EP2167177A1

EP2167177A1 - Test device

Info

Publication number: EP2167177A1
Application number: EP08784928A
Authority: EP
Inventors: Herbert Wachtel
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 2007-07-20
Filing date: 2008-07-21
Publication date: 2010-03-31
Also published as: WO2009012961A1; CA2693898A1; DE102007033860A1; JP2010533523A; DE102007036412A1; US20100186747A1

Abstract

The invention relates to a device (1) for testing the seal between the lips of a user and a mouthpiece (10) during inhalation, wherein the mouthpiece is connected to an inhalation channel (11) provided with a first flowmeter (12), and the device has an escape air channel (21) which bears around the lips and which is provided with a second flowmeter (22).

Description

Tester

The invention relates to a device and a method for testing the tightness between the lips of a user and a mouthpiece during inhalation and to a use of such a device.

Inhaling drugs is becoming more and more important as systemic drugs are increasingly being delivered through the lungs. In order to ensure an optimal dosage of the drugs, different inhalers have been developed, which are suitable for the application of aerosol-shaped and / or powdered medicines. These are known ^® and / or in the documents DE 33 45 722, for example, under the brand names HandiHaler ^®, Spinhaler ^®, Rotahaler ^®, Aerolizer ^®, FlowCaps ^®, Turbo Spin ^®, AIR DPI ^®, Orbital ^®, Directhaler, EP 0591136, DE 43 18 455, WO

91/02558, FR-A-2 146 202, US-A-4 069 819, EP 666085, EP 869079, US 3,991,761, WO 99/45987, WO 200051672, Bell, J. Pharm. 60, 1559 (1971); Cox, Brit. Med. J. 2, 634 (1969). As powder inhalers, single or multi-dose powder inhalers are, in particular, the Spinhaler ^®, Rotahaler ^®, Aerolizer ^®, Inhalator ^®, Han diHaler ^®, Diskhaler ^®, Diskus ^®, Accuhaler ^®, Aerohaler ^®, Eclipse ^®, Turbuhaler ^®, Turbuha- ler ^®, Easyhaler ^®, Novolizer ^®, ^® CLICKHALER, Pulvinal ^®, Novolizer ^®, SkyeHaler ^®, ^® Xcelo- Vair, Pulvina ^®, ^® typhoon, MAGhaler ^®, ^® and the Twisthaler Jethaler ^® known.

For optimum dosing of the active substance, it has been shown in practice that the design of the mouthpiece of the inhaler plays a special role. If the mouthpiece is not ergonomically designed, there may be missed air during inhalation, which may adversely affect optimal dosing of the drug. In particular, in the case of powder inhalers with different inhalation resistance of the devices, it has surprisingly been found that no trend can be predicted with which the incorrect air is sucked in.

It is an object of the invention to provide a test device and a method and a use with which mouthpieces of an inhaler can be tested in practice in terms of their ergonomic design. The above object is achieved by a test apparatus according to claim 1 or a method according to claim 12 or a use according to claim 15. Advantageous developments are the subject of the dependent claims.

According to the invention, the object is achieved, in particular, in that the mouthpiece is connected to an inhalation channel, which has a first flow meter, and the device has a faulty air channel lying around the lips with a second flow meter.

Thus, during the inhalation process, the ratio between an air flow in the inhalation channel and a Fehlluftstrom in the false air duct can be determined quantitatively and from this a statement on the tightness of the mouthpiece between the mouthpiece of an inhaler and the patient's mouth can be derived under practical conditions.

Preferably, the leakage air channel surrounding the lips is formed by means of a mouth bell. Thus, the leakage air flow can be detected and collected, which arises due to leaks in the mouthpiece between the mouthpiece and the patient's mouth.

If the mouth bell has a bead-shaped area of flexible material, the mouth bell can optimally adapt to the area of the face of the patient's mouth. This ensures that the entire incorrect airflow can be detected and collected.

In order to vary a flow resistance in the inhalation channel, it is provided that the amount of air flowing into the inhalation channel can be reduced by means of a diaphragm. Thus, a different flow resistance, as it can occur with different inhalers and drug substances, can be simulated.

In a preferred embodiment, the diaphragm is designed as a perforated diaphragm which can be attached to the inhalation channel and has a different throughflow opening area or hole diameter. educated. This can be done very quickly adjustments to different inhalers or to different drugs.

