CA2653183A1 - Adapter with an attachment for an atomizer - Google Patents
Adapter with an attachment for an atomizer Download PDFInfo
- Publication number
- CA2653183A1 CA2653183A1 CA002653183A CA2653183A CA2653183A1 CA 2653183 A1 CA2653183 A1 CA 2653183A1 CA 002653183 A CA002653183 A CA 002653183A CA 2653183 A CA2653183 A CA 2653183A CA 2653183 A1 CA2653183 A1 CA 2653183A1
- Authority
- CA
- Canada
- Prior art keywords
- atomizer
- amino
- phenyl
- quinazoline
- methoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
- A61M16/08—Bellows; Connecting tubes ; Water traps; Patient circuits
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
- A61M11/006—Sprayers or atomisers specially adapted for therapeutic purposes operated by applying mechanical pressure to the liquid to be sprayed or atomised
- A61M11/007—Syringe-type or piston-type sprayers or atomisers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/0001—Details of inhalators; Constructional features thereof
- A61M15/0021—Mouthpieces therefor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/0065—Inhalators with dosage or measuring devices
Abstract
An adapter comprises an attachment (20) for an atomizer (1) for a fluid (2), in particular one containing a pharamaceutical, as aerosol through an atomizer nozzle (12), wherein the attachment (20) is coupled via a bore (23) to an outlet (22) towards the patient, and an inlet (25) on which a respiratory air tube is to be secured and which is connected to the bore (23) in terms of flow technology in such a way that the main direction of atomization of the fluid (2) is oriented parallel to the direction of flow of a respiratory gas, wherein an opening (27) extending parallel to the bore (23) in the direction of the atomizer (1) is let into a passage (24) assigned to the inlet (25). The opening (27) extends into an area facing towards the atomizer (1) and behind the atomizer nozzle (12).
Description
Adapter with an attachment for an atomizer Specification The invention relates to an adapter with an attachment for an atomizer for a fluid, particu-larly one that contains a medicament, as an aerosol through an atomizer nozzle, wherein the attachment is coupled via a bore to an outlet on the patient side, and with an inlet for a respiratory air tube to be attached thereto that is fluidically connected to the bore such that the main direction of atomisation of the fluid extends parallel to the direction of flow of a respiratory gas, while an opening running parallel to the bore in the direction of the atom-izer is provided in a breach associated with the inlet.
Ventilators are used to supply a patient with a respiratory gas through at least one gas-carrying tube. For example, in the case of a ventilated patient with an inflammatory lung disease such as asthma or COPD ("chronic obstructive pulmonary disease"), there is a need to administer a medicament by inhalation. In these patients, topical treatment in the lungs is often advantageous in order to reduce systemic side-effects. However, it may also be necessary, or therapeutically desirable, to deliver a drug to a ventilated patient for systemic action by the inhalative route.
WO 02/089887 Al discloses a T-shaped adapter for the removable attachment of an atom-izer in a ventilation circuit, in which the adapter has a housing with an upper section hav-ing a first passage therein and a lower section having a second passage adjacent to the first passage. Between the first passage and an inner wall surface of the upper section there is a spring chamber with a spring and a valve seat is formed on an upper edge of the upper sec-tion. The reciprocating valve comprises a valve actuator which is movably accommodated in the second passage and comprises an upper surface for actuating the spring and a valve portion attached to the valve actuator.
In addition, WO 2004/098689 discloses a nebuliser attachment device for connecting a nebuliser to a respiratory air tube of a ventilator, which comprises a respiratory air guiding device with a first connecting device for attaching a breathing line that supplies the respira-tory air. A second connecting device is provided for attaching a breathing line that carries away the respiratory air and a third connecting device serves to attach a nebuliser. A clo-sure device is mounted on the third connecting device, by means of which, when the nebu-liser is connected up, a flow path for an aerosol produced by the nebuliser can be closed off. A closure member is opened when the nebuliser is attached and closed when it is re-moved. The nebuliser connecting device has a disadvantage in that the aerosol produced by the nebuliser is introduced into the tube carrying the respiratory gas in a direction per-pendicular to the direction of flow of the respiratory gas, the angle of entry of the aerosol into the tube carrying the respiratory gas causing a significant impact, with the result that the active substance dissolved in the aerosol is precipitated in the tube, leading to under-dosing of the patient being treated with the active substance.
Moreover, the Journal of Pharmacological and Toxicological Methods 50 (2004) 109-119, ELSEVIER, discloses an adapter with an attachment for a nebuliser located opposite an outlet on the patient side, while an input for the respiratory air tube to be attached thereto starts from the common opening with the attachment and the outlet and a flow channel is formed such that the main direction of atomization of a medicament runs parallel to the di-rection of flow of a respiratory gas. However, no further details on the configuration of the flow channel and the internal construction of the adapter can be inferred from this publica-tion.
Finally, EP 0 521 061 B1 discloses a metering device for delivering a measured amount of a liquid as a spray with droplets of a size suitable for inhalation into the lungs, by deliver-ing the measured amount of liquid through an atomizer that comprises a chamber for hold-ing the measured amount of liquid, an energy store and means for delivering a predeter-mined amount of energy to the energy store. In addition, means are provided for releasing the predetermined amount of energy from the energy store to the chamber, so as to subject the liquid contained therein to a predetermined rise in pressure, from a low pressure to a higher pressure, and initiate the release of the liquid from the chamber. An atomizer serves to atomize the measured amount of pressurised liquid.
The compounds listed below may be used in the device according to the invention on their own or in combination. In the compounds mentioned below, W is a pharmacologically active substance and is selected (for example) from among the betamimetics, anticholiner-gics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine ago-nists, H1-antihistamines, PAF-antagonists and P13-kinase inhibitors. Moreover, double or triple combinations of W may be combined and used in the device according to the inven-tion. Combinations of W might be, for example:
- W denotes a betamimetic, combined with an anticholinergic, corticosteroid, inhibitor, EGFR-inhibitor or LTD4-antagonist, - W denotes an anticholinergic, combined with a betamimetic, corticosteroid, inhibitor, EGFR-inhibitor or LTD4-antagonist, - W denotes a corticosteroid, combined with a PDE4-inhibitor, EGFR-inhibitor or LTD4-antagonist - W denotes a PDE4-inhibitor, combined with an EGFR-inhibitor or LTD4-antagonist - W denotes an EGFR-inhibitor, combined with an LTD4-antagonist.
The compounds used as betamimetics are preferably compounds selected from among al-buterol, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ri-todrine, salmefamol, salmeterol, soterenol, sulphonterol, terbutaline, tiaramide, tolubuterol, zinterol, CHF-1035, HOKU-81, KUL-1248 and - 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulphonamide - 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1 H-quinolin-2-one - 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3 H)-benzothiazolone - 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]
ethanol - 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino] ethanol - 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino] ethanol - 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol - 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino] ethanol - 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-3 5 triazol-3-yl]-2-methyl-2-butylamino} ethanol - 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one - 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol - 6-hydroxy-8- { 1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl } -4H-benzo[ 1,4]oxazin-3-one - 6-hydroxy-8- { 1-hydroxy-2-[2-( ethyl 4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl } -4H-benzo[ 1,4]oxazin-3-one - 6-hydroxy-8- { 1-hydroxy-2-[2-(4-phenoxy-acetic acid)-1,1-dimethyl-ethylamino]-ethyl } -4H-benzo [ 1,4] oxazin-3-one - 8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo [ 1,4] oxazin-3 -one - 6-hydroxy-8- { 1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl } -4H-benzo[ 1,4]oxazin-3-one } -- 6-hydroxy-8- { 1-hydroxy-2-[2-(4-isopropyl-phenyl)-1.1 dimethyl-ethyl amino]
-ethyl 4H-benzo[ 1,4]oxazin-3-one - 8- {2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl } -6-hydroxy-4H-benzo [ 1 ,4] oxazin-3 -one - 8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one - 4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid - 8-{2-[2-(3.4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-2 0 4H-benzo[ 1,4]oxazin-3-one - 1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol - 2-hydroxy-5-(1-hydroxy-2- {2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino } -ethyl)-benzaldehyde - N-[2-hydroxy-5-(1-hydroxy-2- {2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-2 5 ethylamino } -ethyl)-phenyl]-formamide - 8-hydroxy-5-(1-hydroxy-2- {2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino } -ethyl)-1 H-quinolin-2-one - 8-hydroxy-5-[ 1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1 H-quinolin-2-one - 5-[2-(2- {4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl } -ethylamino)-3 0 hydroxy-ethyl]-8-hydroxy-1 H-quinolin-2-one - [3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxyrnethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-5-methyl-phenyl]-urea - 4-(2-{6-[2-(2,6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol 35 - 3-(4- {6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-b enzyl sulphonami de - 3-(3-{7-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}-propyl)-benzylsulphonamide - 4-(2-{6-[4-(3-cyclopentanesulphonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxym ethyl-phenol - N-Adamantan-2-yl-2-(3- {2-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl } -phenyl)-acetamide optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention the acid addition salts of the betamimetics are prefera-bly selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hy-drophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hy-drocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
The anticholinergics used are preferably compounds selected from among the tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, glycopyr-ronium salts, preferably the bromide salt, trospium salts, preferably the chloride salt, tolterodine. In the above-mentioned salts the cations are the pharmacologically active con-stituents. As anions the above-mentioned salts may preferably contain the chloride, bro-mide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate, while chloride, bromide, iodide, sulphate, methanesulphonate or p-toluenesulphonate are preferred as counter-ions. Of all the salts the chlorides, bromides, iodides and methanesulphonates are particularly preferred.
