WO2009013190A1

WO2009013190A1 - Apparatus and method for determining the moisture content of a packaging material

Info

Publication number: WO2009013190A1
Application number: PCT/EP2008/059266
Authority: WO
Inventors: Eduard Balthes; Johannes Geser
Original assignee: Boehringer Ingelheim International Gmbh
Priority date: 2007-07-21
Filing date: 2008-07-16
Publication date: 2009-01-29

Abstract

An apparatus and a method for determining the moisture content of a packaging material (20) for pharmaceutical packaging, in particular blister packs, using the electrical conductivity of the packaging material (20) comprises at least two current electrodes (11/16) for introducing an electric current into the packaging material (20) and at least two measurement electrodes (13, 14) for tapping off an electrical voltage from the packaging material (20).

Description

Apparatus and method for determining the moisture content of a packaging material

The invention relates to a device for determining the moisture content of a packaging material for pharmaceutical packaging, in particular blisters and a method thereof.

The film containers or cavities of a blister packaging produced from the packaging material serve, among other things, as pharmaceutical packaging to protect pharmaceutical active ingredient formulations from environmental influences which may under certain circumstances influence the pharmaceutical quality of the active ingredient formulation. One of the factors determining the quality is the moisture acting on the active substance, which on the one hand can penetrate from the outside by permeation or originate from the packaging material itself and enters from the inner wall into the cavity. Since the blister packaging is well protected against permeation from the outside, moisture present in the cavity can not escape and lead to damage of the active ingredient. The moisture content of foils for the production of blister packaging must therefore be controlled and, if necessary, reduced by drying.

As a rule, the blister pack consists of a cover foil and a bottom foil, wherein the cavities are formed in the bottom foil. The cover film and the bottom film may be composed of one or more layers of different or the same materials. The cover sheet is z with the bottom sheet. B. sealed by gluing, welding or sealing sealed. The cover sheet and / or the carrier film is usually as

Metal and / or plastic and / or paper foil formed. These materials can be present in multiple layers. Typical metal foils include, for example, aluminum foils and aluminum composite foils made of aluminum and, for example, a plastic. As the material for the plastic films, polyvinyl chloride (PVC), cycloolefin copolymer (COC), polychlorotrifluoroethylene (PCFE), polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polycarbonate (PC), polyester (UP), polyacrylate , Polyamide (PA) or other plastics. Often, a blister consists of a cover foil made of aluminum, which covers the bottom foil for receiving the pharmaceutical see product or drug closes. This deep-drawn bottom sheet may also comprise an aluminum foil to prevent the entry of water into the cavity for receiving the pharmaceutical product. To create a further diffusion barrier or to increase the mechanical stability of the blister, optionally at least the aluminum foil of the bottom foil can be covered on one or both sides with further plastic and / or paper foils.

For use, in particular blister packs are provided with the following layer sequence. The cover sheet is made of aluminum and has a thickness of 10 to 80 o microns, preferably from 20 to 50 microns, in particular from 30 to 40 microns. The cover sheet is sealed by means of a heat sealing lacquer to the bottom foil containing the cavities. The bottom film consists on the product-contacting side of a PVC, PP, PE layer o. Ä. with a thickness between 10 and 200 micrometers, preferably between 15 and 50 micrometers, in particular between 20 and 40 micrometers. This film is bonded to an aluminum foil whose thickness is preferably 30 to 60 micrometers, advantageously 35 to 50 micrometers. The aluminum foil is followed by a polyamide film having a thickness between 10 and 40 micrometers, preferably 15 to 30 micrometers. In an alternative bottom film, the PCV film on the side facing the product is replaced by a polypropylene film or the like. In a preferred blister packaging, the cover sheet consists of a 38 micron thick aluminum foil and the heat sealing lacquer. The bottom film is made on the side facing the pharmaceutical product from a 30 micron thick PVC Fo lie, an adjoining 45 micron thick aluminum foil and an outside 20 micron thick polyamide film. 5

It is an object of the invention to provide an apparatus and a method which makes it possible to determine the moisture content of films for the production of packaging, such as blister packs, for pharmaceutical products. The object is achieved according to the invention by a device for determining the moisture content of a packaging material for pharmaceutical packaging, in particular blisters, by means of the electrical conductivity of the packaging material, which line of an electrical current in the packaging material comprises at least two current electrodes and for tapping an electrical voltage from the packaging material at least two measuring electrodes.

