TW200831146A - Powder inhalers - Google Patents

Abstract

The invention relates to a powder inhaler for administering moisture-sensitive pharmaceutical formulations.

Description

200831146 IX. Description of the invention: [Technical field to which the invention pertains] Powder of a pharmaceutical preparation The present invention relates to a method for administering a moisture sensitive end inhaler. ~ [Prior Art] Medical aerosol therapy for lung inhalation with a hemostat, metered dose aerosol or dry powder inhaler plays an important role in the treatment of many diseases (and especially respiratory diseases) The role.

Single-dose and multi-dose devices are known in the field of powder inhalers. These devices may take the form of single-use or reusable devices. In a single dose in a sputum inhaler, 'the administration may take the form of a capsule containing a powder formulation. If a capsule is used as the container, the powder inhaler can be opened by puncturing, crushing or breaking before the inhalation operation. The capsule is such that the powder can be removed from the capsule by the patient's breathing and produce an airborne aerosol that the patient can breathe. It is also possible to distinguish between a multi-dose powder containing a formulation in the form of a powder supply (from which a single dose can be obtained by means of a built-in dosage unit) and a single dose of a powder inhaler having several predetermined dose packages. Examples of inhalers designed in accordance with these two principles are known in the art. An example of a single dose powder inhaler is HandiHaler®, as disclosed in, for example, European Patent No. 1,342,483. German Patent No. 3,348, 370 and German Patent No. 3,336, 486 disclose an inhaler containing a disc-shaped blister pack comprising a plurality of holes arranged in a circle. The individual wells each contain a dose of the inhaled drug powder. The holes are closed on one side by, for example, a sealing film. For the delivery of the drug 126445.doc 200831146

Powder, open the hole. The air passage connects the opened hole to the nozzle of the inhaler. As an example, the inhaler of German Patent No. 3336486 will be explained in more detail. The inhaler comprises a disc-shaped circular blister having a chamber (supply chamber) and having an air inlet and having a plurality of drug-filled bladders therein. The blister is loosely connected to the circular rotatable disc. A plurality of cavities are formed around the disc which are in axial contact with the sachets, i.e., the pouches and cavities are arranged one above the other. The chamber has an air outlet. The inhaler also has a plunger that is arranged such that the plunger pierces the cartridge, thereby opening the cartridge to facilitate release of the medicament into the chamber and inhalation through the orifice. The patent application or the drawings of the U.S. Patent Specification can be consulted, and such documents are specifically described herein. German Patent No. 4106379 describes a blister in which a blister for a pharmaceutical powder or the like can be introduced. The blisters are separated from each other by a strip of material 'which defines at least one of the contents in which the drug is found to be the sigh of the garment for opening the container by pulling the two strips of material apart at the position of the opening opening The device. The user can inhale the drug powder from the open container via an outlet portion (e.g., a nozzle) that is coupled to the open container. — The strip of material may also be a carrier strip containing a plurality of bladders and the other strip may be a covered strip. Each (five) capsule and the field adjacent to the cover strip portion are subsequently formed into a capacity S. In the open position, the drive means for pulling the carrier strip and the cover strip can be provided, for example, by two drive wheels (e.g., gear teeth) that can be held in driving engagement therebetween. Moreover, in this case, the bubble of |=: defines a storage chamber in the inhaler, which is connected to the nozzle by an air passage. 126445.doc 200831146 In either case, the manner in which the powder formulation is packaged in the device is critical to the quality of the product and, therefore, its suitability for inhalation use. In the case of packaging of pharmaceutical powders, there is a difference between primary packaging and secondary packaging. The primary package is characterized by direct contact with the inhalable formulation. The primary package may be wrapped with a second external protection (i.e., secondary packaging) as appropriate. The primary package can be, for example, a capsule, a solid or flexible blister having a plurality of apertures, or a disk comprising a plurality of apertures. The secondary package can be a blister, pouch, bag or other container. This secondary package usually completely seals the primary package. Secondary packaging is used especially when the primary packaging does not provide adequate moisture protection. By way of example, the secondary package (e.g., single or multi-dose powder inhaler) is made from standard commercially available plastic. The primary packaging and, where appropriate, the secondary packaging has the task of preventing chemical or physical changes to the active substance as well as the entire inhalable formulation. In particular, the physical change may be a cohesive change of the active material particles, a change in the adhesion of the active material particles to the excipient and the container wall, or a water-induced chemical degradation, all of which may affect the delivery of the intended fine particle dose. . The term "fine granule S" means the dose of a pharmaceutical formulation that can reach the lungs of a patient. It is affected by the interaction of the micronized active material particles with each other and the interaction of the micronized two-particle particles with the excipient or with the walls of the container. It has been found that specific changes in the moisture level in the package can enhance the extent to which these interactions significantly reduce the fine particle dose. These changes include the infiltration of water into the package and the removal of water from the interior of the package. Thus, the primary purpose of the package is to maintain a constant chemical composition of the atmosphere within the package to prevent physical or chemical changes in the active formulation or to maintain stability of the inhalable formulation. There is a difference between the use of '" stability, and, long-term stability' in this article. The former is aimed at the stability that a short-term inhalable formulation itself must have even if it is not adequately protected by packaging.

Stability is defined as the stability that must be ensured as long as the inhalable formulation is in the unopened package. The choice of suitable materials for secondary packaging depends on two factors: - On the one hand, the material must be able to achieve the desired protective function. - Another aspect] The material must be the material that the secondary package can give in the necessary shape and the secondary package can perform its desired function. The industry often uses Xiezu from the following plastics as materials: polyolefin (poly (ethylene), poly (propylene)), polystyrene, ¥ 讲 汆 汆 汆 ' ' 醯 醯, polyurethane vinegar and polyester. These have the necessary rigidity and mobility to achieve mechanical function. The disadvantage of these (4) is that it is permeable to moisture in terms of moisture, which is caused by its construction method. Therefore, the ridges* are barely capable of packaging to stably store the inhalable powder. SUMMARY OF THE INVENTION Accordingly, the present invention is based on the problem of a powder inhaler having a beta sigh characteristic during long-term storage of a wet-sensitive drug formulation and during storage. The powder inhaler of the present invention is characterized by incorporating a dewatering material at least in a portion of the powder inhaler 126445.doc 200831146. The invention also relates to the use of the powder inhaler of the invention for administering a moisture sensitive inhalable pharmaceutical formulation. [Embodiment] Several powder inhalers are known from the prior art, as described above. Moisture-sensitive respirable formulations which must be stored for long periods in a powder inhaler prior to administration may be better protected when using the powder inhaler of the present invention than when using a comparable powder inhaler known from the prior art (in Prevent external ring _ moisture penetration). The powder inhaler of the present invention is constructed of a dehydrated material in at least one or more components. The components of the powder inhaler can be, for example, an outer wall, a capsule holder, a capsule chamber or a blister disc. Preferably, the dewatering material is incorporated into the wall of the powder inhaler housing, more preferably into the capsule chamber (e.g., in a Handihaler device) or incorporated into a reservoir wall of a reservoir device. The invention preferably relates to an assembly comprising an inhaler for inhaling a powder having a dehydrated material, wherein the inhaler is characterized by a) an upwardly open cup-shaped lower part (1), the lower part being The housing has two opposing ports (2) and has a first hinge member and an engagement pin (3) at the edge of the opening, b) covering the opening of the lower member (1) and including a second hinge member and a screen clamp, a plate (9) of the device (11) and the sieve (10), c) a capsule holder (4) for accommodating the capsule of the capsule '' is constructed perpendicular to the side of the plate (9) facing the lower part a flat surface having a head movable in a direction opposite to the spring, providing a head having one or two sharp pins (6), d) having a mouth tube and (as appropriate) a clip aid (17) and the nozzle (12) of the third hinge member, and 126445.doc -10· 200831146 includes a cover (13) of the fourth hinge member, the lower member (the first one), the flat plate (the second one), The hinge members of the upper member (third) and the cover (fourth) are joined together. In addition, the inhaler comprises an actuating element (7) for impacting the inclined side wall (15) of the recess (8) by the closing member (14) of the cover (13) (grooving (16) as appropriate) The cover (13) is opened and the recess (8) serves as a sliding surface and releases the cover (13) as the starting member (7) continues to advance. The guide of the 忒 (etc.) pin can actually be implemented by means of two laterally mounted guides (18). These guides also have the task of securing the actuating element (7) under prestressing. For this purpose, the guide rod (18) is provided with an end stop at its end remote from the body, which abuts the guide sleeve of the capsule holder (4) in the equilibrium position of the actuating element (7). The guide sleeves are arranged on the outer side of the capsule holder (4). A coil spring (5) is mounted between the two guide rods (18), the coil spring (5) extending along the axial direction of the pin (6), and the coil spring (5) should be used to activate the workpiece (7) It can also be offset to the rest position to match the length of the guide rod (18). Such an inhaler is shown in Figure 1. The present invention is also directed to an active multi-dose inhaler inhaler having a dehydrated material as disclosed in PCT/EP2007/004417. Here, the cover towel is intended to be connected to the transport device (for example, Bang Pu) and/or to the energy storage device (for example, the 'elastic storage device') to be activated by opening and / = the cover. The conveyor and/or energy is generated and stored in the energy storage towel. In particular, when the lid is opened, the delivery medium (more squeezing) is taken up and/or the delivery medium is placed under pressure by the transfer device. Or f or otherwise, the energy generated by opening and/or closing the cover is preferably stored by a biased spring storage device. This can be provided very simply, special 126445.doc -11- 200831146 is not intuitive to operate # # λ # _, so cheap: This can produce a particularly simple and constructive. For example, this is the need for a heart-operated transport setup = Γ or for biasing an elastomeric storage device or the like.

