Inhaler

Inhaler technical field

[0001] The present invention relates to an inhaler for administering powdered medicine from a vesicle cavity, the powdered medicine is in the form of an inhalable substance, a substance preparation or a substance mixture, and the vesicle cavity is opened by a piercing element It is installed in the lower housing part of the housing. The housing is composed of an upper housing part and a lower housing part. The upper housing part is in the form of a mouthpiece and has a suction channel. , The lower shell part has an air inlet opening.

Background technique

[0002] EP 0 911 047 A1 discloses an inhaler for inhaling powdered medicine from a capsule. The inhaler includes a lower portion with two windows and a flat plate in which a capsule seat and an air inlet are located. The suction chamber is further connected with the flat plate, and a tip equipped with two grinding needles and movable by a spring is provided therein. The mouth tube is connected with the upper section of the inhaler, and the cover is connected with the lower section, the flat plate and the upper section in a connected manner. The inhaler has a complicated structure and is used for multiple uses.

[0003] EP 0 835 148 B1 also describes an inhaler for administering drugs from a strip-shaped blister pack, the blister cavity being emptied by means of a squeezing aid. The inhaler basically includes an elongated housing composed of at least two housing parts, which are pivotally connected to each other through a comparative manner, and serve as a support for accommodating the blister strip. The recess is formed in one of the housing parts. The housing has a nozzle on one narrow side and an air inlet on the narrow side opposite to the nozzle, and the air inlet is connected to the nozzle through a gas passage. The gas channel is designed to receive the drug from the vesicle cavity, the drug is released through a pressing piston connected to the housing, when the user of the inhaler squeezes, the pressing out of the piston causes the covering film of the blister cavity to be torn Open, whereby the drug stays in the vesicle cavity or falls into the powder channel of the gas channel. Due to its structure, the inhaler is used for multiple uses.

[0004] In order to effectively inhale the drug, the patient must contact the mouthpiece of the inhaler with the oral mucosa (lip, mouth/pharynx). It was found that there is a problem, that is, the oral mucosa of all people contains a large number of different bacteria and other microorganisms, which may be pathogens. Therefore, the nozzle of the inhaler becomes contaminated during use. The patient and thus the inhaler user is encouraged to clean the nozzle after using the inhaler, but the cleaning behavior is performed in different consistency, taking into account the patient's personal style, his/her age, and the severity of his/her disease. In addition, the inside of the inhaler housing needs to be cleaned, especially to remove drug residues, because if such residues fall off from time to time and are discharged with the actual dose, they can cause regulatory problems (regulatory problems)

[0005] DE 693 19 100 T2 discloses a disposable inhaler activated by breathing. The inhaler includes a tubular housing with two parts forming an air duct, both ends of which are open and one end An air inlet is formed and an air outlet is formed at the other end. The housing has a compartment for storing medicine powder for inhalation, and is equipped with a narrow part adjacent to the compartment to form a turbulent air flow in the narrow part during inhalation, and the turbulent air flow lifts the powder out of the compartment and interacts with it. The air flows are mixed. The compartment is in the form of a recess adjacent to the air inlet, and communicates with the ambient air through a through hole at the bottom of the compartment. The recesses and through holes are covered in an airtight manner by a sealing film, which can be removed from the outside.

Summary of the invention

[0006] An object of the present invention is to provide an inhaler of the type mentioned at the beginning, which is easy to operate by the patient while at the same time

CN 101815552 Β

It has a simple and inexpensive structure.

[0007] According to the present invention, the object is achieved as follows, that is, the inhalation channel of the upper housing part has a unit for dispersing powdered medicine, the unit is connected to the piercing element, and the upper housing part is opposite to the The lower shell part can be moved to open the vesicle cavity.

[0008] The advantage of the inhaler is that it can be manufactured inexpensively for a single use with a small number of independent parts, and only includes absolutely necessary components. The dispersion unit is manufactured integrally with the upper shell part through an injection molding process, or is fixedly and permanently connected to the suction channel through welding, adhesion bonding, pressing or other known joining techniques. The dispersing unit ensures that the drug particles are finely distributed in an inhalable manner in the air inhaled by the user. Due to its design as a single-use inhaler, the inhaler is simple to operate because there is no need for daily cleaning, and drug residues (especially those in the inhalation channel and/or dispersion unit) will not impair drug delivery. The upper casing part (and therefore the nozzle) can be a simple tube form that does not require ergonomic design, and is similar to the lower casing part, and can be made of plastic material. The plastic material is preferably a polymer, a thermoplastic polycondensation product, an addition polymer, a modified natural material or rubber, or a mixture of these plastic materials. Particularly preferred are polyolefin blanks, vinyl chloride polymers, styrene polymers, polyacetal, polyamides, thermoplastic polyesters and polyarylates, or mixtures of these plastic materials. Examples of these plastic materials are polyethylene, polyvinyl chloride, polyoxymethylene, polyacetal propylene M/T diene/styrene (ABS) acrylonitrile/styrene/acrylate (ASA), polyamide, poly Carbonate, poly(ethylene terephthalate), poly(butylene terephthalate) or poly(benzene). These plastic materials The material can be obtained, for example, from the Ensinger company located in Nufringen, Germany.

[0009] Inhalers are known under the trade names HandiHaler®, Spinhaler®, Rotahaler®, Aerolizer®, Flowcaps®'Turbospin®> AIR DPI®, Orbital® and stop]®, and/or in DE 33 45 722, EP 0 591 136, DE 43 18 455, W091/02558, FR-A-2 146 202> US-A-4 069 819, EP 666085, EP869079, US 3, 991, 761, W0 99/45987, W0 20051672 and Bell, J. Pharm. Sci. 60, 1559 (1971); Cox, Bri I. Med. J. 2. Described in 634 (1969). There are known single-dose or multi-dose powder inhalers called powder inhalers, specifically Spinhaler®, Rotahaler®, Aerolizer®, Inhalator®, HandiHaler®, Diskhaler®, Diskus®, Accuhaler®, Aerohaler®, Eclipse® , Turbohaler®, Turbuhaler®, Easyhaler®, Novolizer®, Clickhaler®, Pulvinal®, Novolizer®> Sky eHaler®, Xcelovair®, Pulvina®, Taifun® MAG-haler®, Twisthaler® and Jethaler®»

[0010] The compounds mentioned below can be used alone or in combination in the device of the present invention. In the compounds mentioned below, W is the active ingredient of the drug and is selected from, for example, B mimetic agents, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, H1 -Antihistamine, PAF antagonist and PI3 kinase inhibitor. It can be further combined into a double combination or a triple combination of W and used in the device of the present invention. For example, the combination of W will have: [0011] -W represents a beta mimic in combination with anticholinergics, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists,

[0012] -W represents an anticholinergic in combination with a beta mimic, a corticosteroid, a PDE4 inhibitor, an EGFR inhibitor or an LTD4 antagonist,

[0013] -W represents a corticosteroid in combination with a PDE4 inhibitor, an EGFR inhibitor or an LTD4 antagonist,

CN 101815552 Β

[0014] -W represents a PDE4 inhibitor combined with an EGFR inhibitor or LTD4 antagonist,

[0015] -W represents an EGFR inhibitor combined with an LTD4 antagonist.

