WO2009095160A1

WO2009095160A1 - Nozzle and inhaler and method for producing a nozzle

Info

Publication number: WO2009095160A1
Application number: PCT/EP2009/000253
Authority: WO
Inventors: Stephen T. Dunne
Original assignee: Boehringer Ingelheim Pharma Gmbh & Co. Kg
Priority date: 2008-01-30
Filing date: 2009-01-16
Publication date: 2009-08-06
Also published as: GB0801619D0

Abstract

A nozzle (12), an inhaler (Fig.l) with a nozzle (12) and a method for producing a nozzle are proposed. The nozzle comprises a hole (21) formed in a flat plate (22) by laser drilling. The hole is tapered so that it widens towards the outlet side. The hole comprises a non-circular cross section and an inner sharp edge (28). This supports breaking up of the liquid flow into droplets.

Description

Nozzle and Inhaler and Method for Producing a Nozzle

The present invention relates to a nozzle according to the preamble of claim 1 , to an inhaler according to the preamble of claim 10 and to a method for producing a nozzle.

The present invention relates in particular to the dispensing of an inhalation formulation by means of a nozzle or an inhaler, preferably a gas free-metered dose inhaler.

US 2003/0075623 Al describes a nozzle with one or more nozzle outlets for the atomization of fluids. The nozzle consists of at least two plates which are connected together, possibly by a intermediate layer. At least a base plate has a grooved structure which connects an inlet to nozzle outlet(s). In one embodiment, two or more nozzle outlets are provided which are orientated in such a way that jets issuing from them impinge on one another. The nozzle is typically made from a silicon plate and a glass plate welded together to form the channels. A filter can be inbuilt.

The present invention relates in particular to active inhalers such as an inhaler sold under the brand name "Respimat" shown in its basic structure in WO 91/14468 Al and in a specific embodiment in WO 97/12687 Al (Figs. 6a, 6b). The inhaler has a reservoir for a fluid, which is to be atomised, and a pressure generator with a drive spring for delivering and atomising the fluid. The known inhaler comprises a nozzle with at least two holes for generating at least two impinging jets of the inhalation formulation to be dispensed.

When an inhalation formulation is dispensed, usually only small amounts are discharged. The inhalation formulation has to be atomised in a very defined manner into very fine particles or droplets. Therefore, the nozzle for generating fine jets of the inhalation formulation has to meet very close tolerances and comprises very fine openings or holes.

The known nozzles are difficult to produce and/or result in high manufactur- ing costs. Object of the present invention is to provide a nozzle for atomizing a fluid, in particular a liquid, and an inhaler with such a nozzle, and a method for producing a nozzle, wherein production is facilitated and/or low production costs are possible and/or better atomization can be achieved.

The above object is achieved by a nozzle according to claim 1, by an inhaler according to claim 10 or by a method according to claim 11. Preferred embodiments are subject of the subclaims.

Preferably, the nozzle comprises at least one hole that is tapered such that it widens towards its outlet side. This supports breaking up of the liquid flow into droplets and, thus, atomization. This can be realized easily and/or at low production costs.

Preferably, the nozzle comprises at least one hole comprising a sharp inner edge at its inlet side. This supports breaking up of the liquid flow into droplets and, thus, atomization. This can be realized easily and/or at low production costs.

Preferably, the nozzle comprises at least one hole having an irregular or non- circular cross section, in particular in the form of a square, a star or an oval. This supports breaking up of the liquid flow into droplets and, thus, atomization. This can be realized easily and/or at low production costs.

However, the hole may have any other shape of form.

Preferably, the nozzle is made from a flat plat, wherein at least one hole is formed in the plate by laser drilling. Preferably, any further machining step is not necessary. In particular the form of the plate is not changed. This allows very easy production and/or low production costs.

Two or more holes may be drilled forming parallel nozzles.

In particular, the plate has a thickness of less than 200 μm, preferably of about 10 to 100 μm. Preferably, the hole has a hydraulic diameter of 2 to 100 μm, in particular of 3 to 30 μm, more preferably between 5 and 10 μm.

5 Preferably, the nozzle is formed only by the plate, and/or made of only one single component or piece, e.g. the plate.

Thus, a simple construction of the nozzle can be achieved and/or low production costs are possible. Further, relatively easy production is possible even if i o close tolerances have to be met. The nozzle supports better atomization of the fluid or liquid, in particular of small amounts an inhalation formulation.