The intrusion may also have a gear that converts the opening and/or closing of the cover into a better axial movement for opening the lower-plug hole, and by means of a plug hole, the (four) accumulator is moved and/or advanced, Offset spring storage device, special device (specifically 'intake air') and / or operating counter or other device within the suction. The energy storage device and/or the auxiliary device may be disposed in the annular storage fii or in the respective apertures of the annularly arranged dose containing formulation. Preferably, the present invention is also directed to a passive multi-dose powder inhaler having a dehydrated material, as disclosed in PCT/EP2007/004416. In this inhaled state, the carrier is less than 360. Expanding in the circumferential angle of the inhaler, between two deflecting plates each having at least substantially constant curvature, extending only in the annular section of the inhaler and/or in one of the sections connecting the deflecting plates The device only expands along the circumference or outer wall of the inhaler. The carrier is in the form of a strip and/or a blister strip. Preferably, the plugs are formed by blister pockets. The inhaler also includes a conveyor having a plurality of gears for stepwise advancement and/or deflection of the carrier. The gears have the same diameter and are arranged in a common radius and can be driven by a common drive device (specifically, a sun gear or the like) and/or have the same direction of rotation. Moreover, the dewatering material can be incorporated into the blister disk. In particular, this document does not include capsules for use as primary packaging and blister filled with 126445.doc -12. 200831146 inhalation formulations for powder inhalers: Capsules can be used as described in German Patent No. 10 2005 022 862.3 Contains a graded package of adsorbents in its walls. A blister for an inhaler having a dehydrating agent in its wall is known from European Patent No. 04 025 038.3. In this context, the inhalable formulation is preferably a pharmaceutical powder formulation containing an anticholinergic agent as an active ingredient and having a particle size of less than 1 μm. The compounds listed below can be used in the device of the present invention by themselves or in combination. In the compounds described below, W is a pharmacologically active substance and is selected from the group consisting of, for example, the following substances: betamimetics, anticholinergic agents, corticosteroids, PDE4-inhibitors, LTD4-antagonists , EGFR-inhibitors, dopamine agonists, H1-antihistamines, PAF-antagonists, and PI3-kinase inhibitors. Moreover, a dual or triple combination of W can be formulated and used in the apparatus of the present invention. The combination of W can be, for example: -W represents a combination of betamethome with an anticholinergic agent, a corticosteroid, a quinone 4-inhibitor, an EGFR-inhibitor or a LTD4-antagonist, 0 - W represents an anti-biliary Alkali agents in combination with betamethomes, corticosteroids, PDE4-inhibitors, EGFR inhibitors or LTD4-antagonists, -w means corticosteroids with PDE4-inhibitors, EGFR-inhibitors or ^ LTD4-antagonism A combination of agents, - w represents a combination of a PDE4-inhibitor and an EGFR-inhibitor or a LTD4-antagonist, and -W represents a combination of an EGFR-inhibitor and a LTD4-antagonist. Preferably, the compound used as the betamethome is selected from the group consisting of albuterol, arformoterol, bambuterol, bitolterol, bromine恶特罗126445.doc -13- 200831146 (broxaterol), carbuterol, clenbuterol, fenoterol, formoterol, hexolin (hexoprenaline), ibuterol, isoetharine, isoproterenol, levo-salbutamol, mabuterol, meluadrine, isoproterenol (metaproterenol) ), orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, oxime Salmefamol, salmeterol, soterenol, sulphonterol, terbutaline, tiaramide , tolutrol (tolubut Erol), zinterol, CHF-1035, HOKU-81, KUL-1248 and -3·(4-{6_[2-amino- 2-(4-peryl-3-methyl-) Phenyl)-ethylamino]•hexyloxybutylidene-sulfonamide-5-[2-(5,6-diethyl-diazin-2-ylamino)-1-yl -ethyl]-8-yl-1H-quinolin-2-one-4-hydroxy-7_[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl) }ethyl]-amino}ethyl]-2(3H)-benzothiazolone-1-(2-fluoro-4-hydroxyphenyl)-2·[4-(1-benzimidazolyl)- 2-methyl-2-butylamino]ethanol-1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(l-benzimidazole) ))-2-mercapto-2-butylamino]ethanol-1-[2Η-5-hydroxy-3-oxo-4H-M-benzoxazine-8-yl]-2-[3- (4-N,N-didecylaminophenyl)-2-indolyl-2-propylamino]ethyl 126445.doc -14- 200831146 -1·[2Η-5- carbhydryl , ''benzoxazine I)]_2_[3_(4.methoxyphenyl)-2-methyl-2-propylamine;]ethanol-1-[2Η-5-hydroxy-3-oxo Generation, 'benzoxazine_8_yl}_2_[3_(4_n-butoxyphenyl)·2-methyl-2-propylamino]ethanol-1-[2Η-5- per Base-3_gas _4Η-1,4-benzoxazine-8- Kebu 2-{4_[3-(4-methoxyphenyl)-1,2, ketotriazole-3-yl]-2-methyl-2-ethylamino}ethanol-5-hydroxy-8 -(1-hydroxy-2-isopropylaminobutyl)_2Η-1,4-benzoxazine-3-(4Η)-one-1-(4-amino-3_chloro-5-three Fluoromethylphenyl)·in the third _butylamino)ethanol _ 6·hydroxy-8-{l-hydroxy-2-[2_(4-methoxy-phenyl)-1,1_diindole —ethylamino]ethyl}-4H-benzo[1,4]oxazin-3·one-6-hydroxy-8-{ 1-hydroxy-2-[2_(ethyl-4-phenoxy) -acetic acid)-1,1-dimethyl-ethylamino]-ethyl} -4H-benzo[1,4]indole-3-one-6-hydroxy-8-{·1·hydroxyl -2-[2-(4.phenoxy-acetic acid)_1,1-dimethylethylamino]-ethyl}·4Η-benzo[1,4]oxazin-3-one-8 -{2-[1,1-dimethyl-2-(2.4.6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-trans-yl- 4H-benzo [l,4]^^-3-_ -6-N-yl-8-{1-peryl-2-[2-(4-carbyl-phenyl)-l,l-dimethyl-ethyl Amino]-ethyl}-4H-benzo[1,4]oxazin-3·one-6-hydroxyhydroxy-2-[2·(4-isopropyl-phenyl)-1,1 dimethyl Benzyl-ethylamino]-ethyl}-4Η> benzo[1,4]oxazin-3-one-8-{2-[2-(4-ethyl-phenyl) -1,1-dimercapto-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4-indole-benzo[1,4]oxazin-3·one-8-{2-[2 -(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]- hydroxy-ethyl 126445.doc -15- 200831146 base} -6-hydroxy-4H-benzo[1, 4]oxazin-3 ·keto-4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H·benzo[1,4]] Oxazine _8_yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid-8-{2-[2-(3,4-difluoro-phenyl) -1,1·didecyl-ethylamino]-1-hydroxy·ethyl b 6-hydroxy-4H-benzo[1,4]oxazin-3-one-1-(4-ethoxyl -carbonylamino-3-cyano-5-fluorophenyl)-2-(tris-butylamino)ethanol-2.yl- 5-(1-amino- 2-{2-[4 -(2-propionyl-2-phenyl-ethylamino)-phenyl]ethylamino}-ethyl)-benzaldehyde-yi[2-hydroxy-5-(1-hydroxy-2- {2-[4-(2-Hydroxy-2-phenyl-ethylamino)-phenyl l-ethylamino}-ethyl)-phenyl]-carbenamide-8-.yl-5 -(1-Phenyl-2-{2-[4-(6-decyloxy-2-biphenyl-3-ylamino)-phenyl]-ethylamino}-ethyl)-1Η-quinoline 2-keto-8-hydroxy·5-[1-hydroxy-2-(6-phenethylamino-hexylamino)ethyl]-1H- Lin-2-one-5-[2-(2-{4-[4-(2-amino-2-mercapto-propoxy)-phenylamino]-phenylethylamino)-1 -hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one-[3-(4-{6-[2-]-based 2-(4-yl-amino-3-yl)-benzene ()ethylamino]-hexyloxy}-butyl)-5-methyl-phenyl]-urea-4-(2-{6-[2-(2,6-di-o-benzyl) Oxy)-ethoxy]-hexylamino}_1_transyl-ethyl)-2-methyl-age-3-(4-{6-[2-pyridyl-2-(4-hydroxy-) 3-(methyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzylsulfonamide _ 3-(3-{7-[2-hydroxy-2-(4-hydroxyl) 3-hydroxymethyl-phenyl)-ethylamino]-heptyl 126445.doc • 16 - 200831146 oxy}-propyl)_benzepine xanthine 4-(2-{6-[4- (3. Cyclodecanesulfonyl-phenyl)-butoxy]-hexylaminopyryl 1-hydroxy-ethyl)-2-methyl--N- to bromo-2-yl-2- (3-{2-[2-Pyryl-2-(4-amino-3-methyl-phenyl)-ethylamino]-propylphenyl)-acetamide