Preferably, the flowmeters are constructed as thermal flow sensors, these each containing a platinum sensor which is heated to a constant temperature and the air flow is exposed, and each containing a temperature sensor. The passing air cools the platinum sensor in relation to the flow. The second sensor measures the air temperature and is used for temperature compensation. Such flowmeters are characterized by their fast Ansprechempfindlichkeit- and by a high accuracy. In addition, they have a relatively low pressure loss, so that the pressure conditions and thus also the flow conditions are hardly impaired, in particular in the case of the measuring task or test device according to the invention. Such flowmeters are known for example from TSI. These also have corresponding digital displays for the flow or can be connected directly to computer-aided evaluation systems for more complex evaluations.

In an embodiment, the test device has a distributor block with a coaxial clip on which the mouthpiece and the mouthpiece surrounding the mouthpiece can be interchangeably attached or screwed on. Mouthpiece and mouth bell can thus be easily replaced. The main air flow over the inhalation channel and the erroneous air flow through the incorrect air duct are supplied in the manifold block via the coaxial nozzle to the mouthpiece on the one hand and the mouth bell on the other hand.

The invention preferably provides for the use of the device in one of the previously described embodiments for testing the tightness of mouthpieces in inhalers for the application of aerosol-shaped and / or powdered medicaments. The device described above is used in particular for the objectification of the statement by means of a technical application study and can therefore contribute to the decision-making for an optimal ergonomic design of the mouthpiece.

It is understood that the above and to be explained below Characteristics can be used not only in the specified combination, but also in other combinations. The scope of the invention is defined only by the claims.

The invention will be explained in more detail below with reference to an embodiment with reference to the accompanying drawings. It shows:

1 shows a perspective view of the test device according to the invention,

2 shows a longitudinal section through the test apparatus of FIG. 1,

3 shows a front view of the testing device according to FIG. 1, FIG.

4 shows a rear view of the testing device according to FIG. 1.

The test apparatus 1 according to FIG. 1 comprises as main components or preferably a holder or distribution block 30 on which a mouth bell 20 (adapter) and a mouthpiece 10 are plugged or plugged. In the distribution block 30, the mouthpiece 10 is connected to an inhalation channel 11. The patient's mouth P (dashed lines in FIG. 2 and only schematically indicated) surrounding the mouth bell 20 is fluidically connected to a faulty air channel 21. The inhalation channel 11 and the incorrect air channel 21 preferably each have a flow meter 12, 22, which are preferably constructed as thermal flow sensors. In general, the flowmeters can also be designed in other ways and / or differently. For example, a throttle can be used for the flow measurement, wherein the pressure drop across the throttle is detected.

The mouthpiece 10 is connected to the inhalation channel 11 as shown in FIG. 2 and, in the flow direction on the input side, preferably has a restrictor or aperture 13, preferably in the form of an attachable or also screw-on apertured diaphragm. Thus, a flow resistance can be simulated, as it occurs in inhalers. By means of different plug-on pinhole diaphragms, which have different Durchströmöffnungsflächen, a quick adjustment can be made. The main air flow through the inhaler lationskanal 11 is determined by the flow meter 12.

Furthermore, the prevailing between the inhalation channel 1 1 and the surrounding Fehlluftkanal 21 pressure difference can be increased by means of a diaphragm 13.

Wrong air, which is sucked in as a result of a leak between the mouthpiece 10 and the patient's mouth P, is detected by means of the mouth bell 20 and flows through the total of the incorrect air passage 21, so that the total false air can be determined by the flow meter 22. The design of the mouth bell 20 is such that it seals the face of the patient in the mouth area. It can be provided that the mouth bell has a bead-shaped region made of a flexible elastomer material, which optimally conforms to the facial area and thus leads to an optimal seal between the face and mouth bell 20.

In the distribution block 30, the different air flows during inhalation are separated or detected according to the inhalation channel 11 and the incorrect air channel 21.

A preferably provided coaxial nozzle 31 on the manifold block 30 receives both the mouthpiece 10 and the mouth bell 20. The mouthpiece 10 and the mouthpiece 10 surrounding the mouthpiece 20 can be designed to be plugged or screwed.

