EP2054084A1

EP2054084A1 - Aerosol formulation for the inhalation of beta agonists

Info

Publication number: EP2054084A1
Application number: EP07819952A
Authority: EP
Inventors: Kirsten Radau; Michael Aven; Rainer Weitzel
Original assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2006-08-18
Filing date: 2007-08-16
Publication date: 2009-05-06
Also published as: US20080041369A1; WO2008020057A1; JP2010501022A; TW200817011A; AU2007285747A1; AR062425A1; CO6170341A2; SG174058A1; NZ575425A; CA2660488A1; BRPI0715761A2; MX2009001759A; US20120058980A1; IL197025A0; PE20081319A1; NO20090407L; UY30542A1; KR20090057393A

Abstract

The invention relates to an aerosol formulation for inhalation that is devoid of a propellant and contains one or more compounds of the general formula (1) and an additional active ingredient 2 and 3. In said formula, the groups R1, R2, R3 and X- can be defined as cited in the claims and the description.

Description

AEROSOL FORMULATION FOR THE INHALATION OF BETAAGONISTS

The present invention relates to a propellant-free aerosol formulation comprising one or more compounds of general formula 1,

1

wherein the 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.

DETAILED DESCRIPTION OF THE INVENTION

The pharmaceutical formulations according to the invention are propellant-free pharmaceutical formulations containing as active ingredient one or more compounds of general formula 1

wherein

R ¹ is hydrogen, Ci _-4 alkyl, OC-ι- ₄ alkyl or halogen; R ² is hydrogen, Ci _-4 alkyl, O-Ci _-4 alkyl or halogen;

Is hydrogen, C _1-4 alkyl, O-Ci _-4 alkyl, halogen, OH,

-Od- ₄ -alkylene-COOH or O-Ci _-4 alkylene-COO-Ci _-4 alkyl,

X- 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, maleate, acetate, benzoate, citrate, salicylate, trifluoroacetate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate,

optionally, in the form of their tautomers, enantiomers, mixtures of the enantiomers, racemates, solvates or hydrates; 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, glycopyrronium salts and Trospiumsalzen optionally in the form

Their tautomers, enantiomers, mixtures of enantiomers, racemates, solvates or

Hydrate, at least one pharmacologically acceptable acid, optionally further pharmacologically acceptable excipients, and as a solvent ethanol or a mixture of water and ethanol.

Preference is given to pharmaceutical formulations containing the above-described active compounds 2 and 3 and compounds of the general formula 1 in which

R ^{1 is} hydrogen, methyl, ethyl, fluorine or chlorine; R ^{2 is} hydrogen, methyl, ethyl, fluorine or chlorine;

R ³ is hydrogen, methyl, ethyl, propyl, OH, methoxy, ethoxy, fluorine, chlorine, bromine, 0-CH ₂ -COOH, O-CH ₂ or O-CH ₂ -COOMethyl -COOEthyl,

-O-CH ₂ -CH ₂ COOH, O-CH ₂ -CH ₂ COOMethyl or O-CH ₂ -CH ₂ COOEtIIyI,

-O-CH ₂ -CH ₂ -CH ₂ COOH, O-CH ₂ -CH ₂ -CH ₂ COOMethyl or

-O-CH ₂ -CH ₂ -CH ₂ COOEtIIyI;

X- 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, maleate, acetate, benzoate,

Citrate, salicylate, trifluoroacetate, fumarate, tartrate, oxalate, succinate, benzoate and p-

toluenesulfonate, optionally, in the form of their tautomers, enantiomers, mixtures of enantiomers, racemates, solvates or hydrates.

R ^{1 is} hydrogen or methyl, preferably hydrogen; R ^{2 is} hydrogen or methyl, preferably hydrogen; R ^{3 is} methyl, OH, methoxy, fluorine, chlorine, bromine, O-CH ₂ -COOH or

-O-CH ₂ -COOethyl; X is a mono- or poly-negatively charged anion selected from the group consisting of the group consisting of chloride, bromide, sulfate, methanesulfonate, maleate, acetate, benzoate, citrate, salicylate, trifluoroacetate, fumarate, tartrate and succinate;

optionally, in the form of their tautomers, enantiomers, mixtures of enantiomers, racemates, solvates or hydrates.

Also preferred are pharmaceutical formulations containing the above-described active compounds 2 and 3 and compounds of general formula 1, wherein

R ³ is methoxy, ethoxy, fluorine, chlorine, bromine, 0-CH ₂ -COOH, -O-CH ₂ or O-CH ₂ -COOMethyl -COOEthyl;

and 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.

Also preferred are pharmaceutical formulations containing the above-described active compounds 2 and 3 and compounds of general formula 1, wherein R ^{1 is} hydrogen; R ^{2 is} hydrogen;

R ^{3 is} OH, fluorine, chlorine, methoxy, ethoxy, -O-CH ₂ -COOH, preferably OH, fluorine, chlorine, ethoxy or methoxy,

and X ^{"may have} one of the abovementioned meanings, if appropriate in the form of their tautomers, enantiomers, mixtures of the enantiomers, racemates, solvates or hydrates.

Also preferred are pharmaceutical formulations containing the above-described active compounds 2 and 3 and the compounds of general formula 1 which are selected from the group consisting of:

6-Hydroxy-8- {1-hydroxy-2- [2- (4-methoxyphenyl) -1, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one ;

6-Hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -1, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one ;

6-Hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid) -1, 1-dimethyl-ethylamino] -ethyl} -4H-benzo [1,4] oxazin-3-one ; • 8- {2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -one;

6-Hydroxy-8- {1-hydroxy-2- [2- (4-hydroxyphenyl) -1, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one ;

6-hydroxy-8- {1-hydroxy-2- [2- (4-isopropylphenyl) -1, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4-oxazin-3-one;

• 8- {2- [2- (4-ethylphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one ;

• 8- {2- [2- (4-fluoro-3-methylphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one; • 8- {2- [2- (4-Fluoro-2-methylphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one;

• 8- {2- [2- (2,4-Difluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -one; • 8- {2- [2- (3 _: 5-difluorophenyl) -1 _! 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

• 8- {2- [2- (4-Ethoxy-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one ; • 8- {2- [2- (3,5-dimethylphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -one;

• 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;

• 8- {2- [2- (3 _: 4-difluorophenyl) -1 _! 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

• 8- {2- [2- (2-Chloro-4-fluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one;

• 8- {2- [2- (4-Chloro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one ; • 8- {2- [2- (4-Bromo-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one ;

• 8- {2- [2- (4-Fluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one ;

• 8- {2- [2- (4-Fluoro-3-methoxy-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one;

• 8- {2- [2- (4-Fluoro-2 _: 6-dimethylphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1, 4 ] oxazin-3-one;

• 8- {2- [2- (4-Chloro-2-methylphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one; • 8- {2- [2- (4-Chloro-3-fluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one;

• 8- {2- [2- (4-Chloro-2-fluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one;

• 8- {2- [2- (3-Chloro-4-fluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one;

• 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; • 8- {2- [2- (2,5-Difluoro-4-methoxyphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1, 4 ] oxazin-3-one;

• 8- {2- [2- (4-Fluoro-3,5-dimethylphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1, 4 ] oxazin-3-one; • 8- {2- [2- (3,5-dichloro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -one;

• 8- {2- [2- (4-Chloro-3-methylphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one;

• 8- {2- [2- (3,4,5-trifluorophenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one;

• 8- {2- [2- (3-methylphenyl) -1 _! 1-dimethyl-ethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one and

• 8- {2- [2- (3 _: 4-dichloro-phenyl) -1 _! 1-dimethyl-ethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one, each in the form of an acid addition salt with an acid HX in which X ^"is one of the abovementioned May have meanings, and optionally in the form of their tautomers, enantiomers, mixtures of enantiomers, racemates, solvates or hydrates.