[0016] As the β mimetic agent, the compound preferably used is selected from the group consisting of albuterol (albuterol), arformoterol, bambuterol, bitolterol, broxaterol, broxaterol, Carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isobuterol Lin (isoetharine), isoprenaline (isoprenaline), levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenaline, horse Butterol, procaterol, reproterol, rimiterol, ritodrine, salmefamol, Salmeterol, soterenol, sulphonterol, terbutaline >®tiaramide, tolubuterol, nette Luo (zinterol), (CHF-1035> H0KU-8KKUL-1248 and

[0017] -3-(4-{6-[2-Amino-2-(4-Amino-3-methyl-phenyl)-ethylamino]-hexyloxy}-butyl

Yl)-benzyl-sulfonamide,

[0018] -5-[2-6-Diethyl-Dihydropheny-2-ylamino)-1-Hydroxy-ethyl]-8-Hydroxy-1H-siapin-2-one,

[0019] Qinyl-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]-amino}ethyl

Yl]-2(3H)-benzohorne,

[0020] -1-(2-fluoro-4-phenylphenyl)-2-[4-(1-benzimidazoyl)-2-methyl-2-butylamino]ethanol,

[0021] -l-[3-(4-Methoxybenzyl-amino)-4-phenylphenyl]-2-[4-(1-benzimidazoyl)-2-methyl- 2-butylamino]ethanol,

[0022] -1-[2H-5-Vatyl-3-oxo-4H-1,4-benzoxazine-8-yl]~2~[3-(4-N, N-methylamino benzene

Yl)-2-methyl-2-propylamino]ethanol,

[0023] -1-[2Η-5-|5yl-3-oxo-4 1,4-benzoxazine-8-yl]-2-(3-(4-methoxyphenyl)- 2-methyl-2-propylamino]ethanol,

[0024] -1-C2H-5-Hydroxy-3-oxo-4 1,4-benzoxazine-8-yl]-2-[3-(4-n-butoxybenzene

Yl)-2-methyl-2-propylamino]ethanol,

[0025] -1-[2H-5-Hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl]-2-{4-[3-(4-methoxyphenyl )-1,

2,4-Trisidine-3-yl]-2-methyl-2-butylamino}ethanol,

[0026] -5-Hydroxy-8-(1-Hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazine-3-(4H)-one,

[0027] -1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylamino)ethanol,

[0028] -6-Hydroxy-8- {1-Hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}- 4th-benzo[1,4]oxazin-3-one,

[0029] -6-Hydroxy-8- {1-Hydroxy-2-[2-(4-phenoxy-ethyl acetate)1,1-dimethylethylamino]-ethyl}-4 Day-benzo[1,4]oxazin-3-one,

[0030] -6-Hydroxy-8-{1-Hydroxy-2-[2-(4-phenoxyacetic acid)1,1-dimethyl-ethylamino]-ethyl}-4days- Benzo[1,4]oxazin-3-one,

[0031] -8-{2-[1,1-Dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-Hydroxy-ethyl}-6- suspect

CN 101815552 Β

Yl-4H-benzo[1,4]oxazin-3-one,

[0032] -6-Hydroxy-8-{1-Hydroxy-2-[2-(4-Hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4 Day-benzo[1,4]oxazin-3-one,

[0033] -6-Hydroxy-8- {1-Hydroxy-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]-ethyl}- 4th-benzo[1,4]oxazin-3-one,

[0034] -8-{2-[2-(4-Ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-Hydroxy-ethyl}-6-Hydroxy-4H -Benzo[1,4]oxazin-3-one,

[0035] -8-{2-[2-(4-Ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-Hydroxy-ethyl}-6-Hydroxy- 4Η-benzo[1,4]oxazin-3-one,

[0036] -4-(4-{2-[2-Amino-2-(6-Amino-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-8 -Yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid,

[0037] -8-{2-[2-(3,4-Difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-Hydroxy-ethyl}-6-Hydroxy -4Η-benzo[1,4]oxazin-3-one,

[0038] -1-(4-Ethoxy-Pylamino-3-oxy-5-fluorophenyl)-2-(tert-butylamino)ethanol,

[0039] -2-Phenyl-5-(1-Phenyl-2-{2-[4-(2-Phenyl-2-phenyl-ethylamino)-phenyl]-ethylamino}- Ethyl)-benzaldehyde,

[0040] -Ν-[2-Amino-5-(1-doubtyl-2-{2-[4-(2-doubtyl-2-phenyl-ethylamino)-phenyl]-ethyl Aminoethyl)-phenyl]-formamide,

[0041] -8-Hydroxy-5-(1-Hydroxy-2-{2-[4-(6-Methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino} -Ethyl)-1H-sialo-2-one,

[0042] -8-Hydroxy-5-[l-Hydroxy-2-(6-phenylethylamino-hexylamino)-ethyl]-1H-sialo-2-one, [0043]-5 -[2-(2-{4-[4-(2-Amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-Vatyl-ethyl] -8-Wengji-1H-sialo-2-one,

[0044] -[3-(4-{6-[2-Amino-2-(4-Amino-3-methyl-phenyl)-ethylamino]-hexyloxy}-butyl) -5-methyl-phenyl]-service,

[0045] -4-(2-{6-[2-(2,6-Dichloro-benzyloxy)-ethoxy]-hexylamino}-1-Hydroxy-ethyl)-2-GarnetBase-phenol,

[0046] -3-(4-{6-[2-Hydroxy-2-(4-Hydroxy-3-methyl-phenyl)-ethylamino]-hexyloxy}-butyl)- Benzyl sulfonamide,

[0047] -3-(3-{7-[2-Hydroxy-2-(4-Hydroxy-3-methyl-phenyl)-ethylamino]-heptyloxy}-propyl)- Benzyl sulfonamide,

[0048] -4-(2-{6-[4-(3-cyclopentanesulfonyl-phenyl)-butoxy]-hexylamino-doubtylethyl)-2-doubtmethyl-phenol,

[0049] -N-adamantan-2-yl-2-(3-{2-[2-doubt-2-(4-doubt-3-methyl-phenyl)-ethylaminopropyl }-Phenyl)-acetamide,

[0050] Optionally in the form of its racemate, enantiomer, diastereomer, and optionally in the form of its pharmaceutically acceptable acid addition salt, solvate or hydrate. According to the present invention, the preferred acid addition salt of 3 simulants is selected from hydrochloride, hydrobromide, hydroiodide, sulfate/bisulfate, phosphate/hydrogen phosphate, methanesulfonate, nitrate , Maleate/hydrogen maleate, acetate, citrate/hydrogen citrate, fumarate/hydrogen fumarate, tartrate/hydrogen tartrate

CN 101815552 Β

Salt, oxalate/hydrogen oxalate, succinate/hydrogen succinate, benzoate and p-toluenesulfonate.