</ RTI> in the form of its racemate, enantiomer, diastereomer, and in the form of its pharmaceutically acceptable acid addition salt, solvate or hydrate . According to the present invention, the acid addition salt of betamethicone is preferably k from the lower jaw. Hydrochloric acid hydrochloride, hydrogen desert acid salt, hydrogen block acid salt, hydrogen sulfate hydrogen salt, methanesulfonic acid Hydrogen salt, hydrogen azide, hydrogen maleate, hydrogen acetate, hydrogen citrate, chlorate fumarate, tartaric acid nitrogen salt, oxalic acid salt, hydrogen sulfonate, hydrogen benzoate and P-toluene acid nitrogen salt. The anti-cholinergic test agent used is preferably a compound selected from the group consisting of: a salt of ti〇tr〇pium (preferably a desertified salt) and an oxygen carrier (a salt of a bismuth (preferably a bromide). ), a flutropium salt (preferably a bromide salt), an ipratropium salt (preferably a desertified salt), a glycopyrronium (10) cop sonic nium salt (preferably desertification) The snail, the snail's stiletto (tr〇spi leg) salt (preferably chlorinated salt), tolter S (t〇her〇 dine). In the above salts, the cation is a pharmacologically active ingredient. In terms of anions, the above salts preferably may contain chloride ions, (tetra) 1 ions, sulfate, sulphate, acid, citrate, maleate, acetate, acetate, fumarate , tartrate, oxalate, succinate, $ f ^ft acidate 'at the same time chloride, molybdenum, moth, sulfate, scutellite W acid or p-toluene sulfonate better counterion. Salts &gt; 126445.doc -17- 200831146 Gas ions, bromide ions, iodide ions and methane sulfonate are preferred. Other preferred anticholinergic agents are selected The salts of formula AC-1,

Wherein X represents an anion having a negative charge, preferably an anion selected from the group consisting of fluoride, gas, bromide, cesium, sulfate, acidate, acid phosphate, nitrate, maleate, Acetate, citric acid, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate, preferably having a negatively charged anion, more preferably an anion selected from the group consisting of fluorine Ionic, chloride, bromide, methane retinid and p-toluenesulfonate, especially bromide, may optionally be in the form of their racemates, enantiomers or hydrates. Of particular importance are the pharmaceutical combinations containing the enantiomers of the formula AC-1-enantiomers,

Enantiomers wherein X may have the meanings indicated above. Other preferred anticholinergic agents are selected from the salt of the formula AC-2, 126445.doc -18 - 200831146

AC-2

In an alternate embodiment, the compound of formula AC_2 can also be present in the form of the free base ac_2_base.