If necessary, the device 1 or the coaxial supports 31 may also have a preferably tubular connecting piece 32, as indicated in FIG. 2, on which the respective mouthpiece 10 to be tested is fastened or fastened. Alternatively, the connecting piece 32 may also form part of the mouthpiece 10 or be firmly connected beforehand with the mouthpiece 10 to be tested, so that then the connecting piece 32 with the mouthpiece 10 into the device 1 or the adapter 31 or distribution block 30th are pluggable. However, other constructive solutions are possible here.

As already explained, upstream of the mouthpiece 10 - here in the inhalation channel 11 - preferably the amount of air is detected, which is inhaled. This amount of air is also referred to as inhalation air. Further, preferably, the amount of incorrect air that is sucked in between the mouthpiece 10 and the patient's mouth P or laterally on the mouthpiece 10 during inhalation is detected as incorrect air. Preferably, the detection takes place in the incorrect air channel 21.

If in the present invention of flow measurement or air quantity or quantity is mentioned, either a volume flow or a mass flow - ie rates - or even total quantities can be detected. The term "flow measurement" is to be construed accordingly in particular accordingly. As an alternative or in addition, the total quantities which occur overall via one or more inhalation processes can also be recorded or determined or evaluated from the rats.

The ratio of incorrect air to inhaled air or vice versa is particularly preferably determined or recorded or evaluated.

It is particularly preferred to record or evaluate how the aforementioned ratio or the incorrect air varies as a function of the inhalation resistance, which is particularly preferably adjustable by a throttle or the diaphragm 13.

The compounds mentioned below can be used alone or in combination for use in the device according to the invention. In the compounds listed below, W is a pharmacologically active agent and (for example) selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, HIV antihistamines, PAF antagonists and PI3 kinase inhibitors. Furthermore, two- or three-fold combinations of W can be combined and used for application in the device according to the invention. Exemplary combinations of W are: W represents a betamimetics combined with an anticholinergic, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists, W represents an anticholinergic agent combined with a betamimetics, corticosteroids, PDE4- Inhibitors, EGFR inhibitors or LTD4 antagonists, W represents a corticosteroid combined with a PDE4 inhibitor, EGFR inhibitor or LTD4 antagonist

W represents a PDE4 inhibitor combined with an EGFR inhibitor or LTD4 antagonist - W represents an EGFR inhibitor combined with a LTD4 antagonist.

Preferred betamimetics are compounds selected from the group consisting of albuterol, arformoterol, bambuterol, bitolertrol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine , Metaproterenol, orcprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmefamol, salmetrol, soterenol, sulphoneterol, terbutaline, tiaramide, toluubuterol, zinterol, CHF-1035, HOKU-81, KUL-1248 and

3- (4- {6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethyl-amino] -hexyloxy} -butyl) -benzyl-sulfonamide

5- [2- (5,6-diethyl-indan-2-ylamino) -l-hydroxy-ethyl] -8-hydroxy-lH-quinolin-2-one

4-hydroxy-7- [2 - {[2 - {[3- (2-phenylethoxy) propyl] sulphonyl} ethyl] amino} ethyl] -2 (3H) -benzothiazolone 1- (2-fluoro-4-) hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol - 1 - [3 - (4-methoxybenzylamino) -4-hydroxyphenyl] -2- [4- (1 benzimidazolyl l) -2-methyl-2-butylamino] ethanol 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino] ethanol

l- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol l- [2H- 5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino] ethanol

- 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -l, 2,4-triazole-3 -yl] -2-methyl-2-butylamino} ethanol - 5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1,4-benzoxazine-3- (4H) -one 1- (4- amino-3-chloro-5-trifluoromethylphenyl) -2-tert.-butylamino) ethanol 6-hydroxy-8- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethylethyamino] -ethyl} -4H-benzo [1,4-oxazine] 3-one

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

- 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-dimethylethylamino] ethyl} -4H-benzo [1,4] oxazin-3-one

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

- 8- {2- [2- (4-ethylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -one- 8- {2- [2- (4-Ethoxy-phenyl) -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 [l, 4] oxazin-8-yl) ethylamino] -2 methyl-propyl} -phenoxy) -butyric acid

- 8- {2- [2- (3,4-Difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -on- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert -butylamino) ethanol

2-Hydroxy-5- (1-hydroxy-2- {2- [4- (2-hydroxy-2-phenyl-ethylamino) -phenyl] -ethylamino} -ethyl) -benzaldehyde