Other preferred anticholinergics are selected from among the salts of formula ~/_N O
0-0 .
x AC-wherein X - denotes an anion with a single negative charge, preferably an anion selected from among the fluoride, chloride, bromide, iodide, sulphate, phosphate, methanesulpho-nate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate, preferably an anion with a single negative charge, particularly pref-erably an anion selected from among the fluoride, chloride, bromide, methanesulphonate and p-toluenesulphonate, particularly preferably bromide, optionally in the form of the ra-cemates, enantiomers or hydrates thereof. Of particular importance are those pharmaceuti-cal combinations which contain the enantiomers of formula AC-1-en NLD
-en wherein X - may have the above-mentioned meanings. Other preferred anticholinergics are selected from the salts of formula AC-2 ~
OH
R X
wherein R denotes either methyl or ethyl and wherein X - may have the above-mentioned meanings. In an alternative embodiment the compound of formula AC-2 may also be pre-sent in the form of the free base AC-2-base.
~
OH
\ N
/
AC-2-base Other specified compounds are:
- tropeno12,2-diphenylpropionate methobromide, - scopine 2,2-diphenylpropionate methobromide, - scopine 2-fluoro-2,2-diphenylacetate methobromide, - tropenol 2-fluoro-2,2-diphenylacetate methobromide;
- tropenol 3,3',4,4'-tetrafluorobenzilate methobromide, CA 02653183 2008-11-24 pCT PO1_2029 - scopine 3,3',4,4'-tetrafluorobenzilate methobromide, - tropenol 4,4'-difluorobenzilate methobromide, - scopine 4,4'-difluorobenzilate methobromide, - tropeno13,3'-difluorobenzilate methobromide, - scopine 3,3'- difluorobenzilate methobromide;
- tropenol 9-hydroxy-fluorene-9-carboxylate methobromide;
- tropenol 9-fluoro-fluorene-9-carboxylate methobromide;
- scopine 9-hydroxy-fluorene-9-carboxylate methobromide;
- scopine 9-fluoro-fluorene-9-carboxylate methobromide;
- tropenol 9-methyl-fluorene-9-carboxylate methobromide;
- scopine 9-methyl-fluorene-9-carboxylate methobromide;
- cyclopropyltropine benzilate methobromide;
- cyclopropyltropine 2,2-diphenylpropionate methobromide;
- cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide;
- cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide;
- cyclopropyltropine 9-methyl-xanthene-9-carboxylate methobromide;
- cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide;
- cyclopropyltropine methy14,4'-difluorobenzilate methobromide.
- tropenol 9-hydroxy-xanthene-9-carboxylate methobromide;
- scopine 9-hydroxy-xanthene-9-carboxylate methobromide;
- tropenol 9-methyl-xanthene-9-carboxylate methobromide;
- scopine 9-methyl-xanthene-9-carboxylate methobromide;
- tropenol 9-ethyl-xanthene-9-carboxylate methobromide;
- tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide;
- scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide, The above-mentioned compounds may also be used as salts within the scope of the present invention, wherein instead of the methobromide the salts metho-X are used, wherein X
may have the meanings given hereinbefore for X-.
As corticosteroids it is preferable to use compounds selected from among beclomethasone, betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etipred-nol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, roflepon-ide, triamcinolone, RPR-106541, NS-126, ST-26 and - (S)-fluoromethy16,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-l6-methyl-3-oxo-androsta-1,4-diene-l7-carbothionate - (S)-(2-oxo-tetrahydro-furan-3S-yl)6,9-difluoro-ll-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-l7-carbothionate, g - cyanomethy16a,9a-difluoro-11(3-hydroxy-16a-methyl-3-oxo-17a-(2,2,3,3-tertamethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17(3-carboxylate optionally in the form of the racemates, enantiomers or diastereomers thereof and option-ally in the form of the salts and derivatives thereof, the solvates and/or hydrates thereof.
Any reference to steroids includes a reference to any salts or derivatives, hydrates or sol-vates thereof which may exist. Examples of possible salts and derivatives of the steroids may be: alkali metal salts, such as for example sodium or potassium salts, sulphobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
PDE4-inhibitors which may be used are preferably compounds selected from among en-profyllin, theophyllin, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, arofyllin, atizoram, D-4418, Bay-198004, BY343, CP-325.366, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V-11294A, C1-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and - N-(3,5-dichloro-l-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide - (-)p-[(4aR*,I ObS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s] [ 1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide - (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone - 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone - cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid]
- 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxy-2 5 phenyl)cyclohexan-l-one - cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l-ol]
- (R)-(+)-ethyl [4-(3 -cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]
acetate - (S)-(-) -ethyl [4-(3 -cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]
acetate - 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine - 9-cyclopentyl-5,6-dihydro-7-ethyl-3 -(tert-butyl)-9H-pyrazolo [3,4-c] -1,2,4-triazolo[4,3 -a]pyridine optionally in the form of the racemates, enantiomers or diastereomers thereof and option-ally in the form of the pharmacologically acceptable acid addition salts thereof, the sol-vates and/or hydrates thereof. According to the invention the acid addition salts of the PDE4 inhibitors are preferably selected from among the hydrochloride, hydrobromide, hy-driodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydro-maleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuc-cinate, hydrobenzoate and hydro-p-toluenesulphonate.