Further aspects, features, properties and advantages of the present invention are described in the claims and the subsequent description of a preferred 15 embodiment with reference to the drawing. There are shown in:

Fig. 1 a schematic section of an inhaler in the non-tensioned state;

Fig. 2 a schematic section, rotated by 90° compared with Fig. 1, of the

20 inhaler in the tensioned state;

Fig. 3 a schematic section of a nozzle of the inhaler; and

Fi. g 4 an upside view of the nozzle.

25

In the Figures, the same reference numbers are used for identical or similar parts, even if a repeated description is omitted. In particular identical or corresponding advantages and properties then also result or may be achieved. 0 Figs. 1 and 2 show an inhaler 1 according to the present invention for atomising an inhalation formulation 2 as an aerosol 14, particularly a highly effective pharmaceutical composition or the like, diagrammatically shown in a non-tensioned state (Fig. 1) and in a tensioned state (Fig. 2). 5 The term "aerosol" in this respect is not limited to an inhalation formulation in liquid from, but also encompasses powder formulations. The inhaler 1 is constructed in particular as a portable inhaler and preferably operates without propellant gas. Preferably, the inhaler 1 is portable, works only mechanically and/or is hand-held. However, the present invention may also be applied to inhalers 1 using a propellant, such as so-called MDIs (metered dose inhalers), a gas, such as compressed or liquefied gas or air, or the like, i.e. in particular to all kind of inhalers 1.

The inhalation formulation 2 is preferably a liquid, in particular a solution, suspension or suslution (mixture of solution and suspension), but can have any form and can be e.g. a powder or the like.

When the inhalation formulation 2, preferably a liquid, more particularly a pharmaceutical composition, is nebulised, an aerosol 14 is formed, which can be breathed in or inhaled by a user (not shown). Usually the inhaling is done at least once a day, more particularly several times a day, preferably at set intervals, depending on the complain from which the patient is suffering.

The inhaler 1 has in particular an insertable and preferably exchangeable con- tainer 3 containing the inhalation formulation 2. The container thus forms a reservoir for the inhalation formulation 2, which is to be nebulised. Preferably, the container 3 contains an amount of inhalation formulation 2 or active substance which is sufficient to provide up to 200 dosage units, for example, i.e. to allow up to 200 sprays or applications. A typical container 3, as dis- closed in WO 96/0601 I Al, holds a volume of about 2 to 10 ml.

The container 3 is substantially cylindrical or cartridge-shaped and once the inhaler 1 has been opened the container can be inserted therein from below and changed if desired. It is preferably of rigid construction, the inhalation formulation 2 in particular being held in a collapsible bag 4 in the container 3.

The inhaler 1 has a conveying means, such as a propellant, a pump, an air pump or any other pressure generator or compressed or liquefied gas, in particular a pump or pressure generator 5 for conveying gas, any other fluid and/or the inhalation formulation 2 and for nebulising the inhalation formulation 2, particularly in a preset and optionally adjustable dosage amount. The inhalation formulation 2 may be metered in the inhaler 1 as it is the case in the present embodiment or may be pre-metered in an appropriate storage means, such as a blister with multiple blister pockets or the like.

In the present embodiment, the pressure generator 5 has preferably a holder 6 for the container 3, an associated drive spring 7, only partly shown, with a locking element 8 which can be manually operated to release it, a conveying member, preferably a conveying tube 9, a non-return valve 10 and/or a pres- sure chamber 11. The inhaler 1 comprises further nozzle 12 preferably in the region of a mouthpiece 13. The nozzle 12 will be described later in more detail. The container 3 is fixed in the inhaler 1 via the holder 6 such that the conveying tube 9 penetrates into the container 3. The holder 6 may be constructed so that the container 3 is able to be exchanged.

As the drive spring 7 is axially tensioned the holder 6 with the container 3 and the conveying tube 9 is moved downwards in the drawings, and the inhalation formulation 2 is sucked out of the container 3 into the pressure chamber 11 of the pressure generator 5 through the non-return valve 10. Preferably, the valve 10 is attached to or formed by the conveying tube 9.

After actuation of the locking element 8 the inhalation formulation 2 in the pressure chamber 11 is put under pressure as the conveying tube 9 with its now closed non-return valve 10 is moved back upwards by the relaxation of the drive spring 7 and now acts as a pressing ram or piston. This pressure forces the inhalation formulation 2 through the expulsion or dispensing nozzle 12, whereupon the formulation 2 is nebulised into an aerosol 14, as shown in Fig. 1.