Other specific compounds of AC-2 base: -2,2 · tropinol dibromide methyl bromide, -2,2-diphenylpropionic acid benzalkonium bromide, 2-fluoro-2, 2-diphenylacetic acid sterol ester methyl bromide, -2-fluoro-2,2-diphenylacetate tropinol bromo, -3,3,4,4 匕tetrafluorodiphenyl glycolate Alcohol ester 曱 bromo, -3,3,4,4 * -tetrafluorodiphenyl glycolic acid, East sterol sterol vinegar, '-4,4'-difluorodiphenyl glycolic acid, tropin ester, methyl bromide , -4,4'-difluorodiphenyl glycolic acid sterol ester methyl bromide, -3,3'-difluorodiphenyl glycolic acid tropinol bromo, -3,3^ difluorodiphenyl Terpene glycolate glycolate; -9-hydroxy--9-carboxylic acid tropin ester methyl bromide; -9-fluoro-purine-9-carboxylic acid tropine ester methyl bromide; -9-hydroxy- -9-Erythroyl citrate methyl bromide; 126445.doc -19- 200831146 - gas - -9-tungstic acid ester methyl bromide; -9-methyl- 9-carboxylic acid tropin ester 曱Bromine; - 9-methyl- 9-carboxylic acid sterol ester methyl bromide; - diphenyl glycolic acid cyclopropyl tropine methyl bromide; -2,2-diphenylpropionic acid cyclopropyl trop Ester methyl bromide; -9-hydroxy·xanthene_9_formic acid cyclopropyl Ester methyl bromide; -9-methyl-fluorene-9-formic acid cyclopropyl tropine methyl bromide; -9-methyl-xanthene -9-formic acid cyclopropyl tropine methyl bromide; -9-hydroxy-苐_9_carboxylic acid cyclopropyl tropine methyl bromide; 'murine one' base butyl chlorpyrifo propyl tropine vinegar 淳 -9- carbyl- 咕 咕 -9-carboxylic acid tropin ester 曱 bromine ; 9-hydroxy-xanthene-9-formic acid terpene ester methyl bromide; -9-methyl-xanthene _9·tocopheryl formate 曱 bromine; -9-methyl-xanthene -9-formic acid Terpene alcohol ester methyl bromide; -9-ethyl-xanthene carboxylic acid tropin ester methyl bromide; -9-difluoromethyl-xanthene_9_carboxylic acid tropin ester methyl bromide; -9-hydroxymethyl - 咕 _ _ 9 - formic acid ester methyl bromide. Within the scope of the present invention, the above-mentioned compounds can also be used as a salt, and in addition to the methyl bromide, the salt can be used as the methyl group, wherein the hydrazine can have the meaning given above for hydrazine. As the corticosteroid, a compound selected from the group consisting of beclomethasone, betamethasone, budesonide, butixocort, ciclesonide, is preferably used. , deflazacort, dexamethasone 126445.doc •20- 200831146 (dexamethasone), etiprednoi, flunisolide, fluticasone, loteprednol (1 〇tepredn〇1), mometasone, prednisol〇ne, prednisone, refloneide, triamcinolone, RPR-106541, NS- 126, ST-26 and -6,9-difluoro-17_[(2-furylcarbonyl)oxy]-11-hydroxy-16•methyl_3·oxo-androgen-1,4-diene -17-thiocarbonyl acid (S)-fluoromethyl vinegar, -6,9-difluoro-11-hydroxy-16-mercapto-3-oxo-17·propoxy-androgen _ 1, 4_Icen-17-thioxo acid (S)-(2.oxo-tetrahydro-valprom-3S-yl) ester, -6α,9α-difluoro_11β_hydroxy-16α_methyloxo ·17〇1_(2,2,3,3_tetramethylcyclopropylcarbonyl)oxy-androst-1 , 4-diene_ΐ7β·cyanoacetate, as it is in the form of its racemate, enantiomer or diastereomer, and depending on the case, its salts and derivatives, soluble Formula I and/or hydrate. Any reference to a steroid includes references to any salt or derivative, hydrate or solvate thereof that may be present. Examples of possible salts and derivatives of steroids may be: alkali metal salts (for example, sodium and potassium salts), sulfobenzoates, cantanates, isonicotinic acid salts, acetates, dichloroacetates, and C. An acid salt, a dihydrogen phosphate salt, a palmitate, a neopentanoate or a decanoate. The PDE4-inhibitor which can be used is preferably a compound selected from the group consisting of enprofyllin, the phymne, roflmnilast, cillin (arifl〇, Cil〇milast) 'tofimilast, pumafentrin, lidmilast, arophylline (ar〇fylHn), atizoran (atiz〇r_), D- 4418, Bay-19_4, BY343, CP-325.366, D-4396 (Sch-126445.doc -21 - 200831146 35 1591), 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_two Chloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy·3·cyclopropylmethoxybenzamide-(-)0-[(4&amp;11*,1(^ 8*)-9-ethoxy-1,2,3,4,4&amp;,1〇1}-hexahydro-8-methoxy-2-methylbenzo[s][i,6]naphthalene Pyridin-6-yl]-N,N-diisopropylbenzoquinone_(R)-(+)-1 -(4-bromobenzyl)-4_[(3-cyclopentyloxy)- 4_Methoxyphenyl]_ 2 -deuteroline ketone-3-(cyclopentyloxy-4-methoxyphenyl)cyano_s_indenyl-isosulfide Base])-2-pyrrolidone-cis[4-lacyl-4_(3-cyclopentyloxy-4-yloxyphenyl)cyclohexanoic acid]-2-methoxy Mercapto-4-cyano-4(3_cyclopropylmethoxy-4-tetrafluoromethoxyphenyl)cyclohexan-1-one-cis[4-cyano-4-(3-1⁄4) Propyl methoxy dimethyl methoxyphenyl) cyclohexan-1-ol] -[4-(3-3⁄4戍 yloxy-4-carboxyl-*, t# LT虱 basic group)咣(rhodium-2-ylidene)acetic acid (R)-(+l·ethyl ester