By this embodiment of a moisture determination by measuring or determining the electrical conductivity or the surface resistance of the packaging material, which comprises in particular at least one plastic film, the influence of the contact resistance between the current electrodes and the measuring electrodes and the packaging material can be switched off. A current of typically a few μA is introduced via the current electrodes, whereby the voltage can assume an order of magnitude of 100 V. Since this is above safety extra-low voltage, a contact protection must be provided. Contact resistances on the current electrodes reduce the current introduced at a given voltage. Since the injected current in the device is measured, contact resistance can not affect the measured value.

At the measuring electrodes for tapping the electrical voltage, this is tapped with high impedance, whereby a relatively small current flows through the measuring electrodes and a relatively small voltage drop occurs, which could falsify the measured value. The electrode assembly can be chosen so compact that except flat packaging materials and packages curved shape, such as bottle necks, can be tested.

If the two measuring electrodes for tapping the electrical voltage are arranged on a connecting line between the current electrodes for introducing the electrical current, the conductivity or the sheet resistance of the packaging material and thus its moisture content can be calculated according to simple formulas known to the person skilled in the art.

A particularly simple case of determining the surface resistance is when the measuring electrodes are spaced apart to the same extent as to the nearest current electrode. In this case, the sheet resistance RF can be determined from the impressed current I and the measured voltage U to RF = (π / ln2) * (U / I). Conveniently, the measuring electrodes are arranged between the current electrodes. Preferably, both the current electrodes and the measuring electrodes are designed in the form of concentric rings. Due to these measures, anisotropy in the properties of the packaging material, eg. As in oriented polymers, not on the determination of sheet resistance.

If both current electrodes and measuring electrodes are arranged on both sides of the flat packaging material, then, in addition to the moisture content of the later side of the packaging material facing the product to be packaged, it is also possible to determine the moisture content of the later outer side of the packaging material. In this way, an expected moisture entry into an outer packaging, for example a so-called pouch bag, can be determined or at least estimated. Moisture determination on both sides of the packaging material is furthermore advantageous, since the two values should be the same in the equilibrium state and thus the measurement can be checked.

A substantial protection of the packaging material is achieved by the current electrodes and the measuring electrodes are pressed in a measuring phase to the packaging material and otherwise arranged spaced from the packaging material. Accordingly, a random measurement is possible and the surface touched by the electrodes during the moisture determination can be discharged, for example, from the further processing process.

For continuous measurement of the moisture content of a strip of packaging material, preferably the current electrodes and the measuring electrodes are designed as rollers.

In an embodiment, an insulating housing of a moisture sensor supports an insulation element for insulating the current electrodes and the measuring electrodes. The insulation element is adapted to the shape of the electrodes and absorbs them with play. Furthermore, the design of the humidity measuring head, which can be moved, for example, on a test station, provides safety against a short shot as well as inadvertent contact with the sensor. given electrodes.

Preferably, the insulation element is loaded with spring elements in the direction of the packaging material. The free, the packaging material in the measuring phase contacting ends of the electrodes are outside the measuring phase behind the packaging material facing surface of the insulating member, which is displaced when moving the moisture sensor in the direction of the packaging material against the action of the spring elements in the insulating until the ends of the electrodes rest on the packaging material.

For process control, preferably an evaluation unit which determines the electrical conductivity of the packaging material, a display and / or printing device, which represents the determined values, and a memory unit for detecting the values are provided.

Furthermore, the object is achieved according to the invention by a method for determining the moisture content of a packaging material for a pharmaceutical product, in particular blisters, by means of the electrical conductivity of the packaging material, wherein at least two current electrodes, an electric current passed through the packaging material and by means of at least two measuring electrodes Tension is tapped on the packaging material.