Preferably the inhaler 1 may have a spring pressure of 5 to 200 MPa, preferably 10 to 100 MPa on the fluid, and/or a volume of fluid delivered per stroke of 5 to 100 μl, preferably 10 to 30 μl, most preferably about 15 μl. The fluid is converted into the aerosol 14 the droplets of which have an aerodynamic diameter of up to 20 μm, preferably 3 to 10 μm. The nozzle 12 has preferably a spray angle of 20° to 160°, preferably 80° to 100°. A user (not shown) can inhale the aerosol 14, while an air supply is sucked into the mouthpiece 13 through preferably at least one air supply opening 15, preferably multiple air supply openings 15. Thus, a bypass is formed so that ambient air can be sucked into the mouthpiece 13.

The inhaler 1 comprises preferably an upper housing part 16 and an inner part

17 which is rotatable relative thereto (Fig. 2) having an upper part 17a and a lower part 17b (Fig. 1), while an in particular manually operable housing part

18 is releasably fixed, particularly fitted onto the inner part 17, preferably by means of a retaining element 19. In order to insert and/or replace the container 3 the housing part 18 can be detached from the inhaler 1.

Fig. 3 shows in a very schematic sectional view (not in scale) the nozzle 12 in a prefered embodiment according to the present invention. This nozzle 12 is preferably mounted in or at the inhaler 1 previously described or any other inhaler 1. The mounting means are not shown. The nozzle 12 can be mounted e.g. by clamping or in any other suitable manner.

The nozzle 12 comprises at least one hole 21 for dispensing the fluid, i.e. the inhalation formulation 2. The fluid flow is indicated by arrow 20.

The nozzle 12 comprises a plate 22 which may be formed by any plate portion of a component not shown or the like or which may be a separate or the sole component of the nozzle 12.

The hole 21 is formed in the plate 22. Preferably, the hole 21 is formed by drilling, in particular laser drilling, or punching of the plate 22 or by any other suitable method.

Preferably, the hole 21 is formed in the flat plate 22.

The hole 21 is preferably formed such that its axis runs at least essentially perpendicular to the main plane of the plate 22.

The hole 21 is preferably tapered, in particular such that it widens towards the outlet side 24 of the nozzle 12 or plate 22. Thus, the diameter of the hole 21 is larger on its outlet side 24 than on the inlet side 25 of the nozzle 12 or plate 22. In particular, the holes 21 have a natural cone or taper angle 23. Preferably, the angle is about 10 to 70 degrees, in particular about 30 to 50 degrees.

The mean and/or hydraulic diameter 26 of the hole 21 is preferably about 2 to 50 μm, in particular about 5 to 30 μm.

The term "hydraulic diameter" shall be understood as the diameter of a circular cross section corresponding in areal size to an actual, in particular non- cirucular cross section.

The plate 22 is preferably made of metal, in particular of stainless steel, ceramic, silicon or a composite material. However, any other suitable material could be used as well.

The plate 22 is preferably thin. In particular it has a thickness 27 of less than 200 μm, preferably of about 10 to 100 μm, in particular about 10 to 50 μm.

The fluid (inhalation formulation 2) flows from the inner surface or inlet side 25 to the outer surface or outlet side 24 through the hole 21 in the direction of arrow 20.

The fluid flows in the opposite direction of the taper 23. This may support breaking up of the liquid flow into droplets.

The hole 21 comprises preferably an inner sharp edge 28 (entry edge). This may support breaking up the liquid flow into droplets and, thus, facilitate at- omization of the fluid.

The hole 21 may be round or not canted, in particular oval or circular in cross section. However, preferably, the hole 21 is irregular or non-circular or canted or irregular or polygonal in cross section, e.g. it may be at least essentially square or star shaped or have any other shape. This support breaking up of the liquid flow into droplets and, thus, atomization of the fluid. Some preferred ingredients and/or compositions of the preferably medicinal formulation 2 are listed below. As already mentioned, they are in particular powders or liquids in the broadest sense. Particularly preferably the formulation 2 contains the following:

The compounds listed below may be used in the device according to the invention on their own or in combination. In the compounds mentioned below, W is a pharmacologically active substance and is selected (for example) from among the betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine agonists, Hl -antihistamines, PAF-antagonists and PB -kinase inhibitors. Moreover, double or triple combinations of W may be combined and used in the device according to the invention. Combinations of W might be, for example:

- W denotes a betamimetic, combined with an anticholinergic, corticosteroid, PDE4-inhibitor, EGFR-inhibitor or LTD4-antagonist,

- W denotes an anticholinergic, combined with a betamimetic, corticosteroid, PDE4-inhibitor, EGFR-inhibitor or LTD4-antagonist,

- W denotes a corticosteroid, combined with a PDE4-inhibitor, EGFR- inhibitor or LTD4-antagonist - W denotes a PDE4-inhibitor, combined with an EGFR-inhibitor or LTD4- antagonist

- W denotes an EGFR-inhibitor, combined with an LTD4-antagonist.