N- [2-hydroxy-5- (1-hydroxy-2- {2- [4- (2-hydroxy-2-phenyl-ethylamino) -phenyl] -ethylamino} -ethyl) -phenyl] -formamide

8-Hydroxy-5- (1-hydroxy-2- {2- [4- (6-methoxy-biphenyl-3-ylamino) -phenyl] -ethylamino} -ethyl) -1 H-quinolin-2-one

8-Hydroxy-5- [1-hydroxy-2- (6-phenethylamino-hexylamino) -ethyl] -1H-quinolin-2-one 5 - [2- (2- {4- [4- (2-amino-) 2-methyl-propoxy) -phenylamino] -phenyl (1-ethylamino) -1-hydroxy-ethyl] -8-hydroxy-1H-quinolin-2-one

[3- (4- {6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -hexyloxy} -butyl) -5-methyl-phenyl] -urea - 4- (2- {6- [2- (2,6-dichloro-benzyloxy) -ethoxy] -hexylamino} -l-hydroxy-ethyl) -2-hydroxymethyl-phenol

3- (4- {6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -hexyloxy} -butyl) -benzylsulfonamide 3- (3- {7- [2-hydroxy -2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -heptyloxy} -propyl) -benzylsulfonamide

- 4- (2- {6- [4- (3-cyclopentanesulfonyl-phenyl) -butoxy] -hexylamino} -l-hydroxy-ethyl) -2-hydroxymethyl-phenol

N-adamantan-2-yl-2- (3- {2- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -propyl} -phenyl) -acetamide

optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate ,

Preferred anticholinergic compounds here are compounds which are selected from the group consisting of tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, glycopyrronium salts, preferably the bromide salt Trospium salts, preferably the chloride salt, tolterodine. In the aforementioned salts, the cations are the pharmacologically active ingredients. As anions, the abovementioned salts may preferably contain chloride, bromide, iodine, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate , Succinate, benzoate or p-toluenesulfonate, with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate being preferred as counterions. Of all the salts, the chlorides, bromides, iodides and methanesulfonates are particularly preferred. Likewise preferred anticholinergics are selected from the salts of the formula AC-I

wherein X ^"is a single negatively charged anion, preferably an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-Toluene sulfonate, preferably a singly negatively charged anion, more preferably an anion selected from the group consisting of fluoride, chloride, bromide, methanesulfonate and p-toluenesulfonate, most preferably bromide, optionally in the form of their racemates, enantiomers or hydrates. Of particular importance are those drug combinations which contain the enantiomers of the formula AC-I-ene

contain, wherein X ^{~ can have} the meanings given above. Further preferred anticholinergics are selected from the salts of the formula AC-2

in which R is either methyl or ethyl and in which X "can have the abovementioned meanings In an alternative embodiment, the compound of the formula AC-2 can also be present in the form of the free base AC-2-base.

Further named compounds are:

2,2-diphenylpropionic acid tropol ester methobromide 2,2-diphenylpropionic acid copoprene methobromide 2-fluoro-2,2-diphenylacetic acid copoprene methobromide

2-fluoro-2,2-diphenylacetic acid tropol ester methobromide

3,3 ', 4,4'-tetrafluorobenzylic acid tropol ester methobromide

3,3 ', 4,4'-tetrafluorobenzilate copoprene methobromide

4,4'-Difluorobenzilic acid-tropol ester-methobromide - 4,4'-difluorobenzilic acid copoprene methobromide

3,3'-Difluorobenzilic acid-tropol ester-methobromide 3,3'-difluorobenzilic acid copoprene-methobromide 9-hydroxy-fluorene-9-carboxylic acid-tropol ester-methobromide 9-fluoro-fluoren-9-carboxylic acid-tropol ester-methobromide - 9-hydroxy-fluorene-9-carboxylic acid-co-ester methobromide 9-fluoro-fluorene-9-carbonsäurescopinester methobromide

9-Methyl-fluorene-9-carboxylic acid-tropol ester-methobromide

9-methyl-fluorene-9-carboxylic acid copo-ester methobromide

Benzylic acid cyclopropyltropic ester methobromide 2,2-diphenylpropionic acid cyclopropyltropine ester methobromide

