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    • 专利摘要:

    公开号:AU2008280193A1
    申请号:U2008280193
    申请日:2008-07-17
    公开日:2009-01-29
    发明作者:Heinrich Kladders；Torsten Kuehn；Rolf Kuhn；Burkhard Peter Metzger；Joern-Eric Schulz
    申请人:Boehringer Ingelheim International GmbH；
    IPC主号:A61M15-00
    专利说明:
    WO 2009/013218 PCT/EP2008/059388 Powder inhaler The invention relates to an inhaler with improved operability for inhaling powdered 5 medicaments from capsules that are inserted in a capsule holder arranged in the inhaler prior to use. After the capsules have been placed in the capsule holder, the patient can press an actuating member, which can be set in motion from a resting position and thereby interacts with at least one pin adapted to be pushed into the capsule holder. Using the minimum of one pin the capsule is pierced and the medicament is released. 10 An inhaler of this kind is described for example in EP 0 703 800 BI or EP 0 911 047 Al. The inhaler known from the above mentioned specifications has a dish-shaped lower part and an equally dish-shaped cover which fits it, these two parts being capable of being flipped apart for use, about a joint provided in the edge portion, Between the lower part 15 and the cover, a mouthpiece which can also be flipped open and a plate below it with a capsule holder provided underneath also act on the joint. After the individual assemblies have been flipped open the patient can insert a drug-filled capsule in the capsule holder, pivot the plate and capsule holder and the mouthpiece into the lower part and pierce the capsule by means of a spring loaded actuating member projecting laterally from the lower 20 part. The patient being treated then draws the pharmaceutical composition into his airway by sucking on the mouthpiece. The intention is to improve the known inhalers still further in terms of their handling. 25 This aim is achieved according to the invention with an inhaler in which the actuating member is enlarged and is constructed such that the pin holder is situated above the point of application of the force and below the suspension of the push-button. This results in a genuine reduction in the force required by the user to press the pin or pins 30 through the capsule wall In addition there is a subjective reduction in force for the user on account of the enlarged surface of the push-button compared with the devices known from the prior art. For an inhaler known from the prior art the user has to apply about 35 Newtons in order to pierce the capsule with the pin or pins using the actuating member. In WO 2009/013218 PCT/EP2008/059388 -2 the inhaler according to the invention, 10-25 Newtons, preferably 15-20 Newtons are required. The cover has an inwardly or outwardly extending bead, which is not externally visible. 5 This bead serves to close the cover at the button, which is located on the lower part of the inhaler. To enable the cover to be removed from the lower part the actuating member comprises on its upper side a recess which is inclined so as to form a sliding surface for the closure 10 element in the form of a sloping plane and to release the cover from the lower part on actuation and hence when the actuating member is advanced. The recess in the actuating member may vary in size. The minimum size must be sufficient to enable the cover to be released from the lower part in the manner of a pocket watch. The maximum size depends on the top of the actuating member. The actual opening movement of the cover can then 15 be carried out as before, by the patient grasping the cover and flipping it fully open. The mouthpiece that can be flipped away may be provided with one or two gripping aids that ensure quick and reliable opening of the mouthpiece. Each gripping aid may be arranged so that the contact with the mouthpiece is outside the area that the patient 20 requiring treatment has to place in his mouth for suction. The contact surface for opening and the contact surface for suction are clearly separated from one another by the shape and design of the mouthpiece. Preferably, the gripping aids are located to the left and right of the button and the two gripping aids do not converge in the region of the button. This gives the mouthpiece an optically and practically improved appearance that allows 25 intuitive handling for the user and at the same time provided optimum hygiene conditions. This is particularly important in the area around the mouthpiece, as this component is placed in the oral cavity when the inhaler is used. In one embodiment, to assist the opening movement, at least one other spring element may 30 be disposed between the plate and lower part, which are of suitable dimensions to allow the cover and/or mouthpiece to snap open. Alternatively, an embodiment without a spring element is also possible.
    WO 20091013218 PCT/EP2008/059388 -3 The actuating member is of particular importance at the start of an asthma attack. Thanks to the effective arrangement of the actuating member combined with the reduced force required from the patient the inhaler is significantly easier to operate. This is particularly valuable when patients are suffering from arthritis or similar diseases or have restricted 5 movement in their fingers for other reasons. The actuating member consists of a two-part construction, having an inner part and an outer part that are snap-fitted to one another. The inner part has two parallel guide arms (see below). When the actuating member is actuated, the outer part presses with a part of a 10 circle on the inner part, which then moves in a linear manner to push the pins into the capsule. The actuating member is attached to the plate that can be latched to the lower part. This can be done, for example, by means of snap-fit hooks, latching hooks or similar technical means. 15 Preferably the actuating member is displaceably mounted on the plate or capsule holder. The plate and/or the capsule holder thus form(s) an abutment for the multi-functional actuating member, which slides along the plate as it moves from the resting position into the desired functional position and is thereby guided by means of a guide rail, for example. 20 In a favourable embodiment the actuating member is spring-loaded. The restoring force which is already present in the resting position ensures that after the inhaler has been used the actuating member is returned to the resting position and thus the inhalation process can be started or continued. 25 Advantageously the actuating member comprises a main body and two parallel guide arms engaging thereon. The guide arms project into the lower part and by means of corresponding built-in parts, for example with guide sleeves arranged on the outside of the capsule holder, serve to guide the actuating member during the movement from the resting 30 position into the respective functional positions and back into the resting position.