[0051] As anticholinergics, the compound preferably used is selected from tiotropium salt (tiotropium salt), preferably hydrogen bromide salt; oxitropium salt, preferably hydrogen bromide salt; flutropium salt (flutropium salt), preferably hydrogen bromide; ipratropium salt, preferably hydrogen bromide; glycopyrronium, preferably hydrogen bromide; trospium, preferably salt Salt; tolterodine. In the above-mentioned salts, the cation represents the active ingredient of the drug. The above-mentioned salt may preferably contain hydrochloride, hydrobromide, hydroiodate, sulfate, phosphate, methanesulfonic acid anion, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate. , Succinate, benzoate or p-toluenesulfonate, wherein hydrochloride, hydrobromide, hydroiodate, sulfate, methanesulfonate or p-toluenesulfonate is preferably a counter ion. Among all the salts, hydrochloride, hydrogen bromide, iodide and methanesulfonate are particularly preferred.

[0052] The same preferred anticholinergics are selected from salts of formula AC-1

[0053]

<img file="CN101815552B_D0001.tif" />

[0054] Wherein, X" represents a negatively charged anion, preferably selected from hydrofluorate, hydrochloride, hydrobromide, hydroiodate, sulfate, phosphate, methanesulfonate anion, nitrate, and maleate. , Acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulfonate anions, preferably a monovalent negatively charged anion, particularly preferably selected from hydrofluorate, hydrochloride, Hydrobromide, methanesulfonate anion and p-toluenesulfonate anion, particularly preferably hydrobromide, optionally its racemate, enantiomer or hydrate. A pair of formula AC-1-en Pharmaceutical combinations of enantiomers are particularly preferred,

[0055]

<img file="CN101815552B_D0002.tif" />

AC-1-βη

[0056] Wherein, X" may have the above-mentioned meaning. Other preferred anticholinergics are selected from salts of formula AC-2,

[0057]

<img file="CN101815552B_D0003.tif" />

'AC-2

[0058] Wherein, R may represent methyl or ethyl, and wherein X" may have the above-mentioned meaning. In an alternative embodiment, the formula

The AC-2 compound can also be in the free base form AC-2-base.

CN 101815552 Β

[0059]

<img file="CN101815552B_D0004.tif" />

[0060] Other mentioned compounds are:

[0061] -2,2-diphenyl tropine propionate methyl bromide,

[0062] -2,2-diphenylpropionate methyl bromide,

[0063] -2-fluoro-2,2-diphenylacetic acid ryopin ester methyl bromide,

[0064] 2-fluoro-2,2-diphenyl tropine acetate methyl bromide,

[0065] -3,3,,4,4,-Tropinol-Tetrafluorobenzylglycolate methyl bromide,

[0066] -3,3,,4,4,-tetrafluorobenzylglycol acid benzalkonium bromide,

[0067]-4,4'-difluorobenzylglycolate tropine methyl bromide,

[0068] -4,4'-difluorobenzilate methyl bromide,

[0069] -3, 3'-difluorobenzylglycolate tropine methyl bromide,

[0070]-3,3'-difluorobenzylglycolate methyl bromide,

[0071] -9-Hydroxy-W-9-tropine formate methyl bromide,

[0072] -9-fluoro->-9-tropine formate methyl bromide,

[0073] -9-Hydroxy-W-9-benzopin formate methyl bromide,

[0074] -9-Fluorine->-9-Nyropinate methyl bromide,

[0075] -9-methyl-W -9-tropine formate methyl bromide,

[0076] The methyl bromide of -9-methyl-W-9-formic acid benzoate,

[0077]-cyclopropyltropine diphenylglycolate methyl bromide,

[0078] -2,2-diphenylpropionate cyclopropyltropine methyl bromide,

[0079] -9-Hydroxy-Jyxanthene-9-carboxylate cyclopropyltropine methyl bromide,

[0080] -9-Methyl-W-9-cyclopropyltropine formate methyl bromide,

[0081] -9-methyl-xanthene-9-carboxylate cyclopropyltropine methyl bromide,

[0082] -9-Hydroxy-W-9-cyclopropyltropine formate methyl bromide,

[0083] -4,4'-methyl difluorobenzilate cyclopropyltropine methyl bromide,

[0084] -9-Hydroxy-Jiexanthene-9-tropineol formate methyl bromide,

[0085] -9-Hydroxy-Jiexanthene-9-benzopin formate methyl bromide,

[0086] -9-methyl-xanthene-9-tropine formate methyl bromide,

[0087] The methyl bromide of -9-methyl-xanthene-9-benzopin formate,

[0088] -9-ethyl-xanthene-9-tropine formate methyl bromide,

[0089] -9-difluoromethyl-xanthene-9-tropineol ester methyl bromide,

[0090] The methyl bromide of -9-suspicion-methyl-xanthene-9-benzyl formate.

[0091] The above-mentioned compounds can also be used in the form of salts within the scope of the present invention, in which salt metho-X is used to replace the methyl bromide, wherein X may have the above-mentioned anti-X "The meaning.

CN 101815552 Β

[0092] As corticosteroids, preferably used compounds are selected from beclomethasone (beclomethasone), betamethasone (betamethasone), budesonide (budesonide), butixocort (butixocort), ciclesonide (ciclesonide), Deflazacort, dexamethasone> (etiprednol), flunisolide, fluticasone, loteprednol, mometasone, prednisone Prednisolone> (rofleponide), triamcinolone> RPR-106541, NST26, ST-26 and

[0093] -6,9-Difluoro-17-[(2-Suranylpyridyl)oxy]-11-Hydroxy-16-methyl-3-oxo-androphane-1,

4-diene-17-methionine (S)-fluoromethyl ester,

[0094] -6,9-Difluoro T1-Hydroxy-16-methyl-3-oxo-17-propionyloxy-androphane-1,4-diene-17-methionine (S )-(2-oxo-tetrahydro-furan-3S-yl) ester,

[0095] -6 α, 9 α -Difluoro-11 β yl-16 α -methyl-3-oxo-17 α-(2, 2, 3, 3-tetramethylcyclopropyl dialyl)oxy -Androphane Τ, 4-diene Τ7 Β -oxymethyl carboxylate,

[0096] Optionally in the form of its racemates, enantiomers, diastereomers, and optionally in the form of its salts and derivatives, its solvates or hydrates. Any reference to steroids includes salts or derivatives, hydrates or solvates that can exist. Examples of possible salts and derivatives of the steroids may be: alkali metal salts such as sodium or potassium salts, sulfobenzoates, phosphate/hydrogen phosphate, isonicotinate, acetate, dichloro Acetate, propionate, dihydrogen phosphate, brown thick acid, trimethyl acetate or furoate.