The LTD4-antagonists used are preferably compounds selected from among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321 and - 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2- hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic acid, - 1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-l-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid - [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl] oxymethyl]phenyl] acetic acid optionally in the form of the racemates, enantiomers or diastereomers thereof and option-ally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof. According to the invention these acid addition salts are preferably se-lected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydro-phosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocit-rate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate. By salts or derivatives which the LTD4-antagonists may optionally be capable of forming are meant, for example: alkali metal salts, such as for example so-dium or potassium salts, alkaline earth metal salts, sulphobenzoates, phosphates, isonicoti-nates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
EGFR-inhibitors which may be used are preferably compounds selected from among cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]-2 5 amino} -7-cyclopropylmethoxy-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]-amino } -7-cyclopropylmethoxy-quinazoline - 4-[(3 -chloro-4- fluorophenyl) amino] - 6- { [4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl] amino } -7-cyclopropylmethoxy-quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-cyclopentyloxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl] amino } -7-cyclopropylmethoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6- { [4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6- { [4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl] amino } -7-cyclopropylmethoxy-quinazoline CA 02653183 2008-11-24 pC.r PO 1-2029 - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy] -7-methoxy-quinazo line - 4-[(3-chloro-4-fluorophenyl)amino]-6-( {4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-l-yl } amino)-7-cyclopropylmethoxy-quinazoline 5 - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl] amino } -7-cyclopentyloxy-quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6- { [4-(N,N-to-(2-methoxy-ethyl)-amino)-1-oxo-buten-l-yl] amino } -7-cyclopropylmethoxy-quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-1 o buten-l-yl } amino)-7-cyclopropylmethoxy-quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-l-yl } amino)-7-cyclopropylmethoxy-quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-( {4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-l-yl } amino)-7-cyclopropylmethoxy-quinazoline - 4-[(3 -chloro-4-fluorophenyl)amino] -6- { [4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl] amino } -7-((R)-tetrahydrofuran-3 -yloxy)-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl] amino } -7-((S)-tetrahydrofuran-3 -yloxy)-quinazoline - 4- [(3 -chloro-4-fluorophenyl)amino] -6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-2 0 oxo-2-buten-l-yl } amino)-7-cyclopentyloxy-quinazoline - 4-[(3 -chloro-4-fluorophenyl)amino]-6-{ [4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-l-yl] amino } -7-cyclopentyloxy-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl] amino } -7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl] amino } -7- [(S)-(tetrahydrofuran-2-yl)methoxy] -quinazoline - 4-[(3-ethynyl-phenyl)amino]-6.7-to-(2-methoxy-ethoxy)-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-.yl)-propyloxy]-6-[(vinyl-carbonyl) amino] -quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine - 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl] amino } -7-ethoxy-quinoline - 4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl } -furan-2-yl)quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl] amino } -7-methoxy-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-l-yl]-amino } -7-[(tetrahydrofuran-2-yl)methoxy] -quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-to-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-l-yl } amino)-7- [ (tetrahydro furan-2-yl)methoxy] -quinazo line - 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-buten-l-yl] amino } -quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy] -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy] -7-[(R)-(tetrahydrofuran-2-yl)methoxy] -quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-l-yl]-ethoxy} -7-methoxy-quinazoline - 4- [(3-chloro-4-fluoro-phenyl)amino]-6-[ 1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6-(tetrahydropyran-3 -yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6- { 1-[(morpholin-4-yl)carbonyl]-piperidin-4-yl-oxy} -7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6- { 1-[(methoxymethyl)carbonyl]-piperidin-4-yl-oxy} -7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6-(piperi din-3 -yloxy)-7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline - 4- [ (3 -chloro-4-fluoro-phenyl) amino] -6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino] -6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6- {trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-l-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6- {trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-l-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6- {trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-l-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-l-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3 -chloro-4-fluoro-phenyl) amino] -6-(cis-4- {N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino } -cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4- [ (3 -chloro-4-fluoro-phenyl) amino] -6-(cis-4- {N-[(morpholin-4-yl)carbonyl]-N-methyl-amino } -cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6-(cis-4- {N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino } -cyclohexan-1-yloxy)-7-methoxy- quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-l-2 0 yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-ethoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[ 1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-l-yloxy)-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-[ 1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-3 0 methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-l-yl)carbonyl]-N-methyl-amino } -cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3 -chloro-4-fluoro-phenyl)amino] -6-(cis-4- {N-[(4-methyl-piperazin-l-yl)carbonyl]-3 5 N-methyl-amino } -cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4- [ (3 -chloro-4-fluoro-phenyl) amino] -6- {cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-l-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6- { 1-[2-(2-oxopyrrolidin-l-yl)ethyl]-piperidin-4-yloxy} -7-methoxy-quinazoline - 4-[(3 -chloro-4-fluoro-phenyl) amino] -6- { 1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy} -7-(2-methoxy-ethoxy)-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-1 o ethoxy)-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-l-yloxy)-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6- {cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-l-yloxy} -7-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-[ 1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6- { 1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline - 4- [ (3 -chloro-4-fluoro-phenyl) amino] -6- { 1-[(cis-2,6-dimethyl-morpholin-yl)carbonyl]-piperidin-4-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6- { 1-[(2-methyl-morpholin-4-yl)carbonyl]-2 5 piperidin-4-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6- { 1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1 ]hept-5-yl)carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6- { 1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6- { 1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6- { 1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-l-yloxy]-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)ami:lo]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-l-yloxy]-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4- {N-[(morpholin-4-yl)carbonyl]-N-methyl-amino } -cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4- [ (3 -chloro-4-fluoro-phenyl) amino] -6- [2 -(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7- [ (S)-(tetrahydrofuran-2-yl)methoxy] -quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention these acid addition salts are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hy-dromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofu-marate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
The dopamine agonists used are preferably compounds selected from among bromocriptin, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol, ropini-rol, talipexol, tergurid and viozan, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention these acid addition salts are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hy-droacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydro-benzoate and hydro-p-toluenesulphonate.
H 1-Antihistamines which may be used are preferably compounds selected from among epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ke-totifen, emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, pro-methazine, ebastine, desloratidine and meclozine, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention these acid addition salts are preferably selected from among the hydrochloride, hydrobro-5 mide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hy-drosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
Any inhalable compounds, including also inhalable macromolecules as disclosed in EP 1 10 003 478, may be used as pharmaceutically effective substances, formulations or mixtures of substances. Preferably, substances, formulations or mixtures of substances administered by inhalation may be used for treating respiratory complaints.
In addition, the compound may come from the groups of ergot alkaloid derivatives, the 15 triptans, the CGRP-inhibitors, the phosphodiesterase-V inhibitors, optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharma-cologically acceptable acid addition salts, the solvates and/or hydrates thereof.
Examples of ergot alkaloid derivatives are dihydroergotamine and ergotamine.
The aim of the invention is to provide an adapter of the type mentioned hereinbefore, which while being of simple construction ensures optimum introduction of a generated aerosol into a tube for ventilating an, in particular, human patient.
According to the invention the aim is achieved by the fact that the opening extends into an area facing the atomizer behind the atomizer nozzle.
The atomizer, in the form of an inhaler, is attached to the adapter for a ventilator system such that a flow channel for the respiratory gas is provided, which ensures that the entire dose of the atomized fluid, i.e. the full amount of aerosol generated by the atomizer, is conveyed by the respiratory gas to the patient, as a result of the respiratory gas behind the atomizer nozzle being conveyed into the corresponding flow channel and thereby carrying the spray mist with it. The aerosol generated by the atomizer is absorbed immediately at its place of origin by the respiratory gas flowing through the adapter and is conveyed with low impact in the tube to the ventilated patient, as the main direction of atomization of the fluid runs parallel to the direction of flow of the respiratory gas.
Accordingly, the venti-lated patient is supplied with dissolved active substances in aerosol form and long-term in-halative medication provided by the atomizer can be continued once the patient has been hooked up to the ventilation system, or medication or the administration of active sub-stances to the patient connected to the ventilator system can take place. A
ventilation mask or a tracheal tube or the like may be connected to the outlet on the patient side, in a manner known from the prior art.
According to one feature, the attachment for the atomizer may be partially matched in its geometry to a mouthpiece of the atomizer into which the atomizer nozzle projects which comprises in its wall, in an area remote from the inhalation opening; at least one cut-out which is fluidically connected to the opening for the respiratory gas.
Accordingly, when a patient is treated further with a ventilator system, the atomizer can be used, and it can be used even without the ventilator system. Preferably, the mouthpiece is provided with two opposing cut-outs through which the respiratory gas or the air sucked in automatically by the patient flows, in order to inhale for example particles of the medicament which are des-tined for the lungs.
Preferably, the attachment for the atomizer rests on a shoulder of the atomizer. The at-tachment may be fixed in sealed manner to the for example cylindrical shoulder of the at-omizer.
Preferably, the opening in the region of the mouthpiece is in the form of a groove. The groove is relatively easy to produce and once the mouthpiece has been placed in the at-tachment the groove forms with a corresponding wall of the mouthpiece a flow channel which is closed around its circumference.
Expediently, the breach associated with the inlet for the respiratory gas runs perpendicu-larly to the bore. The respiratory gas accordingly passes into the breach, is diverted at the end of it into the flow channel formed by the groove and the corresponding wall of the mouthpiece, flows through the cut-outs into the mouthpiece in which it changes direction once again, and carries the aerosol generated by the atomizer nozzle in the mouthpiece through the bore, so as to supply the patient both with respiratory gas and with the me-dicament.
According to a further feature, at least one valve is provided which fluidically separates the atomiser from the respiratory gas and carries the respiratory gas from the inlet directly to the outlet on the patient side. Thus, the ventilation of the patient may be effected either through the atomizer or directly.