In the drug combinations according to the invention, the active ingredient 2 is selected from the group of steroids consisting of budesonide, beclomethasone, fluticasone, ciclesonide or a metabolite thereof. Optionally, the aforementioned steroids have chiral carbon centers. In this case, 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.

In the drug combinations according to the invention, 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). Optionally, the aforementioned anticholinergics have chiral carbon centers. In this case, 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.

In the salts 3.1 to 3.6 mentioned above, 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.

Among the 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. Of all the salts, the chlorides, bromides, iodides and methanesulfonates are particularly preferred.

In the case of the trospium salts (3.6), the chloride is particularly preferred. For the other salts 3.2 to 3.6, the methanesulfonates and bromides are of particular importance. Of particular importance are drug combinations containing tiotropium salts (3.1), oxitropium salts (3.2) or Ipratropiumsalze (3.4), wherein the respective bromides are particularly important according to the invention. Of particular importance is tiotropium bromide (3.1).

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. In the case of tiotropium bromide, 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.

USED TERMS AND DEFINITIONS

The term "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. 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 / propyl, butyl includes / butyl, sec-butyl and te / f-butyl, etc.

The term "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.

Examples of acid addition salts with pharmacologically acceptable acids are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, Hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate understood. Of the above-mentioned acid addition salts, the salts of hydrochloric acid, methanesulfonic acid, benzoic acid and acetic acid are particularly preferred in the present invention.

By 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.

Within the meaning of the invention, metabolites of steroids are understood to mean steroids resulting from the metabolism or metabolic metabolism. Thus, it may be that the pharmaceutically active steroid actually corresponds to a metabolite of the steroid used. If the metabolites are stable from a pharmaceutical point of view, they can also be used directly. For example, des-ciclesonide, when administered to the lung, represents a pharmaceutically active metabolite of ciclesonide (D. Ukena, Pulmonology 2005; 59; 689-695).

Ciclesonide des-ciclesonide

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 σ or π bonds and can be in equilibrium. Examples of possible tautomeric forms of the compounds of formula 1 are

or

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

/ M,

wherein the radicals R ¹ , R ² , R ³ and X ^" may have the meanings given above. In the present invention, particularly preferred are those compounds according to the invention of formula 1 are used, in which 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. An optionally in the context of the present invention reference to the compound V is as

Reference to the pharmacologically active free base contained in the salts 1 of the following formula

wherein the radicals R ¹ , R ² and R ³ may have the meanings given above.

Another aspect of the present invention relates to pharmaceutical formulations containing an active ingredient 2 and 3 and a free base of the formula V wherein the radicals R ¹ , R ² and R ^{3 may have} the abovementioned meanings, optionally in the form of their tautomers, enantiomers, mixtures the enantiomers, racemates, solvates or hydrates, at least one pharmacologically acceptable acid, optionally further pharmacologically acceptable excipients, as well as the solvent water, ethanol or a mixture of water and ethanol. Another aspect of the present invention relates to the use of the pharmaceutical formulations according to the invention for the manufacture 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.

Preferably, 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.

Also preferred is the use of the pharmaceutical formulations of the invention for the manufacture of a medicament for the treatment of pulmonary emphysema which has its origin in COPD (chronic obstructive pulmonary disease) or α1-proteinase inhibitor deficiency.

Also preferred is the use of the pharmaceutical formulations of the invention for the preparation of a medicament for the treatment of restrictive lung diseases selected from the group consisting of allergic alveolitis, restrictive pulmonary diseases such as asbestosis or silicosis induced by occupational noxae and restriction due to lung tumors such as lymphangiosis carcinomatosa, bronchoalveolar carcinoma and lymphomas.

Also preferred is the use of the pharmaceutical formulations according to the invention for the manufacture of a medicament for the treatment of 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 different Genesis, such as aspiration and left ventricular failure, radiation-induced pneumonitis or fibrosis, collagenosis, such as lupus erythematosus, systemic scleroderma or sarcoidosis, granulomatosis, such as, for example, Boeck's disease, idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF).

Also preferred is the use of the pharmaceutical formulations according to the invention for the production of a medicament for the treatment of cystic fibrosis or cystic fibrosis.

Also preferred is the use of the pharmaceutical formulations according to the invention for the manufacture of a medicament for the treatment of bronchitis, such as, for example, bronchitis due to bacterial or viral infection, allergic bronchitis and toxic bronchitis.

Also preferred is the use of the pharmaceutical formulations according to the invention for the preparation of a medicament for the treatment of bronchiectasis.

Also preferred is the use of the pharmaceutical formulations according to the invention for the preparation of a medicament for the treatment of ARDS (adult respiratory distress syndrome).

Also preferred is the use of 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.

More preferably, 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. Of particular importance is also the above-mentioned use for 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. In addition, another aspect of the present invention relates to the use of the pharmaceutical formulations of the invention for the manufacture of a medicament for stimulating stem cell mobilization.

Furthermore, 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. It is particularly desirable to provide a drug formulation which can be therapeutically useful by a single application per day (single dose). An application once a day has the advantage that the patient can get used to the regular intake of the drug at certain times of day relatively quickly.

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. In order to obtain an optimal active ingredient distribution of the active substances in the lung, 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. In the context of the present invention, preference is given to those nebulizers in which an amount of less than 100 microliters, preferably less than 50 microliters, more preferably less than 35 microliters of active substance solution, preferably with one stroke or two strokes, but also up to four strokes, too an aerosol having an average particle size (or particle diameter) of less than 20 microns, preferably less than 10 microns, can be so nebulised that the inhalable fraction of the aerosol already corresponds to a therapeutically effective amount.

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. In such a nebulizer, a drug solution is transferred by means of high pressure of up to 500 bar in a respirable aerosol and sprayed. In the context of the present invention description, reference is expressly made to the cited references in their entirety.

In such inhalers, the solution formulations are stored in a reservoir. It is necessary that 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. In addition, 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.

For atomizing the solution, a special nozzle is used, as described for example in patent application WO 94/07607 or patent application WO 99/16530. Both are hereby incorporated by reference.