[0097] As a PDE4 inhibitor |, the compound preferably used is selected from enprofyllin (enprofyllin), theophyllin (theophyllin), roflumilast (rof lum setast), cilomilast (arif lo) (cset ondlast), tofimast, pumafentrin, lirimast, arofyllin, atizoram, D-4418 , Bay-198004, BY343, CP-325, 366, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PDT68787, T-440 , T-2585, V-11294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and

[0098] -N- (3,5-Dichloro-1-oxo-pyrino-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide,

[0099] -(i) p-[(4aR*, 10bS*)-9-ethoxy-1,2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzona Phenyl-6-yl]-N, N-diisopropylbenzamide,

-(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidine ketone,

-3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N^z -[N-2-oxy-S-methyl-isothioadenoyl] section

Yl)-2-pyrrolidone,

-Cis [4-oxy-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid],

[0103] -2-Methoxyl-4-oxy-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one,

-Cis [4-oxy-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol],

-(R)-(+)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene] acetate,

-(S)-(-)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene] acetate,

[0107] -9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(2-® phenyl)-9 hepto[3,4-c]-1,2 ,4-Three Jie sit and [4,3-a] adjacent noise,

[0108] -9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9day-pyrido[3,4-men-1,2,4- Three Jie sit and [4,3-a] adjacent noise,

Optionally in its racemate, enantiomer, diastereomeric form, and optionally in its pharmaceutically acceptable acid addition

CN 101815552 Β

In salt, solvate or hydrate form. The acid addition salt of the preferred PDE4 inhibitor according to the present invention is selected from hydrochloride, hydrobromide, hydroiodide, sulfate/bisulfate, phosphate/hydrogen phosphate, methanesulfonate, nitrate , Maleate/hydrogen maleate, acetate, citrate/hydrogen citrate, fumarate/hydrogen fumarate, tartrate/hydrogen tartrate, oxalate/hydrogen oxalate , Succinate/hydrogen succinate, benzoate and p-toluenesulfonate.

[0110] As the LTD4 antagonist LI, the compound preferably used is selected from montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN- 001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321 and

[0111] T-(((R)-(3-(2-(6,7-difluoro-2-sialidyl)vinyl)phenyl)-3-(2-(2-Hydroxy-2 -Propyl)phenyl)thio)methylcyclopropane-acetic acid,

[0112] T-(((1(R)-3 (3-(2-(2,3-dichlorothiopheno[3,2-b]binoyl)-(E)-vinyl) Phenyl-1-methylethyl)phenyl)propyl)sulfanyl)methyl)cyclopropaneacetic acid,

[0113]-[2-[[2-(4-tert-butyl-2-sulphate)-5-benzosionyl]oxymethyl]phenyl]acetic acid,

[0114] Optionally in its racemate, enantiomer, diastereoisomer form, and optionally in its pharmaceutically acceptable acid addition salt, solvate or hydrate form. According to the present invention, these acid addition salts are preferably selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, sulfate/bisulfate, phosphate/hydrogen phosphate, methanesulfonate, nitrate, and sodium hydroxide. Lyric acid/hydrogen maleate, acetate, citrate/hydrogen citrate, fumarate/fumarate, tartrate/hydrogen tartrate, oxalate/hydrogen oxalate, succinic acid Salt/Hydrogen succinate, benzoate and p-toluenesulfonate. Salts or derivatives optionally formed by LTD4 antagonists can be understood as, for example, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts, sulfobenzoates, phosphate/bisulfate, isonicotinate , Acetate, propionate, dihydrogen phosphate, brown thick acid salt, trimethyl acetate or furoate.

[0115] As EGFR inhibitors, preferably used compounds are selected from cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and

[0116] -4-[(3-chloro-4-fluorophenyl)aminomorpho-4-yl)-1-oxo-2-buten-1-yl]-amino} -7-cyclopropylmethyl Oxy-salicylate,

[0117] -4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N, N-dimethylamino)-1-oxo-2-butene T-yl] -Amino} -7-cyclopropylmethoxy-sialidone,

[0118] -4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N, N-dimethylamino)-1-oxo-2-butene T-yl] -Amino} -7-cyclopropylmethoxy-sialidone,

[0119] -4-[(R)-(l-phenyl-ethyl)aminomorpho-4-yl)-1-oxo-2-buten-1-yl]-amino}-7-cyclopentan Oxy-salicylate,

[0120] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-m-4-yl)- 1-Oxy-2-buten-1-yl]amino} -7-cyclopropylmethoxy-sialyl,

[0121] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpho-4-yl)- 1-oxo-2-buten-1-yl]aminotetrahydrofuran-3-yl)oxy]-sialyl, [0122]-4-[(3-chloro-4-fluoro-phenyl )Amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-m-4-yl)-1-oxo-2-buten-1-yl]amino} -7-Cyclopropylmethoxy-Saline,

[0123] -4-[(3-Chloro-4-fluoro-phenyl)amino]-6-[2-($)-6-methyl-2-oxo-morpho-4-yl)-ethoxybase]-7-methoxy-sialidyl,

[0124] -4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-[N-(2-Methoxy-Ethyl)-Tianmethyl-Ammonia

Yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-sialyl,

CN 101815552 Β

[0125] -4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(Ν,Ν-dimethylamino)-1-oxo-2-buten-1-yl ] Amino}-7-cyclopentyloxy-siamidine

[0126] -4-[(R)-(l-phenyl-ethyl)amino]-6-{[4-(N, N-bis-(2-methoxy-ethyl)-amino)- 1-Oxy-2-buten-1-yl]amino} -7-cyclopropylmethoxy-sialyl,

[0127] -4-[(R)-(l-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-tianethyl-ammonia

Yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-sialyl,

[0128] -4-[(R)-(l-Phenyl-ethyl)amino]-6-({4-[N-(2-Methoxy-ethyl)-Tianmethyl-Ammonia

Yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-sialyl,

[0129] -4-[(R)-(l-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-pyranyl-amino

Yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-sialyl,

[0130] -4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(Ν, N-dimethylamino)-1-oxo-2-buten-1-yl ] Amino} -7- ((R)-tetrahydrofuran-3-yloxy)-sialidin,

[0131] -4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(Ν, N-dimethylamino)-1-oxo-2-buten-1-yl ] Amino} -7- ((S)-tetrahydrofuran-3-yloxy)-sialidin,

[0132] -4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-methylamino

Yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-sialyl,

[0133] -4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-methyl-amino)-1-oxo-2-butene T -Amino} -7-cyclopentyloxy-sialyl,

[0134] -4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(Ν, N-dimethylamino)-1-oxo-2-buten-1-yl ] Aminotetrahydrofuran-2-yl)methoxy]-siamidine,

[0135] -4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(Ν, N-dimethylamino)-1-oxo-2-buten-1-yl ] Aminotetrahydrofuran-2-yl)methoxy]-siamidine,

[0136] -4-[(3-Ethydrynyl-phenyl)amino]-6,7-one-(2-methoxy-ethoxy)-sialyl,

[0137] -4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpho-4-yl)-propyloxy]-6-[(vinyl group) Amino]-saliva,

[0138] -4-[(R)-(1-phenyl-ethyl)amino]-6-(4-doubtyl-phenyl)-7days-pyrrolomites, [0139]-3 -Oxy-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(Ν, N-dimethylamino)-1-oxo-2-butene T-yl] Amino} -7-ethoxy-sialo,

[0140] -4-{[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methylsulfonylethyl)amine

Yl]methyl} -pyran-2-yl) sialyl,

[0141] -4-[(R)-(l-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpho-4-yl) -1-oxo-2-butene T-yl]amino} -7-methoxy-sialidyl,

[0142] -4-[(3-chloro-4-fluorophenyl)aminomorpho-4-yl)-1-oxo-2-buten-1-yl]aminotetrahydrofuran-2-yl) Methoxy]- saliva,

[0143] -4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N, N-bis-(2-methoxy-ethyl)-ammonia

Yl]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-siamidine,

[0144] -4-[(3-Ethynyl-phenyl)amino]-6 -{[4-(5,5-dimethyl-2-oxo-morphol-4-yl)-1-oxo -2-buten-1-yl]amino}-siamidine,