The compounds used as betamimetics are preferably compounds selected from among albuterol, arformoterol, bambuterol, bitolterol, broxaterol, car- buterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproter- enol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmefamol, salmeterol, soterenol, sulphonterol, terbutaline, tiaramide, tolubuterol, zinterol, CHF-1035, HOKU-81, KUL-1248 and

- 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]- hexy loxy } -bury l)-benzy 1-sulphonamide

- 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 - l-(2-fluoro-4-hydroxyphenyl)-2-[4-(l-benzimidazolyl)-2-methyl-2- butylamino]ethanol

- l-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(l- benzimidazolyl)-2-methyl-2-butylamino]ethanol

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

- 1 -[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-l,4-benzoxazin-8-yl]-2-[3-(4-n- l o buty loxyphenyl)-2-methy 1-2-propy lamino]ethanol

- l-[2H-5-hydroxy-3-oxo-4H-l,4-benzoxazin-8-yl]-2-{4-[3-(4- methoxyphenyl)-l,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol

- 5-hydroxy-8-(l-hydroxy-2-isopropylaminobutyl)-2H-l,4-benzoxazin-3- (4H)-one

15 - l-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol

- 6-hydroxy-8-{ l-hydroxy-2-[2-(4-methoxy-pheny I)- 1,1 -dimethy 1- ethylamino]-ethyl}-4H-benzo[l,4]oxazin-3-one

- 6-hydroxy-8-{ l-hydroxy-2-[2-( ethyl 4-phenoxy-acetate)- 1, 1 -dimethy 1- ethy lamino] -ethyl } -4H-benzo[ 1 ,4] oxazin-3 -one 0 - 6-hydroxy-8-{ l-hydroxy-2-[2-(4-phenoxy-acetic acid)- 1,1 -dimethy 1- ethylamino]-ethyl}-4H-benzo[l,4]oxazin-3-one

- 8- {2-[ 1 , 1 -dimethy l-2-(2.4.6-trimethy lpheny l)-ethy lamino]- 1 -hydroxy- ethyl}-6-hydroxy-4H-benzo[l,4]oxazin-3-one

- 6-hydroxy-8-{ l-hydroxy-2-[2-(4-hydroxy-pheny I)- 1,1 -dimethy 1- 5 ethylamino]-ethyl}-4H-benzo[l,4]oxazin-3-one

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

- 8- { 2- [2-(4-ethy 1-pheny I)- 1 , 1 -dimethy 1-ethy lamino] - 1 -hy droxy-ethy 1 } -6- hydroxy-4H-benzo[ 1 ,4] oxazin-3 -one 0 - 8-{2-[2-(4-ethoxy -phenyl)- 1, 1 -dimethy 1-ethy lamino]- 1-hy droxy-ethy 1} -6- hydroxy-4H-benzo[ 1 ,4] oxazin-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 5 - 8-{2-[2-(3.4-difluoro-phenyl)- 1 , 1 -dimethyl-ethylamino]- 1-hydroxy-ethyl}- 6-hydroxy-4H-benzo[ 1 ,4]oxazin-3-one l-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert- butylamino)ethanol

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

- 8-hydroxy-5-(l-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)- phenyl]-ethylamino}-ethyl)-lH-quinolin-2-one 8-hydroxy-5-[l-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-lH- quinolin-2-one

- 5-[2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}- ethylamino)-l-hydroxy-ethyl]-8-hydroxy-lH-quinolin-2-one [3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-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-hydroxymethyl-phenyl)-ethylamino]- hexyloxy}-butyl)-benzylsulphonamide

- 3-(3-{7-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]- hepty loxy } -propy l)-benzy lsulphonamide

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

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

optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention the acid addition salts of the betamimetics are preferably selected from among the hydrochlo- ride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hy- dromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hy- drocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydro- benzoate and hydro-p-toluenesulphonate.

