation according to the invention is according to the invention at about 0.1 to 1600 mg per 100 ml, preferably at about 0.5 to 1000 mg per 100 ml, particularly preferred 0.75 to 200 mg per 100 ml. particularly preferably 100 ml of the formulations according to the invention contain about 1 to about 100 mg 1 1.
• the pH of the formulation according to the invention is preferably in a range from 2.0 and 6.5, preferably between 2.2 and 5.0, particularly preferably between about 3.0 and 4.5.
• 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, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid.
• 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, methanesulfonic acid and benzenesulfonic acid.
• Preferred inorganic acids are hydrochloric acid and sulfuric acid, wherein the hydrochloric acid is of particular importance according to the invention.
• the organic acids are ascorbic acid, fumaric acid and citric acid
• citric acid is particularly preferred according to the invention.
• 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 or antioxidants, such as, for example, 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 drug formulation, are pharmacologically acceptable with the abovementioned acid.
• the formulations according to the invention may contain complexing agents as further constituents.
• 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, e.g. Sodium EDTA, or disodium EDTA. Preference is given to using disodium edetate, if appropriate in the form of its hydrates, particularly preferably in the form of its dihydrate.
• complexing agents are used in the context of the formulations according to the invention, their content is preferably in a range from 1 to 50 mg per 100 ml, more preferably in a range from 2 to 15 mg per 100 ml of the formulation according to the invention.
• the formulations according to the invention preferably contain a complexing agent in an amount of about 4 to 12 mg per 100 ml, particularly preferably about 10 mg per 100 ml of the formulation according to the invention.
• 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.
• the formulation according to the invention may be added further pharmacologically acceptable excipients.
• any pharmacologically acceptable and therapeutically useful substance which is not an active ingredient, but can be formulated together with the active ingredient 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 excipients and additives include, for example, stabilizers, antioxidants and / or preservatives that extend the useful life of the finished drug formulation as well as 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, BHA (butylhydroxyanisole), BHT (butylhydroxytoluene), TBHQ (tert-butylhydroxyquinone), vitamin A, vitamin E, ⁇ - Tocopherol and similar vitamins or provitamins occurring in the human organism, preferred antioxidants are BHT and ⁇ -tocopherol.
• Preservatives may be used to protect the formulation from contamination with pathogenic germs. Suitable preservatives are those known in the art, in particular benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentrations known from the prior art.
• the formulation of the invention benzalkonium chloride is added.
• the amount of benzalkonium chloride is between 1 mg and 50 mg per 100 ml formulation, preferably about 2 to 15 mg per 100 ml, more preferably about 3 to 12 mg per 100 ml, more preferably about 4 to 10 mg per 100 ml of the inventive Formulation.
• Benzalkonium chloride can also be used according to the invention in admixture with other preservatives.
• Preferred formulations contain, apart from the solvent water and the compounds of the formula 1, only benzalkonium chloride, sodium edetate 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). at
• nebulizer Hand atomizing glass
• 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. Special locking devices ensure that only the smallest particles escape, while the larger ones flow back into the reservoir and can be re-atomised.
• strong evaporation occurs, which, due to the evaporation cold, leads to a cool aerosol and a concentration of the active ingredient solution.
• Ultrasonic Nebulizer - A piezoelectric crystal is excited by high-frequency alternating voltage to vibrate, which are transmitted via a transfer medium to the active ingredient solution and release it from her finest liquid droplets, but also heat the liquid.
• compositions of the invention with compounds of formula 1 are preferably used in an inhaler of the type described above to
• WO 97/12687 a further developed embodiment of the preferred inhaler is disclosed in WO 97/12687 (see there in particular FIGS. 6a and 6b and the relevant parts of the description).
• 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 hollow piston with valve body,
• An output flange in which the hollow piston is attached, and which is located in the upper housing part
• the hollow piston with valve body corresponds to a disclosed in WO 97/12687 devices. It partially protrudes into the cylinder of the pump housing and is arranged axially displaceably in the cylinder.
• FIGS. 1-4 in particular FIG. 3, and the associated parts of the description of the above-mentioned.