[0145] -4-[(3-Chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxy-morazin-4-yl)ethoxy

CN 101815552 Β

base]-7-methoxy-sialidyl,

[0146] -4-[(3-Chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxy-morazin-4-yl)ethoxy Tetrahydropyran-2-yl) methoxy]-sialid,

[0147] -4-[(3-Chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxy-morazin-4-yl)ethoxy Tetrahydropyran-2-yl) methoxyl sialyl,

[0148] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpho-4-yl)-piperidin-1-yl] Ethoxy} -7-methoxy-sialyl,

[0149] -4-[(3-chloro-4-fluoro-phenyl)amino-tert-butoxy dialyl)-piperidin-4-yloxy]-7-methoxy-sialidyl,

[0150] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohex-1-yloxy)-7-methoxy-sialyl Sit down,

[0151] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulfonylamino-cyclohex-1-yloxy)-7-methoxy -Sit down,

[0152] -4-[(3-Chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-sializidine,

[0153] -4-[(3-Chloro-4-fluoro-phenyl)aminomethyl-piperidin-4-yloxy)-7-methoxy-sializidine,

[0154] -4-[(3-Chloro-4-fluoro-phenyl)aminomorpho-4-yl)pyridyl]-piperidin-4-yl-oxy}-7-methoxy-sialyl Sit down,

[0155] -4-[(3-Chloro-4-fluoro-phenyl)aminomethoxymethyl)pyridyl]-piperidin-4-yloxy}-7-methoxy-sialidyl ,

[0156] -4-[(3-Chloro-4-fluoro-phenyl)amino]-6-(piperazin-3-yloxy)-7-methoxy-oxazol,

[0157] -4-[(3-Chloro-4-fluoro-phenyl)amino(2-acetylamino-ethyl)-piperidin-4-yloxy

base]-7-methoxy-sialidyl,

[0158] -4-[(3-Chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-sialyloxy,

[0159] -4-[(3-Chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-Hydroxy-sializidine ,

[0160] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxyethoxy)- Sit down,

[0161] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]-cyclohex-1-yloxy } -7-Methoxy-Saline,

[0162] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morphol-4-yl) dialylamino]-cyclohex-1-yl Oxy} -7-methoxy-sialyl group,

[0163] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpho-4-yl)sulfonylamino]-cyclohex-1-yl Oxy} -7-methoxy-sialyl group,

[0164] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylaminoethoxy)- Sit down,

[0165] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulfonylamino

CN 101815552 Β

-Ethoxy)-sialyl,

[0166] -4-[(3-Chloro-4-fluoro-phenyl)aminopiperidin-1-yl)pyridyl]-piperidin-4-yloxy}-7-methoxy-sialidyl call out,

[0167] -4-[(3-Chloro-4-fluoro-phenyl)amino]-6-(1-amino dialylmethyl-piperidin-4-yloxy)-7-methoxy-sial Sit down,

[0168] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-small-[(tetrahydropyran-4-yl) dialyl]-N-methyl Yl-amino}-cyclohex-1-yloxy)-7-methoxy-sialyloxy,

[0169] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morphol-4-yl) dialyl]-N-methyl -Amino}-Cyclohex-1-yloxy)-7-Methoxy-Saline,

[0170] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpho-4-yl)sulfonyl]-N-methyl -Amino}-Cyclohex-1-yloxy)-7-Methoxy-Saline,

[0171] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulfonylamino-cyclohex-1-yloxy)-7-methoxy -Sit down,

[0172] -4-[(3-Chloro-4-fluoro-phenyl)aminomethanesulfonyl-piperazin-4-yloxy)-7-ethoxy-sializidine,

[0173] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-(2-methoxy- Ethoxy)-saliva,

[0174] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-[l-(2-methoxy-acetyl)-piperazin-4-yloxy

Radical]-7-(2-methoxy-ethoxy)-sialidyl,

[0175] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohex-1-yloxy)-7-methoxy- Sit down,

[0176] -4-[(3-Ethynyl-phenyl)amino tert-butoxy dialyl)-piperidin-4-yloxy]-7-methoxy-sialidyl,

[0177] -4-[(3-Ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-sialyloxy,

[0178] -4-[(3-Chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl) dialyl]-N-methyl -Amino}-Cyclohex-1-yloxy)-7-Methoxy-Saline,

[0179] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-small-[(4-methyl-piperazin-1-yl) dial

Yl]-N-methyl-amino}-cyclohex-1-yloxy)-7-methoxy-sialyloxy,

[0180] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morphol-4-yl) dialylamino]-cyclohex-1-yl Oxy} -7-methoxy-sialyl group,

[0181] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperno-4 -Yloxy} -7-methoxy-sialyl,

[0182] -4-[(3-chloro-4-fluoro-phenyl)aminomorpho-4-yl) dialyl]-piperidin-4-yloxy}-7-(2-methoxy- Ethoxy)-saliva,

[0183] -4-[(3-Ethynyl-phenyl)aminoacetyl-piperazin-4-yloxy)-7-methoxy-sializidine,

[0184] -4-[(3-Ethydrynyl-phenyl)aminomethyl-piperazin-4-yloxy)-7-methoxy-sialyloxy,

[0185] -4-[(3-Ethynyl-phenyl)amino]-6-(1-methylsulfonyl-piperidin-4-yloxy)-7-methoxy-sial

CN 101815552 Β

Sit down,

[0186] -4-[(3-Chloro-4-fluoro-phenyl)aminomethyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-siamidine call out,

[0187] -4- [(3-Chloro-4-fluoro-phenyl)aminoisopropoxy dialyl-piperidin-4-yloxy)~7~methoxy-sializidine,

[0188] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohex-1-yloxy)-7-methoxy- Sit down,

[0189] -4- [(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methylamino] -Cyclohex-1-yloxy}-7-methoxy-sialyloxy,

[0190] -4-[(3-Ethynyl-phenyl)amino]-6-(piperazin-4-yloxy)-7-methoxy-sialidol,

[0191] -4-[(3-Ethyl-phenyl)amino]-6-[l-(2-methoxy-acetyl)-piperazin-4-yloxy

base]-7-methoxy-sialidyl,

[0192] -4-[(3-Ethynyl-phenyl)amino(morpho-4-yl)pyridyl]-piperazino-4-yloxy}-7-methoxy-sialidyl ,

[0193] -4-[(3-Chloro-4-fluoro-phenyl)aminocis-2,6-dimethyl-moxan-4-yl) dial

Yl]-piperazin-4-yloxy}-7-methoxy-sialyloxy,

[0194] -4-[(3-Chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morphol-4-yl) dialyl]-piperidin-4- Oxy group} -7-methoxy-sialyl group,

[0195] ~4-[(3-chloro-4-fluoro-phenyl)amino](S, S)-(2-oxa-5-aza-bicyclo[2. 2. 1] hept-5- Yl)Palyl]-piperidin-4-yloxy}-7-methoxy-sialyloxy,

[0196] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(Ν-methyl-N-2-methoxyethylamino) dial