    WO 2009/0 13218 PCT/EP2008/059388 -4 The guide arms may comprise end stops at their end remote from the main body, which abut on the guide sleeves in the resting position. In this way the actuating member is put under tension. 5 The guide arms may be of any desired shape and arrangement (e.g. convergent or divergent). In addition, more than two guide arms may be provided. In all, the actuating member has two abutment regions; one is for the inside of the button and the other is for the outside of the button. 10 In a preferred embodiment the main body of the actuating member may have a grooved surface. This grooved surface may be on the top or at the side. Preferably, the grooved surface will be in a gripping depression provided in the actuating member. The gripping surface acts both as a design element and as a means to provide optimum grip 15 during actuation. It is located on the main body of the actuating member outside the inhaler region and therefore does not come into contact with the patient's mouth. In addition, the grooved surfaces may be smaller in area than the overall surface of the actuating member while still guaranteeing safe and rapid use of the inhaler, 20 Advantageously the upper grooved surface in the resting position has a recess in its region close to the cover for accommodating the closure element of the cover. Within the recess the side wall directed towards the lateral grooved surface is inclined so that as the main body is pushed in, this side wall forms a sliding surface for the closure element and in this way the closure element together with the cover is lifted out of the latched position. 25 Advantageously the plate latched to the lower part can be detached from the lower part so that the plate can be pivoted away from the lower part. This pivot function makes cleaning of the inhaler easier. The engagement between plate and lower part can be achieved using the retaining flaps mentioned earlier. 30 It is also possible to construct the inhaler according to all the embodiments so that the actuating member having the minimum of one pin which can penetrate into the capsule holder is attached to the plate such that it can be released from the lower part and swivelled WO 2009/013218 PCT/EP2008/059388 away together with the plate latched to the lower part. Preferably, the actuating member is attached to the plate so that the two parts together form a pivotable unit. To assist in the understanding of the invention it will now be described more fully by 5 reference to the Figure (Figure 1) that follows, wherein: Fig. 1: is an exploded view with actuating member and mouthpiece with gripping aid 10 Fig. I shows the inhaler in an exploded view. The essential assemblies are the lower part 6 which accommodates the plate 3 and is covered by the latter, the mouthpiece 2 which can be latched to the lower part 6 via the retaining lugs of the screen housing 12 and the cover 15 1 which is formed to complement the lower part 6. In the closed position of the inhaler the closure element 14 on the cover I engages on the plate 3 and is held there by frictional engagement. It is also possible to obtain interlocking engagement by the provision of bead-like structures on the closure element 14. For the 20 closure element 14 on the cover 1 to engage on the plate 3, the outer actuating member 7 comprises a recess into which the closure element 14 is lowered during the closing operation. The recess is provided with an inclined side wall and is located in the area nearest the cover. 25 The actuating member consists of an outer actuating member 7 and an inner actuating member 10. In order to open the cover I first of all the outer actuating member 7 is moved or pressed in the direction of the inhaler. The closure element 14 on the cover I impacts the inclined side wall of the recess, which, as the closure element 14 continues to advance, acts as a sliding surface and ensures release of the cover 1. 30 The recess 16 connects the outer and inner actuating member 7, 10 by means of a suspension in the form of a snap-fit hook, pin or other suspension means, for example.
    WO 2009/013218 PCT/EP2008/059388 The suspension 16 may be round or oval in shape. The oval may be arranged in a horizontal or vertical position or in any position. Preferably, the recess 16 is a so-called oblong hole, i.e. an elongate hole which allows optimum guidance of the pin in the axial direction, so as to ensure precise piercing of the 5 capsule. The lower part 6 is cup-shaped and accommodates the whole of the capsule holder 5 arranged on the underside of the plate 3. However, in order to insert a capsule filled with medicament (not shown) in the capsule holder 5, the mouthpiece 2 must also be flipped out 10 of the way. In the embodiment according to Fig. 1 this is done by acting on the outer actuating member 7. In this opened position of the cover 1 and mouthpiece 2 the capsule can be placed in the capsule holder 5 through an opening in the plate 3. Then the mouthpiece 2 is swivelled 15 back again and closed again by latching the retaining lugs of the screen housing 12 in the plate 3. The screen housing 12 contains the screening mesh 13 in its centre, The screening mesh 13 is made of standard commercial materials such as metal or plastics, for example. In the latter case, the screen may be made by injection moulding. For releasing the active substance the outer actuating member 7 is actuated. Its construction is such that 20 the pin holder is located above the point of application of the force and below the suspension of the button, On the inner actuating member 10 there is at least one pin, but preferably two perpendicularly offset, parallel pins 8, 11, moving continuously as the actuating member 7, 10 is pushed in towards the capsule (not shown) and perforating it. The perforation process can be observed through an inspection window (not shown). 25 In the capsule holder 5 there is one or at least two tubular pin passages which are aligned axially in accordance with the direction of movement of the pin or pins 8, 11. On the one hand these ensure that the pin or pins 8, 11 are correctly aimed at the capsule (not shown) and on the other hand they provide additional guidance of the actuating member 7, 10. 30 However, the essential guiding is done by two guide arms 15 arranged laterally. The guide arms 15 also have the task of holding the actuating member 7, 10 under spring bias. For this purpose the guide arms 15 are provided at their end remote from the main body with end stops which abut on the guide sleeves of the capsule holder 5 in the resting position of WO 2009/013218 PCT/EP2008/059388 -7 the actuating member 7, 10. The guide sleeves are located on the outside of the capsule holder 5. Between the guide arms 15 is arranged a helical spring 9 which extends parallel to the pin or pins 8, 11 in its axial direction, the helical spring 9 being matched to the length of the guide arms 15 such that the actuating member 7, 10 is under tension even in 5 the resting position. The individual assemblies made up of the lower part 6, plate 3, mouthpiece 2 and cover 1 are connected by means of hinge recesses and a spindle 4 and are all movable or pivotable relative to one another about this spindle . 10 The pins used may be any pins known to the skilled man. They may be solid or hollow pins. Preferably, solid pins are used. In particular, the upper pin (facing the mouthpiece) may be a triangular pin with a triangular point. The lower pin may be a standard pin with a standard point, as laid down in the German DIN standard, for example. 15 Altematively the upper pin may be a standard pin with a standard point and the lower pin may be a triangular pin with a triangular point. As a second alternative it is possible to use two triangular pins with triangular points or two standard pins with standard points. 20 The capsules used may be any of the capsules known in the art for powder inhalers (such as (hard) gelatine, plastic or metal capsules). A plastic capsule, in particular, may be used in the inhaler according to the invention, as disclosed in WO 00/07572, EP 1 100 474. The inhaler may have an inspection window. However, this is not essential for it to 25 function in the intended manner. Similarly, all the components of the inhaler may be modified by methods known to the skilled man and according to the possibilities availability in plastics technology. Possible modifications include, for example, reinforcing or altering the wall thickness. However, 30 these possibilities are not absolutely essential to the operation of the inhaler. The inhaler may also be coated on its inside or outside by methods known in the art.