9-hydroxy-xanthene-9-carbonsäurecyclopropyltropinester methobromide

9-methyl-fluorene-9-carbonsäurecyclopropyltropinester methobromide

9-methyl-xanthene-9-carbonsäurecyclopropyltropinester methobromide 9-Hydroxy-fluorene-9-carboxylic acid cyclopropyltropine ester methobromide 4,4'-difluorobenzilate methylcyclopropyltropine ester methobromide 9-hydroxy-xanthene-9-carboxylic acid-tropol ester-methobromide 9-hydroxy-xanthene-9-carboxylic acid-co-ester methobromide - 9-methyl-xanthene-9 -carboxylic acid-tropol ester-methobromide 9-methyl-xanthene-9-carboxylic acid-co-ester methobromide 9-ethyl-xanthene-9-carboxylic acid-tropol ester-methobromide 9-difluoromethyl-xanthene-9-carboxylic acid-tropol ester-methobromide 9-hydroxymethyl-xanthene-9-carboxylic acid-co-ester methobromide The above In the context of the present invention, these compounds can also be used as salts in which, instead of the methobromide, the salts Metho-X are used, where X may have the meanings given above for X ^" .

Preferred corticosteroids here are compounds selected from the group consisting of beclomethasone, betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone , RPR-106541, NS-126, ST-26 and 6,9-difluoro-17 - [(2-furanylcarbonyl) oxy] -1-hydroxy-16-methyl-3-oxo-androsta-1, 4- dien-17-carbothionic acid (S) -fluoromethyl ester

6,9-Difluoro-1 1 -hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionic acid (S) - (2-oxo-tetrahydrofuran-3S-yl ) cyanomethyl esters, όα-α-difluoro-1-hydroxy-1α-methyl-S-oxo-α-α-yl-1-yl-tert-methylcyclopropylcarbonyl) oxy-androsta-1,4-diene-17β-carboxylic acid, optionally in Form of their racemates, enantiomers or diastereomers and optionally in the form of their salts and derivatives, their solvates and / or hydrates. Any reference to steroids includes reference to their optional salts or derivatives, hydrates or solvates. Examples of possible salts and derivatives of the steroids can be: alkali metal salts, such as, for example, sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. Preferred PDE4 inhibitors are compounds selected from the group consisting of enprofylline, theophylline, roflumilast, arifloin (cilomilast), tofimilast, pumafentrin, lirimilast, arofylline, atizoram, D-4418, bay 198004, BY343, CP-325,366, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V-11294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and

N- (3,5-dichloro-1-oxo-pyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide

- (-) p - [(4αR *, 1 ObS *) - 9-ethoxy-1,2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo [s] [1,6] naphthyridine -6-yl] -N, N-diisopropylbenzamide (R) - (+) - 1- (4-bromobenzyl) -4 - [(3-cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone 3- (cyclopentyloxy-4 -methoxyphenyl) -1- (4-N '- [N-2-cyano-S-methylisothioureido] benzyl) -2-pyrrolidone

cis [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid]

2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane-1-one cis [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol] - (R) - (+) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene] acetate (S) - (-) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene] acetate 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3,4-c] -l, 2,4-triazolo [4, 3- a] pyridine

9-cyclopentyl-5,6-dihydro-7-ethyl-3 - (/ he / -butyl) -9H-pyrazolo [3,4-c] -l, 2,4-triazolo [4,3-a] pyridine optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts of the PDE4 inhibitors are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro p-toluenesulfonate. Preferred LTD4 antagonists here are compounds selected from the group consisting of montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078 , VUF-K-8707, L-733321 and

- 1 - (((R) - (3- (2- (6,7-Difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2-hydroxy-2-propyl) phenyl) thio) methylcyclopropane -acetic acid,

- l - (((l (R) -3 (3- (2- (2,3-dichlorothieno [3,2-b] pyridin-5-yl) - (E) -ethenyl) phenyl) -3- ( 2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropaneacetic acid

[2 - [[2- (4-tert-butyl-2-thiazolyl) -5-benzofuranyl] oxymethyl] phenyl] acetic acid, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate , Examples of salts or derivatives which the LTD4-antagonists are capable of forming include: alkali metal salts, such as, for example, sodium or potassium salts, alkaline earth salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogenphosphates, palmitates, pivalates or also furoate.