This method eliminates the influence of contact resistance and improves the accuracy of the measurement.

Preference is given to the current electrodes for generating the electric current

DC voltage and / or an AC voltage applied and / or the DC voltage and the AC voltage are applied in succession in succession. Thus, depending on the type of packaging material, a suitable for a reliable and accurate determination of the moisture signal waveform can be used. The use of AC voltage is particularly suitable for preventing electrostatic charging.

Protection against contact and an improvement in the safety of operating personnel is achieved by applying the DC voltage and / or the AC voltage when the current electrodes abut the packaging material. Since the voltage used to generate a sufficient current can be above safety low voltage, such a procedure is particularly suitable to improve the safety for the operator.

In an embodiment, the electrical voltage between the first measuring electrode and the second measuring electrode is determined in a calibration step on packaging material having a known moisture content. By measuring the moisture-dependent conductivity of the packaging material, the process can be adapted to different materials or their layers.

If the device and / or the method for determining the moisture content of packaging material for blister packs is used, the moisture entering the cavity of the blister pack can be estimated and optionally dried.

If the device and the method for controlling a film-drying device for drying packaging material used for blister packs, the moisture content can be effectively limited both in the direction of the cavity and in an outer packaging by targeted removal of residual moisture from the packaging material.

The invention will be explained in more detail below with reference to two exemplary embodiments with reference to the accompanying drawings. Show it:

Fig.l is a schematic side view of a device according to the invention for

Moisture analyzers

A schematic plan view of a device in an alternative embodiment.

According to FIG. 1, the device comprises a moisture measuring head 1 for determining the moisture of a packaging material 20, which is used as a bottom film for a blister pack for phar- serves pharmaceutical products and consists of a product facing inner layer 21, for example of PVC or PP, an aluminum layer 22 and an outer layer 23, for example, from oPA exists. In the present case, the moisture content of the inner layer 21 is determined, which is of primary importance, since the inner layer 21 faces, at least in sections, the pharmaceutical active substance received in cavities of the blister pack.

The moisture measuring head 1 comprises an insulating housing 10, at the underside facing the packaging material 20, current electrodes 11, 16 for introducing an electrical current into the packaging material 20 and measuring electrodes 13, 14 for tapping an electrical voltage from the packaging material 20 protrude from a corresponding recess. The current electrodes 11, 16 and the measuring electrodes 13, 14 are held in the top of the insulating housing 10 and connectable to a measuring device, not shown. The current electrodes 11, 16 and the measuring electrodes 13, 14 are arranged in openings of an insulating element 17, which is mounted circumferentially in the insulating housing 10 slidably. The insulation element 17 electrically separates the current electrodes 11, 16 and the measuring electrodes 13, 14 from each other and protects operating personnel from contact with the current electrodes 11, 16, which are at least temporarily under electrical voltage. 16, spring elements 12, 15 acting between the insulating housing 10 and the insulation element 17, that the insulating element 17 is immersed in the insulating housing 10 when the moisture measuring head 1 is pressed against the packaging material 20, whereby the current electrodes 11, 16 and the measuring electrodes 13, 14 with their respective free ends get electrical contact with the packaging material 20. If the moisture measuring head 1 is lifted off the packaging material 20, the spring elements 12, 15 press the insulating element 17 into the position shown in FIG. 1, in which the current electrodes 11, 16 and the measuring electrodes 13, 14 are largely protected against inadvertent contact. The insulation element 17 may be embodied in one piece or in several pieces, with the possibility of further spring elements 12, 15 being provided in the case of a multi-piece insulation element 17 in order to achieve the described protective effect.

The current electrodes 11, 16 and the measuring electrodes 13, 14 are in the illustrated embodiment leadership example arranged side by side at equal intervals. However, arrangements are also possible in which the current electrodes 11, 16 and the measuring electrodes 13, 14 are not arranged linearly and / or not equidistantly. The free end of the current electrodes 11, 16 and the measuring electrodes 13, 14 facing the packaging material 20 may be configured flat, curved or provided with one or more tips.