    WO 2009/013218 PCT/EP2008/059388 It may be used for the inhalation of all kinds of powdered medicaments which it is therapeutically advisable to administer by inhalation. The compounds listed below may be used in the device according to the invention on their 5 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, H1 -antihistamines, PAF-antagonists and P13-kinase inhibitors. Moreover, double or triple combinations of W may be combined and used in the device 10 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, 15 - 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. 20 The compounds used as betamimetics are preferably compounds selected from among albuterol, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmefamol, salmeterol, soterenol, sulphonterol, terbutaline, tiaramide, 25 tolubuterol, zinterol, CHF-1035, HOKU-81, KUL-1248 and - 3-(4- {6-[2-hydroxy-2-(4-hydroxy-3 -hydroxymethyl-phenyl)-ethyl amino] -hexyloxy) butyl)-benzyl-sulphonamide - 5-[2-(5 6-diethyl-indan-2-ylamino)- I -hydroxy-ethyl] -8-hydroxy- 1 H-quinolin-2-one - 4-hydroxy-7-[ 2- {[2- { [3 -(2-phenylethoxy)propyl] sulphonyl) ethyl]-amino} ethyl] 30 2(3H)-benzothiazolone - 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1 -benzimidazolyl)-2-methyl-2-butylarnino]ethanol - 1-[3-( 4 -inethoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1 -ben2imidazolyl)-2-methyl 2-butyl amino] ethanol WO 2009/013215 PCT!EP2008/059388 -1 -[2H-5 -hydroxy-3 -oxo-4-- 1 ,4-benzoxazin-8-yI] -2-[3-(4-N,N-dimethylaminophenyl) 2 -methyl-2-propylamino] ethanol - l-[2H-5-hydroxy-3 -oxo-4H- 1 ,4-berizoxazin-8-yl] -2-[3 -(4-methoxyphenyl)-2-methyl-2 propylamino] ethanol 5 - I -[2H-5-hydroxy-3 -oxo-4H-1I,4-benzoxazin-8 -yl]- 2 - [3 -(4-n-butyloxyphenyl) -2-methyl 2-propyl amino] ethanol - 1 -[2H-5-hydroxy-3-oxo-4-11,4-benzoxazin-8-yl]-2- {4-[3-(4-rnethoxyphenyl)- I ,2,4. triazol-3-yl]-2-methyl-2-butylamino }ethanol - 5 -hydroxy-8-( 1 -hydroxy-2-isopropylamrinobutyl)-2H- I ,4-benzoxazin-3 -(4H)-one 10 - I -(4-amino-3 -chloro-5 -trifluoromethylphenyl)-2-tert.-butylainino)ethanoI - 6-hydToxy-8- (I1 -hydroxy-2- r2-(4-methoxy-phenyl)- 1, 1 -dim ethyl -ethylaminol -ethyl)} 4H-benzo[ 1,4]oxazin-3 -one - 6-hydroxy-8- (1 -hydroxy-2-[2-( ethyl 4-phenoxy- acetate)- 1, 1 -dimethyl- ethyl amino] ethyl)} -4H-benzo[ [1,4]oxazin-3 -one 1 5 - 6-hydroxy-8- (1-hydroxy-2-[2-(4-phenoxy-acetic acid)- 1, 1 -dimethyl-ethyl amino] ethyl)} -4H-berizo[ I ,4]oxazin-3-one -8- { 2-[1.1 -dimethyl-2-(2 4,6-trirnethylphenyl)-ethylarnino] -1 -hydroxy-ethyl } hydroxy-4H4-benzo[ 1 ,4joxazin-3-oiie -6-hydroxy- 8- (1I -hydroxy-2-[2-(4-hydroxy-phenyl)-I I, -dimnethyl- ethylamino] -ethlyl 20 4H-benzo[ 1,4]oxazin-3-one -6-hydToxy-8- { 1 -hydroxy-2-(2-(4-isopropyl-phenyI)- 1. 1 dimethyl- ethyl amino) -ethyl) 4H-benzo[ 1,4]oxazin-3 -one -8- f{2-[2-(4-ethyl-phenyl)- I1,1I -dimethyl-ethylainino]- 1 -hydroxy-ethyl } -6-hydroxy-4H4 benzo[ 1,4]oxazin-3-one 25 - 8- f 2-[2-(4-ethoxy-phenyl)- 1, 1 -dimethyl-ethylarnino]- 1 -hydroxy-ethyl I -6-hydroxy-4H benzo( 1 ,4]oxazin-3-one - 4-(4- {2-[2-hydroxy-2-(6-hydroxy-3-oxo-3.A-dihydro-2H-benzo[ I ,4]oxazin-8-yl) ethyl arnino] -2-methyl -propyl}I -phenoxy)-butyric acid -8- {2-[2-(3 .4-difluoro-phenyl)- 1,1-dimnethyl-ethylamino -1l-hydroxy-ethyl)}-6-hydroxy 30 4H--benzo[ 1 ,4]oxazin-3 -one - (4-ethoxy-carbonyl amnino-3 -cyano -5 -fl uorophenyl)-2 -(tert-butyl amino) ethano I -2-hydToxy-5-(l1-hydroxy-2- {2-[4-(2-hydroxy-2-phenyl-ethyl amino)-phenyl] uthylamino) -ethyl) -b enz aldehyde WO 2009/013218 PCT/EP2008/059388 -10 - N-[2-hydroxy-5-(I -hydroxy-2- { 2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl] ethylamino }-ethyl)-phenyl]-formamide - 8-hydroxy-5-(1 -hydroxy-2- {2-[4-(6-methoxy-biphenyl-3 -ylamino)-phenyl) ethylamino}-ethyl)-l H-quinolin-2-one 5 - 8-hydroxy-5-[1 -hydroxy-2-(6-phenethylnamino-hexyl amino)-ethyl] -1 H-quinolin-2-one - 5-[22- {4- [4-(2-amino-2-methyl-propoxy)-phenylamino) -phenyl} -ethylamino)- I hydroxy-ethyl]-8-hydroxy- 1 H-quinolin-2-one - [3-(4- { 6-[2-hydroxy-2-(4-hydroxy-3 -hydroxynethyl-phenyl)-ethylamino] -hexyloxy) butyl)-5-methyl-phenyl]-urea 10 - 4-(2- {6-[2-(2.6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1 -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 -hydroxyrnethyl-phenyl)-ethylamino] -heptyloxy} 15 propyl)-benzylsulphonamide - 4-(2- (6- [4-(3 -cyclopentanesulphonyl-phenyl)-butoxy] -hexylamino} -1 -hydroxy-ethyl) 2-hydroxymethyl -phenol - N-Adamantan-2-yl-2-(3- {2-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-propyl} -phenyl)-acetamide 20 