It is an object of the present invention to provide an aqueous, ethanolic or aqueous ethanolic formulation of the compound of formula 1 which satisfies the high standards which are necessary in order to optimally nebulize a solution by means of the inhalers mentioned above. The active ingredient formulations according to the invention must also have a sufficient pharmaceutical grade, i. they should be pharmaceutically stable over a shelf life of a few years, preferably at least twelve months, more preferably 18 months. These 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.

According to the invention, the formulation preferably contains the active compounds 2 and 3 and only one compound of the formula 1. However, the formulation may also contain a mixture of different salts of the formula 1. If the pharmaceutical formulations of the invention contain various salts of the formula 1 are according to the invention those formulations in which the different salts represent different salts of the same free base of formula V.

The concentration of the compound of formula 1 based on the proportion of pharmacologically active free base V in the pharmaceutical formulation of the invention is according to the invention at about 0.1 to 1000 mg per 100 ml, preferably at about 0.5 to 500 mg per 100 ml, particularly preferred 1 to 250 mg per 100 ml. particularly preferably 100 ml of the formulations of the invention comprise about 2 to about 100 mg 1 ^1.

According to the invention, the concentration of the compound of the formula 2 in the pharmaceutical formulation according to the invention is about 10 to 6000 mg per 100 ml, preferably 10 to 5000 mg per 100 ml, preferably 50 to 5000 mg per 100 ml, preferably 50 to 3000 mg per 100 ml, more preferably 75 to 3500 mg per 100 ml.

The concentration of the compound of the formula 3 based on the proportion of pharmacologically active free cation of the salt 3.1 in the pharmaceutical formulation of the invention is according to the invention at about 0.1 to 2000 mg per 100 ml, preferably at about 1 to 1000 mg per 100 ml, particularly preferred 0.75 to 500 mg per 100 ml. More preferably, 100 ml of the formulations according to the invention contain about 5 to about 100 mg of the free cation of the salt 3.1.

The pharmaceutical formulations according to the invention contain as solvent pure ethanol or mixtures of ethanol and water. If ethanol-water mixtures are used, the percentage by volume of ethanol in these mixtures is preferably in the range between 30 and 99% ethanol, particularly preferably in the range from 40 to 97% ethanol. For the purposes of the present invention, very particularly preferred pharmaceutical formulations contain as solvent pure ethanol or water mixtures containing between 50 and 96%, particularly preferably between 67 and 95% ethanol, in particular between 67 and 93% ethanol. Optionally, other co-solvents and solubilizers such as benzyl alcohol, γ-butyrolactone or diethylene glycol monoethyl ether can be used in addition to ethanol and water. According to the invention, however, a further solvent is not used. If the compounds 1 and 2 are dissolved in ethanol or in mixtures of ethanol and water, 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. For this purpose, pharmacologically acceptable inorganic or organic acids can be used. Examples of preferred inorganic acids are selected from the group consisting of hydrochloric acid, phosphoric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid. Examples of 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. Among the organic acids, ascorbic acid, fumaric acid, methanesulfonic acid and citric acid are preferred, with citric acid being particularly preferred according to the invention. Optionally, 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. Optionally, 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.

Furthermore, the adjustment of the pH can also be carried out via a pharmacologically acceptable buffer system. For this purpose, pharmacologically acceptable inorganic or organic buffer systems can be used. Examples of 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. In the context of the present invention, 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. Preference is given to using disodium edetate, if appropriate in the form of its hydrates, particularly preferably in the form of its dihydrate. Further, 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.

If 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. Preferably, 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.

The formulation according to the invention may be added further pharmacologically acceptable excipients. In this context, 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), tris (2,4-di-tert-butylphenyl) phosphite and tetrakis [methylene (3,5-di-tert-butylhydroxyhydrocinnamate)] methane. Preferred are BHT or tocopherols, more preferably BHT.

If 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.

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 amount of, for example, admixed 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 formulation according to the invention. Benzalkonium chloride can also be used according to the invention in admixture with other preservatives. For ethanol / water mixtures of 50 to 93% VA / can be dispensed with an additional preservative, which here this property already exists in the solvent mixture.

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.

NEBULIZER

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. There are stationary devices as well as small devices for on the way. These are of course still bigger than MDI's and DPI's. 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 μm). 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. During inhalation, 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 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. For this reason, reference should again be made expressly to the patent documents described at the outset, to which reference is hereby incorporated by reference. As described above, 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. Essentially, 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

• a pump housing, which is fixed in the upper part of the housing, and that at its

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 fastened, and which is located in the upper part of the housing,

• a locking mechanism, which is located in the upper part of the housing,

• 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. In the case of a plurality of nozzle openings, preferably two, 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. In a nozzle body having at least two nozzle openings on the outlet side, 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. As already mentioned, 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 Schraubschubgetriebe, stretched by an external torque that is generated when turning the upper housing part against the spring housing in the lower housing part. In this case, 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. There is e.g. from a radially elastically deformable ring made of plastic or metal. The ring is arranged in a plane perpendicular to the atomizer axis. After tensioning the spring, the locking surfaces of the locking member push in the path of the output flange and prevent the relaxation of the spring. The locking member is triggered by a button. The release button is connected or coupled to the locking member. To trigger the locking mechanism, the shutter button is parallel to the ring plane, and preferably in the atomizer, moved; while the deformable ring is deformed in the ring plane. Constructive details of the locking mechanism are described in WO 97/20590.

The lower housing part is pushed in the axial direction over the spring housing and covers the storage, the drive of the spindle and the reservoir for the fluid.

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. 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.

If necessary, 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 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.

Further design details are disclosed in PCT applications WO 97/12683 and WO 97/20590, the contents of which are hereby incorporated by reference.

The components of the atomizer (nebulizer) 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.

In Figures 6 a / b of WO 97/12687, show the nebuliser (Respimat ^®) is described, 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 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). Within the upper housing part is the stop (60) on which the output flange rests with a relaxed spring. At the output flange is the Stop (61) on which the output flange rests when the spring is cocked. After tensioning the 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. About the spring housing, the lower housing part (70) is pushed. Within the spring housing is the replaceable reservoir (71) for the fluid (72) to be atomized. Of 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).

In the lateral surface of the spring housing, the spindle (74) for the mechanical

Counter attached. 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.

If the formulation according to the invention by means of the method described above (Respimat ^®) nebulized, 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. Preferably, 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.

If the formulation is by means of the above-described Respimat ^® -Geräts be administered nasally, 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.

Thus, 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.

This object is achieved by 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,

• and a dimensionally stable flange which is tightly attached to the foil bag, and which is designed as a detachable connecting element for attaching the container to a sampling nozzle,

• and at least one weld with which the foil pouch is attached

Is closed at least one end, and which runs essentially transversely to the bag axis, • and a sealing point in dimensionally stable flange,

• and an extraction point for the liquid in the area of the dimensionally stable flange.