The anticholinergics used are preferably compounds selected from among the 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 above- mentioned salts the cations are the pharmacologically active constituents. As anions the above-mentioned salts may preferably contain the chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p- toluenesulphonate, while chloride, bromide, iodide, sulphate, methanesulphonate or p-toluenesulphonate are preferred as counter-ions. Of all the salts the chlorides, bromides, iodides and methanesulphonates are particularly preferred.

Other preferred anticholinergics are selected from among the salts of formula AC-I

wherein X ^~ denotes an anion with a single negative charge, preferably an anion selected from among the fluoride, chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate, preferably an anion with a single negative charge, particularly preferably an anion selected from among the fluoride, chloride, bromide, methanesulphonate and p- toluenesulphonate, particularly preferably bromide, optionally in the form of the racemates, enantiomers or hydrates thereof. Of particular importance are those pharmaceutical combinations which contain the enantiomers of formula AC-l-en

wherein X " may have the above-mentioned meanings. Other preferred anticholinergics are selected from the salts of formula AC-2

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

Other specified compounds are: tropenol 2,2-diphenylpropionate methobromide, scopine 2,2-diphenylpropionate methobromide, scopine 2-fluoro-2,2-diphenylacetate methobromide, tropenol 2-fluoro-2,2-diphenylacetate methobromide; tropenol 3,3',4,4'-tetrafluorobenzilate methobromide, scopine 3,3',4,4'-tetrafluorobenzilate methobromide, tropenol 4,4'-difluorobenzilate methobromide, scopine 4,4'-difluorobenzilate methobromide, tropenol 3,3'-difluorobenzilate methobromide, scopine 3,3'- difluorobenzilate methobromide; tropenol 9-hydroxy-fluorene-9-carboxylate methobromide; tropenol 9-fluoro-fluorene-9-carboxylate methobromide; scopine 9-hydroxy-fluorene-9- carboxylate methobromide; - scopine 9-fluoro-fluorene-9- carboxylate methobromide; tropenol 9-methyl-fluorene-9- carboxylate methobromide; scopine 9-methyl-fluorene-9- carboxylate methobromide; cyclopropyltropine benzilate methobromide; cyclopropyltropine 2,2-diphenylpropionate methobromide; - cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide; cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide; cyclopropyltropine 9-methyl-xanthene-9-carboxylate methobromide; cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide; cyclopropyltropine methyl 4,4'-difluorobenzilate methobromide. - tropenol 9-hydroxy-xanthene-9-carboxylate methobromide; scopine 9-hydroxy-xanthene-9-carboxylate methobromide; tropenol 9-methyl-xanthene-9-carboxylate -methobromide; scopine 9-methyl-xanthene-9-carboxylate -methobromide; tropenol 9-ethyl-xanthene-9-carboxylate methobromide; - tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide; scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide,

The above-mentioned compounds may also be used as salts within the scope of the present invention, wherein instead of the methobromide the salts metho- X are used, wherein X may have the meanings given hereinbefore for X^".

As corticosteroids it is preferable to use compounds selected from among be- clomethasone, betamethasone, budesonide, butixocort, ciclesonide, deflaza- cort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mome- tasone, prednisolone, prednisone, rofleponide, triamcinolone, RPR- 106541, NS- 126, ST-26 and

(S)-fluoromethyl 6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-l 1 -hydroxy - 16-methy 1-3-oxo-androsta- 1 ,4-diene- 17-carbothionate (S)-(2-oxo-tetrahydro-furan-3S-yl)6,9-difluoro- 1 1 -hydroxy- 16-methyl- 3-oxo- 17-propiony loxy-androsta- 1 ,4-diene- 17-carbothionate, cyanomethyl 6α,9α-difluoro-l lβ-hydroxy-16α-methyl-3-oxo-17α- (2,2,3, S-tertamethylcyclopropylcarbonyOoxy-androsta-l^-diene-πβ- carboxylate

optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the salts and derivatives thereof, the solvates and/or hydrates thereof. Any reference to steroids includes a reference to any salts or derivatives, hydrates or solvates thereof which may exist. Examples of possible salts and derivatives of the steroids may be: alkali metal salts, such as for example sodium or potassium salts, sulphobenzoates, phosphates, isoni- cotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.