Yl]-piperazin-4-yloxy}-7-methoxy-sialyloxy,

[0197] -4-[(3-Chloro-4-fluoro-phenyl)aminoethyl-piperidin-4-yloxy)-7-methoxy-e sulfonol,

[0198] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl) dialyl]-piperazin-4-yloxy} -7-Methoxy-Saline,

[0199] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-piperyl]-piperidin-4-yl Oxy} -7-methoxy-sialyl group,

[0200] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulfonyl-N-methyl-amino)-cyclohex-1- Oxy]-7-methoxy-sialidyl,

[0201] -4-[(3-Chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-methyl-amino)-cyclohex-1-yloxybase]-7-methoxy-sialidyl,

[0202] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohex-1-yloxy)~7~methoxy- Sit down,

[0203] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulfonyl-N-methyl-amino)-cyclohex-1- Oxy]-7-methoxy-sialidyl,

-4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohex-1-yloxy)-7-methoxy -Sit down,

[0205] -4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morphol-4-yl) dialyl]-N-methyl

CN 101815552 Β

Yl-amino}-cyclohex-1-yloxy)-7-methoxy-sialyloxy,

[0206] -4-[(3-Chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxy-morpho-4-yl)-ethoxy Yl]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-sializidine,

[0207] -4-[(3-Chloro-4-fluoro-phenyl)aminomethanesulfonyl-piperidin-4-yloxy)-7-methoxy-sializidine,

[0208] -4-[(3-Chloro-4-fluoro-phenyl)amino]-6-(1-oxy-piperazin-4-yloxy)-7-methoxy-sializidine ,

[0209] Optionally in the form of its racemate, enantiomer, diastereomer, and optionally in the form of its pharmaceutically acceptable acid addition salt, solvate or hydrate. According to the present invention, these acid addition salts are preferably selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, sulfate/bisulfate, phosphate/hydrogen phosphate, methanesulfonate, nitrate, and sodium hydroxide. Lyric acid/hydrogen maleate, acetate, citrate/hydrogen citrate, fumarate/fumarate, tartrate/hydrogen tartrate, oxalate/hydrogen oxalate, succinic acid Salt/Hydrogen succinate, benzoate and p-toluenesulfonate.

[0210] As a dopamine agonist, the compound preferably used is selected from bromocriptin, cabergoline, alpha-dihydroergocryptin, lisuride, pergolide, and pragm Pramipexol, roxindol, ropinirol, talipexol, terguride and viozan, optionally its racemate, enantiomer, Diastereoisomeric form, and optionally its pharmaceutically acceptable acid addition salt, solvate or hydrate form. According to the present invention, these acid addition salts are preferably selected from hydrochloride, hydrobromide, hydroiodide, sulfate/bisulfate, phosphate/hydrogen phosphate, methanesulfonate, nitrate, and sodium hydroxide. Lysoate/hydrogen maleate, acetate, citrate/hydrogen citrate, fumarate/fumarate, tartrate/hydrogen tartrate, oxalate/hydrogen oxalate, succinic acid Salt/Hydrogen succinate, benzoate and p-toluenesulfonate.

[0211] As the H1-antihistamine, the compound preferably used is selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, and Carbastine (levocabastine), (loratidine), mizolastine (mizolastine), ketotifen (ketotifen), emedastine (emedastine), dimetindene (dimetindene), clemastine (clemastine), Piper aniline (bamipine), (cexchlorpheniramine), pheniramine (pheniramine), doxylamine (doxylamine), chlorphenoxamine (chlorphenoxamine), dimenhydrinate (dimenhydrinate), diphenhydramine (diphenhydramine), general Promethazine> ebastine, desloratidine and meclozine, optionally its racemates, enantiomers, or diastereomers Structure form, and optionally its pharmaceutically acceptable Acid addition salt, solvate or hydrate form. According to the present invention, these acid addition salts are preferably selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, sulfate/bisulfate, phosphate/hydrogen phosphate, methanesulfonate, nitrate, and sodium hydroxide. Lysoate/hydrogen maleate, acetate, citrate/hydrogen citrate, fumarate/fumarate, tartrate/hydrogen tartrate, oxalate/hydrogen oxalate, succinic acid Salt/Hydrogen succinate, benzoate and p-toluenesulfonate.

[0212] Any inhalable compound, such as an inhalable polymer, such as those disclosed in EP 1 003 478, can be used as a pharmaceutically active substance, substance preparation or substance mixture. Preference is given to the use of substances, substance preparations or substance mixtures used in the field of inhalation for the treatment of respiratory diseases.

[0213] The compound may be further derived from ergot alkaloid derivatives, triptans, CGRP inhibitors, phosphodiesterase V inhibitors, optionally its racemates, enantiomers or Diastereoisomeric form, optionally in the form of a pharmaceutically acceptable acid addition salt, solvate or hydrate.

CN 101815552 Β

[0214] As ergot alkaloid derivatives: dihydroergotamine, ergotamine.

[0215] The piercing element is preferably arranged at a certain distance from the blister, and is arranged at least one first clip connection between the upper housing part and the lower housing part. The locked position and the position defined by at least one second clip connection protrude into the opened vesicle cavity. Due to the connection of the first clip, the upper housing part is firmly fixed at a position relative to the lower housing part: that is, this position can prevent the blister cavity from being unintentionally opened; and because of the second clip connection, it can be The simple operation of the inhaler during inhalation is ensured because the upper housing part is fixedly held on the lower housing part when the blister cavity is opened and the inhaler is dedicated to inhaling medicine.

[0216] In one embodiment, each piercing element has a triangular tip, one piercing element is arranged in the suction channel area, and one piercing element is laterally offset therefrom. The piercing element basically in the form of a knife tip opens the vesicle cavity in such a way that during inhalation, the airflow enters the vesicle cavity through one opening and carries the powdered drug through the other opening into the inhalation channel, and thereby enters the patient. Due to the shape of the piercing element, the user of the inhaler needs to apply a relatively small force to pierce the covering film of the vesicle cavity, thereby ensuring the release rate of the inhaled drug.

[0217] When the inhaler is used only once, it is not absolutely necessary that the piercing element has a long service life, that is, it is suitable for opening a large number of vesicle cavities. Therefore, the piercing element can advantageously be made of plastic material. The piercing elements can be made, for example, of semi-finished products, or, preferably, they can be made integrally with the dispersion unit by, for example, an injection molding process.

[0218] In an alternative embodiment, the piercing element is made of metal. The metal can be a so-called stainless steel, which is used in the medical field and allows the piercing element to be made thinner and sharper than plastic materials, with the result that an even relatively stable covering film covering the vesicle cavity can be pierced.