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, 25 hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate. The anticholinergics used are preferably compounds selected from among the tiotropium 30 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 phannacologically active WO 2009/013218 PCT/EP2008/059388 -11 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 5 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 00 X- HO - S 10 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, 15 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-i-en 20 ON O 0 O x- HO0 - s NS AC-i-en wherein X may have the above-mentioned meanings. Other preferred anticholinergics are selected from the salts of formula AC-2 WO 2009/013218 PCT/EP2008/059388 -12 H N AC-2 wherein R denotes either methyl or ethyl and wherein X - may have the above-mentioned 5 meanings. In an alternativen embodiment the compound of formula AC-2 may also be present in the form of the free base AC-2-base. H N AC-2-base 10 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; 15 - 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, 20 scopine 3,3'- difluorobenzilate methobromide; - tropenol 9-hydroxy-fluorene-9-carboxyl ate methobromide; tropenol 9-fluoro-fluorene-9-carboxylate methobromide; - scopine 9-hydroxy-fluorene-9- carboxylate methobromide; - scopine 9-fluoro-fluorene-9- carboxylate methobromide; WO 2009/013218 PCT/E 2008/059388 - 13 - tropenol 9-methyl-fluorene-9- carboxylate methobromide; - scopine 9-methyl-fluorene-9- carboxylate methobromide; - cyclopropyltropine benzilate methobromide; - cyclopropyltropine 2,2-diphenylpropionate methobromide; 5 - 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, 10 - 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; 15 - 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 20 may have the meanings given hereinbefore for X. As corticosteroids it is preferable to use compounds selected from among beclomethasone, betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, 25 rofleponide, triamcinolone, RPR-106541, NS-126, ST-26 and - (S)-fluoromethyl 6,9-difluoro- 1 7-f (2-furanylcarbonyl)oxy) -11 -hydroxy- 1 6-methyl-3 oxo-androsta- 1,4-diene- 1 7-carbothionate - (S)-(2-oxo-tetrahydro-furan-3S-yl) 6,9-difluoro- 11-hydroxy-16-methyl-3-oxo-17 propionyloxy-androsta- 1,4-diene- I 7-carbothionate, 30 - cyanomethyl 6d,9d-difluoro- 11p-hydroxy-166-nethyl-3-oxo-176-(2,2,3,3 tetranethylcyclopropylcarbonyl)oxy-androsta- 1,4-diene- 1 7-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 WO 2009/013218 PCT/EP2008/059388 - 14 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, isonicotinates, acetates, dichloroacetates, propionates, 5 dihydrogen phosphates, palmitates, pivalates or furoates. PDE4-inhibitors which may be used are preferably compounds selected from among enprofyllin, theophyllin, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, arofyllin, atizoram, D-4418, Bay-198004, BY343, CP-325.366, D-4396 (Sch-351591), 10 AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V- 1i294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and - N-(3,5-dichloro- I -oxo-pyridin-4-yl)-4-difluoromethoxy-3 cyclopropylmethoxybenzamide - (-)p-[(4aR*, 1 ObS *)-9-ethoxy- 1,2,3,4,4a, 10 b-hexahydro-8-methoxy-2 15 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)- I -(4-N'-[N-2-cyano-S-methyl isothioureido]benzyl)-2-pyrrolidone - cis [4-cyano-4-(3 -cyclopentyloxy-4-methoxyphenyl)cyclohexane- 1 -carboxylic acid] 20 - 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxy phenyl)cyclohexan- I-one - cis [4-cyano-4-(3 -cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan- 1-ol) - (R)-(+)-ethyl [4-(3 -cyclopentyloxy-4-methoxypbenyl)pyrrolidin-2-ylidene]acetate - (S)-(-)-ethyl(4-(3 -cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene] acetate 25 - 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-(tert-butyl)-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 30 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 PDE4 inhibitors are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, WO 2009/013218 PCT/EP2008/059388 - 15 hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate. The LTD4-antagonists used are preferably compounds selected from among montelukast, 5 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, - 1 -(((1(R)-3(3-(2-(2,3-dichlorothieno(3,2-blpyridin-5-yl)-(E)-ethenyl)pheny)-3-(2-(1 10 hydroxy- 1 -methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid - [2- [ [2-(4-tert-butyl-2-thiazolyl)-5 -benzofuranyl)oxymethy)phenyl] acetic acid