-[4-(3-3⁄4pentyloxy-4-methyl)|μ bond, L Τ虱 basic group) pyrrolidine-2-ylideneacetic acid (S) -(·&quot;)-ethyl -9-cyclopentyl _5,6-dihydro _7_gan, Λ _ _3-(2·thienyl)-9Η·pyrazolo[3,4- c]-l,2,4- Dipyrexine [4,3-a]n ratio π 126445.doc -22- 200831146 -9-cyclopentyl·5,6-dihydroethyl _3-(t-butyl)_9H_pyrazole And [3,4&lt;]-1,2,4-triazolo[4,34]pyridine is optionally in the form of its racemate, enantiomer or diastereomer, and optionally It is in the form of its pharmaceutically acceptable acid addition salt, its solvate or hydrate. According to the present invention, the acid addition salt of betamethicone is preferably selected from the group consisting of hydrogen hydrochloride, hydrobromide, hydroiodide, hydrogen sulfate, hydrogen phosphate, and hydrogen methanesulfonate. Hydrogen azide, hydrogen maleate, hydrogen acetate, hydrogen citrate, hydrogen fumarate, hydrogen tartrate, hydrogen oxalate, hydrogen succinate, hydrogen benzoate and p-toluenesulfonic acid Hydrogen salt. The LTD4-antagonist used is preferably a compound selected from the group consisting of: montelukast, pranlukast, zarfihikast, 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)vinyl)phenyl)_3_(2_(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic acid, vinyl)phenyl)-3-(2-(1- Hydroxy_丨_methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid _ [2-[[2-(4•t-butyl-2-thiazolyl)_5•benzoyl) Furanyloxymethyl]phenyl]acetic acid is, if appropriate, in the form of its racemate, enantiomer or diastereomer, and optionally as its pharmaceutically acceptable acid addition In the form of salts, solvates and/or hydrates. According to the present invention, the acid addition salt of betamethicin is preferably derived from the following materials: hydrochloride, hydrobromide, hydro sulphate, 126445.doc -23- 200831146 hydrogen sulphate, phosphoric acid Hydrogen salt, sulphuric acid hydrogen sulfonate, hydrogen azide salt, hydrogen maleate, hydrogen acetate, hydrogen citrate, hydrogen fumarate, hydrogen hydrogen tartrate, hydrogen oxalate, hydrogen succinate, Clandoleic acid hydrogen salt and p-toluene acid hydrogen salt. A salt or derivative capable of forming a LTD4-antagonist, as the case may be, for example, an alkali metal salt (for example, sodium or _ salt), a soil test metal salt, a styryl benzoate, a linoleic acid salt, and an isoniazid test Acid salt, acetate, propionate, dish acid salt, palmitate, pivalate or citrate. The EGFR-inhibitor which can be used is preferably a compound selected from the group consisting of cetuximab, trastuzumab, EEGF, Mab ICR-62 and -4-[(3-chloro) 4-fluorophenyl)amino]_6-{[4-(morphinyl)-1 oxo-2-buten-1-yl]aminophenyl 7-cyclopropylmethoxy-quinazoline琳•Μ(3·Chloro-4-fluorophenyl)amino]]6_{[4_(n,n•diethylamino)oxy-2-butenyl]aminobicyclopropylmethoxy _ quinazoline-4-[(3_chloro-'fluorophenyl)amino]_6_{[4_(ν,ν_dimethylamino)_^ oxo-2-butene-;1_ Aminobutyr 7-cyclopropylmethoxy-quinazoline-4-[(R)JKphenylethyl)amino]_6-{[4-(morpholin-4-yl)-1 -oxo-2-butenyl-yl]-amino}·7-cyclopentyloxy-quinazoline-4_[0 chlorofluoro-phenyl)amino]methyl_2_oxo-? Lolinyl)-1-oxo-2-butan-1-yl]aminophenyl 7-cyclopropylmethoxy-quinoline • 4-[(chlorofluorophenyl)amino]·6· {[4-((Κ&gt;6-Methyl-2-oxo- oxo) 1-oxo-2-butan-1-yl]aminopyr 7_[(s)_(tetrahydrocampyl) )oxy l·saliva 126445.doc •24· 200831146 _ 4-[(3-chloro-4- -phenyl)amino]_6_{[4_((11)_2_methoxymethyl·6-oxo-morpholine-4-yl)]-oxo-2-buten-1-yl]amine }}_7_cyclopropyl oxime-喧嗤琳_ 4_[(3_gas_4-fluoro-phenyl)amino]·6_[2-(〇6-methyl_2_oxo_? Porphyrin_4-yl)-ethoxy]-7-methoxy-啥 琳 -4-4·[(3- gas_4_fluorophenyl)amino]_6_({4-[Ν·(2_曱oxy_ethyl)_Ν-methyl-amino]-1-oxo-2-buten-1-yl}amino)_7-cyclopropylmethoxy-quinoline -4- (3-Chloro-4-fluorophenyl)amino]-6][4&gt;_(Ν,Ν•dimethylamino]oxy-2-buten-1-yl]amino} - 7 - Cyclodecyloxy-quinazoline-4-[(R)-(l-phenyl-ethyl)amino]]6-{[4-(Ν5Ν-bis-(2-methoxy-ethyl) -amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-4- -4-[(RHl-phenylethyl)amino] {4_[N-(2-methoxy-ethyl)-N-ethylamino)-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy -4-[(R)-(l-phenyl-ethyl)amino]·6·({4-[]Νμ(2-methoxy-ethyl)_N_methyl-amino]-1- Oxo-2-butene-l-yl}amino)-7-cyclopropylmethoxy_'-4-((R)-(l-phenyl-B ) Amino] -6 - ({4- [N- (tetrahydro.喃4_yl)-N-methyl-amino]-1.oxo-2-butene-l-yl}amino)-7-cyclopropylmethoxy--4-[(3 -Chloro-4-fluorophenyl)amino]-6_{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]aminopurine tetrahydrofuran_3 _基氧&gt; quinazole 126445.doc -25- 200831146 琳_ '[(3-chloro-4-fluorophenyl)amine kib^'(7)'...dimercaptoamine oxime oxo 2 butyl -1 -[(3_chlorofluorophenyl)amino -6-({4-[Ν-(2-methoxyethyl)·Ν·methyl-amino]-1-oxo-2-butene-yl}amino)_7_cyclopentyl Oxy-quinazoline 4[(3fluoro-4-fluorophenyl)amino]-6 - {[4-(Ν-cyclopropylindolyl-amine)-l-oxo-2-butene Alken-1-yl]amino}-7·cyclopentyloxy-quinazoline-4-[(3-chloro+fluorophenyl)amino]_6—{[4-(N,N-dimethyl Amino)dioxy-2-buten-1-yl]amino}_7_[(R)·(tetrahydrofuran-2-yl)methoxy]·啥口坐琳-M(3-chloro+fluoro Phenyl)amino]]6-{[4·(Ν,Ν_dimethylamino)+oxo-2-butene-1·yl]aminophenyl 7-[(S)-(tetrahydrofuran_2 _基)曱oxy]_ _ _ 4- [(3-ethynyl-phenyl)amino]-6·7-bis-(2-methoxy-ethoxybenzoquino-4-[(3-chloro-4.fluorophenyl)amino]- 7-[3-(morpholine-4-yl)-propyloxy] winter [(hyperyl)amino]- 噎嗤 ^ ^ - 4-[(R)-(l-phenyl, Ethyl)amino] winter (4-hydroxy-phenyl)_711_. pyrrolo[2,3-d] bleed _ 3-cyano-heart [(3- fluoro-4-fluorophenyl)amino group ]-6_{[4_(Ν,Ν·dimethylamino)-1_oxo-2-butene-1_yl]aminopyr 7-ethoxy-quinoline-4-{[3- Chloro-4-(3-fluoro-benzyloxy)-phenyl]aminodibu 6_(5-{[(2_methane 126445.doc -26- 200831146 sulfonyl-ethyl)amino]methyl Bufuran-2-yl)quinazoline-4-[(R)-(l-phenylethyl)amino]-6-{[4-((R)-6-methyl-2-H)啉 _4_yl)-1-oxo-2·buten-1-yl]amino}-7-decyloxy_quinacles-4·[(3-chloro-4-fluorophenyl) Amino]_6-{[4-(morphin-4-yl)_1_oxo 9-en-1-yl]-amino}_7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline -4·[(3-chloro-4-fluorophenyl)amino]-6-({4-[Ν,Ν_bis-(2.methoxy)-amino]-1-oxo- 2-butene-l-yl}amino)-7-[(tetrahydrofuranmethoxy)-quinazoline_4-[(3-ethynyl) Amino]-6-{{ζμ(5·5_dimethyl-2-oxo-morphinylbu-1-oxo-2-buten-1-yl)amino}-quinazoline -4_[(3·Ga-4-fluorophenyl)amino]_6-[2_(2.2_Dimethyl_6-oxo-morphinyl)-ethoxy]-7-methoxy- Quinazoline _ 4·[(3- gas _4·!^phenyl)amino]·Μ2·(2·2_dimethyl·6-oxo-morpholin-4-yl)-ethoxy ]•孓[(RHwhydrofuran-2-yl)methoxy]•quinazoline_4-[(3-Gas-4-oxo-phenyl)amino]_7_[2_(2·2_dimethyl Oxo-oxo-morpholin-4-yl)-ethoxy]_6_[(8)-(tetrahydrofuran-2-yl)methoxy]-quinazoline _ 4-[(3- gas-4-fluoro Phenyl)amino]_6-{2-[4-(2-oxo-cylinyl)_hexahydropyridin-1-yl]•ethoxy}_7-methoxy-quinazoline- 4-[(3-Ga-4-fluoro-phenyl)amino] Winter [ι_(Third-Butoxy-oxy)-hexahydropyridinium·4·yloxy]-7-methoxy -quinazoline-4([3- gas-4_fluoro-phenyl)amino]_6-(trans-4-amino-cyclohexyloxy)-7-methoxy-oxime琳126445.doc -27- 200831146 -'[(3-chloro+fluoro-phenyl)amino]-6-(trans-4-methanesulfonylamino-cyclohex-1-yloxy)_7_ Methoxy-喧峻琳-4-[(3- Chloro-4-fluoro-phenyl)amino]-6-(tetrahydroσ-pyran-3-yloxy)-7-methoxy-喧嗤琳-4-[(3-chloro-4-fluoro) -phenyl)amino]-6-(1-methyl-hexahydroacridin-4-yloxy)-7-decyloxy-嗤嗤