In operation, the current electrodes 11, 16 introduce an electrical current into the packaging material 20. The resulting voltage drop is tapped off with the measuring electrodes 13, 14 and fed to a high-impedance input voltage measuring device, not shown here. To carry out the process can be used AC or DC. Before a moisture determination, the arrangement can be calibrated by a measurement on packaging material 20 having a known moisture content.

The moisture measuring head 1 can be part of a portable measuring device that serves to determine the moisture content during a goods receipt inspection. It can be provided that a plurality of moisture measuring heads 1 are arranged for checking the upper and lower sides of packaging material 20 at several points of a production device.

According to FIG. 2, the moisture measuring head 1 comprises current electrodes 11, 16 and measuring electrodes 13, 14, which are designed in the form of concentric rings. The outside arranged current electrode 11 and the inside arranged current electrodes 16 are used to introduce the electrical current into the corresponding layer of the packaging material 20. By means of the interposed measuring electrodes 13, 14, the electrical voltage is tapped. The current electrodes 11, 16 and the measuring electrodes 13, 14 are pressed by recesses of the insulating member 17 to the packaging material 20, not shown here. The concentric alignment and the annular configuration of the current electrodes 11, 16 and the measuring electrodes 13, 14 has the effect that the orientation of an anisotropic packaging material 20 does not influence the measurement result in the moisture determination. 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 combinations of W can be combined and used for application in the device according to the invention. Exemplary combinations of W would be:

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

Preferred betamimetics are compounds which are selected from the group consisting of albuterol, arformoterol, bambuterol, bitoltrol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol,

Isoetharines, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmefamol, salmeterol, soterenol, sulphonterol, 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) -1-hydroxy-ethyl] -8-hydroxy-1H-quino-lin-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] ethano 1 1 - [3 - (4-Methoxybenzylamino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethano 1

1 - [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino] ethano 1

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

1 - [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) -1,2,4-o triazo 1 3 -yl] -2-methyl-2-butylamino} ethano 1

5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1,4-benzoxazine-3- (4H) -one 1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-tert , -butylamino) ethano 1 6-Hydroxy-8- {1-hydroxy-2- [2- (4-methoxyphenyl) -1,1-dimethylethylamino] ethyl} -4H-benzo [1,4] oxazine 3-one 5 - 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -l, 1-dimethyl-ethylamino] -ethyl} -4H-benzo [1, 4] oxazin-3-one

6-Hydroxy-8- {1-hydroxy-2- [2- (4-phenoxyacetic acid) -1,1-dimethylethylamino] ethyl} -4H-benzo [1,4-oxazin-3-one

8- {2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) ethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4-oxazine] 3-one

6-hydroxy-8- {1-hydroxy-2- [2- (4-hydroxyphenyl) -1,1-dimethyl-ethylamino] -ethyl} -

4H-benzo [l, 4] oxazin-3-one

6-hydroxy-8- {1-hydroxy-2- [2- (4-isopropylphenyl) -1,1-dimethyl-ethylamino] -ethyl} -

4H-Benzo [1,4] oxazin-3-one 5,8- (2- [2- (4-ethylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy 4H-benzo [l, 4] oxazin-3-one

8- (2- [2- (4-Ethoxy-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one

4- (4- {2- [2-hydroxy-2- (6-hydroxy-3-oxo-3,4-dihydro-2H-benzo [1,4-oxazin-8-yl) -o-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 l- (4-ethoxy-carbonylamino-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-methoxybiphenyl-3-ylamino) -phenyl] ethylamino} -ethyl) -1 H-quinoline-2-one

8-hydroxy-5 - [1-hydroxy-2- (6-phenethylamino-hexylamino) -ethyl] -1 H-quino-lin-2-one

5- [2- (2- {4- [4- (2-Amino-2-methyl-propoxy) -phenyl-amino] -phenyl} -ethyl-amino) -1-hydroxy-ethyl] -8-hydroxy-1H-quino lin-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} -1-hydroxy-ethyl) -2-hydroxymethyl-1-pheno-1-3- (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} -1-hydroxyethyl) -2-hydroxymethyl-1-pheno-1

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 preferably selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate,

Hydrofumarate, hydrotartrate, hydrooxalate, 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-Toluenesulfonate, 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

may have the above mentioned meanings wherein R is either methyl or ethyl and wherein X ^~. In an alternative embodiment, the compound of the formula AC-2 may also be present in the form of the free base AC-2-base.