optionally in the f6rm of the racemates, enantiomers or diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates andlor hydrates thereof According to the invention these acid addition salts are preferably 15 selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate. By salts or derivatives which the LTD4-antagonists may optionally be capable of forming are meant, for example: alkali metal salts, such as for 20 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 25 cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and - 4- [(3 -chloro-4-fluorophenyl)amino]-6- {{4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yl) amino } -7-cyclopropylmethoxy-quinazoline 4- [(3 -chloro-4-fluorophenyl) amino]-6- {[4-(N,N-diethylamnino)-1 -oxo-2-buten-1 -yl] amino} -7-cyclopropylmethoxy-quinazoline 30 - 4-[(3 -chloro-4-fluorophenyl)amino]-6- {[4-(N,N-dimethylamino)- 1 -oxo-2-buten- 1 yl]arnino) -7-cyclopropylmethoxy-quinazoline - 4-[(R)-(1 -phenyl-ethyl)amino]-6- { [4-(morpholin-4-yl)- 1 -cxo-2-buten- 1-yl]amino }-7 cyclopentyloxy-quinazoline WO 2009/013218 PCT/EP2008/059388 - 16 - 4-[ (3-chloro-4-fluoro-pbenyl)amino]-6- {[4-((R)-6-methyl-2-oxo-morpholin-4-yl)- I oxo-2-buten- 1 -yl]amino) -7-cyclopropylmethoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino] -6- {[4-((R)-6-methyl-2-oxo-morpholin-4-yl)- 1 oxo-2-buten-1-yl]amino) -7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline 5 - 4-[(3-chloro-4-fluoro-phenyl)amino]-6- ([4-((R)-2-methoxymethyl-6-oxo-morpholin-4 yl)-l -oxo-2-buten- 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-methoxy-ethyl)-N-methyl-amino]-1 10 oxo-2-buten- 1-yl) amino)-7-cyclopropylmethoxy-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)- 1 -oxo-2-buten- 1 yl]amino} -7-cyclopentyloxy-quinazoline - 4-[(R)-(1 -phenyl-ethyl)amino]-6- {[4-(N,N-bis-(2-methoxy-ethyl)-amino)- I -oxo-2 buten- l-yl] amino) -7-cyclopropylmethoxy-quinazoline 15 - 4-[(R)-(l -phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]- I -oxo-2 buten- l-yl) amino)-7-cyclopropylmethoxy-quinazoline - 4-[(R)-(1 -phenyl-ethyl)amino]-6-( 4- [N-(2-methoxy-ethyl)-N-methyl-amino]- I -oxo-2 buten- l-yl } amino)-7-cyclopropylmethoxy-quinazoline - 4-[(R)-(] -phenyl-ethyl)amino]-6-({4- [N-(tetrahydropyran-4-yl)-N-methyl-amino)- 1 20 oxo-2-buten-1-yl) amino)-7-cyclopropylmethoxy-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6- {[4-(N,N-dimethylamino)-1 -oxo-2-buten- 1 y1] amino) -7-((R)-tetrahydroffuran-3 -yloxy)-quinazoline - 4- [(3 -chloro-4-fluorophenyl)amino]-6- { [4-(N,N-dimethylamino)- 1 -oxo-2-buten- 1 ylJamino) -7-((S)-tetrahydrofuran-3-yloxy)-quinazoline 25 - 4- [(3 -chloro-4-fluorophenyl)amino]-6-(f{4-[N-(2-methoxy-ethyl)-N-methyl-amino) -1 oxo-2-buten- 1 -yl Iamino)-7-cyclopentyloxy-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino)-6- {[4-(N-cyclopropyl-N-methyl-amino)- 1 -oxo-2 buten- 1-yl] amino) -7-cyclopentyloxy-quinazoline - 4-((3 -chloro-4-fluorophenyl)amino] -6- { [4-(N,N-dimethylamino)- 1 -oxo-2-buten- 1 30 yl] amino) -7-[(R)-(tetrahydroffuran-2-yl)methoxy] -quinazoline - 4- [(3 -chloro-4-fluorophenyl)amino] -6- { (4-(NN-dimethylamino)- I -oxo-2-buten- I yl]amino) -7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline - 4-[(3-ethynyl-phenyl)ami no]-6.7-bis-(2-methoxy-ethoxy)-quinazoline WO 2009/013218 PCT/EP2008/05938 S -17 -4- [(3 -chloro-4-fluoropheny])amino] -7-[3 -(morpholin-4-yl)-propyloxy]-6- [(vinyl carbony]) amino] -quinazoline -4-[(R)-( I-phenyl-ethyl)amino) -6-(4-hydroxy-phenyl)-7}{-pyrrolo [2,3 -d]pyrimidine -3-cyano-4-[(3 -chloro-4-fluorophenyl)amino]-6- { [4-(IN,N-dimethylarnino)- I -oxo-2 5 buten- I -yI] amino I -7-ethoxy-quino line -4- f [3-chloro-4-(3 -fluoro-benzyloxy)-phenyl] amino I -6-(5-f{ [(2-methanesuiphonyl ethyl) aminolrnethyl) }-furan-2 -yl)quinazoline -4-IXR)-( 1-phenyl-ethyl)amino]-6- { [4-((R)-6-methyl-2-oxo-morpholin-4-y))- I -oxo-2 butcn- 1 -yl]amino} -7-methoxy-quinazo line 10 -4- [(3 -chl aro -4- fluorophenyl) amino] -6- { [4-(morpholin-4-yl)-I -oxo-2-buten- I1-yl3 amino)~ -7-[(tetrahychofuran-2-yl)mnethoxy]-quinazoline -4- [(3 -chloro-4- fluorophenyl) amino] -6-( {4-[N,N-bis-(2-methox y-ethyl). amino] - I -oxo 2-buten- I -yI }amino)-7- [(tetrahydroftiran-2-yl)methoxy] -quinazoline -4-[(3-cthynyl-phenyl)amino]-6- { [4-(5 .5-dimethyl-2-oxo-morpholin-4.yl)- 1 -oxo-2 15 buten- 1 -yI] amino)} -quinazoline - 4- [(3 -chl oro-4-fluoro-ph eny]) amino] -6- [2 -(2.2 -dimcthyl-6-oxo-morphol in -4-yl) ethoxyj -7-methoxy-quinazoline - 4-[(3 -chl oro -4-fluoro-phenyl) amino] -6- [ 2- (2.2 2-dimethyl -6-oxo-rnorphol