-4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morphin-4-yl)carbonyl]-hexahydropyridin-4-yloxybu 7_A Oxy-quinazoline-4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-hexahydro 0-pyridin-4· --oxy}_7_methoxy-quinazoline _ 4_[(3-chloro-4-fluoro-phenyl)amino]-6-(hexahydropyridyloxy)-7-methoxy-啥°坐琳-4·[(3·Chloro-4-fluoro-phenyl)amino]-6-[l_(2-ethanesulfonylamino-ethylhexahydroton 17-dec-4-yloxy ]-7-methoxy·啥u sitting _ 4-[(3·chlorofluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)_7•ethoxy-oxime嗤琳四氢11夫喃-3 -yloxy)·7- 4-[(3-chloro-4·g-phenyl)amino] thio-linal tetrahydrofuran-4-yloxy 7-(2- -4-[(3-chloro-4-fluoro-phenyl)amino]-6-(methoxy-ethoxy)-quinazoline-4-[(3· Chloro-4-fluoro-phenyl)amino]·6]trans, 4_[(dimethylamino) arylamino]-cyclohex-1-yloxy}-7-fluorenyl 啥嗤淋• 4_[(3_Chloro-4_fluoro-phenyl)amino]_6, {反_4七七淋_4_yl)alkylamino]-cyclohex-1-yloxy}- 7·methoxy 嗤 126445.doc •28- 200831146 -4 -[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylamino]-cyclohex-1-yloxy} -7-methoxy-quinazoline-4·[(3-chloro-4(fluoro-phenyl)amino]-6-(tetrahydrofuran-4_yloxy)_7_(2-ethylhydrazine Amino-ethoxy)-quinazoline•4-[(3-chloro-4-vapor-phenyl)amino]-6-(tetrahydropyranyl-4-yloxy)-7-( 2_ methanesulfonylamino-ethoxy)-quinazoline-4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(hexahydroσ-pyridyl) Carbonyl hexahydro σ ratio biting -4 yloxy}-7 methoxy-啥ϋ sitting _ - 4-[(3- gas · 4 · fluoro-phenyl) amino group] winter (1 - amine Carbocarbonylmethyl-hexahydrotonate bite 4-yloxy)-7-methoxy-quinazolin-4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis -4-{N-[(tetrahydrou-pyranyl-4)ylcarbonyl]-indole-methyl-aminobicyclohexan-1-yloxy)_7_methoxy_嗤峻琳-4- [(3-Chloro-4-a-phenyl)amino]-6-(cis-4-{Ν-[(吗琳_4_yl))] N-methyl-amino}-ring Hex-1-yloxy)-7-methoxy-啥啥琳-4-[(3-chloro·4·fluoro·phenyl)amino]-6-(cis-4, {N-[( Morpholine·4_yl)sulfonyl•yl]·Ν-methyl-aminobicyclohexan-1-yloxy)_7- Oxy-喧唆琳-4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulfonylamino-cyclohex-1-ylfluorenyl) -7.Methoxy-quinazoline-4-[(3-mur-4-yl-phenyl)amino]_6·(1-曱院sulfonyl-hexahydro).淀冬冬-基基)-7-ethoxy-喧 琳 -4--4-[(3·chloro-4-fluoro-phenyl)amino]-6-(1-methyl sulphate yellow wine- Hexahydro-α-p--4-yloxy)-7-(2-methoxyethoxy)quinazoline-4_[(3-chloro-4-fluoro-phenyl)amino]_6- [1-(2-Methoxy-ethenyl)-hexahydroindole-4.yloxy]-7-(2.methoxy-ethoxy)-啥 琳 126 126445.doc -29- 200831146 -4-[(3-Chloro-4-fluoro-phenyl)amino]-6-(cis-amylamino-cyclohexyloxy)-7-methoxy-啥吐琳- 4-[(3-ethynyl-phenyl)amino]-6-[1-(t-butyloxycarbonyl)-hexahydroindol-4-yloxy]-7-methoxy-啥 琳 _ _ 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydroσ-pyranyloxy)_7_methoxy-喧嗤 -4--4-[(3 - gas - 4-fluoro-phenyl)amino]-6-(cis_4-{Ν-[(hexahydropyridin-1-yl)carbonyl]-indole-methyl-amino}-cyclohexan-1-yloxy ))-7_methoxy 啥 啥 琳 - 4-[(3-chloro-4-fluoro-phenyl)amino]-6~(cis_4_{Ν:[(4_曱-pyrazine) + yl)carbonyl]-fluorene-methyl-amino}-cyclohex-1-yloxy)-7-methoxy-quinazoline-4-[(3- gas-4-fluoro-phenyl) Amino]-6-{cis-4-[(morpholin-4-yl)carbonyl Amino]-cyclohex-1-yloxy}-7-decyloxy-quinazoline-4-[(3m-phenyl)amino] winter {1-[2-(2-oxou) Bilobidine small group) ethyl]-six rats ° bit -4-yloxy}-7-methoxy-啥嗤琳-4-[(3- gas-4-fluoro-phenyl)amino group -6-{1-[(morpholin-4-yl)carbonylbihexahydropyridin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline-4 -[(3-ethynyl-phenyl)amino]-6-(1-ethenyl-hexahydro^Bist _4_yloxy)-7-methoxy-啥嗤琳-4-[ (3-ethynyl-phenyl)amino]-6-(1-methyl-hexahydropyridin-4-yloxy)-7-methoxy-啥σ sitting -4-[(3-acetylene) Alkyl-phenyl)amino]-6-(1-carboindole fluorenyl-hexahydro σ ratio _4_ yloxy)-7-methoxy quinazoline-4-[(3 - gas- 4-fluoro-phenyl)amino]-6-(1-methyl-hexahydroσ ratio -4-yloxy)-7(2-decyloxyethoxy) 喧 喧 琳 126 126445. Doc -30- 200831146 -4-[(3-Chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxyalkyl·hexahydropyridin-4-yloxy) -7-methoxy-quinazoline-4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohex-1-yloxy )-7-methoxy-u-quineline-4-[(3-chloro-4-fluoro- Amino]-6]{cis-4_[N-(2-methoxy-ethinyl)-N-methyl-amino]-cyclohex-1-yloxy}_7_decyloxy -啥ΰ坐琳-4-[(3-ethynyl-phenyl)amino]-6_(hexahydroindole-4-yloxy)-7-methoxy-σ奎峻琳