[0219] The piercing elements are preferably punched out from a plate made of metal and bent toward the plate at an acute angle so that they face the direction of the vesicle cavity. The plate with two piercing elements is easy to handle and install. In addition, the geometry of the piercing elements and their position relative to the covering membrane of the vesicle cavity ensure a relatively large flow opening through which almost all the drug can be discharged from the cavity. The plate is advantageously connected to the dispersion unit in a positive-locking and/or friction-locked manner. The plate may for example be in the form of an insert and can be connected to the unit in an injection molding operation. However, it is also possible to provide a plate with two holes at a distance from each other, through which the plastic pins of the welding unit can pass. Of course, it is also possible that the board is clamped or adhesively bonded to the unit. [0220] The lower housing part advantageously has two opposing clip projections, and the corresponding clip openings enter different planes of the upper housing part. By cooperating with the protruding part of the clip, the opening of the clip determines the opposite of the lower housing part in the transport state of the inhaler (in which the blister cavity is not opened) and the use state (in which the blister cavity is fully opened by the piercing element). In the position of the upper housing part. Said The clip opening and the clip protruding part are simple to manufacture without additional cost, and the user has a touch perception and visual indication of the position of the upper housing part relative to the lower housing part and thus the state of the inhaler. In addition, the size of the clip connection can be such that on the one hand, it can prevent the upper shell part from unintentionally moving relative to the lower shell part to open the vesicle cavity, and on the other hand, the blister cavity can be opened by applying an acceptable force. . In order to reduce the force required to move the upper housing part relative to the lower housing part, the clip protruding part is provided at the free end of the opposing locking arms. To help open the vesicle cavity, the clip opening has the form of a slot in the plane where the vesicle cavity is opened. When the clip protrusion reaches the position of the narrow clip opening, the tip of the piercing element pierces the covering film of the vesicle cavity. When the upper shell part and the lower shell part are squeezed and guided together within the range determined by the slit, a relatively small force is applied to puncture and the blister cavity is opened.

CN 101815552 Β

[0221] The upper housing part is preferably installed to be movable relative to the lower housing part. The movable installation can be implemented simply and is not susceptible to failure. An anti-torsion device can optionally be provided to facilitate installation and operation.

[0222] According to another development mode, the upper housing part has a circular or elliptical cross section and extends conically in the direction of the air outlet, and the lower housing part with a circular or elliptical cross section is installed therein , The air inlet is formed on the free end surface of the lower shell part. The conical form of the cylindrical or elliptical upper housing part ensures that the lips of the user of the inhaler tightly rest on the upper housing part serving as the nozzle, whereby the main airflow is sucked through the inhaler during inhalation. The air outlet on the free end surface of the lower casing part does not interfere with the operation of the inhaler during inhalation, because the casing can be gripped tightly from the periphery. In addition, the relatively simple geometric shapes of the upper housing part and the lower housing part can be manufactured at low cost.

[0223] According to yet another alternative development method, the cross section of each of the upper housing part and the lower housing part is disc-shaped, and the lower housing part is installed in the upper housing part. Therefore, the shell composed of the upper shell part and the lower shell part is basically cylindrical. The easy-to-manufacture disc shape also ensures that the lips rest relatively tightly on the lower housing part.

[0224] In order to use other medicine packaging for dispensing, the blister cavity containing the powdered medicine is preferably set in the holder of the housing by the manufacturer. The vesicle cavity used to receive the drug has proven to be valuable in the context of providing effective protection from environmental influences.

[0225] In order to protect the inhaled medicine and the inhaler from environmental influences, the inhaler is provided with an airtight outer packaging, especially a film container. Such outer packaging is commercially available. Alternatively or additionally, the nozzle and/or the air inlet are tightly closed by a movable cover. The result of these measures is to minimize the packaging cost while protecting the inside of the inhaler containing the medicine from the influence such as moisture that can destroy the medicine.

[0226] In still another embodiment of the present invention, the medicine is stored in the vesicle cavity upstream of the unit for dispersing the powdered medicine as viewed in the flow direction, and enters the inhalation channel of the nozzle through the central hole of the unit The unit has at least one radial inlet communicating with the flow hole leading to the suction channel. During inhalation, the airflow enters the vesicle cavity through one opening and carries the drug through the other opening of the vesicle cavity into the central hole of the unit for dispersing the drug. The air flow entering the unit through the radial inlet is used to make the medicine form a vortex, accompanied by the fine distribution of the medicine powder particles in the flow hole. In the further flow path, the powder particles enter the inhalation channel formed in the upper housing part of the inhaler, and thereby enter the lungs of the user of the inhaler. In order to ensure a high output rate of the medicine, the central hole of the unit is arranged to be aligned with one of the piercing elements.

[0227] In order to generate a high flow rate, the central hole is surrounded by an annular space, air flows through the annular space and an inflow port leads to the annular space, and the outer wall of the flow hole overlaps the inner wall of the annular space.

[0228] In order to generate a directional flow during inhalation, which will form as many small powder particles as possible, two diametrically opposed inlets are provided, the width of which is slightly larger than the diameter of the inner wall. In an alternative embodiment, at least two mutually offset inflow ports are provided to flow channels located on opposite sides of the unit, which communicate with each other. This achieves a relative cyclonic flow. The inner wall preferably has an axial hole for fluid communication between the hole and the flow hole. It is also possible that the unit has a drug guide plate in its flow hole. In another way, the guide plate is fixed on a central ring inserted into the unit. All these measures to direct the airflow are used to form the finest possible powder by pulverizing larger drug particles.

[0229] It will be understood that the features that have been mentioned above and that will be explained below can not only be used in each type of

CN 101815552 Β

The combination described in the situation, but also can be used in other combinations. The scope of the present invention is only determined by the claims.

Description of the drawings

[0230] The present invention is explained in detail below with the aid of exemplary embodiments and with reference to the accompanying drawings, in which:

[0231] FIG. 1 shows a front view of the inhaler of the present invention,

[0232] FIG. 2 shows a cross-sectional view of the inhaler of FIG. 1 along the line II-II,

[0233] FIG. 3 shows a cross-sectional view of the inhaler of FIG. 1 along the line III-III,

[0234] FIG. 4 shows a cross-sectional view of the inhaler of FIG. 1 along the line IV-IV,

[0235] FIG. 5 shows a side view of the inhaler of FIG. 1,

[0236] FIG. 6 shows a cross-sectional view of the inhaler of FIG. 5 along the line VI-VI,

[0237] FIG. 7 shows an enlarged side view reproducing detail VII of FIG. 6,

[0238] FIG. 8 shows a detailed cross-sectional view of FIG. 7 along the line VIII-VIII,

[0239] FIG. 9 shows a detailed cross-sectional view of FIG. 7 along the line IX-IX,

[0240] FIG. 10 shows a detailed cross-sectional view of FIG. 7 along the line XX-X,

[0241] FIG. 11 shows an enlarged side view reproducing detail VII of FIG. 6 in an alternative embodiment,

[0242] FIG. 12 shows a detailed cross-sectional view of FIG. 11 along the line XII-XII,

[0243] FIG. 13 shows a detailed cross-sectional view of FIG. 11 along the line XIII-XIII,

[0244] FIG. 14 shows a detailed cross-sectional view of FIG. 11 along the line XIV-XIV,

[0245] FIG. 15 shows an enlarged side view that reproduces the detail VII of FIG. 6 in a second alternative embodiment,

[0246] FIG. 16 shows a detailed cross-sectional view of FIG. 15 along the line XVI-XVI,

[0247] FIG. 17 shows a detailed cross-sectional view of FIG. 15 along the line XVII-XVII,

[0248] FIG. 18 shows a detailed cross-sectional view of FIG. 15 along the line XVIII-XVIII,

[0249] FIG. 19 shows an enlarged side view that reproduces the detail VII of FIG. 6 in a third alternative embodiment,

[0250] FIG. 20 shows a detailed cross-sectional view of FIG. 19 along the line XX-XX,

[0251] FIG. 21 shows a detailed cross-sectional view of FIG. 19 along the line XX1-XX1,

[0252] FIG. 22 shows a cross-sectional view of the details of FIG. 19 along the line XXII-XXII,

[0253] FIG. 23 shows an enlarged side view that reproduces the detail VII of FIG. 6 in a fourth alternative embodiment,

[0254] FIG. 24 shows a detailed cross-sectional view of FIG. 25 along the line XXIV-XXIV,

[0255] FIG. 25 shows a detailed cross-sectional view of FIG. 25 along the line XXV-XXV, and

[0256] FIG. 26 shows a detailed cross-sectional view of FIG. 25 along the line XXVI-XXVI.