in-4-yI) ethoxy] -7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline 20 -4-[(3 -Qbl oro -4-fluoro -pheniyl) amino] -7 -[2- (2.2 -dimethyl -6-oxo-morpholin-4-yl) ethoxy] -6-[(S )-(tetrahydrofuran-2-yJ )methoxy]-quinazoline 4 4- [(3 -chloro-4-fluoro-phenyl) amino] -6 -{2-[4-(2-oxo -morphol in-4-yl)-piperi din- 1 -y]] ethoxy) -7-methoxy-quinazoline -4- [(3 -chloro-4-fluoro-phenyl)amnino]-6-( I -(tert. -butyloxycarbonyl)-piperidin-4-yloxy) 25 7-rnethoxy-qumnazoline -4- [(3 -chl oro-4-fluoro-phenyl) amino] -6- (trans-4-amino- cyclohexan- 1 -yloxy) -7 methox y-quinazo line -[(3 -chl oro-4-fluoro-phenyl) amino] -6-(trans-4-methanesulphonyl amino- cyclohexan I -yloxy)-7-methoxy-quinazoline 30 -4- [(3 -chloro-4-flucoro-phenyI) amino) -6-(tetrahydropyran-3 -yloxy)-7-mcthoxy q uinazolime -4- [(3 -chloro-4-fluoro-phenyl)amino] -6-( 1 -methy1-piperidin-4-yloxy)-7-inethoxy quinazoline WO 2009/013218 PCT/ETP2008/059388 . 4- [(3-chloro-4-fluoro-pheniyl)amnino]-6- (1 -[(morpholin-4-yl)carbonyl)-piperidin-4-y oxy) -7 -methoxy-quinazoline - 4- [ (3 -chloro-4-fluoro-phenyl) amino] -6- (1 -[(methoxymethyl)carbonyl) -piperidin-4-yl oxy) -7-methoxy-quinazoline 5 - 4- [(3-chloro-4-fluoro-phenyl) amino] -6 -(piperidin- 3-yloxy)-7-methoxy-quinazo line - 4- [(3 -chloro -4-fluoro -phenyl) amino] -6- [1 -(2-acetyl amino-ethyl)-piperidin-4-yl oxy] -7 methoxy-quinazoline . 4- [ (3 -chloro-4- fluoro-phenyl) amino] -6-(tetrahydropyran-4-yl oxy)- 7-ethoxy quinazoline 10 - 4- [ (3 -chloro-4- fluoro-ph enyl) amino] -6-((S)-teTrahydro furan-3 -yloxy)-7 -hydrox y quin azo line - 4- [ (3 -ch loro-4- fluoro-phenyl) amino) -6-(tetrahydropyran -4-yloxy)-7 -(2-methoxy ethoxy)-quinazolinle - 4.[ (3 -chloro-.-fluoro -phenyl) amino] -6- (trans-4- [ (dirnethyl amino)sulphonyl amino] 15 cyclohexan- I -yloxy} -7-methoxy-quinazoline - 4- [(3 -chloro-4- fluoro-phenyl) amino] -6. {trans.4- [(morpholfin-4-y])carb onyl amino] cyclohexan- I -yloxy} -7-methoxy-quinazoline -4- [(3 -chloro-4-fluoro-phenyl) axinoj-6-. trans -4- ( (morpholin-4-yl) sulphonyl amino)] cyclohexan- I -yloxy -7-ttoxy-quinazohine 20 -4-f(3 -chloro-4-fluoro-phenyl)ainino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino ethoxy)-quinazoline -4- [ (3 -chloro-4- fluoro-pb enyl) amino] -6-(tetrahydropyran-4-yl oxy)-7- (2 methanesulphonylamino-ethoxy)-quinazoline -4- [(3 -chloro-4-fluoro-ph enyl) amino] -6- { 1 -{(piperidin- I -y])carbonyl ]-pip eridin-4 25 yloxy} -7-methoxy-quinazoline -4- [(3-chloro-4-fiuoro-phenyl)amino] -6-( 1 -aminocarbonylmethyl-piperidin-4-yloxy)-7 methoxy-quinazoline -4- [ (3 -cliloro-4- fluoro-phenyl) amino] -6 -(cis-4- {N- [(tetrahydropyran-4-yl)carbonyl] -N methyl -amino) -cyclohex an- I -yloxy)-7-methoxy-quinazoline 30 -4- [ (3 -ch loro-4-fluoro-phenyl) amino] -6 -(ci s-4- (N- [(morpholin-4-yl)carbonyl]-N methyl -amino) -cyclohexan- I -yloxy)-7-methoxy-quinazoline -4-[(3-chloro-.4-fluoro-phenyl)amino]-6-(cis-4- f{N-[(morpholin-4-yl)sulphonyl]-N m-ethyl-amino) -cyclohexan-1I-yloxy)-7-rnethoxy- quinazolirie WO 2009/1013218 PCT/EP2008)05938 -19 . 4- [(3 -chloro-4-fluoro-phenyl)arnino]-6-(trans-4-ethansulphony1amino-cyclohexan- I1 yloxy)- 7-methoxy-quinazo line - 4- [ (3 -chloro-4- fluoro-phenyl) amino] -6-(1I -methanesulphonyl-piperidin-4-yloxy)-7 ethoxy-quinazoline 5 -4-[(3 -chloro-4-fluoro-phenyl)arnino]-6-( I -methianesulphonyl-piperidin-4-yloxy)-7-(2 methoxy-ethoxy).-quinazoline - 4- [(3 -chloro-4-fluoro-pheny)axnino]-6-[ 1-(2-methoxy-acetyl)-piperidin-4-yloxy] -7-(2 nietho xy- ethoxy)-quinazo line - 4- [(3 -chloro-4- fluoro-phenyl) arino]-6-(cis-4-acetyl amino -cyclohex an- I -yloxy)-7 10 rnethoxy-quinazoline - 4- [(3 -ethynyl-phenyl)axnino] -6-( 1 -(tert.-buityloxycarbonyl)-piperidin-4-yloxy) -7 mctho xy-quinazo line - 4-[(3 -ethynyl-ph enyl)amino] -6-(tctrahydropyran-4-yloxyj -7-methoxy-quinazoline -4- [(3 -chloro-4. fluoro-ph enyl)amnino] ..6 .(cis 4- {N-[(piperidin- I -yl)carbonyfl-N-rnethyl 15 amino I -cyclohexan- 1 -y o xy) -7 -methoxy-qui nazo line 4* [(33-ch~oro-4- fluoro-phenyl) amino] .6 -(cis.4. {N- [(4-methy] -pip erazin- 1 -yl)carbonyl] N -methyl -amino) -c;yclohexan-1 -yloxy)-7-methoxy-quinazoline - 4- [(3 -chloro-4-fhioro-phenyl)amninoj-6- { cis-4- [(morpholin-4-yl)carbonyl amino] cyclohexan- I -yloxy} -7-niethoxy-qui-nazoline 20 - 440( -chl oro-4- fluoro-ph enyl) amino] -6- 1 -[2-(2-oxopy-rolidin- I -yl)ethyll-pipe-idin-4 yloxy) -7-methoxy-quinazoline - 4-[1(3 -chloro-4- fluoro-pheny]) amino] -6- { 1 -[(morpholin-4-y)caxbonyl] -piperidin-4 yl oxy} -7-(2-methoxy-ethoxy)-quinazoline - 4-[(3 -ethynyl-phenyl)amino]-6-( I -acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline 25 - 4-[(3 -ethynyl-phenyl)aminoj-6-( 1 -methyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4- [(3 -ethynyl-phenyl)amino]-6-( I -methanesulphonyl-piperidin-4-yloxy)-7-methoxy quinazoline - 4 -[ (3 -chloro-4- fluoro-phenyl) amino] -6 -(1I -methyl-piperidin-4-yloxy)-7(2-methoxy ethoxy)-quirxazoline 30 -4-[(3-cbloro-4-fluoro-phenyl)amino]-6-( I -isopropyloxycarbonyl-piperidin-4-yloxy)-7 metboxy-quinazoline *4- [(3 -chloro-4- fluoro-phenyl) amino] -6- (ci s-4-methyl amino -cyclollex an- I -yloxy)-7 methoxy-quiniazolirie WO 2009/013218 PCT/,EP2008/05938 B - 20.