-4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-ethenyl)-hexahydroindole-4-yloxy]-7-methoxy啥嗤-啥嗤琳-4-[(3·ethynyl-phenyl)amino]-6-{1-[(morpholinyl)carboxy]hexahydro. Than -4-yloxy}-7-methoxy-quinoxaline-4-[(3-chloro-4-phenylphenyl)amino]-6-{1-[(cis_2,6) _Dimethyl-morpholine yl)weiki]-hexahydroindole 唆-4-yloxybu 7-methoxy 啥 啥 琳 -4 [[3-chloro-4-fluoro-phenyl Amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-hexahydro.唆-4-yloxy}-7-methoxy 啥 啥 琳 _ 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{l_[(s,s)_ (2_oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidine-4-yloxy}_7_methoxy_喧嗤琳4· [(3-Chloro-4-fluoro-phenyl)amino]methyl^^2_methoxyethyl-amino)carbonyl]-hexahydroacridin-4-yloxy}_7-methoxy _ quinazoline-ethyl·hexachloropyrene than _4_yloxy-4-[(3-chloro-4-IL-phenyl)amino]yl)-7-methoxyquinazoline Oxyethyl)carbonyl]-hexa-4-[(3-chloro-4-a-phenyl)amino] 126445.doc -31- 200831146 Hydroacridin-4-yloxy}-7-methoxy -quinazoline-4-[(3-chloro-4-fluoro-phenyl)amino]-6_{l-[(3-methoxypropyl-amino)-carbonyl]-hexahydro-sigma ratio Pyridin-4-yloxybu 7-methoxy-quinazoline-4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(&gt;1-曱Alkylsulfonyl-&gt;1-methyl-amino)-cyclohex-1-yloxymethoxy-quinazoline-4-[(3-chloro-4-fluoro-phenyl)amino] -6·[cis-4-(indolyl-indole-methyl-amino)-cyclohex-1-yloxy]-7-methoxy-quinazoline-4-[(3_ Chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1- Oxy)-7-methoxy-quinazolin-4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(&gt; 1-carcinogen xanthine)- ]^-Methyl-amino)-cyclohex-1-yloxy]-7-methoxy-喧喧琳-4-[(3-chloro-4-fluoro-phenyl)amino]-6 -(trans-4-dimethylamino-cyclohexyl-fluorenyl-yloxy)-7-decyloxy-hydrazino-4-[(3-chloro-4-fluoro-phenyl)amino] -6 (trans-4-{N-[(morpholine-4-yl)carbonyl]_N-methyl-aminosuccinyloxy)_7_decyloxy-啥啥琳4-[(3-chloro -4-fluorophenyl)amino]]6_[2-(2_2-dimethyloxo- hollyinyl)-ethoxy]_7_[(8)_(tetrahydrofuran-2-yl)methoxy ] _ oxazoline-4_[(3-chloro-4-ylfluoro-phenyl)amino]_6_(1_methanesulfonyl _hexahydro σ-pyridyloxy)·7-methoxy-oxime吐琳[(气氟-本基基基基基)-6·( 1 _ cyano-hexahydrocarbyloxymethoxy-quinazoline as its racemate, enantiomer a form of a body, a diastereomer, and optionally a pharmaceutically acceptable acid addition salt, a solvate or a form of water 126445.doc -32 - 200831146. According to the invention 'betamethome The acid addition salt of the class is preferably selected from the following Substance: hydrogenate, hydrobromide, hydroiodide, hydrogen sulfate, hydrogen phosphate, hydrogen methanesulfonate, hydrogen azide, hydrogen maleate, hydrogen acetate, hydrogen citrate Hydrogen fumarate, hydrogen tartrate, hydrogen oxalate, hydrogen succinate, hydrogen benzoate and hydrogen p-toluenesulfonate. The dopamine agonist used is preferably a compound selected from the group consisting of bromocriptin, cabergoline (〇 匕 61^〇111^), and 〇1-dihydro ergolocine (alpha-diliydroergocryptine). ), lisuride, pergolide, pramipexol, roxindol, ropinirol, talixo, special Tergurid and viozan, as the racemate, enantiomer, diastereomer, as appropriate, and optionally as a pharmaceutically acceptable acid addition salt, solvate The form of a substance or hydrate. According to the present invention, the acid addition salt of the betamethine is preferably selected from the group consisting of hydrochloride, hydrobromide, hydrocyanate, hydrogen sulfate, hydrogen phosphate, hydrogen methanesulfonate. Salt, hydrogen azide, hydrogen maleate, hydrogen acetate, hydrogen citrate, hydrogen fumarate, hydrogen hydrogen tartrate, hydrogen oxalate, hydrogen succinate, hydrogen benzoate and hydrazine Hydrogen benzenesulfonate. The H1-antihistamine which can be used is preferably a compound selected from the group consisting of: epinastine, cetirizine, azelastine, and fexofenadine. , levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, Clemastine, glutamine 126445.doc •33· 200831146 (bamipine), cexchlorpheniramine, pheniramine, doxylamine, chlorpheniramine (chl〇r〇phen 〇xamine), dimenhydrinate, diphenhydramine, promethazine, ebastine, desl〇ratidine, and meclozine , as the case may be in the form of its racemates, enantiomers, diastereomers, and optionally in the form of its pharmaceutically acceptable acid addition salts, solvates or hydrates. According to the present invention, the acid addition salt of the betamethome is preferably selected from the group consisting of: hydrochloride, hydrobromide, hydroiodide, hydrogen sulfate, hydrogen phosphate, methanesulfonic acid Hydrogen salt, hydrogen azide, hydrogen maleate, hydrogen acetate, hydrogen citrate, hydrogen fumarate, hydrogen tartrate, hydrogen oxalate, hydrogen succinate, chloride benzoate and p-toluene Hydrogen sulfonate. Inhalable macromolecules as disclosed in European Patent No. 1,003,478 can also be used. Further, the compound may be derived from a group of ergot alkaloid derivatives, triptan, CGRP inhibitors, phosphodiesterase ν inhibitors as the racemates, as appropriate The form of the enantiomer or diastereomer, and optionally in the form of its pharmaceutically acceptable acid addition salts, solvates and/or hydrates. Examples of ergot alkaloid derivatives are dihydroergotamine and ergotamine. Preferably, the material for the powder inhaler of the present invention may be a polymer composition comprising at least one thermoplastic polymer, at least one dehydrating agent, and optionally at least one elastomer and/or plasticizer and/or other fibers. . This material does not contain gelatin or cellulose or starch or its derivatives. 126445.doc -34- 200831146 The preferred polymer composition consists, for example, of the following: 60-80 by weight 1/. - one or more thermoplastic polymers, • b) 20-40% by weight of one or more dehydrating agents, • Other substances. Preferably within the dehydrating agent is 1〇_4〇% by weight, more preferably 2〇_3 〇% by weight. • In particular, the polymer component of the plastic may be, for example, the following thermoplastic polymers: polystyrene, polyolefin, polyamide, polyvinyl chloride or polyurethane. Particularly preferred is polyethylene (Hostalen), especially polyethylene having the following properties: between 9 〇〇 kg / m 3 and 丨〇〇〇 kg / m 3 , preferably from 940 kg / m 3 Up to 98 〇 kg / m 3, especially preferably 96 〇 kg / m 3 (high density polyethylene) · 'polycarbonate, polyester, polypropylene or polyethylene terephthalate. Dehydrating agents which can be used include, for example, silicone, zeolite, alumina, magnesium sulfate, molecular sieves and the like. Finally, the polymer composition may also contain other inorganic φ or organic additives having the following functions: plasticizers, stabilizers, dyes, pigments or the like. Preferably, a dewatering material which can be processed by injection molding or blow molding, i.e., a plastic containing a dehydrating agent, is used. Further preferred is a plastic material which does not require the use of a release agent which causes the filler (i.e., pharmaceutical formulation) to adhere to the wall. This has the advantage that it is not necessary to clean the inside of the plug hole to remove the release agent to meet the legal requirements for limiting the release agent for the primary package (for example, in accordance with DAB (German Pharmacopoeia)). In the preferred embodiment, the dehydrated material does not exhibit any significant adhesion to the medicinal/chemical substance (specifically, particles having a size suitable for entry into the lungs) of any 126445.doc-35-200831146. This ensures more accurate administration, especially for the lung-bound fine fraction of pharmaceutical preparations. Further information regarding the composition or process can be found in the prior art, in particular, European Patent No. 599690, European Patent No. 432438 or European Patent No. 400460. In one embodiment, the wall of the inhalation steaming module can include zones having different polymer/dehydrating agent compositions. In other embodiments, the wall of the inhaler assembly is constructed from at least 2 layers (i.e., the inner layer and at least one outer layer thereon). Thus, one layer of the inhaler assembly is comprised of a polymer composition that does not contain any dehydrating agent and the other layer contains a dehydrating agent. When it is intended to prevent the active substance, adjuvant or formulation from being absorbed by water, the powder inhaler of the present invention provides all of the above advantages, which can be applied to the preparation of inhalable powder by spray drying and/or in an amorphous form. Active substances, adjuvants and formulations. The preferred inhaler of the present invention is, for example, a device of the trade name, as described in, for example, European Patent No. 1,342,483. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The preferred embodiment of the present invention relates to an inhaler comprising a powder for inhaling a pharmaceutical composition and a two-piece capsule, wherein the inhaler is: a) opening the cup-shaped portion τ upward a component having two opposing ports in its casing and having a first hinge member at the edge of the opening and an engagement pin 'b) covering the opening of the lower member and including the second hinge member, 0 a suction chamber for accommodating a capsule, which is configured to be perpendicular to a plane of the flat plate toward the flat side of the lower jaw and provided thereon with a head movable to the opposite side of the spring 126445.doc -36-200831146 a head of two sharp pins, d) a nozzle having a nozzle tube and a third hinge member, and e) a cover including a fourth hinge member, a lower member (1st), a flat plate (2nd), an upper portion The hinge members of the component (3rd) and the cover (4th) are joined together. EXAMPLES As an example, five multi-dose powder inhalers were used to calculate the amount of water that permeates through the walls of the reservoir and the amount of water that may be trapped by the dehydrating agent incorporated therein. Table 1 shows the mass, wall thickness and surface area of all relevant inhaler assemblies. Table 1: Inhaler component size Inhaler Polymer mass [g] Surface area [cm 2] Wall thickness [cm] Budefat White component poly(alkyl terephthalate) 1.5 7.73 0.113 Round assembly random poly ( Propylene) 0.2 0.84 0.076 Pointed assembly random poly(propylene) 0.5 3.77 0.111 CertiHaler container poly(alkyl terephthalate) 1.5 9.27 0.115 cap poly(alkyl terephthalate) 0.8 4.62 0.800 EasyHaler container (Carbonate) 2.9 21.13 0.120 Cover random poly(propylene) 0.8 1.77 0.090 Novolizer container poly(styrene) 2.1 18.78 0.137 lid random poly(propylene) 0.5 1.80 0.117 Turbu-Haler opaque component random poly(propylene) 1.4 8.69 0.074 perforated component random poly(propylene) 0.5 2.79 0.062