Preferably, the atomizer for the adapter described hereinbefore is designed to deliver a spe-cific amount of the fluid, which contains in particular a medicament, in the form of an aerosol through the atomizer nozzle provided inside the mouthpiece, from a pressure store, while a mechanical pressure generator acts on the measured amount of fluid in the pressure store which is to be released abruptly for atomization, and the mouthpiece comprises at least one opening which, when viewed in the direction of atomisation, is formed behind the nozzle. Preferably, the pressure generator comprises a holder for a replaceable storage container that holds the fluid, an associated drive spring with a release button and a con-veying tube, while axial tensioning of the drive spring shifts the holder with the storage container and the conveying tube in an opposite direction to the mouthpiece, and sucks fluid out of the storage container into a pressure chamber and actuation of the release but-ton causes relaxation of the tensioned drive spring which moves the conveying tube in the direction of the mouthpiece and at the same time acts on the fluid to expel it through the atomiser nozzle under pressure. Advantageously, the atomiser nozzle comprises a filter system for producing two spray jets that meet to produce a spray mist.
It will be appreciated that the features mentioned hereinbefore and those still to be de-scribed hereinafter may be used not only in the particular combination specified but also in other combinations. The scope of the invention is defined only by the claims.
The invention is explained in more detail hereinafter by an illustrative embodiment with reference to the associated drawings, wherein:
3 o Fig.1 is a partial view of a longitudinal section through an adapter according to the invention and Fig.2 is a sectional view of an atomizer for use with the adapter according to Fig. 1.
The atomizer 1 serves to atomize a fluid 2, in particular a highly effective medicament or the like, and is constructed as a portable inhaler that operates without propellant gas.
When the fluid 2, preferably a liquid, is atomised, an aerosol is formed that can be breathed in by a user (not shown).
The atomizer 1 has a replaceable storage container 3 with the fluid 2, which is substantially cylindrical or cartridge-shaped and can be inserted in the opened atomizer 1 from below.
In the rigid storage container 3 is a bag 4 that holds the fluid 2. For atomizing the fluid 2 in a predetermined adjustable amount, the atomizer 1 comprises a pressure generator 5 1 o having a holder 6 for the container 3, a drive spring 7 with a release button 8 which is to be operated manually to release the tension, a conveying tube 9 with a non-return valve 10 inserted therein, a pressure chamber 11 and an atomizer nozzle 12 with an associated mouthpiece 13.
When the drive spring 7 is axially tensioned by rotating a lower housing part 18 with an inner part 17 releasably attached thereto, relative to an upper housing part 16 formed on the mouthpiece 13, the holder 6 with the storage container 3 and the conveying tube 9 is moved downwards and fluid is sucked out of the container 3 through the non-return valve 10 into the pressure chamber 11 of the pressure generator 5. During the subsequent abrupt 2 o relaxation of the drive spring 7 by the actuation of the release button 8, the fluid 2 in the pressure chamber 11 is put under pressure by the drive spring 7 moving the conveying tube 9 upwards and is expelled through the nozzle 12, whereupon atomization takes place. The atomization results, for example, in particles in the m or nm size range, preferably lung-bound particles about 5 m in size, which form a mist or jet of aerosol. A
user can inhale the aerosol, while supply air or respiratory gas can be taken in via cut-outs 15 in the mouthpiece 13.
In order to be able to administer the fluid 2 as an aerosol in conjunction with a ventilator system for a patient, particularly a human, the adapter 19 is provided, which has an at-tachment 20 for the atomizer 1, the attachment 20 having a region 21 which is adapted in its geometry to the mouthpiece 13 of the atomizer 1. Opposite the attachment 20, the adapter 19 has an outlet 22 on the patient side which is fluidically connected to the attach-ment 20 through a bore. For coupling to a respiratory air tube, the adapter 19 is provided with ari inlet 25 that comprises a passage 24, while the inlet 25 of cylindrical cross-section is aligned with the passage 24 extending coaxially thereto at right angles to the bore 23.
The passage 24 which is in the form of a blind hole terminates in an opening 27 in the form of a groove 26 which runs parallel to the bore 23 and extends as far as the cut-outs 15 in the mouthpiece 13 that are located underneath the atomiser nozzle 12.
The respiratory gas passes from the respiratory air tube into the breach 24 and at its end is diverted into the flow channel formed by the groove 26 and a corresponding wall of the mouthpiece 13, at the end of which the respiratory gas passes through the cut-outs 15 into 1 o the mouthpiece 13. In the mouthpiece 13 the respiratory gas is again diverted in its direc-tion of flow underneath the atomizer nozzle 12 and carries the aerosol generated by the at-omizer nozzle 12 in the mouthpiece 13 through the bore 23, to supply the patient both with respiratory gas and with the medicament, while inside the mouthpiece 13 the main direc-tion of atomization of a medicament is aligned parallel to the direction of flow of the respi-ratory gas.
Ventilators are used to supply a patient with a respiratory gas through at least one gas-carrying tube. For example, in the case of a ventilated patient with an inflammatory lung disease such as asthma or COPD ("chronic obstructive pulmonary disease"), there is a need to administer a medicament by inhalation. In these patients, topical treatment in the lungs is often advantageous in order to reduce systemic side-effects. However, it may also be necessary, or therapeutically desirable, to deliver a drug to a ventilated patient for systemic action by the inhalative route.
WO 02/089887 Al discloses a T-shaped adapter for the removable attachment of an atom-izer in a ventilation circuit, in which the adapter has a housing with an upper section hav-ing a first passage therein and a lower section having a second passage adjacent to the first passage. Between the first passage and an inner wall surface of the upper section there is a spring chamber with a spring and a valve seat is formed on an upper edge of the upper sec-tion. The reciprocating valve comprises a valve actuator which is movably accommodated in the second passage and comprises an upper surface for actuating the spring and a valve portion attached to the valve actuator.
In addition, WO 2004/098689 discloses a nebuliser attachment device for connecting a nebuliser to a respiratory air tube of a ventilator, which comprises a respiratory air guiding device with a first connecting device for attaching a breathing line that supplies the respira-tory air. A second connecting device is provided for attaching a breathing line that carries away the respiratory air and a third connecting device serves to attach a nebuliser. A clo-sure device is mounted on the third connecting device, by means of which, when the nebu-liser is connected up, a flow path for an aerosol produced by the nebuliser can be closed off. A closure member is opened when the nebuliser is attached and closed when it is re-moved. The nebuliser connecting device has a disadvantage in that the aerosol produced by the nebuliser is introduced into the tube carrying the respiratory gas in a direction per-pendicular to the direction of flow of the respiratory gas, the angle of entry of the aerosol into the tube carrying the respiratory gas causing a significant impact, with the result that the active substance dissolved in the aerosol is precipitated in the tube, leading to under-dosing of the patient being treated with the active substance.
Moreover, the Journal of Pharmacological and Toxicological Methods 50 (2004) 109-119, ELSEVIER, discloses an adapter with an attachment for a nebuliser located opposite an outlet on the patient side, while an input for the respiratory air tube to be attached thereto starts from the common opening with the attachment and the outlet and a flow channel is formed such that the main direction of atomization of a medicament runs parallel to the di-rection of flow of a respiratory gas. However, no further details on the configuration of the flow channel and the internal construction of the adapter can be inferred from this publica-tion.
Finally, EP 0 521 061 B1 discloses a metering device for delivering a measured amount of a liquid as a spray with droplets of a size suitable for inhalation into the lungs, by deliver-ing the measured amount of liquid through an atomizer that comprises a chamber for hold-ing the measured amount of liquid, an energy store and means for delivering a predeter-mined amount of energy to the energy store. In addition, means are provided for releasing the predetermined amount of energy from the energy store to the chamber, so as to subject the liquid contained therein to a predetermined rise in pressure, from a low pressure to a higher pressure, and initiate the release of the liquid from the chamber. An atomizer serves to atomize the measured amount of pressurised liquid.
The compounds listed below may be used in the device according to the invention on their own or in combination. In the compounds mentioned below, W is a pharmacologically active substance and is selected (for example) from among the betamimetics, anticholiner-gics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine ago-nists, H1-antihistamines, PAF-antagonists and P13-kinase inhibitors. Moreover, double or triple combinations of W may be combined and used in the device according to the inven-tion. Combinations of W might be, for example:
- W denotes a betamimetic, combined with an anticholinergic, corticosteroid, inhibitor, EGFR-inhibitor or LTD4-antagonist, - W denotes an anticholinergic, combined with a betamimetic, corticosteroid, inhibitor, EGFR-inhibitor or LTD4-antagonist, - W denotes a corticosteroid, combined with a PDE4-inhibitor, EGFR-inhibitor or LTD4-antagonist - W denotes a PDE4-inhibitor, combined with an EGFR-inhibitor or LTD4-antagonist - W denotes an EGFR-inhibitor, combined with an LTD4-antagonist.