Preferred EGFR inhibitors are compounds selected from the group consisting of cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and

- 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (morpholin-4-yl) -1-oxo-2-butene-1-ylamino] -7-cyclopropylmethoxy-quinazoline

4- [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-diethylamino) -1-oxo-2-butene-1-yl] -amino} -7- cyclopropylmethoxy-quinazoline

- 4- [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy -quinazoline - 4 - [(R) - (1-phenyl-1-ethyl) amino] -6- {[4- (morpholin-4-yl) -1-oxo-2-butene-1-yl] amino} -7 - cyclopentyloxy-quinazoline

- 4- [(3-Chloro-4-fluoro-phenyl) amino] -6- {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo - 2-butene-1-yl-amino} -7-cyclopropylmethoxy-quinazoline

5 - 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2 -but-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] -quinazoline

- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -2-methoxymethyl-6-oxo-morpholin-4-yl]-1-oxo-2-ol butylen-yl] amino} -7-cyclopropylmethoxy-quinazoline

- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -o-7-methoxy -quinazoline

- 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -l-oxo-2-butene-1 - yl} amino) -7-cyclopropylmethoxyquinazoline

4- [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy quinazoline

15 - 4- [(R) - (1-phenylethyl) amino] -6- {[4- (N, N-bis (2-methoxyethyl) amino] -1-oxo-2- butene-1-yl] amino} -7-cyclopropylmethoxyquinazoline

- 4 - [(R) - (1-Phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxyethyl) -N-ethyl-amino] -l-oxo-2-butene 1 -y 1} amino) -7-cyclopropylmethoxy-quinazoline

4 - [(R) - (1-Phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -l-oxo-2-butene -l-yl} amino) -7-cyclopropylmethoxy-quinazoline

- 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methylamino] -1-oxo-2-butene l-yl} amino) -7-cyclopropylmethoxyquinazoline

4- [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - ((R) tetrahydrofuran-3-yloxy) quinazoline 25-4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-butene-1 - yl] amino} -7 - ((S) -tetrahydrofuran-3-yloxy) -quinazoline

4 - [(3-Chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -l-oxo-2-butene-1-yl } amino) -7-cyclopenty-loxy-quinazoline

4- [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N -cyclopropyl-1-N-methyl-1-amino) -1-oxo-2-30-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline

- 4- [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(R ) - (tetrahydrofuran-2-yl) methoxy] -quinazoline - 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(S. ) - (tetrahydrofuran-2-yl) methoxy] -quinazoline

- 4 - [(3-ethynylphenyl) amino] -6,7-bis (2-methoxy-ethoxy) -quinazoline 4 - [(3-chloro-4-fluorophenyl) -amino] -7- [3- ( phosphoryl-4-yl) -propyloxy] -6 - [(vinylcarbonyl) amino] quinazoline

- 4 - [(R) - (1-Phenyl-ethyl) -amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine 3-cyano-4 - [(3-chloro 4-fluoro-phenyl) -amino] -6 - {[4- (N, N-dimethylamino) -l-oxo-2-buten-1-yl] -amino} -7-ethoxy-quinoline 4 - {[3-chloro 4- (3-fluoro-benzyloxy) -phenyl] -ammo} -6- (5 - {[(2-methanesulfonyl-ethyl) -amino] -methyl} -furan-2-yl) -quinazoline

- 4- [(R) - (1-phenyl-1-ethyl) amino] -6- {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo -2-butene-1-yl-1-amino-7-methoxy-quinazoline

4- [(3-chloro-4-fluorophenyl) amino] -6- {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} - 7- [ (tetrahydrofuran-2-yl) methoxy] quinazoline - 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N, N-bis (2-methoxy-ethyl) -amino] -l-oxo-2-buten-1-yl} amino) -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline 4- [(3-ethynylphenyl) amino] -6- {[4- ( 5,5-dimethyl-2-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino} quinazoline

- 4- [(3-Chloro-4-fluoro-phenyl) amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline

- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] - 7 - [(R) - (tetrahydrofuran-2-yl) methoxy] -quinazoline

- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] - 6 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [4- (2-oxo-morpholin-4-yl) - piperidin-1-yl] ethoxy} -7-methoxy-quinazoline

- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline 4 - [(3-chloro-4-yl) 4-fluoro-phenyl) amino] -6- (trans-4-amino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline - 4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-3-oxy) -7-methoxy-quinazoline

- 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl] -piperidin-4-yl-oxy} -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(methoxymethyl) -carbonyl] -piperidin-4-yl-oxy} -7-methoxy-quinazoline

4- [(3-Chloro-4-fluoro-phenyl) amino] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline

- 4- [(3-Chloro-4-fluoro-phenyl) amino] -6- [1- (2-acyl-amino-ethyl) -piperidin-4-yloxy] -7-methoxy-quinazoline

4-[(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazoline 4 - [(3-chloro-4-fluoro-phenyl) -amino] - 6 - ((S) -tetrahydrofuran-3-yloxy) -7-hydroxyquinazoline 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2 -methoxyethoxy) quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(dimethylamino) sulfonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline

- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(morpholin-4-yl) carbonylamino] -cyclohexane-1-yloxy} -7-methoxy-quinazoline - 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(4-fluoro-4-yl) -sulfonylamino] -cyclohexane-1-yloxy} -7-methoxy-quinazoline

- 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-acetylamino-ethoxy) -quinazoline

- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylamino-ethoxy) -quinazoline

- 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1- (piperidin-1-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline

- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-aminocarbonylmethyl-piperidin-4-yloxy) -7-methoxy-quinazoline - 4- [(3-chloro-4-fluoro phenyl) amino] -6- (cis-4- {N - [(tetrahydropyran-4-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline - 4- [(3-chloro-4-fluoro-phenyl) amino] -6- (cis-4- {N- [(morpholin-4-yl) -carbonyl] -N-methyl-amino} -cyclohexane-1 yloxy) -7-methoxy-quinazoline

- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -sulfonyl] -N-methyl-amino} -cyclohexane 1 - yloxy) -7-methoxy-quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-ethanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-ethoxy-quinazoline 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline

- 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7- (2-methoxyethoxy) -quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (cis-4-acetylamino-cyclohexan-1-yloxy) -7-methoxy-quinazolin-4 - [(3-ethynyl-phenyl) -amino ] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline

- 4 - [(3-ethynylphenyl) amino] -6- (tetrahydropyran-4-yloxy) -7-methoxy-quinazoline

- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(piperidin-1-yl) -carbonyl] -N-methyl-amino} -cyclohexan-1-one yloxy) -7-methoxy-quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(4-methylpiperazin-1-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {cis-4 - [(4-methyl-4-yl) -carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline

- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [2- (2-oxopyrrolidin-1-yl) -ethyl] -piperidin-4-yloxy} -7-methoxy-quinazoline

- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7- (2-methoxyethoxy ) -quinazoline 4 - [(3-ethynyl-phenyl) -amino] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline

- 4 - [(3-ethynylphenyl) amino] -6- (1-methylpiperidin-4-yloxy) -7-methoxy-quinazoline-4- [(3-ethyl-1-phenyl) amino] -6 - (1-Methanesulfonyl-1-piperidin-4-yloxy) -7-methoxy-quinazoline 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methyl-piperidin-4-yloxy) -7 (2-methoxy-ethoxy) -quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-isopropyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline - 4- [(3-chloro-4-fluoro-pheny l) amino] -6- (cis-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4- [N- (2-methoxy-acetyl) -N-methyl-amino] -cyclohexan-1-yloxy} - 7-methoxy-quinazoline

- 4 - [(3-ethynylphenyl) amino] -6- (piperidin-4-yloxy) -7-methoxyquinazoline - 4- [(3-ethyl-1-phenyl) amino] -6- [1 - (2-methoxy-acetyl) -piperidin-4-yloxy] -7-methoxy-quinazoline

- 4 - [(3-ethynylphenyl) amino] -6- {1- (morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline

- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(cis-2,6-dimethyl-morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7 methoxy-quinazoline

- 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2-methyl-morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline

- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(S, S) - (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl ) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(N-methyl-N-2-methoxyethyl - amino) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-ethyl-piperidin-4-yloxy) -7-methoxy-quinazoline

4- [(3-Chloro-4-fluoro-phenyl) amino] -6- {1 - [(2-methoxyethyl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(3-methoxy-propyl-amino) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline

- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexane-1-yloxy] -7-methoxy-quinazoline - 4- [(3-Chloro-4-fluoro-phenyl) amino] -6- [cis-4- (N -acetyl-1-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy quinazoline - 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexane-1-yloxy] -7-methoxy-quinazoline - 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (trans-4-dimethylamino-cyclohexan-1-oxy) -7-methoxy-quinazoline

- 4- [(3-chloro-4-fluoro-phenyl) amino] -6- (trans-4- {N- [(4-fluoro-4-yl) carbonyl] -N-methyl-amino} -cyclohexane 1-oxy) -7-methoxy-quinazoline 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) - ethoxy] - 7 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline

- 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline

- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

Preferred dopamine agonists are compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viozan, optionally in the form of their racemates , Enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate. As Hl -Antihistaminika here preferably compounds are used, which are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, Cexchlorpheniramin, pheniramine, doxylamine , Chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclocine, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

As pharmaceutically active substances, substance formulations or mixtures of substances all inhalable compounds are used, such. also inhalable macromolecules, as disclosed in EP 1 003 478. Preferably, substances, substance formulations or substance mixtures are used for the treatment of respiratory diseases, which are used in the inhalation area.

Furthermore, the compound may be derived from the group of derivatives of ergot alkaloids, triptans, CGRP inhibitors, phosphodiesterase V inhibitors, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, their solvates and / or or hydrates.

As derivatives of ergot alkaloids: dihydroergotamine, ergotamine.

Claims

claims

1. A device (1) for testing the tightness between the lips of a user and a mouthpiece (10) during inhalation, characterized in that the mouthpiece (10) with an inhalation channel (11) of the device (1) is connected or connectable, the Preferably, a first flow meter (12), and in that the device (1) around the lips, in particular sealing, abutting or assignable incorrect air channel (21) or adapter with a second flow meter (22).

2. Apparatus according to claim 1, characterized in that the incorrect air channel (21) or adapter by means of a mouth bell (20) is formed or provided with or connected.

3. Apparatus according to claim 2, characterized in that the mouth bell (20) has a bead-shaped region of flexible material.

4. Device according to one of claims 1 to 3, characterized in that in the inhalation channel (11) inflowing amount of air, in particular by means of a diaphragm (13), reducible or throttled or variable.

5. Device according to one of claims 1 to 3, characterized in that between the inhalation channel (11) and the surrounding Fehlluftkanal (21) prevailing or occurring pressure difference by means of a diaphragm (13) can be increased.

6. Apparatus according to claim 4 or 5, characterized in that the diaphragm (13) as on the inhalation channel (11) attachable pinhole is formed with different Durchströmöffnungsfläche.

7. Device according to one of claims 1 to 6, characterized in that the flow measuring devices (12, 22) are constructed as thermal flow sensors, in particular wherein these each have a platinum sensor which is heated or heated to a constant temperature and the air flow is exposed, and each contain a temperature sensor.

8. Device according to one of claims 1 to 7, characterized in that the device (1) for releasable receiving or holding or connection with the mouthpiece to be tested (10) is formed.

9. Device according to one of claims 1 to 8, characterized in that the adapter or a mouth bell (20) surrounds the mouthpiece (10).

10. Device according to one of claims 1 to 9, characterized in that the device (1) for releasably holding or receiving the adapter or a mouth bell (20) is formed.

1 1. Device according to one of claims 1 to 10, characterized in that the device (1) has a distributor block (30) with a Koaxialstutzen (31), on which the mouthpiece (10) and a mouthpiece (10) surrounding the mouth bell (20) exchangeable plugged or screwed.

12. A method for testing the tightness between the lips or mouth (P) of a user and a mouthpiece (10) during inhalation, wherein air is inhaled through the mouthpiece (10) and preferably the amount of inhaled air upstream of the mouthpiece (10). is detected as inhalation air, wherein the amount is detected at the side of the mouthpiece (10) over-inhaled air as incorrect air.

13. The method according to claim 12, characterized in that the ratio of incorrect air to inhaled air or vice versa is determined or evaluated.

14. The method according to claim 12 or 13, characterized in that the inhalation resistance of the mouthpiece (10), in particular by means of a throttle, is varied or adjusted.

15. Use of the device according to one of claims 1 to 11 for testing the tightness of mouthpieces (10) in inhalers for the application of aerosol-shaped and / or powdered medicaments.