The amount of water absorption shown in Table 2 was obtained from the two possible filling concentrations (e.g., 10% by weight and 40% by weight) of the dehydrating agent in the polymer. Calculated by equation (1). 126445.doc 37- 200831146 Table 2: Summary of the mass and water absorption of the shell assembly containing the powder formulation in the selected inhaler. Mass of the inhaler reservoir assembly [g] Mass of the reservoir wall * [g] Water absorption (10% by weight) [mg]** Water absorption (40% by weight) [mg]** Budefat 2.7 2.2 44 175 CertiHaier 2.3 2.3 46 185 EasyHaler 6.7 3.7 74 295 Novolizer 4.0 2.6 52 210 TurbuHaler 1.9 1.8 36 145 *Several components In some cases, the general ** water absorption corresponds to 20% of the dehydrating agent. The intrinsic weight is used in the calculation formula (1) of Table 2: WK = mR.x%.20% (1) WK : Water absorption [g ] mR : mass of the reservoir wall X: The weight percentage of the dehydrating agent assumes the only water passage through the permeation of the component wall. Thus, different amounts of water influx (permeability) of different polymers can be obtained and these amounts are compared to the respective amounts of water absorbed in Table 3. 126445.doc 38- 200831146 Table 3: Comparison of the water absorption of the inhaler component discussed with the water permeating the inhaler via the component wall. Polymer/mass [g] Water absorption (40% by weight) [mg] Each month does not contain Water permeation amount of the dehydrating agent container wall * [亳克] Budefat White component poly(alkyl terephthalate) 120 3,1 Round assembly random poly(propylene) 15 0.1 Point assembly random poly(propylene 40 0.2 CertiHaler container poly(alkyl terephthalate) 120 3.7 Cover poly(alkyl terephthalate) 65 2.7 EasyHaler container poly(carbonate) 230 8.1 Cover random poly(propylene) 65 0.1 Novolizer Container poly(styrene) 170 63.1 Cover random poly(propylene) 40 0.1 Turbu-Haler opaque component random poly(propylene) 110 0.5 perforated component random poly(propyl) 35 0.2

* Wall thickness and chemical identity of the polymer should be considered, according to Polymerhandbook (Brandrup, Wiley-Interscience, 1998) at 25. The calculated permeation amount of 〇 and 75% rh outside (0% rh inside) is used in the calculation formula (2) of Table 3: ^=δΡ:Α^.¥(Η2〇) (2) d RT v } WP : water Permeability [g] Δρ : The difference in gas flow pressure between the outside of the reservoir and the internal measurement, here set to 2411 Pa, corresponding to 75% relative humidity at 25 °C) A ·· Surface of the reservoir assembly t: Penetration time (Set to 30 days in this case) d : Wall thickness of the reservoir assembly P: Permeability coefficient [cm 2 / (s. Pa)] P (poly(styrene)) = 1 〇 -1 (&gt; cm 2 /(s'Pa) 126445.doc -39- 200831146 P(poly(alkyl terephthalate)/poly(carbonate) producing iO-11 cm 2/(s · Pa) P (atactic poly(propylene) ))==10-12 cm 2/(s.Pa) M(H2〇) : 18 g/mole, Mo Mo mass of water: 8·314 J/(Kiol), gas constant τ · 298 K ( 25°c), ambient temperature

Pnorm · 101325 Pa 5 Standard pressure As can be seen from Table 3, the use of dewatering materials is related to preventing the moisture level of the formulation. Assuming that the original sealed reservoir is sealed, even a small amount of dehydrating agent can protect the formulation in all inhalers. However, the water provided by the actual opening of the storage container can also be combined in a large amount by using a dewatering material in the wall of the container. [Simple description of the diagram] Figure 1 is a diagram of the inhaler. [Main component symbol description] Open cup-shaped lower part 2 Port 3 Engagement pin 4 Capsule holder for taper 5 Coil spring 6 Pin 7 Actuating member 8 Recessed seat 9 Flat plate 126445.doc -40- 200831146 ίο Sieve 11 Sieve Gripper 12 nozzle 13 cover 14 closure member 15 inclined side wall 16 groove 17 clamp

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Claims (1)

200831146 X. Patent application scope: A powder inhaler with a moisture sensitive inhalable formulation, characterized in that at least A — _ dehydrated material is included in a part of the end inhaler. The 'personal inhaler of '1' is characterized by the inclusion of a dewatering material in the outer wall of the casing. 3. 4. 5. Incorporate dehydrated material into the capsule chamber of the powder inhaler of claim 1. The powder inhaler of claim 1 incorporates a dewatering material in the blister disk. The powder inhaler of claim 1 is characterized in that the powder inhaler is characterized by the powder inhaler. It is characterized by the inclusion of dehydrated material in the wall of the reservoir vessel of a reservoir-type multi-dose powder inhaler. 2. The powder inhaler of claim 1 wherein the powder inhaler is comprised of a polymer composition comprising at least one thermoplastic polymer, at least one dehydrating agent, optionally at least one elastomer, and/or optionally Plasticizers and / or other fibers. The powder inhaler of the item 6 is characterized in that the dehydrating agent is present in an amount of from 3% by weight to 4% by weight. For example, the powder inhaler of claim 7 is characterized in that the dehydrating agent is present in an amount of from 2% by weight to 30% by weight. The powder inhaler of claim 7 or 8, wherein the dehydrating agent comprises silicone, zeolite, alumina, magnesium sulfate, molecular sieve. 10. A powder inhaler according to any one of the preceding claims, characterized in that it is a systemic/dose or multi-dose powder inhaler. 11. A powder inhaler according to any one of claims 1 to 8 which is characterized in that it is smokable. 7. 7. 8. 9. 126445.doc 200831146 The formulation can be used to treat respiratory discomfort. A powder inhaler according to any one of claims 1 to 8, characterized in that the inhalable formulation is moisture sensitive, which comprises an active anticholinergic agent preferably selected from the following, betamethine Betamimetics, steroids, phosphodiesterase-Ιν·inhibitors, LTD4_antagonists, egfr-kinase inhibitors, dopamine agonists, H1-antihistamines, PAF-antagonists, pi3_ kinase inhibitors, P38 MAP-kinase inhibitors, anti-allergic agents, ergot alkaloid derivatives, triptans, CGRp-antagonists, phosphodiesterase-V-inhibitors, combinations of such active substances, and containing species Or a plurality of pharmaceutical formulations of such active substances. 126445.doc