PDE4-inhibitors which may be used are preferably compounds selected from among enprofyllin, theophyllin, roflumilast, ariflo (cilomilast), tofimilast, pu- mafentrin, lirimilast, arofyllin, 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-l-oxo-pyridin-4-yl)-4-difluoromethoxy-3- cyclopropylmethoxybenzamide

- (-)p-[(4αR*,10bS*)-9-ethoxy-l,2,3,4,4a, 10b-hexahydro-8-methoxy-2- methylbenzo[s][l,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide

- (R)-(+)-l-(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-l- carboxylic acid] - 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxy- pheny l)cy clohexan- 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]- 1,2,4- triazolo[4.3-a]pyridine - 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(terf-buty l)-9H-pyrazolo[3.4-c]- 1 ,2,4- triazolo[4.3-a]pyridine

optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts thereof, the solvates and/or hydrates thereof. According to the invention the acid addition salts of the betamimetics are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hy- drocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

The LTD4-antagonists used are preferably compounds selected from among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN- 91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321 and - l-(((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-yI)-(E)- etheny l)pheny l)-3-(2-( 1 -hydroxy- 1 -methy lethy l)pheny I)- propyl)thio)methyl)cyclopropaneacetic acid - [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid

optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof. According to the invention the acid addition salts of the betamimetics are preferably selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hy- drocitrate, hydrofiimarate, hydrotartrate, hydroxalate, hydrosuccinate, hydro- benzoate and hydro-p-toluenesulphonate. By salts or derivatives which the LTD4-antagonists may optionally be capable of forming are meant, for exam- ple: alkali metal salts, such as for example sodium or potassium salts, alkaline earth metal salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.

EGFR-inhibitors which may be used are preferably compounds selected from among cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and

- 4- [(3 -chloro-4-fluoropheny l)amino] -6- { [4-(morpholin-4-y I)- 1 -oxo-2- buten-l-yl]amino}-7-cyclopropylmethoxy-quinazoline

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

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

- 4-[(R)-( 1 -pheny 1-ethy l)amino]-6-{ [4-(morpholin-4-y I)- 1 -oxo-2-buten- 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-buten- l-yl]amino}-7-cy clopropylmethoxy- quinazoline

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo- moφholin-4-yl)-l-oxo-2-buten-l-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)-l-oxo-2-buten-l-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-methoxy-ethyl)-N- methy 1-amino]- 1 -oxo-2-buten- 1 -y 1 } amino)-7-cy clopropy lmethoxy- quinazoline

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

- 4-[(R)-(l-phenyl-ethyl)amino]-6-{[4-(N,N-to-(2-methoxy-ethyl)-amino)- 1 -oxo-2-buten- 1 -y l]amino} -7-cy clopropy lmethoxy-quinazoline

- 4-[(R)-(l-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl- amino]-l-oxo-2-buten-l-yl}amino)-7-cyclopropylmethoxy-quinazoline - 4-[(R)-(I -pheny l-ethyl)amino]-6-({4-[N-(2-methoxy-ethy l)-N-methyl- amino]-l-oxo-2-buten-l-yl}amino)-7-cyclopropy lmethoxy-quinazoline - 4-[(R)-(l-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl- amino]-l-oxo-2-buten-l-yl}amino)-7-cyclopropylmethoxy-quinazoline

- 4- [(3 -chloro-4-fluoropheny l)amino]-6- { [4-(N,N-dimethy lamino)- 1 -oxo-2- buten-l-yl]ammo}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline - 4- [(3 -chloro-4-fluoropheny l)amino] -6- { [4-(N,N-dimethy lamino)- 1 -oxo-2- buten- 1 -y 1] amino } -7-((S)-tetrahy drofuran-3 -y loxy )-quinazoline

- 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N- methyl-amino]-l-oxo-2-buten-l-yl}amino)-7-cyclopentyloxy-quinazoline

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

- 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethy lamino)- l-oxo-2- buten-l-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline

- 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)- l-oxo-2- buten-l-yl]amino}-7-[(S)-(tetrahydroruran-2-yl)methoxy]-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6.7-to-(2-methoxy-ethoxy)-quinazoline

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

- 4-[(R)-(I -phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3- djpyrimidine - 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)- 1 -oxo-2-buten- 1 -y l]amino}-7-ethoxy-quinoline

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

- 4-[(R)-(l-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-moφholin-4- y I)- 1 -oxo-2-buten- 1 -y l]amino} -7-methoxy-quinazoline

- 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-l-oxo-2- buten-l-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline

- 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-to-(2-methoxy-ethyl)- amino]-l-oxo-2-buten-l-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]- quinazoline