In a further embodiment, 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. In this case, the dimensionally stable flange on the side of the film bag, preferably in the vicinity of one end of the film bag, welded tight. However, the foil bag can also be sealed at one end by a weld and at the other end by the dimensionally stable flange. In this case, 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. In a further embodiment, 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. Furthermore, 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. Furthermore, 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. Such a press fit allows the attachment of the container to the sampling nozzle and a sufficiently tight fit of the dimensionally stable flange on the sampling nozzle. Furthermore, the container after its emptying be deducted from the sampling nozzle without damaging the sampling neck.

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.

Within or at one of the ends of the guide channel may be provided a sealing point. The sealing point may consist of a ring in one on the

Inner wall of the guide channel attached groove is located. 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. At the 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.

In a further embodiment, 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. In another embodiment, the film bag may consist of a composite film of plastic and metal. The composite foil preferably consists of two or three interconnected slides. Furthermore, 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. In another embodiment, 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. Instead of 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.

In a further embodiment, the inner film of the composite film consists of a copolymer, for example a polyethylene copolymer of ethylene-acrylic acid. For the outer plastic film of the composite film, 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. As a result, the seam-like welding of the plastic of the inner foil is facilitated during the production of the foil bag. In the case of the composite 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 μm to 100 μm, a middle foil of metal with a thickness of 8 μm to 20 μm and an outer foil made of plastic with a thickness of 10 μm to 40 μm.

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. 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.

During the transition of liquid from the container into the sampling nozzle, the film bag settles flat due to the effect of the external pressure. Through the opening in the sleeve or through the gap between the sleeve and dimensionally stable flange, air enters the space between the sleeve and the foil bag and causes the pressure equalization. Thus, no valve is required in the foil bag, and the liquid in the foil bag does not come into contact with air.

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. For this film, 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, for example, 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.

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. 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.

It may be expedient, instead of or in addition to the interference fit (frictional connection) between the container and the withdrawal nozzle, to provide 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. When inserting the container in the removal device grab the snap hooks in a recess in

Flange, for example, in a circumferential groove or behind an edge of the dimensionally stable flange, a. 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 formulation examples set forth below serve to further illustrate without limiting the subject matter of the present invention to the compositions exemplified.

EXAMPLES

As already mentioned, 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 3: 6-Hydroxy-8- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4-oxazine] 3-one hydrochloride

Example 4: 6-Hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -1, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4-oxazine] 3-one hydrochloride

Example 5: 6-Hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid) -1, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4-oxazine] 3-one hydrochloride

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 8: 6-Hydroxy-8- {1-hydroxy-2- [2- (4-isopropylphenyl) -1, 1-dimethylethylamino] ethyl} -4 H -benzo [1,4] oxazine-3 -one hydrochloride

Example 9: 8- {2- [2- (4-Ethylphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4-oxazine] 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 20: 8- {2- [2- (4-Bromophenyl) -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 25: 8- {2- [2- (4-Chloro-3-fluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1, 4] oxazin-3-one acid addition salt;

Example 26: 8- {2- [2- (4-Chloro-2-fluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1, 4] oxazin-3-one acid addition salt; Example 27: 8- {2- [2- (3-Chloro-4-fluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -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.

optionally in the form of an acid addition salt with an acid HX in which X ^{"may have} one of the meanings given above, and optionally in the form of their tautomers, enantiomers, mixtures of the enantiomers, racemates, solvates or hydrates.

The table below summarizes inventive formulation examples. The abbreviation EDTA means 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:

# r 2 3.1 ¹ EtOH Propyl BHA BHT OC EDTA pH

(Base) (mg) (Cation) / H ₂ O gallate (mg) (mg) Toco- (mg) Value

(mg) (mg) (% (mg) pherol (HCl) m / m) (mg)

1 9 400 11 70 100 - 2 .7

2 9 250 23 70 50 - 3 .0

3 45 500 45 70 3 3 .5

4 100 400 23 70 50 0.5 3 .0

5 45 400 23 70 100 - 3 .0

6 45 800 23 80 0.5 3 .0

7 45 250 11 80 1 3 .5

17 45 2000 23 90 100 1 3 .5

18 100 2000 11 95 100 50 - 3 .5

19 45 4000 23 95 100 - 3 .0

20 9 2500 45 95 100 _ 3 .0

B) The table below summarizes inventive formulation examples of the R enantiomer of the compound Example 3, the active ingredient 2 and the active compound 3.1 in the form of base and cation. 100 ml of pharmaceutical preparation contain: # _{1 C} N r 2 3.1 ¹ EtOH Propyl BHA BHT OC EDTA pH

(Base) (mg) (Cation) / H ₂ O gallate (mg) (mg) Toco- (mg) Value

(mg) (mg) (% (mg) pherol (HCl) m / m) (mg)

1 9 400 11 70 100 - 2 .7

2 9 250 23 70 50 - 3 .0

3 45 500 45 70 3 3 .5

4 100 400 23 70 50 0.5 3 .0

5 45 400 23 70 100 - 3 .0

6 45 800 23 80 0.5 3 .0

7 45 250 11 80 1 3 .5

11 100 1200 23 90 100 - 3 .0

12 9 2500 45 90 1 3 .5

13 45 2000 23 90 50 - 3 .0

14 45 2000 23 90 100 - 3 .0

15 45 2000 23 90 100 - 3 .0

16 45 2000 23 90 100 - 3 .0

17 45 2000 23 90 100 1 3 .5

18 100 2000 11 95 100 50 - 3 .5

19 45 4000 23 95 100 - 3 .0

20 9 2500 45 95 100 _ 3 .0

C) The table below summarizes inventive formulation examples of the R enantiomer of the compound Example 7, the active ingredient 2 and the active compound 3.1 in the form of base and cation. 100 ml of pharmaceutical preparation contain:

# r 2 3.1 ¹ EtOH Propyl BHA BHT OC EDTA pH

(Base) (mg) (Cation) / H ₂ O gallate (mg) (mg) Toco- (mg) Value

(mg) (mg) (% (mg) pherol (HCl) m / m) (mg)

1 9 400 11 70 100 - - 2.7

9 250 23 70 50 - 3.0

3 45 500 45 70 3 3.5

4 100 400 23 70 50 0.5 3.0 _l 5 _C N 45 400 23 70 100 - 3.0

6 45 800 23 80 0.5 3 .0

7 45 250 11 80 1 3 .5

8 100 1200 45 80 100 - 2 .7

9 45 1200 23 80 100 - 3 .5

10 100 1000 11 90 50 - 2 .7

11 100 1200 23 90 100 - 3 .0

12 9 2500 45 90 1 3 .5

13 45 2000 23 90 50 - 3 .0

14 45 2000 23 90 100 - 3 .0

15 45 2000 23 90 100 - 3 .0

16 45 2000 23 90 100 - 3 .0

17 45 2000 23 90 100 1 3 .5

18 100 2000 11 95 100 50 - 3 .5

19 45 4000 23 95 100 - 3 .0

20 9 2500 45 95 100 _ 3 .0

D) The table below summarizes inventive formulation examples of the R-enantiomer of the compound Example 9, the active ingredient 2 and the active compound 3.1 in the form of base and cation. 100 ml of pharmaceutical preparation contain:

# r 2 3.1 ¹ EtOH Propyl BHA BHT OC EDTA pH

(Base) (mg) (Cation) / H ₂ O gallate (mg) (mg) Toco- (mg) Value

(mg) (mg) (% (mg) pherol (HCl) m / m) (mg)

1 9 400 11 70 100 - - 2.7

9 250 23 70 50 - 3.0

3 45 500 45 70 3 3.5

4 100 400 23 70 50 0.5 3.0

5 45 400 23 70 100 - - - 3.0

6 45 800 23 80 0.5 3.0

7 45 250 11 80 1 3.5

8 100 1200 45 80 100 - - 2.7

9 45 1200 23 80 100 3.5

10 100 1000 11 90 50 - 2.7

11 100 1200 23 90 100 - - 3.0 12 9 2500 45 90 3.5

13 45 2000 23 90 50 3.0

14 45 2000 23 90 100 3.0

15 45 2000 23 90 100 3.0

16 45 2000 23 90 100 3.0

17 45 2000 23 90 100 3.5

18 100 2000 11 95 100 50 3.5

19 45 4000 23 95 100 3.0

20 9 2500 45 95 100 3.0

E) The table below summarizes inventive formulation examples of the R enantiomer of the compound Example 14, the active ingredient 2 and the active compound 3.1 in the form of base and cation. 100 ml of pharmaceutical preparation contain:

# r 2 3.1 ¹ EtOH Propyl BHA BHT OC EDTA pH

(Base) (mg) (Cation) / H ₂ O gallate (mg) (mg) Toco- (mg) Value

(mg) (mg) (% (mg) pherol (HCl) m / m) (mg)

1 9 400 11 70 100 - .7

2 9 250 23 70 50 - 3 .0

3 45 500 45 70 3 3 .5

4 100 400 23 70 50 0.5 3 .0

5 45 400 23 70 100 - ^I _ll ^C 3 _C _C NNN .0

6 45 800 23 80 0.5 3 .0

7 45 250 11 80 1 3 .5

8 100 1200 45 80 100 - .7

9 45 1200 23 80 100 - - - 3 .5

10 100 1000 11 90 50 - .7

11 100 1200 23 90 100 - 3 .0

12 9 2500 45 90 1 3 .5

13 45 2000 23 90 50 - 3 .0

14 45 2000 23 90 100 - - - 3 .0

15 45 2000 23 90 100 - 3 .0

16 45 2000 23 90 100 - 3 .0

17 45 2000 23 90 100 1 3 .5

18 100 2000 11 95 100 - 50 _ 3 .5 19 45 4000 23 95 100 3.0

20 9 2500 45 95 100 3.0

F) The table below summarizes inventive formulation examples of the R-enantiomer of the compound Example 17, the active ingredient 2 and the active compound 3.1 in the form of base and cation. 100 ml of pharmaceutical preparation contain:

# r 2 3.1 ¹ EtOH Propyl BHA BHT OC EDTA pH

(Base) (mg) (Cation) / H ₂ O gallate (mg) (mg) Toco- (mg) Value

(mg) (mg) (% (mg) pherol (HCl) m / m) (mg)

1 9 400 11 70 100 - 2 .7

2 9 250 23 70 50 - 3 .0

3 45 500 45 70 3 3 .5

4 100 400 23 70 50 0.5 3 .0

5 45 400 23 70 100 - 3 .0

6 45 800 23 80 0.5 3 .0

7 45 250 11 80 1 3 .5

8 100 1200 45 80 100 - .7

9 45 1200 23 80 100 - - - 3 .5

10 100 1000 11 90 50 - .7

11 100 1200 23 90 100 - 3 .0

12 9 2500 45 90 1 ^lI ^C ^C 3NN .5

13 45 2000 23 90 50 - 3 .0

14 45 2000 23 90 100 - - - 3 .0

15 45 2000 23 90 100 - 3 .0

16 45 2000 23 90 100 - 3 .0

17 45 2000 23 90 100 1 3 .5

18 100 2000 11 95 100 - 50 - 3 .5

19 45 4000 23 95 100 - - - 3 .0

20 9 2500 45 95 100 _ 3 .0

G) 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: # r 2 3.1 ¹ EtOH Propyl BHA BHT OC EDTA pH

(Base) (mg) (Cation) / H ₂ O gallate (mg) (mg) Toco- (mg) Value

(mg) (mg) (% (mg) pherol (HCl) m / m) (mg)

1 9 400 11 70 100 - 2.7

2 9 250 23 70 50 - 4.0

3 45 500 45 70 1 3.5

4 100 400 23 70 50 0.5 3.0

5 45 400 23 70 100 - 3.0

6 45 800 23 80 0.5 4.0

7 45 250 11 80 0.5 3.5

8 100 1200 45 80 50 - 3.0

9 45 1200 23 80 100 - 3.5

10 100 1000 11 90 50 - 2.7

11 100 1200 23 90 100 - 3.0

12 9 2500 45 90 0.5 3.5

13 45 2000 23 90 50 - 3.0

14 45 3500 23 90 100 - 3.0

15 45 2000 23 90 100 - 3.0

16 45 3600 23 90 100 - 3.0

17 45 3500 23 90 50 0.5 3.5

18 100 2000 11 95 100 50 - 3.5

19 45 4000 23 95 100 - 3.0

20 9 2500 45 95 100 _ 3.0

H) The table below summarizes inventive formulation examples of the R enantiomer of the compound Example 3, the active ingredient 2 and the active compound 3.1 in the form of base and cation. 100 ml of pharmaceutical preparation contain:

R # 2 3.1 ¹ EtOH propyl BHA BHT OC- EDTA pH

(Base) (mg) (Cation) / H ₂ O gallate (mg) (mg) Toco- (mg) Value (mg) (mg) (% (mg) pherol (HCl) m / m) (mg)

1 9 400 11 70 - - 100 - - 2,7

2 9 250 23 70 - - - 50 - 4.0

3 45 500 45 70 - - - - 1 3.5 4 100 400 23 70 50 0.5 3.0

5 45 400 23 70 100 - 3.0

6 45 800 23 80 0.5 4.0

7 45 250 11 80 0.5 3.5

8 100 1200 45 80 50 - 3.0

9 45 1200 23 80 100 - 3.5

10 100 1000 11 90 50 - 2.7

11 100 1200 23 90 100 - 3.0

12 9 2500 45 90 0.5 3.5

13 45 2000 23 90 50 - 3.0

14 45 3500 23 90 100 - 3.0

15 45 2000 23 90 100 - 3.0

16 45 3600 23 90 100 - 3.0

17 45 3500 23 90 50 0.5 3.5

18 100 2000 11 95 100 - 50 - 3.5

19 45 4000 23 95 100 - 3.0

20 9 2500 45 95 100 3.0

I) The following table summarizes inventive formulation examples of the R-enantiomer of the compound Example 7, the active ingredient 2 and the active compound 3.1 in the form of base and cation. 100 ml of pharmaceutical preparation contain:

# r 2 3.1 ¹ EtOH Propyl BHA BHT OC EDTA pH

(Base) (mg) (Cation) / H ₂ O gallate (mg) (mg) Toco- (mg) Value

(mg) (mg) (% (mg) pherol (HCl) m / m) (mg)

1 9 400 11 70 100 - - 2.7

2 9 250 23 70 50 - 4.0

3 45 500 45 70 1 3.5

4 100 400 23 70 50 0.5 3.0

5 45 400 23 70 100 - - - 3.0

6 45 800 23 80 0.5 4.0

7 45 250 11 80 0.5 3.5

8 100 1200 45 80 50 - - 3.0

9 45 1200 23 80 100 3.5

10 100 1000 11 90 50 - 2.7 11 100 1200 23 90 100 3.0

12 9 2500 45 90 0.5 3.5

13 45 2000 23 90 50 3.0

14 45 3500 23 90 100 3.0

15 45 2000 23 90 100 3.0

16 45 3600 23 90 100 3.0

17 45 3500 23 90 50 0.5 3.5

18 100 2000 11 95 100 50 3,5

19 45 4000 23 95 100 3.0

20 9 2500 45 95 100 3.0

J) The table below summarizes inventive formulation examples of the R enantiomer of the compound Example 9, the active ingredient 2 and the active compound 3.1 in the form of base and cation. 100 ml of pharmaceutical preparation contain:

# r 2 3.1 ¹ EtOH Propyl BHA BHT OC EDTA pH

(Base) (mg) (Cation) / H ₂ O gallate (mg) (mg) Toco- (mg) Value

(mg) (mg) (% (mg) pherol (HCl) m / m) (mg)

1 9 400 11 70 100 - 2.7

2 9 250 23 70 50 - 4.0

3 45 500 45 70 1 3.5

4 100 400 23 70 50 0.5 3.0

5 45 400 23 70 100 - 3.0

6 45 800 23 80 0.5 4.0

7 45 250 11 80 0.5 3.5

8 100 1200 45 80 50 - 3.0

9 45 1200 23 80 100 - - - 3.5

10 100 1000 11 90 50 - 2.7

11 100 1200 23 90 100 - 3.0

12 9 2500 45 90 0.5 3.5

13 45 2000 23 90 50 - 3.0

14 45 3500 23 90 100 - - - 3.0

15 45 2000 23 90 100 - 3.0

16 45 3600 23 90 100 - 3.0

17 45 3500 23 90 50 0.5 3.5 18 100 2000 11 95 - 100 50 3.5

19 45 4000 23 95 100 - - 3.0

20 9 2500 45 95 - 100 - 3.0

K) The following table summarizes inventive formulation examples of the R-enantiomer of the compound Example 14, the active ingredient 2 and the active ingredient 3.1 in the form of base and cation. 100 ml of pharmaceutical preparation contain:

# r 2 3.1 ¹ EtOH Propyl BHA BHT OC EDTA pH

(Base) (mg) (Cation) / H ₂ O gallate (mg) (mg) Toco- (mg) Value

(mg) (mg) (% (mg) pherol (HCl) m / m) (mg)

1 9 400 11 70 100 - 2.7

2 9 250 23 70 50 - 4.0

3 45 500 45 70 1 3.5

4 100 400 23 70 50 0.5 3.0

5 45 400 23 70 100 - 3.0

6 45 800 23 80 0.5 4.0

7 45 250 11 80 0.5 3.5

8 100 1200 45 80 50 - 3.0

9 45 1200 23 80 100 - 3.5

10 100 1000 11 90 50 - 2.7

11 100 1200 23 90 100 - 3.0

12 9 2500 45 90 0.5 3.5

13 45 2000 23 90 50 - 3.0

14 45 3500 23 90 100 - 3.0

15 45 2000 23 90 100 - 3.0

16 45 3600 23 90 100 - 3.0

17 45 3500 23 90 50 0.5 3.5

18 100 2000 11 95 100 50 - 3.5

19 45 4000 23 95 100 - 3.0

20 9 2500 45 95 100 _ 3.0 L) The table below summarizes inventive formulation examples of the R enantiomer of the compound Example 17, the active ingredient 2 and the active compound 3.1 in the form of base and cation. 100 ml of pharmaceutical preparation contain:

# r 2 3.1 ¹ EtOH Propyl BHA BHT OC EDTA pH

(Base) (mg) (Cation) / H ₂ O gallate (mg) (mg) Toco- (mg) Value

(mg) (mg) (% (mg) pherol (HCl) m / m) (mg)

1 9 400 11 70 100 - 2.7

2 9 250 23 70 50 - 4.0

3 45 500 45 70 1 3.5

4 100 400 23 70 50 0.5 3.0

5 45 400 23 70 100 - 3.0

6 45 800 23 80 0.5 4.0

7 45 250 11 80 0.5 3.5

8 100 1200 45 80 50 - 3.0

9 45 1200 23 80 100 - 3.5

10 100 1000 11 90 50 - 2.7

11 100 1200 23 90 100 - 3.0

12 9 2500 45 90 0.5 3.5

13 45 2000 23 90 50 - 3.0

14 45 3500 23 90 100 - 3.0

15 45 2000 23 90 100 - 3.0

16 45 3600 23 90 100 - 3.0

17 45 3500 23 90 50 0.5 3.5

18 100 2000 11 95 100 50 - 3.5

19 45 4000 23 95 100 - 3.0

20 9 2500 45 95 100 _ 3.0

M) 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: # r 2 3.1 ¹ EtOH Propyl BHA BHT OC EDTA pH

(Base) (mg) (Cation) / H ₂ O gallate (mg) (mg) Toco- (mg) Value

(mg) (mg) (% (mg) pherol (HCl) m / m) (mg)

1 7 735 7 70 100 - 2.7

2 15 368 30 70 50 0.5 4.0

3 30 735 15 70 1 3,5

4 120 368 7 70 50 - 3.0

5 60 735 30 70 100 - 3.0

6 7 735 15 80 0.5 4.0

7 15 1471 7 80 0.5 3.5

8 30 735 30 80 50 - 3.0

9 120 1471 15 80 100 - 3.5

10 60 2942 7 90 50 - 2,7

11 7 2942 30 90 100 - 3.0

12 15 1471 15 90 0.5 3.5

13 30 735 7 90 50 - 3.0

14 120 2942 30 90 100 - 3.0

15 60 1471 15 90 100 - 3.0

16 7 4000 7 90 100 - 3.0

17 15 2942 30 90 50 0.5 3.5

18 30 1471 15 95 100 50 - 3.5

19 120 4000 15 95 100 - 3.0

20 60 2942 7 95 100 3.0

N) The table below summarizes inventive formulation examples of the R-enantiomer of the compound Example 3, the active ingredient 2 and the active compound 3.1 in the form of base and cation. 100 ml of pharmaceutical preparation contain:

# r 2 3.1 ¹ EtOH Propyl BHA BHT OC EDTA pH

(Base) (mg) (Cation) / H ₂ O gallate (mg) (mg) Toco- (mg) Value

(mg) (mg) (% (mg) pherol (HCl) m / m) (mg)

1 7 735 7 70 100 - - 2,7

2 15 368 30 70 50 0.5 4.0

3 30 735 15 70 1 3,5

4 120 368 7 70 50 - - 3.0 5 60 735 30 70 100 - 3.0

6 7 735 15 80 0.5 4.0

7 15 1471 7 80 0.5 3.5

8 30 735 30 80 50 - 3.0

9 120 1471 15 80 100 - 3.5

10 60 2942 7 90 50 - 2,7

11 7 2942 30 90 100 - 3.0

12 15 1471 15 90 0.5 3.5

13 30 735 7 90 50 - 3.0

14 120 2942 30 90 100 - 3.0

15 60 1471 15 90 100 - 3.0

16 7 4000 7 90 100 - 3.0

17 15 2942 30 90 50 0.5 3.5

18 30 1471 15 95 100 50 - 3.5

19 120 4000 15 95 100 - 3.0

20 60 2942 7 95 100 _ 3.0

O) The table below summarizes inventive formulation examples of the R-enantiomer of the compound Example 7, the active ingredient 2 and the active compound 3.1 in the form of base and cation. 100 ml of pharmaceutical preparation contain:

# r 2 3.1 ¹ EtOH Propyl BHA BHT OC EDTA pH

(Base) (mg) (Cation) / H ₂ O gallate (mg) (mg) Toco- (mg) Value

(mg) (mg) (% (mg) pherol (HCl) m / m) (mg)

1 7 735 7 70 100 - - 2,7

2 15 368 30 70 50 0.5 4.0

3 30 735 15 70 1 3,5

4 120 368 7 70 50 - - 3.0

5 60 735 30 70 100 - - - 3.0

6 7 735 15 80 0.5 4.0

7 15 1471 7 80 0.5 3.5

8 30 735 30 80 50 - - 3.0

9 120 1471 15 80 100 3.5

10 60 2942 7 90 50 - 2,7

11 7 2942 30 90 100 - - 3.0 12 15 1471 15 90 0.5 3.5

13 30 735 7 90 50 3.0

14 120 2942 30 90 100 3.0

15 60 1471 15 90 100 3.0

16 7 4000 7 90 100 3.0

17 15 2942 30 90 50 0.5 3.5

18 30 1471 15 95 100 50 3.5

19 120 4000 15 95 100 3.0

20 60 2942 7 95 100 3.0

P) The table below summarizes inventive formulation examples of the R-enantiomer of the compound Example 9, the active ingredient 2 and the active compound 3.1 in the form of base and cation. 100 ml of pharmaceutical preparation contain:

# r 2 3.1 ¹ EtOH Propyl BHA BHT OC EDTA pH

(Base) (mg) (Cation) / H ₂ O gallate (mg) (mg) Toco- (mg) Value

(mg) (mg) (% (mg) pherol (HCl) m / m) (mg)

1 7 735 7 70 100 - 2.7

2 15 368 30 70 50 0.5 4.0

3 30 735 15 70 1 3,5

4 120 368 7 70 50 - 3.0

5 60 735 30 70 100 - 3.0

6 7 735 15 80 0.5 4.0

7 15 1471 7 80 0.5 3.5

8 30 735 30 80 50 - 3.0

9 120 1471 15 80 100 - - - 3.5

10 60 2942 7 90 50 - 2,7

11 7 2942 30 90 100 - 3.0

12 15 1471 15 90 0.5 3.5

13 30 735 7 90 50 - 3.0

14 120 2942 30 90 100 - - - 3.0

15 60 1471 15 90 100 - 3.0

16 7 4000 7 90 100 - 3.0

17 15 2942 30 90 50 0.5 3.5

18 30 1471 15 95 100 - 50 3,5 19 120 4000 15 95 100 3.0

20 60 2942 7 95 100 3.0

Q) The table below summarizes inventive formulation examples of the R-enantiomer of the compound Example 14, the active ingredient 2 and the active compound 3.1 in the form of base and cation. 100 ml of pharmaceutical preparation contain:

# r 2 3.1 ¹ EtOH Propyl BHA BHT OC EDTA pH

(Base) (mg) (Cation) / H ₂ O gallate (mg) (mg) Toco- (mg) Value

(mg) (mg) (% (mg) pherol (HCl) m / m) (mg)

1 7 735 7 70 100 - 2.7

2 15 368 30 70 50 0.5 4.0

3 30 735 15 70 1 3,5

4 120 368 7 70 50 - 3.0

5 60 735 30 70 100 - 3.0

6 7 735 15 80 0.5 4.0

7 15 1471 7 80 0.5 3.5

8 30 735 30 80 50 - 3.0

9 120 1471 15 80 100 - - - 3.5

10 60 2942 7 90 50 - 2,7

11 7 2942 30 90 100 - 3.0

12 15 1471 15 90 0.5 3.5

13 30 735 7 90 50 - 3.0

14 120 2942 30 90 100 - - - 3.0

15 60 1471 15 90 100 - 3.0

16 7 4000 7 90 100 - 3.0

17 15 2942 30 90 50 0.5 3.5

18 30 1471 15 95 100 - 50 - 3,5

19 120 4000 15 95 100 - - - 3.0

20 60 2942 7 95 100 3.0

R) The table below summarizes inventive formulation examples of the R-enantiomer of the compound Example 17, the active ingredient 2 and the active compound 3.1 in the form of base and cation. 100 ml of pharmaceutical preparation contain: r 2 3.1 ¹ EtOH Propyl BHA BHT OC EDTA pH

(Base) (mg) (Cation) / H ₂ O gallate (mg) (mg) Toco- (mg) Value

(mg) (mg) (% (mg) pherol (HCl) m / m) (mg)

7,735,770,100 - 2,7

15 368 30 70 50 0.5 4.0

30 735 15 70 1 3,5

120 368 7 70 50 - 3.0

60,735 30 70 100 - 3.0

7 735 15 80 0.5 4.0

15 1471 7 80 0.5 3.5

30 735 30 80 50 - 3.0

120 1471 15 80 100 - 3.5

60 2942 7 90 50 - 2.7

7 2942 30 90 100 - 3.0

15 1471 15 90 0.5 3.5

30,735,790,50 - 3,0

120 2942 30 90 100 - 3.0

60 1471 15 90 100 - 3.0

7 4000 7 90 100 - 3.0

15 2942 30 90 50 0.5 3.5

30 1471 15 95 100 50 - 3.5

120 4000 15 95 100 - 3.0

60 2942 7 95 100 _ 3.0

Claims

1. Pharmaceutical formulation containing as active ingredient one or more compounds of general formula 1

wherein

R ¹ is hydrogen, Ci _-4 alkyl, O-Ci _-4 alkyl or halogen; R ² is hydrogen, Ci _-4 alkyl, O-Ci _-4 alkyl or halogen;