    - 4- [(3 -chloro-4-fl'uoro-phenyl) amino] -6- { cis-4-[(N-(2-methoxy-acetyl)-N -m ethyl amino]-cyclohexan- 1 -yloxy) -7-methoxy-quinazoline - 4- [(3 -ethynyl-phenyl) amino] -6-(piperidin-4-yloxy) -7-methoxy-quin aZoline - 4- [(3 -ethynyl -phenyl) amino] -6-[1 -(2-methoxy- acetyl)-piperidin-4-yloxyj -7 -methoxy 5 quinazoline - 4-[(3 -ethynyI-pbenyl)amino]-6- (1 -[(morpholin-4-yl)carbonylj -piperidin-4-yloxy} -7 rnethoxy-quinazoline - 4- [(3 -ch Ioro -4- fluoro-phenyl) amino] -6- { 1 -[(cis-2,6-dimethyi-morpholin-4 yl)oarbonyl ]-piperidin-4-yloxy )-7-methoxy-quinazoline 10 - 4- [(3 -chloro-4-fluoro-pheny1)aminol-6- { I -((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 jhept-5 yl)carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl)amino] -6- { 1 -[(N-niethyl -N-2-methoxyethyl 15 arni no)carbonyl] -piperidin-4-yl oxy} -7-rnethoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)arnino]-6-( I -ethyl -piperi din-4-yloxy) -7 -mc thoxy quinazoline - 4- [(3 -chloro-4-fluoro-phenyl)amnino]-6- 1 -[(2-methoxyethyl)carbonyl] -piper-idinl-4 yloxy) -7-niethoxy-quinazo line 20 - 4- [(3 -chloro-4- fluoro -phenyl) amino) -6 -f 1- -[(3 -methoxyprop yl -amino)- carb onyl] piperidin-4-yloxy) -7-methoxy-quinazoline . 4- [(3 -chilore-4-fluoro-ph enyl) amino] -6- [ci s-4- (N-methanesulphonyl -N-m ethyl]-arnino) cyclohexan- 1 -yloxy] -7-methoxy-quinazoline - 4- ((3 -chloro-4-fluoro-phenyl)amninoj-6- [ci s-4-(N-acetyl-N-methyl-amino)-cyclohexan 25 1 -yl oxy] -7-rnethoxy-qui nazo line - 4- [(3 -chl oro -4-fluoro -phenyl) amino] -6-(trans -4-methyl amino-cyclohex an- I -yloxy)-7 methoxy-quinazoline - 4 -f(3 -chloro-4- fluoro-phenyl) amino] -6- [trans-4-(N -methanesulphonyl-N-methyl amino)- cyclohexan- I -yloxy] -7-methoxy-quinazoline 30 -4- [(3 -chloro-4-fluoro-phenyl) amino] -6-(trans-4-dimethylamino-cyclohexan- 1 -yloxy) 7-methoxy-quinazoline - 4- [(3 -chloro-4- fluoro-phenyl) amino) -6-(trans-4 - {N-[(morpholin-4-yl)carbonyl]-N methyl -amino) -cyclohexan- I -yloxy)-7 "methoxy-.quinazoline WO 2009/0132 18 PCT/EP2008/059388 -21 - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2.2-dimethyl-6-oxo-morpholin-4-yl) ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1 -methanesulphonyl-piperidin-4-yloxy)-7 methoxy-quinazoline 5 - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-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 these acid addition salts are preferably selected from 10 among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofurnarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p tol uenesulphonate. 15 The doparnine agonists used are preferably compounds selected from among bromocriptin, cabergoline, alpha-dihydroergocryptinc, 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 20 these acid addition salts are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate. 25 HI-Antihistamines which may be used are preferably compounds selected from among epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine, phenirainine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozine, optionally in the form of the 30 racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention these acid addition salts are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphaite, hydrophosphate, WO 2009/013218 PCT/EP2008/059388 - 22 hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p toluenesulphonate. 5 The pharmaceutically active substances, substance formulations or substance mixtures used may be any inhalable compounds, including, for example, inhalable macromolecules, as disclosed in EP 1 003 478. Preferably, substances, substance formulations or substance mixtures that are used by inhalation may be used to treat respiratory complaints 10 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 addition salts, the solvates and/or hydrates thereof. 15 Examples of ergot alkaloid derivatives are dihydroergotamine and ergotamine.