- 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-moφholin-4-yl)- 1 -oxo-2-buten- 1 -yljamino} -quinazoline

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

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-moφholin-4-yl)- piperidin- 1 -yl]-ethoxy }-7-methoxy-quinazoline

5 - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[l-(tert.-butyloxycarbonyl)- piperidin-4-yloxy]-7-methoxy-quinazoline

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-l- yloxy)-7-methoxy-quinazoline

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino- l o cyclohexan- 1 -y loxy )-7-methoxy-quinazoline

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

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

15 - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ l-[(morpholin-4-yl)carbonyl]- piperidin-4-yloxy}-7-methoxy-quinazoline

- 4- [(3 -chloro-4-fluoro-pheny l)amino] -6- { 1 - [(methoxy methy l)carbony 1] - piperidin-4-yloxy}-7-methoxy-quinazoline

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy- 0 quinazoline

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

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7- ethoxy-quinazoline 5 - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofiiran-3-yloxy)-7- hydroxy-quinazoline

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

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4- 0 [(dimethylamino)sulphonylamino]-cyclohexan-l-yloxy}-7-methoxy- quinazoline

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(moφholin-4- yl)carbonylamino]-cyclohexan-l-yloxy}-7-methoxy-quinazoline

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4- 5 yl)sulphonylamino]-cyclohexan-l-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- methanesulphonylamino-ethoxy)-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ l-[(piperidin-l-yl)carbonyl]- piperidin-4-y loxy } -7-methoxy-quinazoline

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(l-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-l-yloxy)-7-methoxy- quinazoline

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(moφholin-4- yl)carbonyl]-N-methyl-amino}-cyclohexan-l-yloxy)-7-methoxy- quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(moφholin-4- yl)sulphonyl]-N-methyl-amino}-cyclohexan-l-yloxy)-7-methoxy- quina- zoline

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino- cy clohexan- 1 -y loxy )-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(l-methanesulphonyl-piperidin-4- yloxy)-7-ethoxy-quinazoline

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(l-methanesulphonyl-piperidin-4- yloxy)-7-(2-methoxy-ethoxy)-quinazoline

- 4- [(3 -chloro-4-fluoro-pheny l)amino] -6- [ 1 -(2 -methoxy-acety l)-piperidin-4- yloxy]-7-(2-methoxy-ethoxy)-quinazoline

- 4-[(3-chloro-4-fluoro-pheny l)amino]-6-(cis-4-acetylamino-cyclohexan- 1 - yloxy)-7-methoxy-quinazoline

- 4-[(3-ethynyl-phenyl)amino]-6-[l-(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-[(piperidin-l- yl)carbonyl]-N-methyl-amino}-cyclohexan-l-yloxy)-7-methoxy- quinazoline - 4- [(3 -chloro-4-fluoro-pheny l)amino] -6-(cis-4- (N- [(4-methy 1-piperazin- 1 - yOcarbonylJ-N-methyl-aminoj-cyclohexan- 1 -yloxy)-7-methoxy- quinazoline

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4- y^carbonylaminoj-cyclohexan-l-yloxyl-T-methoxy-quinazoline

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

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ l-[(moφholin-4-yl)carbonyl]- piperidin-4-y loxy } -7-(2-methoxy-ethoxy )-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-(l-acetyl-piperidin-4-yloxy)-7-methoxy- quinazoline

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

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

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

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(l-isopropyloxycarbonyl-piperidin- 4-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methy lamino-cy clohexan- 1 - yloxy)-7-methoxy-quinazoline

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

- 4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-[l-(2-methoxy-acetyl)-piperidin-4-yloxy]-

7-methoxy-quinazoline

- 4-[(3-ethynyl-phenyl)amino]-6-{ l-[(morpholin-4-yl)carbonyl]-piperidin-4- yloxy} -7-methoxy-quinazoline

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

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ l-[(2-methyl-moφholin-4- yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

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

- 4- [(3 -chloro-4-fluoro-pheny l)amino] -6-( 1 -ethy l-piperidin-4-y loxy )-7- methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ l-[(2-methoxyethyl)carbonyl]- piperidin-4-yloxy}-7-methoxy-quinazoline

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ l-[(3-methoxypropyl-amino)- carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

- 4- [(3 -chloro-4-fluoro-pheny l)amino] -6- [cis-4-(N-methanesulphony 1-N- methyl-amino)-cyclohexan-l-yloxy]-7-methoxy-quinazoline

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)- cy clohexan- 1 -y loxy ]-7-methoxy-quinazoline