Is hydrogen, C _1-4 alkyl, O-Ci _-4 alkyl, halogen, OH,

-O-Ci _-4 -alkylene-COOH or O-Ci _-4 alkylene-COO-Ci _-4 alkyl,

X ^"is 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 the enantiomers, racemates, solvates or hydrates; 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 active compound 3 selected from the group consisting of tiotropium salts, oxitropium salts, flutropium salts, ipratropium salts, glycopyrronium salts and trospium salts, optionally in the form of their tautomers, enantiomers, mixtures of the enantiomers, racemates, solvates or hydrates, at least one pharmacologically acceptable acid, optionally further pharmacologically acceptable excipients, and as a solvent ethanol or a mixture of water and ethanol.

2. Drug formulation according to claim 1, characterized in that it contains both active substances 2 and 3 and one or more compounds of formula 1, wherein

R ^{3 is} hydrogen, methyl, ethyl, propyl, OH, methoxy, ethoxy, fluorine, chlorine, bromine, 0-CH ₂ -COOH, O-CH ₂ -COOMethyl or 0-CH ₂ -COOEtIIyI, -O-CH ₂ -CH ₂ COOH, O-CH ₂ -CH ₂ COOMethyl or 0-CH ₂ -CH ₂ COOEtyl, -O-CH ₂ -CH ₂ -CH ₂ COOH, O-CH ₂ -CH ₂ -CH ₂ COOMethyl or

-O-CH ₂ -CH ₂ -CH ₂ COOEtIIyI;

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, maleate, acetate, benzoate, citrate, salicylate, Trifluoroacetate, fumarate, tartrate, oxalate, succinate, benzoate and p-

toluenesulfonate,

3. A pharmaceutical formulation according to claim 1, characterized in that it contains both active ingredients 2 and 3 and one or more compounds of formula 1, wherein

-O-CH ₂ -COOethyl;

X ^"is a singly or multiply negatively charged anion selected from the group consisting of selected from the group consisting of chloride, bromide, sulfate,

Methanesulfonate, maleate, acetate, benzoate, citrate, salicylate, trifluoroacetate, fumarate, tartrate and succinate; optionally, in the form of their tautomers, enantiomers, mixtures of enantiomers, racemates, solvates or hydrates.

4. A pharmaceutical formulation according to any one of claims 1 to 3, wherein the active ingredient 2 is selected from the group consisting of budesonide, ciclesonide or a metabolite thereof, optionally in the form of their tautomers, enantiomers, mixtures of enantiomers, racemates, solvates or hydrates.

5. A pharmaceutical formulation according to any one of claims 1 to 3, wherein the active ingredient 3 is selected from the group consisting of tiotropium bromide, oxitropium bromide or ipratropium bromide, optionally in the form of their tautomers, enantiomers, mixtures of enantiomers, racemates, solvates or hydrates.

6. A pharmaceutical formulation according to any one of claims 1 to 4, wherein the pharmacologically acceptable acid is selected from the inorganic acids hydrochloric acid, phosphoric acid, hydrobromic acid, nitric acid and sulfuric acid or from the organic acids 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.

7. A pharmaceutical formulation according to any one of claims 1 to 5, characterized by a pH of 2.0 to 6.5.

8. A pharmaceutical formulation according to any one of claims 1 to 7, characterized in that the content of 1 ¹ , 2 and 3.1 ^{1 is} independently from each other about 0.5 to 6000 mg per 100 ml solution.

9. A pharmaceutical formulation according to any one of claims 1 to 9, characterized in that they contain a complexing agent as further pharmacologically acceptable excipient.

10. Medicament formulation according to claim 9, characterized in that the content of complexing agent is 0.1 to 200 mg per 100 ml of solution.

11. A pharmaceutical formulation according to any one of claims 1 to 10, characterized in that it contains as an additional pharmacologically acceptable excipient an antioxidant.

12. A pharmaceutical formulation according to any one of claims 1 to 11, characterized in that it is selected as another pharmacologically acceptable excipient an antioxidant selected from the group consisting of ascorbic acid, propyl gallate, butylated hydroxyanisole, butylated hydroxytoluene, tert-butylhydroxyquinone, tris (2,4-di-tert - butylphenyl) phosphite and tetrakis [methylene (3,4-di-tert-butylhydroxyhydrocinnamate)] methane, tocopherol, naringenin and resveratrol.

13. A pharmaceutical formulation according to any one of claims 1 to 12, characterized in that they contain as solvent a mixture of water and ethanol.

14. A pharmaceutical formulation according to any one of claims 1 to 13, characterized in that they contain as co-solvent benzyl alcohol, γ-butyrolactone or diethylene glycol monoethyl ether.

15. A pharmaceutical formulation according to claim 13, characterized in that it contains as solvent a mixture of water and ethanol, in which the percentage volume fraction of ethanol in the range between 30 and 99% ethanol.

16. Pharmaceutical formulation containing as active ingredient a free base of formula Y.

wherein the radicals R ¹ , R ² and R ³ may have the meanings mentioned in claims 1 to 3, optionally in the form of their tautomers, enantiomers, mixtures of enantiomers, racemates, solvates or hydrates; 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 active compound 3 selected from the group consisting of tiotropium salts, oxitropium salts, flutropium salts, ipratropium salts, glycopyrronium salts and trospium salts, optionally in the form of their tautomers, enantiomers, mixtures of the enantiomers, racemates, solvates or hydrates, at least one pharmacologically acceptable acid, optionally further pharmacologically acceptable excipients, and as a solvent ethanol or a mixture of water and ethanol.

17. A pharmaceutical formulation according to claim 16, wherein the active ingredient 2 is selected from the group consisting of budesonide, ciclesonide or a metabolite thereof optionally in the form of their tautomers, enantiomers, mixtures of enantiomers, racemates, solvates or hydrates.

18. A pharmaceutical formulation according to claim 16, wherein the active ingredient 3 is selected from the group consisting of tiotropium bromide, oxitropium bromide or ipratropium bromide, optionally in the form of their tautomers, enantiomers, mixtures of enantiomers, racemates, solvates or hydrates.

19. Use of a pharmaceutical formulation according to any one of claims 1 to 18 for the manufacture of a medicament for the treatment of respiratory diseases.

20. An inhalation kit consisting of a pharmaceutical formulation according to any one of claims 1 to 18 and a suitable for nebulization of this pharmaceutical formulation inhaler.

21. Inhalation kit according to claim 20, wherein the inhaler is the Respimat ^® is.