The compounds used as betamimetics are preferably compounds selected from among al-buterol, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ri-todrine, salmefamol, salmeterol, soterenol, sulphonterol, terbutaline, tiaramide, tolubuterol, zinterol, CHF-1035, HOKU-81, KUL-1248 and - 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulphonamide - 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1 H-quinolin-2-one - 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3 H)-benzothiazolone - 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]
ethanol - 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino] ethanol - 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino] ethanol - 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol - 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino] ethanol - 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-3 5 triazol-3-yl]-2-methyl-2-butylamino} ethanol - 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one - 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol - 6-hydroxy-8- { 1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl } -4H-benzo[ 1,4]oxazin-3-one - 6-hydroxy-8- { 1-hydroxy-2-[2-( ethyl 4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl } -4H-benzo[ 1,4]oxazin-3-one - 6-hydroxy-8- { 1-hydroxy-2-[2-(4-phenoxy-acetic acid)-1,1-dimethyl-ethylamino]-ethyl } -4H-benzo [ 1,4] oxazin-3-one - 8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo [ 1,4] oxazin-3 -one - 6-hydroxy-8- { 1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl } -4H-benzo[ 1,4]oxazin-3-one } -- 6-hydroxy-8- { 1-hydroxy-2-[2-(4-isopropyl-phenyl)-1.1 dimethyl-ethyl amino]
-ethyl 4H-benzo[ 1,4]oxazin-3-one - 8- {2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl } -6-hydroxy-4H-benzo [ 1 ,4] oxazin-3 -one - 8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one - 4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid - 8-{2-[2-(3.4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-2 0 4H-benzo[ 1,4]oxazin-3-one - 1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol - 2-hydroxy-5-(1-hydroxy-2- {2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino } -ethyl)-benzaldehyde - N-[2-hydroxy-5-(1-hydroxy-2- {2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-2 5 ethylamino } -ethyl)-phenyl]-formamide - 8-hydroxy-5-(1-hydroxy-2- {2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino } -ethyl)-1 H-quinolin-2-one - 8-hydroxy-5-[ 1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1 H-quinolin-2-one - 5-[2-(2- {4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl } -ethylamino)-3 0 hydroxy-ethyl]-8-hydroxy-1 H-quinolin-2-one - [3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxyrnethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-5-methyl-phenyl]-urea - 4-(2-{6-[2-(2,6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol 35 - 3-(4- {6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-b enzyl sulphonami de - 3-(3-{7-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}-propyl)-benzylsulphonamide - 4-(2-{6-[4-(3-cyclopentanesulphonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxym ethyl-phenol - N-Adamantan-2-yl-2-(3- {2-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl } -phenyl)-acetamide optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention the acid addition salts of the betamimetics are prefera-bly selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hy-drophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hy-drocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
The anticholinergics used are preferably compounds selected from among the tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, glycopyr-ronium salts, preferably the bromide salt, trospium salts, preferably the chloride salt, tolterodine. In the above-mentioned salts the cations are the pharmacologically active con-stituents. As anions the above-mentioned salts may preferably contain the chloride, bro-mide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate, while chloride, bromide, iodide, sulphate, methanesulphonate or p-toluenesulphonate are preferred as counter-ions. Of all the salts the chlorides, bromides, iodides and methanesulphonates are particularly preferred.
Other preferred anticholinergics are selected from among the salts of formula ~/_N O
0-0 .
x AC-wherein X - denotes an anion with a single negative charge, preferably an anion selected from among the fluoride, chloride, bromide, iodide, sulphate, phosphate, methanesulpho-nate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate, preferably an anion with a single negative charge, particularly pref-erably an anion selected from among the fluoride, chloride, bromide, methanesulphonate and p-toluenesulphonate, particularly preferably bromide, optionally in the form of the ra-cemates, enantiomers or hydrates thereof. Of particular importance are those pharmaceuti-cal combinations which contain the enantiomers of formula AC-1-en NLD
-en wherein X - may have the above-mentioned meanings. Other preferred anticholinergics are selected from the salts of formula AC-2 ~
OH
R X
wherein R denotes either methyl or ethyl and wherein X - may have the above-mentioned meanings. In an alternative embodiment the compound of formula AC-2 may also be pre-sent in the form of the free base AC-2-base.
~
OH
\ N
/
AC-2-base Other specified compounds are:
- tropeno12,2-diphenylpropionate methobromide, - scopine 2,2-diphenylpropionate methobromide, - scopine 2-fluoro-2,2-diphenylacetate methobromide, - tropenol 2-fluoro-2,2-diphenylacetate methobromide;
- tropenol 3,3',4,4'-tetrafluorobenzilate methobromide, CA 02653183 2008-11-24 pCT PO1_2029 - scopine 3,3',4,4'-tetrafluorobenzilate methobromide, - tropenol 4,4'-difluorobenzilate methobromide, - scopine 4,4'-difluorobenzilate methobromide, - tropeno13,3'-difluorobenzilate methobromide, - scopine 3,3'- difluorobenzilate methobromide;
- tropenol 9-hydroxy-fluorene-9-carboxylate methobromide;
- tropenol 9-fluoro-fluorene-9-carboxylate methobromide;
- scopine 9-hydroxy-fluorene-9-carboxylate methobromide;
- scopine 9-fluoro-fluorene-9-carboxylate methobromide;
- tropenol 9-methyl-fluorene-9-carboxylate methobromide;
- scopine 9-methyl-fluorene-9-carboxylate methobromide;
- cyclopropyltropine benzilate methobromide;
- cyclopropyltropine 2,2-diphenylpropionate methobromide;
- cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide;
- cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide;
- cyclopropyltropine 9-methyl-xanthene-9-carboxylate methobromide;
- cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide;
- cyclopropyltropine methy14,4'-difluorobenzilate methobromide.
- tropenol 9-hydroxy-xanthene-9-carboxylate methobromide;
- scopine 9-hydroxy-xanthene-9-carboxylate methobromide;
- tropenol 9-methyl-xanthene-9-carboxylate methobromide;
- scopine 9-methyl-xanthene-9-carboxylate methobromide;
- tropenol 9-ethyl-xanthene-9-carboxylate methobromide;
- tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide;
- scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide, The above-mentioned compounds may also be used as salts within the scope of the present invention, wherein instead of the methobromide the salts metho-X are used, wherein X
may have the meanings given hereinbefore for X-.
As corticosteroids it is preferable to use compounds selected from among beclomethasone, betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etipred-nol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, roflepon-ide, triamcinolone, RPR-106541, NS-126, ST-26 and - (S)-fluoromethy16,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-l6-methyl-3-oxo-androsta-1,4-diene-l7-carbothionate - (S)-(2-oxo-tetrahydro-furan-3S-yl)6,9-difluoro-ll-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-l7-carbothionate, g - cyanomethy16a,9a-difluoro-11(3-hydroxy-16a-methyl-3-oxo-17a-(2,2,3,3-tertamethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17(3-carboxylate optionally in the form of the racemates, enantiomers or diastereomers thereof and option-ally in the form of the salts and derivatives thereof, the solvates and/or hydrates thereof.
Any reference to steroids includes a reference to any salts or derivatives, hydrates or sol-vates thereof which may exist. Examples of possible salts and derivatives of the steroids may be: alkali metal salts, such as for example sodium or potassium salts, sulphobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
PDE4-inhibitors which may be used are preferably compounds selected from among en-profyllin, theophyllin, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, arofyllin, atizoram, D-4418, Bay-198004, BY343, CP-325.366, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V-11294A, C1-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and - N-(3,5-dichloro-l-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide - (-)p-[(4aR*,I ObS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s] [ 1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide - (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone - 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone - cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid]
- 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxy-2 5 phenyl)cyclohexan-l-one - cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l-ol]
- (R)-(+)-ethyl [4-(3 -cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]
acetate - (S)-(-) -ethyl [4-(3 -cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]
acetate - 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine - 9-cyclopentyl-5,6-dihydro-7-ethyl-3 -(tert-butyl)-9H-pyrazolo [3,4-c] -1,2,4-triazolo[4,3 -a]pyridine optionally in the form of the racemates, enantiomers or diastereomers thereof and option-ally in the form of the pharmacologically acceptable acid addition salts thereof, the sol-vates and/or hydrates thereof. According to the invention the acid addition salts of the PDE4 inhibitors are preferably selected from among the hydrochloride, hydrobromide, hy-driodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydro-maleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuc-cinate, hydrobenzoate and hydro-p-toluenesulphonate.