    WO 2009/013218 PCT/EP2008/059388 - 23 List of reference numerals I cover 5 2 mouthpiece 3 plate 4 spindle 5 capsule holder 6 lower part 10 7 outer actuating member 8 pin 9 helical spring 10 inner actuating member 11 pin 15 12 screen housing 13 screening mesh 14 closure element 15 guide arms(s) 16 recess 20
    权利要求:
    Claims (8)
    [1] 2. Inhaler according to Claim 1, characterised in that 10-25 Newtons, preferably 15-20 Newtons, have to be applied in order to perforate the capsule by moving the outer actuating member (7). 30 3. Inhaler according to Claim I or 2, characterised in that the actuating member (7, 10) is displaceably mounted on the plate (3) and/or on the capsule holder (5). WO 2009/013218 PCT/EP2008/059388 -25
    [2] 4. Inhaler according to Claim 1, 2 or 3, characterised in that the actuating member (7, 10) is spring-loaded.
    [3] 5. Inhaler according to Claim 1, characterised in that the actuating member is in two 5 parts, such that it consists of an outer actuating member (7) which is operated by the patient and an inner actuating member (10), the inner actuating member (10) being attached to the outer actuating member (7) and the inner actuating member containing the guide arms (15) and the pin holders with the pins (8, 11). 10 6. Inhaler according to Claim 5, characterised in that the outer actuating members (7) may be grooved and may preferably comprise an upper and at least one lateral grooved surface.
    [4] 7. Inhaler according to Claim 1, characterised in that the outer actuating member (7) 15 has, on its upper side, a recess which is inclined so as to form a sliding surface for the closure element (14) in the form of a sloping plane.
    [5] 8. Inhaler according to Claim 1, characterised in that the piercing of the capsule is carried out using one or more, preferably two, perpendicularly offset, parallel pins 20 (8, 11) that are moved by the actuation of the outer actuating member (7) and perforate the capsule. 9, Inhaler according to Claim 8, characterised in that the pin or pins (8, 11) are passed through tubular pin passages . 25
    [6] 10. .Inhaler according to Claim 9, characterised in that the pin or pins (8, 11) are each passed through a laterally mounted guide arm (15) .
    [7] 11. Inhaler according to Claim 10, characterised in that the laterally mounted guide 30 arm or arms (15) hold the actuating member (7, 10) under tension.
    [8] 12. Inhaler according to one or more of Claims I - 11, characterised in that a plastic capsule is used . WO 2009/013218 PCT/EP2008/059388 -26 13. Inhaler according to one or more of Claims 1 - 12 for inhaling powdered medicaments. 5
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    同族专利:
    公开号 | 公开日
    DK2178589T3|2014-04-14|
    JP4995324B2|2012-08-08|
    EA017563B1|2013-01-30|
    TW200922644A|2009-06-01|
    TN2010000027A1|2011-09-26|
    KR101496196B1|2015-02-26|
    DE102007036411A1|2009-02-12|
    EP2178589B1|2014-02-26|
    MA31528B1|2010-07-01|
    CA2699982C|2015-06-30|
    AU2008280193B2|2014-07-31|
    WO2009013218A1|2009-01-29|
    BRPI0814784A2|2015-03-03|
    PL2178589T3|2014-08-29|
    BRPI0814536A2|2015-01-27|
    US8539947B2|2013-09-24|
    UY31234A1|2009-03-02|
    AR067618A1|2009-10-14|
    ES2465674T3|2014-06-06|
    BRPI0814536B1|2019-10-08|
    CN101754780A|2010-06-23|
    NZ583349A|2012-09-28|
    ECSP099830A|2010-01-29|
    CN101754780B|2013-03-13|
    US20100275917A1|2010-11-04|
    CO6290711A2|2011-06-20|
    PE20090752A1|2009-07-10|
    EP2178589A1|2010-04-28|
    EG25932A|2012-10-24|
    BRPI0814536B8|2021-06-22|
    KR20100037612A|2010-04-09|
    JP2010533527A|2010-10-28|
    CA2699982A1|2009-01-29|
    EA201000126A1|2010-08-30|
    CL2008002137A1|2009-09-11|
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    USD831190S1|2016-11-08|2018-10-16|Alfred Von Schuckmann|Inhaler|
    PL234586B1|2017-08-31|2020-03-31|Pulinno Spolka Z Ograniczona Odpowiedzialnoscia|Inhaler of a single dose of dry powder|
    法律状态:
    2014-11-27| FGA| Letters patent sealed or granted (standard patent)|
    优先权:
    申请号 | 申请日 | 专利标题
    DE102007033861.0||2007-07-20||
    DE102007033861A|DE102007033861A1|2007-07-20|2007-07-20|Inhaler for inhalation of powdered medicaments, has lower part, which is closed with lockable plate, and operating organ is mounted at plate and capsule holder and is enhanced|
    DE102007036411.5||2007-08-02||
    DE102007036411A|DE102007036411A1|2007-07-20|2007-08-02|powder inhaler|
    PCT/EP2008/059388|WO2009013218A1|2007-07-20|2008-07-17|Powder inhaler|
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