Further named compounds are:

2,2-diphenylpropionate methobromide

2-fluoro-2,2-Diphenylessigsäurescopinester methobromide

2-fluoro-2,2-diphenylacetate methobromide

3,3 ', 4,4'-Tetrafluorbenzilsäuretropenolester methobromide 3,3 ', 4,4'-Tetrafluorbenzilsäurescopinester methobromide

4,4'-difluorobenzilate methobromide

4,4'-Difluorbenzilsäurescopinester methobromide

3,3'-Difluorobenzylic acid tropol ester methobromide - 3,3'-difluorobenzilic acid copoprene methobromide

9-hydroxy-fluorene-9-carbonsäuretropenolester methobromide

9-fluoro-fluorene-9-carbonsäuretropenolester methobromide

9-hydroxy-fluorene-9-carbonsäurescopinester methobromide

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

9-methyl-fluorene-9-carbonsäurescopinester methobromide

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

9-Hydroxy-xanthene-9-carboxylic acid cyclopropyl tropine ester methobromide - 9-methyl-fluorene-9-carboxylic acid cyclopropyl tropine ester methobromide

9-methyl-xanthene-9-carbonsäurecyclopropyltropinester methobromide

9-hydroxy-fluorene-9-carbonsäurecyclopropyltropinester methobromide

4,4'-Difluorbenzilsäuremethylestercyclopropyltropinester methobromide

9-Hydroxy-xanthene-9-carboxylic acid-tropol ester-methobromide - 9-hydroxy-xanthene-9-carboxylic acid-co-ester methobromide

9-methyl-xanthene-9-carbonsäuretropenolester methobromide

9-methyl-xanthene-9-carbonsäurescopinester methobromide

9-ethyl-xanthene-9-carbonsäuretropenolester methobromide

9-Difluoromethyl-xanthene-9-carboxylic acid-tropol ester-methobromide - 9-hydroxymethyl-xanthene-9-carboxylic acid-co-ester methobromide

The abovementioned compounds can also be used in the context of the present invention as salts in which, instead of the methobromide, the salts Metho-X are used, where X may have the meanings given above for X ^" .

As corticosteroids here preferably compounds are used, the are 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] -11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionic acid (S) -fluoromethyl ester

6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionic acid (S) - (2-oxo-tetrahydrofuran-3 S-yl ) ester,

- 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α- (2,2,3,3-tertamethylcyclopropylcarbonyl) oxy-androsta-1,4-diene-17β-cyanomethyl cyanamide optionally in the 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 may 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 here are compounds selected from the group consisting of enprofylline, theophylline, roflumilast, A-riflo (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 ^ OE) * 9-ethoxy-1,2 , 3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo [s] [1, 6] naphthyridin-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-methyl isothioureido] 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) cyclohexane-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] -1,4,4-triazolo [4,3-ajpyridine

9-cyclopentyl-5,6-dihydro-7-ethyl-3- (tert -butyl) -9H-pyrazolo [3,4-c] -1,4,4-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, hydro fumarate, hydrotartrate, hydrooxalate, 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-benzo-furanyl] -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 whose formation the LTD4 antagonists are capable of are: alkali metal salts, such as, for example, sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, Pivalate or 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-yl] amino} -

7-cyclopropylmethoxy-quinazoline

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

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

4 - [(R) - (1-phenylethyl) 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) -l-oxo]

2-butene-1-yl] amino} -7-cy clopropylmethoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -l-oxo-

2-butene-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-butene - 1 -yl] amino} -7-cyclopropylmethoxy-quinazoline

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

7-methoxy-quinazoline

4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N- (2-methoxyethyl) -N-methylamino] -1-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 - 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - {[4- (N, N-bis (2-methoxy-ethyl) -amino] -l-oxo-2-butene 1 -ylamino} -7-cyclopropylmethoxy-quinazoline