The LTD4-antagonists used are preferably compounds selected from among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321 and - 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2- hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic acid, - 1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-l-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid - [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl] oxymethyl]phenyl] acetic acid optionally in the form of the racemates, enantiomers or diastereomers thereof and option-ally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof. According to the invention these acid addition salts are preferably se-lected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydro-phosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocit-rate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate. By salts or derivatives which the LTD4-antagonists may optionally be capable of forming are meant, for example: alkali metal salts, such as for example so-dium or potassium salts, alkaline earth metal salts, sulphobenzoates, phosphates, isonicoti-nates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
EGFR-inhibitors which may be used are preferably compounds selected from among cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]-2 5 amino} -7-cyclopropylmethoxy-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]-amino } -7-cyclopropylmethoxy-quinazoline - 4-[(3 -chloro-4- fluorophenyl) amino] - 6- { [4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl] amino } -7-cyclopropylmethoxy-quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-cyclopentyloxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl] amino } -7-cyclopropylmethoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6- { [4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6- { [4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl] amino } -7-cyclopropylmethoxy-quinazoline CA 02653183 2008-11-24 pC.r PO 1-2029 - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy] -7-methoxy-quinazo line - 4-[(3-chloro-4-fluorophenyl)amino]-6-( {4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-l-yl } amino)-7-cyclopropylmethoxy-quinazoline 5 - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl] amino } -7-cyclopentyloxy-quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6- { [4-(N,N-to-(2-methoxy-ethyl)-amino)-1-oxo-buten-l-yl] amino } -7-cyclopropylmethoxy-quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-1 o buten-l-yl } amino)-7-cyclopropylmethoxy-quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-l-yl } amino)-7-cyclopropylmethoxy-quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-( {4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-l-yl } amino)-7-cyclopropylmethoxy-quinazoline - 4-[(3 -chloro-4-fluorophenyl)amino] -6- { [4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl] amino } -7-((R)-tetrahydrofuran-3 -yloxy)-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl] amino } -7-((S)-tetrahydrofuran-3 -yloxy)-quinazoline - 4- [(3 -chloro-4-fluorophenyl)amino] -6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-2 0 oxo-2-buten-l-yl } amino)-7-cyclopentyloxy-quinazoline - 4-[(3 -chloro-4-fluorophenyl)amino]-6-{ [4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-l-yl] amino } -7-cyclopentyloxy-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl] amino } -7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl] amino } -7- [(S)-(tetrahydrofuran-2-yl)methoxy] -quinazoline - 4-[(3-ethynyl-phenyl)amino]-6.7-to-(2-methoxy-ethoxy)-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-.yl)-propyloxy]-6-[(vinyl-carbonyl) amino] -quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine - 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl] amino } -7-ethoxy-quinoline - 4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl } -furan-2-yl)quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl] amino } -7-methoxy-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-l-yl]-amino } -7-[(tetrahydrofuran-2-yl)methoxy] -quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-to-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-l-yl } amino)-7- [ (tetrahydro furan-2-yl)methoxy] -quinazo line - 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-buten-l-yl] amino } -quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy] -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy] -7-[(R)-(tetrahydrofuran-2-yl)methoxy] -quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-l-yl]-ethoxy} -7-methoxy-quinazoline - 4- [(3-chloro-4-fluoro-phenyl)amino]-6-[ 1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6-(tetrahydropyran-3 -yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6- { 1-[(morpholin-4-yl)carbonyl]-piperidin-4-yl-oxy} -7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6- { 1-[(methoxymethyl)carbonyl]-piperidin-4-yl-oxy} -7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6-(piperi din-3 -yloxy)-7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline - 4- [ (3 -chloro-4-fluoro-phenyl) amino] -6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino] -6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6- {trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-l-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6- {trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-l-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6- {trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-l-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-l-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3 -chloro-4-fluoro-phenyl) amino] -6-(cis-4- {N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino } -cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4- [ (3 -chloro-4-fluoro-phenyl) amino] -6-(cis-4- {N-[(morpholin-4-yl)carbonyl]-N-methyl-amino } -cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6-(cis-4- {N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino } -cyclohexan-1-yloxy)-7-methoxy- quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-l-2 0 yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-ethoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[ 1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-l-yloxy)-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-[ 1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-3 0 methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-l-yl)carbonyl]-N-methyl-amino } -cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3 -chloro-4-fluoro-phenyl)amino] -6-(cis-4- {N-[(4-methyl-piperazin-l-yl)carbonyl]-3 5 N-methyl-amino } -cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4- [ (3 -chloro-4-fluoro-phenyl) amino] -6- {cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-l-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6- { 1-[2-(2-oxopyrrolidin-l-yl)ethyl]-piperidin-4-yloxy} -7-methoxy-quinazoline - 4-[(3 -chloro-4-fluoro-phenyl) amino] -6- { 1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy} -7-(2-methoxy-ethoxy)-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-1 o ethoxy)-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-l-yloxy)-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6- {cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-l-yloxy} -7-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-[ 1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6- { 1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline - 4- [ (3 -chloro-4-fluoro-phenyl) amino] -6- { 1-[(cis-2,6-dimethyl-morpholin-yl)carbonyl]-piperidin-4-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6- { 1-[(2-methyl-morpholin-4-yl)carbonyl]-2 5 piperidin-4-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6- { 1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1 ]hept-5-yl)carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6- { 1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6- { 1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6- { 1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-l-yloxy]-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)ami:lo]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-l-yloxy]-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4- {N-[(morpholin-4-yl)carbonyl]-N-methyl-amino } -cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4- [ (3 -chloro-4-fluoro-phenyl) amino] -6- [2 -(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7- [ (S)-(tetrahydrofuran-2-yl)methoxy] -quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention these acid addition salts are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hy-dromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofu-marate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
The dopamine agonists used are preferably compounds selected from among bromocriptin, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol, ropini-rol, talipexol, tergurid and viozan, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention these acid addition salts are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hy-droacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydro-benzoate and hydro-p-toluenesulphonate.
H 1-Antihistamines which may be used are preferably compounds selected from among epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ke-totifen, emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, pro-methazine, ebastine, desloratidine and meclozine, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention these acid addition salts are preferably selected from among the hydrochloride, hydrobro-5 mide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hy-drosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
Any inhalable compounds, including also inhalable macromolecules as disclosed in EP 1 10 003 478, may be used as pharmaceutically effective substances, formulations or mixtures of substances. Preferably, substances, formulations or mixtures of substances administered by inhalation may be used for treating respiratory complaints.
In addition, the compound may come from the groups of ergot alkaloid derivatives, the 15 triptans, the CGRP-inhibitors, the phosphodiesterase-V inhibitors, optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharma-cologically acceptable acid addition salts, the solvates and/or hydrates thereof.
Examples of ergot alkaloid derivatives are dihydroergotamine and ergotamine.
The aim of the invention is to provide an adapter of the type mentioned hereinbefore, which while being of simple construction ensures optimum introduction of a generated aerosol into a tube for ventilating an, in particular, human patient.
According to the invention the aim is achieved by the fact that the opening extends into an area facing the atomizer behind the atomizer nozzle.
The atomizer, in the form of an inhaler, is attached to the adapter for a ventilator system such that a flow channel for the respiratory gas is provided, which ensures that the entire dose of the atomized fluid, i.e. the full amount of aerosol generated by the atomizer, is conveyed by the respiratory gas to the patient, as a result of the respiratory gas behind the atomizer nozzle being conveyed into the corresponding flow channel and thereby carrying the spray mist with it. The aerosol generated by the atomizer is absorbed immediately at its place of origin by the respiratory gas flowing through the adapter and is conveyed with low impact in the tube to the ventilated patient, as the main direction of atomization of the fluid runs parallel to the direction of flow of the respiratory gas.