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan- 1 -y loxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N- methy l-amino)-cyclohexan- 1 -y loxy]-7-methoxy-quinazoline

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino- cyclohexan- 1 -y loxy)-7-methoxy-quinazoline

- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4- yl)carbonyl]-N-methyl-amino}-cy clohexan- 1 -yloxy)-7-methoxy- quinazoline

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

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

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

optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention the acid addition salts of the betamimetics are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hy- dromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hy- drocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydro- benzoate and hydro-p-toluenesulphonate. The dopamine agonists used are preferably compounds selected from among bromocriptin, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol, ropinirol, talipexol, tergurid and viozan, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention the acid addition salts of the be- tamimetics are preferably selected from among the hydrochloride, hydrobro- mide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydro fumarate, hydro- tartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p- toluenesulphonate.

Hl -Antihistamines which may be used are preferably compounds selected from among epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine, doxylamine, chlorophenoxam- ine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozine, optionally in the form of the racemates, enantiomers, di- astereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention the acid addition salts of the betamimetics are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hy- droacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

It is also possible to use inhalable macromolecules, as disclosed in EP 1 003 478 Al or CA 2297174 Al .

In addition, the compounds may come from the groups of ergot alkaloid derivatives, the triptans, the CGRP-inhibitors, the phosphodiesterase-V inhibitors, optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addi- tion salts, the solvates and/or hydrates thereof. Examples of ergot alkaloid derivatives are dihydroergotamine and ergotamine.

List of Reference Numbers

1 inhaler

2 inhalation formulation

3 container

4 bag

5 pressure generator

6 holder

7 drive spring

8 locking element

9 conveying tube

10 nonreturn valve

11 pressure chamber

12 nozzle

13 mouthpiece

14 aerosol

15 air supply opening

16 upper housing part

17 inner part

17a upper part of the inner part

17b lower part of the inner part

18 housing part (lower part)

19 retaining element

20 fluid flow

21 hole

22 plate

23 cone or taper angle

24 outlet side

25 inlet side

26 diameter of hole

27 thickness

28 edge

Claims

Claims:

1. Nozzle (12) with at least one hole (21) for dispensing a fluid, in particular an inhalation formulation (2), characterized in that the hole (21) is tapered such that it widens towards its outlet side (24), and/or that the hole (21) comprises a sharp inner edge (28) at its inlet side (25) and/or an irregular or non-circular cross section.

2. Nozzle according to claim 1, characterized in that the nozzle (12) comprises a plate (22) in which the at least one hole (21) is formed.

3. Nozzle according to claim 2, characterized in that the plate (22) is made of metal, in particular stainless steel, ceramic, silicon, a composite material or plastics.

4. Nozzle according to claim 2 or 3, characterized in that the plate (22) is thin, in particular has a thickness of less than 200 μm, preferably of about to 50 μm.

5. Nozzle according to one of claim 2 to 4, characterized in that the plate (22) is flat.

6. Nozzle according to one of the previous claims, characterized in that the hole (21) is formed by laser drilling.

7. Nozzle according to one of the previous claims, characterized in that the hole (21) has a hydraulic diameter of 2 to 50 μm, in particular of 3 to 40 μm, preferably between 5 and 130 μm.

8. Nozzle according to one of the previous claims, characterized in that the hole (21) is round or not canted, in particular at least essentially circular or oval.

9. Nozzle according to one of claims 1 to 7, characterized in that the hole (21) is canted, polygonal or irregular, in particular at least essentially square or star shaped.

10. Inhaler (1) for dispensing of an inhalation formulation (2) as an aerosol (14), comprising: a conveying means for conveying and/or nebulising the inhalation formulation (2) and a nozzle (12), characterized in that the nozzle (12) is formed according to one of the previous claims.

11. Method for producing a nozzle (12) from a flat plate (22), wherein at least one hole (21) is formed in the plate (22) by laser drilling.

12. Method according to claim 1 1, characterized in that the hole (21) is tapered such that it widens towards its outlet side (24).

13. Method according to claim 11 or 12, characterized in that the hole (21) is formed with a sharp inner edge (28) at its inlet side (25).

14. Method according to one of claims 11 to 13, characterized in that at least two holes (21) are formed such that axes (23) of the holes (21) intersect with each other at the outlet side (24).

15. Method according to one of claims 1 1 to 14, characterized in that the nozzle (12) is formed according to one of claims 1 to 9.