[0257] The inhaler is used to administer a powdered drug from a vesicle cavity that is set by the manufacturer on the support 3, the cross section of the support 3 is disc-shaped and is in line with the lower part of the housing 2. Part 1 is connected. The lower housing part 1 is equipped with two opposite clip protrusions 4, the two opposite clip protrusions 4 are arranged on the free end of the lock arm 7, and enter the nozzle form of the upper housing part 6 different In the corresponding clip opening 5 in the plane. The lower housing part 1 further has an air inlet 9 at the bottom 8 thereof, and when inhaling, the airflow enters the interior of the housing 2 from the surrounding environment through the air inlet 9. When the inhaler is in a transport state, wherein the blister cavity is contained in the housing 2 unopened, the clip protruding portion 4 engages in the clip opening 5 adjacent to the lower housing portion 1 and forms a first clip Connect 10, the current lower shell

CN 101815552 Β

When the part is in such a position relative to the upper housing part 6, the piercing element 11 for opening the vesicle cavity is at a distance from the vesicle cavity. To open the blister cavity, the lower shell part moves relative to the upper shell part, and the clip protrusion 4 engages in the slotted clip opening 5 adjacent to the top end of the upper shell part and forms a second clip connection. Since the first clip connection 10 is connected to the second clip connection, the user of the inhaler can simultaneously observe the state of the blister cavity with naked eyes and tactile prompts. In order to prevent the upper housing part from twisting relative to the lower housing part, they have an elliptical cross-section, and the upper housing part 6 gradually shrinks toward its top end to form an ergonomically favorable contact for the lips of the inhaler user surface.

[0258] The piercing elements 11 are stamped out from the plate 12 made of metal, are separated from each other at a certain distance, and are bent at an acute angle relative to the plate 24, so that they face the support 3 of the blister cavity. In order to form a relatively large opening in the covering film of the vesicle cavity while applying a relatively small force, each piercing element has a triangular tip. The plate 12 is equipped with a central hole 13 in which the central needle 14 of the unit 15 for dispersing powdered medicine is bitten. After applying pressure in a heated state, the central needle 14 tightly fixes the plate 12. The plate 12 is placed in such a way that a piercing element 11 is arranged in the area of the suction channel 16 of the upper housing part 6, and a piercing element 11 is laterally offset therefrom. The separately manufactured unit 15 is fixedly inserted in the suction channel 16 of the nozzle.

[0259] The medicine is stored in the vesicle cavity upstream of the unit 15 for dispersing powdered medicine in the flow direction, and enters the inhalation channel 16 of the nozzle through the central hole 17 of the unit 15 and the inhalation channel 16 Widening in the direction toward the air outlet 18, the central hole 17 is located above the piercing element 11 connected to the suction channel 16 of the upper housing part 6.

[0260] According to FIGS. 7-10, the unit 15 has two inflow ports 19 for air from the surrounding environment on each side. The inflow ports 19 are each offset from the center and offset from each other, and communicate tangentially. The flow hole 20 is connected to the suction channel 16 and appears almost as an extension of the central hole 17. Due to the arrangement of the inflow port 19, a cyclone-shaped turbulent flow is formed in the flow hole 20 during inhalation; this turbulence and the drug-loaded air flow through the central hole 17 ensure the fine distribution of the drug powder particles. [0261] In the unit 15 according to FIGS. 11-14, an inflow port 19 for air from the surrounding environment is also provided on each side, and the inflow ports 19 are each arranged off-center in the unit 15 and offset from each other, It leads tangentially to the flow hole 20 connected to the suction channel 16, and the central hole 17 is in the form of a fan-shaped opening 21 with rounded corners 22.

[0262] The unit 15 according to FIGS. 15-18 is equipped with a deflector plate 23, which is conically above the central hole 17 and extends coaxially with the flow hole 20, the conical guide plate 23 The tip 24 points to the support 3 of the vesicle cavity containing the drug, and the guide plate 23 has a smaller diameter than the flow hole 20, thereby forming an annular space 24 with an inner wall 25 between the central hole 17 and the flow hole 20, The inhaled air flows through the annular space 24, and the outer wall 26 of the flow hole 20 overlaps the inner wall 25 and the guide plate 23 of the annular space 24. The guide plate 23 is connected to the inner wall 25 through the rib 27 to form a peripheral hole 28 so as to flowly connect the central hole 17 and the flow hole 20. In order to create more turbulence in the drug-laden airflow, the two inflow ports 19 are arranged diametrically opposite in the unit 15 and have a width slightly larger than the diameter of the inner wall 25.

[0263] In the unit 15 according to 19-22, the inflow ports 19 for air from the surrounding environment are each arranged off-center in the unit 15 and offset from each other, each embedded on each side and first tangentially leading to the annular space 24, and then lead to the flow hole 20 vertically. As explained above, the guide plate 23 bridged with the center hole 17 is conical and placed coaxially with the center hole 17 and the flow hole 20.

[0264] In the unit 15 according to 23-26, the inflow ports 19 for air from the surrounding environment are each arranged off-center in the unit 15 and offset from each other, each embedded on each side and first tangentially leading to the guide Plate 23 bridged flow

CN 101815552 Β

Moving hole 20. The guide plate 23 is connected to the center ring 29 inserted in the unit 15 through the rib 27. In the area of the center ring 29, the outer diameter of the guide plate 23 is larger than the diameter of the flow hole 20.

[0265] A standard test was performed to compare an inhalation device with a piercing element and an inhalation device with a piercing element and a guide plate. A standard formulation containing BIBW 2948 was used as the test substance. The test was used to study the release of powder. The following results were found.

[0266] Dose: 30 mg of 25% test formulation (7.5 mg active ingredient)

[0267]

<td>test</td><td>1</td><td>2</td>

<td>Inhalation device</td><td>Standard with piercing element and no guide plate</td><td>Standard with piercing element and guide plate</td>

<td>FPD_(4kPa) &lt;μ m/mg(Vk/%)</td><td>1. 5(23. 7)</td><td>1. 9(&amp; 9)</td>

<td>MMAD/um(GSD)</td><td>4. 2(1. 9)</td><td>3. 9(1. 9)</td>

<td>FPD(_lkPa)/FPD(4kp_a)</td><td>0. 27</td><td>0. 56</td>

<td></td><td></td><td></td>

<td>Jie Jie Jie Chen)/%</td><td>20. 5</td><td>24. 7</td>

CN 101815552 Β