Accordingly, the venti-lated patient is supplied with dissolved active substances in aerosol form and long-term in-halative medication provided by the atomizer can be continued once the patient has been hooked up to the ventilation system, or medication or the administration of active sub-stances to the patient connected to the ventilator system can take place. A
ventilation mask or a tracheal tube or the like may be connected to the outlet on the patient side, in a manner known from the prior art.
According to one feature, the attachment for the atomizer may be partially matched in its geometry to a mouthpiece of the atomizer into which the atomizer nozzle projects which comprises in its wall, in an area remote from the inhalation opening; at least one cut-out which is fluidically connected to the opening for the respiratory gas.
Accordingly, when a patient is treated further with a ventilator system, the atomizer can be used, and it can be used even without the ventilator system. Preferably, the mouthpiece is provided with two opposing cut-outs through which the respiratory gas or the air sucked in automatically by the patient flows, in order to inhale for example particles of the medicament which are des-tined for the lungs.
Preferably, the attachment for the atomizer rests on a shoulder of the atomizer. The at-tachment may be fixed in sealed manner to the for example cylindrical shoulder of the at-omizer.
Preferably, the opening in the region of the mouthpiece is in the form of a groove. The groove is relatively easy to produce and once the mouthpiece has been placed in the at-tachment the groove forms with a corresponding wall of the mouthpiece a flow channel which is closed around its circumference.
Expediently, the breach associated with the inlet for the respiratory gas runs perpendicu-larly to the bore. The respiratory gas accordingly passes into the breach, is diverted at the end of it into the flow channel formed by the groove and the corresponding wall of the mouthpiece, flows through the cut-outs into the mouthpiece in which it changes direction once again, and carries the aerosol generated by the atomizer nozzle in the mouthpiece through the bore, so as to supply the patient both with respiratory gas and with the me-dicament.
According to a further feature, at least one valve is provided which fluidically separates the atomiser from the respiratory gas and carries the respiratory gas from the inlet directly to the outlet on the patient side. Thus, the ventilation of the patient may be effected either through the atomizer or directly.
Preferably, the atomizer for the adapter described hereinbefore is designed to deliver a spe-cific amount of the fluid, which contains in particular a medicament, in the form of an aerosol through the atomizer nozzle provided inside the mouthpiece, from a pressure store, while a mechanical pressure generator acts on the measured amount of fluid in the pressure store which is to be released abruptly for atomization, and the mouthpiece comprises at least one opening which, when viewed in the direction of atomisation, is formed behind the nozzle. Preferably, the pressure generator comprises a holder for a replaceable storage container that holds the fluid, an associated drive spring with a release button and a con-veying tube, while axial tensioning of the drive spring shifts the holder with the storage container and the conveying tube in an opposite direction to the mouthpiece, and sucks fluid out of the storage container into a pressure chamber and actuation of the release but-ton causes relaxation of the tensioned drive spring which moves the conveying tube in the direction of the mouthpiece and at the same time acts on the fluid to expel it through the atomiser nozzle under pressure. Advantageously, the atomiser nozzle comprises a filter system for producing two spray jets that meet to produce a spray mist.
It will be appreciated that the features mentioned hereinbefore and those still to be de-scribed hereinafter may be used not only in the particular combination specified but also in other combinations. The scope of the invention is defined only by the claims.
The invention is explained in more detail hereinafter by an illustrative embodiment with reference to the associated drawings, wherein:
3 o Fig.1 is a partial view of a longitudinal section through an adapter according to the invention and Fig.2 is a sectional view of an atomizer for use with the adapter according to Fig. 1.
The atomizer 1 serves to atomize a fluid 2, in particular a highly effective medicament or the like, and is constructed as a portable inhaler that operates without propellant gas.
When the fluid 2, preferably a liquid, is atomised, an aerosol is formed that can be breathed in by a user (not shown).
The atomizer 1 has a replaceable storage container 3 with the fluid 2, which is substantially cylindrical or cartridge-shaped and can be inserted in the opened atomizer 1 from below.
In the rigid storage container 3 is a bag 4 that holds the fluid 2. For atomizing the fluid 2 in a predetermined adjustable amount, the atomizer 1 comprises a pressure generator 5 1 o having a holder 6 for the container 3, a drive spring 7 with a release button 8 which is to be operated manually to release the tension, a conveying tube 9 with a non-return valve 10 inserted therein, a pressure chamber 11 and an atomizer nozzle 12 with an associated mouthpiece 13.
When the drive spring 7 is axially tensioned by rotating a lower housing part 18 with an inner part 17 releasably attached thereto, relative to an upper housing part 16 formed on the mouthpiece 13, the holder 6 with the storage container 3 and the conveying tube 9 is moved downwards and fluid is sucked out of the container 3 through the non-return valve 10 into the pressure chamber 11 of the pressure generator 5. During the subsequent abrupt 2 o relaxation of the drive spring 7 by the actuation of the release button 8, the fluid 2 in the pressure chamber 11 is put under pressure by the drive spring 7 moving the conveying tube 9 upwards and is expelled through the nozzle 12, whereupon atomization takes place. The atomization results, for example, in particles in the m or nm size range, preferably lung-bound particles about 5 m in size, which form a mist or jet of aerosol. A
user can inhale the aerosol, while supply air or respiratory gas can be taken in via cut-outs 15 in the mouthpiece 13.
In order to be able to administer the fluid 2 as an aerosol in conjunction with a ventilator system for a patient, particularly a human, the adapter 19 is provided, which has an at-tachment 20 for the atomizer 1, the attachment 20 having a region 21 which is adapted in its geometry to the mouthpiece 13 of the atomizer 1. Opposite the attachment 20, the adapter 19 has an outlet 22 on the patient side which is fluidically connected to the attach-ment 20 through a bore. For coupling to a respiratory air tube, the adapter 19 is provided with ari inlet 25 that comprises a passage 24, while the inlet 25 of cylindrical cross-section is aligned with the passage 24 extending coaxially thereto at right angles to the bore 23.
The passage 24 which is in the form of a blind hole terminates in an opening 27 in the form of a groove 26 which runs parallel to the bore 23 and extends as far as the cut-outs 15 in the mouthpiece 13 that are located underneath the atomiser nozzle 12.
The respiratory gas passes from the respiratory air tube into the breach 24 and at its end is diverted into the flow channel formed by the groove 26 and a corresponding wall of the mouthpiece 13, at the end of which the respiratory gas passes through the cut-outs 15 into 1 o the mouthpiece 13. In the mouthpiece 13 the respiratory gas is again diverted in its direc-tion of flow underneath the atomizer nozzle 12 and carries the aerosol generated by the at-omizer nozzle 12 in the mouthpiece 13 through the bore 23, to supply the patient both with respiratory gas and with the medicament, while inside the mouthpiece 13 the main direc-tion of atomization of a medicament is aligned parallel to the direction of flow of the respi-ratory gas.
Claims (9)
1. Adapter with an attachment (20) for an atomizer (1) for a fluid (2), particularly one that contains a medicament, as an aerosol through an atomizer nozzle (12), wherein the attachment (20) is coupled via a bore (23) to an outlet (22) on the patient side, and with an inlet (25) for a respiratory air tube to be attached thereto that is fluidi-cally connected to the bore (23) such that the main direction of atomisation of the fluid (2) extends parallel to the direction of flow of a respiratory gas, while an opening (27) running parallel to the bore (23) in the direction of the atomizer (1) is provided in a breach (24) associated with the inlet (25), characterised in that the opening (27) extends into an area facing the atomizer (1) behind the atomizer noz-zle (12).
2. Adapter according to claim 1, characterised in that the attachment (20) for the at-omizer (1) is matched in its geometry in parts to a mouthpiece (13) of the atomizer (1) into which the atomizer nozzle (12) projects and which comprises in its wall, in an area remote from the inhalation opening, at least one cut-out (15) which is flu-idically connected to the opening (27) for the respiratory gas.
3. Adapter according to claim 1 or 2, characterised in that the attachment (20) for the atomizer (1) rests on a shoulder of the atomizer (1).