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

5 - 4 - [(R) - (1-Phenyl-ethyl) -amino] -6- ({4- [N- (2-methoxy-ethyl) -N-methyl-amino]-1-oxo-2-butene - 1 -yl} amino) -7-cyclopropylmethoxy-quinazoline

4- [(R) - (1-phenylethyl) amino] -6- ({4- [N- (tetrahydropyran-4-yl) -N-methyl-amino] -1-oxo-2-butene-1 -yl} amino) -7-cyclopropylmethoxyquinazoline 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino)-1-oxo-2-butene-1 - o yljamino} -7 - ((R) -tetrahydrofuran-3-yloxy) quinazoline

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

4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N- (2-methoxyethyl) -N-methylamino] -1-oxo-2-butene-1-yl } amino) -7-cyclopentyloxy-quinazoline 5 - 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N-cyclopropyl-N-methyl-amino)-1-oxo-2-one] butene-1-ylamino] -7-cyclopentyloxy-quinazoline

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

4 - [(3-ethynyl-phenyl) amino] -6,7-bis- (2-methoxy-ethoxy) -quinazoline

4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (morpholin-4-yl) -propyloxy] -6 - [(vinylcarbonyl) amino] quinazoline

4 - [(R) - (1-phenylethyl) amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine 5 - 3-cyano-4 - [(3 chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino)-1-oxo-2-butene]

1 -yl] amino} -7-ethoxy-quinoline

4- {[3-Chloro-4- (3-fluoro-benzyloxy) -phenyl] -amino} -6- (5- {[(2-methanesulfonyl-ethyl) -amino] -methyl} -furan-2-yl) -quinazoline

- 4 - [(R) - (1-phenylethyl) amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl] -l-oxo-2-one 0-butene-1-ylamino] -7-methoxy-quinazoline

4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (morpholin-4-yl) -1-oxo-2-butene-1-ylamino} - 7- [(tetrahydrofuran-2- yl) methoxy] quinazole 4 - [(3-Chloro-4-fluorophenyl) amino] -6- ({4- [N, N-bis (2-methoxy-ethyl) -amino] -1-oxo-2-butene-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-butene-1-ylamino] - 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-oxo-morpholin-4-yl) -ethoxy] -

7- [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] - 6- [(S) - (tetrahydro furan-2-yl) methoxy] quinazole

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {2- [4- (2-oxo-morpholin-4-yl) -piperidin-1-yl] -ethoxy} -7-methoxy -chinazo lin

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazolin-4 - [(3-chloro 4-fluoro-phenyl) -amino] -6- (trans-4-amino-cyclohexane-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-ylxy) -7-methoxy-quinazolin-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- (piperidine-3-oxy) -7-methoxy-quinazoline

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

4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazolin-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] -cyclohexane-1-yl-oxy} -7-methoxy-quinazolin-4 - [(3 -Chloro-4-fluoro-phenyl) -amino] -6- {trans-4- [(morpholin-4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline

4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- {trans-4- [(morpholin-4-yl) -sulfinylamino] -cyclohexan-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 - [(piperidine-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} -cyclohexane-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} -cyclohexan-1-yloxy ) -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-ethanesulfonylamino-cyclo-hexan-1-yloxy) -7-methoxy-quinazoline-4 - [(3-chloro-4- fluorophenyl) 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-methoxyethoxy) quinazoline

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

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-acetylamino-cyclo-hexan-1-yloxy) -7-methoxy-quinazoline 4 - [(3-ethynylphenyl) amino] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline

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

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

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(4-methylpiperazin-1-yl) carbonyl] -N-methylamino} -cyclohexane - 1-oxy) -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4 - [(morpholin-4-yl) carbonylamino] -cyclohexane-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-ethynylphenyl) amino] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazolin-4 - [(3-ethynyl-phenyl) -amino] -6- ( l-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline

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

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

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-methylamino-cyclohexane-1-ylxy) -7-methoxy-quinazoline

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

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

4 - [(3-ethynylphenyl) 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-methoxyquinazoline - 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-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methylamino-cyclohexane-1-yloxy) -7-methoxy-quinazoline

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

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

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

7- [(S) - (tetrahydro furan-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 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.