• 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
• volumes of from 10 to 50 microliters are preferred, volumes of from 10 to 20 microliters are particularly preferred, and a volume of from 10 to 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-99/16530; 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 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 3 to 10 microns.
• the locking mechanism includes a spring, preferably a cylindrical helical compression spring, as a memory for the mechanical energy.
• the spring acts on the
• the -18- 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 tensioned via a force-transmitting gear, for example a screw thrust gear, by an external torque which is generated when the housing upper part is rotated against the spring housing in the housing bottom 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, e.g. 180 degrees.
• the driven part Simultaneously with the tensioning of the spring, the driven part is displaced in the upper housing part by a predetermined path, the hollow piston is withdrawn within the cylinder in the pump housing, whereby a subset of the fluid from the reservoir is sucked into the high-pressure chamber in front of the nozzle.
• the storage container contains the 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. 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 the holder
• the hollow piston (57) fastened in the output flange (56) of the locking mechanism projects partially into the cylinder of the pump housing.
• the hollow piston carries the valve body (58).
• the hollow piston is sealed by means of the seal (59).
• Within the upper housing part is the stop (60) on which the output flange rests with a relaxed spring.
• 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 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 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.
• the present invention further relates to an inhalation kit consisting of one of the pharmaceutical preparations according to the invention described above and an inhaler suitable for the nebulization of this pharmaceutical formulation.
• 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.
• EXAMPLE 1 YL) -PROPYLAMINO] -I-HYDROXY-ETHYLH-HYDROXY-PHENYL) -
• the compound is known from EP 43940.
• the individual diastereomers of this embodiment can be obtained by conventional methods known in the art.
• EXAMPLE 2 N- (5- ⁇ 2- [1,1-DIMETHYL-3- (2-OXO-4H-BENZO [D] [1,3] OXAZIN-1-YL) - PROPYLAMINO] -I-HYDROXY- ETHYL®-HYDROXY-PHENYL) -METHANSULFONAMI D
• the compound is known from EP 43940.
• the (R) and (S) enantiomers of this embodiment can be obtained by conventional methods known in the art.
• the compound is known from EP 43940.
• the individual diastereomers of this embodiment can be obtained by conventional methods known in the art.
• EXAMPLE 4 N- (5- ⁇ 2- [3- (4,4-DIMETHYL-2-OXO-4H-BENZO [D] [1, 3] OXAZIN-1-YL) -1, 1-DIMETHYL-PROPYLAMINO ] -I-HYDROXY-ETHYLH-HYDROXY-PHENYL) -
• the compound is known from EP 43940.
• the (R) and (S) enantiomers of this embodiment can be obtained by conventional methods known in the art.
• EXAMPLE 5 N- (2-HYDROXY-5- ⁇ 1-HYDROXY-2- [3- (6-HYDROXY-4,4-DIMETHYL-2-OXO-4H-BENZO [D] [I 1 S] OXAZI NI -YL) -I 1 I -DIMETHYL-PROPYLAMINO] -ETHYLJ-PHENYL) -
• EXAMPLE 6 N- (2-HYDROXY-5- ⁇ 1-HYDROXY-2- [3- (6-METHOXY-4,4-DIMETHYL-2-OXO-4H-BENZO [D] [I 1 S] OXAZI NI -YL) -I 1 I -DIMETHYL-PROPYLAMINO] -ETHYLJ-PHENYL) -
• the compound is known from EP 43940.
• the (R) and (S) enantiomers of this embodiment can be obtained by conventional methods known in the art.
• N- (5- ⁇ 2- [1,1-Dimethyl-3- (2-oxo-4,4-dipropyl-4H-benzo [d] [1,3] oxazin-1-yl) -propylamino] 1-hydroxy-ethyl ⁇ -2-hydroxyphenyl) -methanesulfonamide 260 mg (0.386 mmol) of N- (2-benzyloxy-5- ⁇ 2- [1, 1-dimethyl-3- (2-oxo-4 , 4-dipropyl-4H-benzo [d] [1,3] oxazin-1-yl) -propylamino] -1-hydroxy-ethyl ⁇ -phenyl) -methanesulfonamide hydrochloride in 8 ml of methanol are dissolved in the presence of 26 mg of palladium Charcoal (10%) hydrogenated at room temperature.