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 are preferably compounds 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. Preferred in accordance with 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 substance mixtures all inhalable compounds are used, such as, for example, inhalable macromolecules, as disclosed in EP 1 003 478. Preferably, substances, sub- Stamping formulations or substance mixtures used for the treatment of respiratory diseases, which are used in the inhalation field.

Furthermore, the compound may be derived from the group of derivatives of ergot alkaloids, the triptans, the CGRP inhibitors, the 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 hydrates.

As derivatives of ergot alkaloids: dihydroergotamine, ergotamine.

Claims

claims

1. Apparatus for determining the moisture content of a packaging material (20) for pharmaceutical packaging, in particular blisters, by means of the electrical conductivity of the packaging material (20), which is used to initiate an electrical

Current in the packaging material (20) at least two current electrodes (11, 16) and for tapping an electrical voltage from the packaging material (20) at least two measuring electrodes (13, 14).

2. Apparatus according to claim 1, characterized in that the two measuring electrodes (13, 14) for tapping the electrical voltage on a connecting line between the current electrodes (11, 16) are arranged for introducing the electric current.

3. Apparatus according to claim 1 or 2, characterized in that the measuring electrodes (13,14) are spaced apart to the same extent as to the respective nearest current electrode (11, 16).

4. Device according to one of claims 1 to 3, characterized in that the measuring electrodes (13, 14) between the current electrodes (11, 16) are arranged.

5. Apparatus according to claim 1 or 4, characterized in that both the current electrodes (11, 16) and the measuring electrodes (13, 14) are designed in the form of concentric rings.

6. Device according to one of claims 1 to 4, characterized in that both current electrodes (11, 16) and measuring electrodes (13, 14) are arranged on both sides of the sheet-like packaging material (20).

7. Device according to one of claims 1 to 5, characterized in that the current electrodes (11, 16) and the measuring electrodes (13, 14) pressed in a measuring phase to the packaging material (20) and otherwise arranged spaced from the packaging material (20) are.

8. The device according to claim 1, characterized in that the current electrodes (11, 16) and the measuring electrodes (13,14) are designed as rollers.

9. Device according to one of claims 1 to 6, characterized in that an insulating housing (10) of a moisture measuring head (1) an insulation element (17) for the insulation of the current electrodes (11, 16) and the measuring electrodes (13,14) superimposed.

10. The device according to claim 9, characterized in that the insulation element (17) is loaded with spring elements (12, 15) in the direction of the packaging material (20).

11. Device according to one of claims 1 to 10, characterized by an evaluation unit which determines the electrical conductivity of the packaging material (20) 5, a display and / or printing device, which represents the determined values, and a memory unit for detecting the Values.

12. A method for determining the moisture content of a packaging material (20) for a pharmaceutical product, in particular blisters, by means of the electrical conductivity of the packaging material (20), wherein at least two current electrodes (11, 16) an electric current through the packaging material ( 20) and by means of at least two measuring electrodes (13,14) an electrical voltage on the packaging material (20) is tapped.

13. The method according to claim 8, characterized in that to the current electrodes (11, 16) for generating the electric current, a DC voltage and / or an AC voltage is applied and / or the DC voltage and the AC voltage are applied in succession in succession. 14. The method according to any one of claims 8 or 9, characterized in that the DC voltage and / or the AC voltage is applied when the current electrodes (11, 16) abut the packaging material (20).

15. The method according to any one of claims 8 to 10, characterized in that in a calibration step on packaging material (20) having a known moisture content, the electrical voltage between the first measuring electrode (13) and the second measuring electrode (14) is determined.

16. Use of a device and / or a method according to one of the preceding claims for determining the moisture content of packaging material (20) for blister packs.

17. Use of a device and / or a method according to one of the preceding claims for controlling a film drying device for drying packaging material (20) for blister packs.