• the (R) and (S) enantiomers of this embodiment can be obtained by conventional methods known in the art.
• the (R) -enantiomer of this embodiment is of particular importance in the present invention.
• EXAMPLE 8 N- [5- (2- ⁇ 1,1-Dimethyl-S-SPI RO (CYCLOHEXAN-I, 4'-2H-3 ', 1'-BENZOXAZINE) -2'-OXO-1-YL ] -PROPYLAMINO ⁇ -1-HYDROXY-ETHYL) -2-HYDROXY-PHENYL] -METHANSULFONAMIDE
• the (R) and (S) enantiomers of this embodiment can be obtained by conventional methods known in the art.
• the (R) -enantiomer of this embodiment is of particular importance in the present invention.
• the (R) and (S) enantiomers of this embodiment can be obtained by conventional methods known in the art.
• the (R) -enantiomer of this embodiment is of particular importance in the present invention.
• EXAMPLE 10 N- (5- ⁇ 2- [3- (4,4-DIETHYL-2-OXO-4H-BENZO [D] [1, 3] OXAZIN-1-YL) -1, 1-DIMETHYL-PROPYLAMINO ] -I-HYDROXY-ETHYLH-HYDROXY-PHENYL) -
• the (R) and (S) enantiomers of this embodiment can be obtained by conventional methods known in the art.
• the (R) -enantiomer of this embodiment is of particular importance in the present invention.
• the rotation of (R) -N- (5- ⁇ 2- [3- (4 : 4-diethyl-2-oxo-4H-benzo [d] [1,3] oxazin-1-yl) -1, 1 -dimethyl-propylamino] -1-hydroxy-ethyl ⁇ -2-hydroxyphenyl) -methanesulfonamide hydrochloride (cocrystallized with one molecule of acetone) is -28.8 ° (c 1%, in methanol at 20 0 C).
• EXAMPLE 1 1 N- (5- ⁇ 2- [3- (4,4-DIETHYL-6-FLUORO-2-OXO-4H-BENZO [D] [1,3] OXAZIN-1-YL) -I 1 I -DIMETHYL-PROPYLAMINO] -I-HYDROXY-ETHYLH-HYDROXY-PHENYL) -
• the (R) and (S) enantiomers of this embodiment can be obtained by conventional methods known in the art.
• the (R) -enantiomer of this embodiment is of particular importance in the present invention.
• EXAMPLE 12 N- (5- ⁇ 2- [3- (4,4-DIETHYL-7-FLUORO-2-OXO-4H-BENZO [D] [1,3] OXAZIN-1-YL) -I 1 I -DIMETHYL-PROPYLAMINO] -I-HYDROXY-ETHYLH-HYDROXY-PHENYL) -
• EXAMPLE 13 N- (5- ⁇ 2- [3- (4,4-DIETHYL-8-METHOXY-2-OXO-4H-BENZO [D] [1,3] OXAZIN-1-YL) -I 1 I -DIMETHYL-PROPYLAMINO] -I-HYDROXY-ETHYLH-HYDROXY-PHENYL) -
• the (R) and (S) enantiomers of this embodiment can be obtained by conventional methods known in the art.
• the (R) -enantiomer of this embodiment is of particular importance in the present invention.
• Example 11 100 ml of drug formulation contained in purified water or water for injections:

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• 2007
  • 2007-08-20 PE PE2007001122A patent/PE20080425A1/es not_active Application Discontinuation
  • 2007-08-21 CA CA002661442A patent/CA2661442A1/en not_active Abandoned
  • 2007-08-21 JP JP2009525053A patent/JP2010501523A/ja active Pending
  • 2007-08-21 TW TW096130913A patent/TW200820974A/zh unknown
  • 2007-08-21 EP EP07802747A patent/EP2056837A1/de not_active Withdrawn
  • 2007-08-21 US US11/842,472 patent/US20080053430A1/en not_active Abandoned
  • 2007-08-21 WO PCT/EP2007/058655 patent/WO2008023005A1/de active Application Filing
  • 2007-08-21 UY UY30555A patent/UY30555A1/es not_active Application Discontinuation
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