4. Adapter according to one of claims 1 to 3, characterised in that the opening (27) in the region of the mouthpiece (13) is formed as a groove (26).
5. Adapter according to one of claims 1 to 4, characterised in that the breach (22) associated with the inlet (25) for the respiratory gas runs perpendicularly to the bore (23).
6. Adapter according to claim 1, characterised in that at least one valve is provided which fluidically separates the atomiser (1) from the respiratory gas and carries the respiratory gas from the inlet (25) directly to the outlet (22) on the patient side.
7. Atomizer for an adapter according to one of claims 1 to 6, characterised in that the atomizer (1) is designed to deliver a specific amount of the fluid (2), which con-tains in particular a medicament, in the form of an aerosol through the atomizer nozzle (12) provided inside the mouthpiece (13), from a pressure store, while a me-chanical pressure generator (5) acts on the measured amount of fluid (2) in the pres-sure store which is to be released abruptly for atomization, and the mouthpiece (13) comprises at least one cut-out (15) which, when viewed in the direction of atomisa-tion, is formed behind the atomizer nozzle (12).
8. Atomizer according to claim 7, characterised in that the pressure generator (5) comprises a holder (6) for a replaceable storage container (3) that holds the fluid (2), an associated drive spring (7) with a release button (8) and a conveying tube (9), while axial tensioning of the drive spring (7) shifts the holder (6) with the stor-age container (3) and the conveying tube (9) in an opposite direction to the mouth-piece (13), and sucks fluid (2) out of the storage container (3) into a pressure cham-ber (11) and actuation of the release button (8) causes relaxation of the tensioned drive spring (7) which moves the conveying tube (9) in the direction of the mouth-piece (13) and at the same time acts on the fluid (2) to expel it through the atomiser nozzle (12) under pressure.
9. Atomizer according to claim 7 or 8, characterised in that the atomiser nozzle comprises a filter system for producing two spray jets that meet to produce a spray mist.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102006025884A DE102006025884A1 (en) | 2006-06-02 | 2006-06-02 | Adapter with a connector for a nebulizer |
| DE102006025884.3 | 2006-06-02 | ||
| PCT/EP2007/055381 WO2007141201A1 (en) | 2006-06-02 | 2007-06-01 | Adapter with an attachment for an atomizer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2653183A1 true CA2653183A1 (en) | 2007-12-13 |
Family
ID=38353123
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002653183A Abandoned CA2653183A1 (en) | 2006-06-02 | 2007-06-01 | Adapter with an attachment for an atomizer |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP2023990A1 (en) |
| JP (1) | JP2009538655A (en) |
| CA (1) | CA2653183A1 (en) |
| DE (1) | DE102006025884A1 (en) |
| WO (1) | WO2007141201A1 (en) |
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7837235B2 (en) | 2004-01-08 | 2010-11-23 | Boehringer Ingelheim International Gmbh | Device for clamping a fluidic component |
| US9265910B2 (en) | 2009-05-18 | 2016-02-23 | Boehringer Ingelheim International Gmbh | Adapter, inhalation device, and nebulizer |
| US9545487B2 (en) | 2012-04-13 | 2017-01-17 | Boehringer Ingelheim International Gmbh | Dispenser with encoding means |
| US9724482B2 (en) | 2009-11-25 | 2017-08-08 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US9744313B2 (en) | 2013-08-09 | 2017-08-29 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US9757750B2 (en) | 2011-04-01 | 2017-09-12 | Boehringer Ingelheim International Gmbh | Medicinal device with container |
| US9827384B2 (en) | 2011-05-23 | 2017-11-28 | Boehringer Ingelheim International Gmbh | Nebulizer |
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| US10004857B2 (en) | 2013-08-09 | 2018-06-26 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10011906B2 (en) | 2009-03-31 | 2018-07-03 | Beohringer Ingelheim International Gmbh | Method for coating a surface of a component |
| US10016568B2 (en) | 2009-11-25 | 2018-07-10 | Boehringer Ingelheim International Gmbh | Nebulizer |
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| US10124129B2 (en) | 2008-01-02 | 2018-11-13 | Boehringer Ingelheim International Gmbh | Dispensing device, storage device and method for dispensing a formulation |
| US10124125B2 (en) | 2009-11-25 | 2018-11-13 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10195374B2 (en) | 2014-05-07 | 2019-02-05 | Boehringer Ingelheim International Gmbh | Container, nebulizer and use |
| US10722666B2 (en) | 2014-05-07 | 2020-07-28 | Boehringer Ingelheim International Gmbh | Nebulizer with axially movable and lockable container and indicator |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7963955B2 (en) | 1998-02-27 | 2011-06-21 | Boehringer Ingelheim International Gmbh | Container for a medicinal liquid |
| EP2135632A1 (en) * | 2008-06-20 | 2009-12-23 | Boehringer Ingelheim International Gmbh | Inhalator |
| CA2882405C (en) | 2013-03-15 | 2019-12-03 | Trudell Medical International | Ventilator circuit, adapter for use in ventilator circuit and methods for the use thereof |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4225928A1 (en) * | 1992-08-05 | 1994-02-10 | Ritzau Pari Werk Gmbh Paul | Atomizer device with heating device |
| DE19520622C2 (en) * | 1995-06-06 | 2003-05-15 | Pari Gmbh | Device for atomizing fluids |
| US6725858B2 (en) * | 2001-05-07 | 2004-04-27 | Hudson Respiratory Care Inc. | Valved aerosol tee adapter assembly |
| KR100815216B1 (en) * | 2001-06-15 | 2008-03-19 | 오츠카 세이야쿠 가부시키가이샤 | Dry powder inhalation system for transpulmonary administration |
| JP2005530535A (en) * | 2002-05-16 | 2005-10-13 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | System including nozzle and fixing means thereof |
| DE10320143A1 (en) * | 2003-05-06 | 2004-12-16 | Pari GmbH Spezialisten für effektive Inhalation | Nebulizer connection device for respirators or the like |
| CA2557020A1 (en) * | 2004-02-24 | 2005-09-01 | Boehringer Ingelheim International Gmbh | Atomiser |
| DE102005029498B4 (en) * | 2005-06-24 | 2007-08-30 | Pari GmbH Spezialisten für effektive Inhalation | Inhalation therapy device |
-
2006
- 2006-06-02 DE DE102006025884A patent/DE102006025884A1/en not_active Withdrawn
-
2007
- 2007-06-01 WO PCT/EP2007/055381 patent/WO2007141201A1/en active Application Filing
- 2007-06-01 EP EP07729782A patent/EP2023990A1/en not_active Withdrawn
- 2007-06-01 CA CA002653183A patent/CA2653183A1/en not_active Abandoned
- 2007-06-01 JP JP2009512610A patent/JP2009538655A/en active Pending
Cited By (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9027967B2 (en) | 2004-01-08 | 2015-05-12 | Boehringer Ingelheim International Gmbh | Device for clamping a fluidic component |
| US7837235B2 (en) | 2004-01-08 | 2010-11-23 | Boehringer Ingelheim International Gmbh | Device for clamping a fluidic component |
| US10124129B2 (en) | 2008-01-02 | 2018-11-13 | Boehringer Ingelheim International Gmbh | Dispensing device, storage device and method for dispensing a formulation |
| US10011906B2 (en) | 2009-03-31 | 2018-07-03 | Beohringer Ingelheim International Gmbh | Method for coating a surface of a component |
| US9265910B2 (en) | 2009-05-18 | 2016-02-23 | Boehringer Ingelheim International Gmbh | Adapter, inhalation device, and nebulizer |
| US9682202B2 (en) | 2009-05-18 | 2017-06-20 | Boehringer Ingelheim International Gmbh | Adapter, inhalation device, and atomizer |
| US10124125B2 (en) | 2009-11-25 | 2018-11-13 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10016568B2 (en) | 2009-11-25 | 2018-07-10 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US9724482B2 (en) | 2009-11-25 | 2017-08-08 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US9943654B2 (en) | 2010-06-24 | 2018-04-17 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US9757750B2 (en) | 2011-04-01 | 2017-09-12 | Boehringer Ingelheim International Gmbh | Medicinal device with container |
| US9827384B2 (en) | 2011-05-23 | 2017-11-28 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US9545487B2 (en) | 2012-04-13 | 2017-01-17 | Boehringer Ingelheim International Gmbh | Dispenser with encoding means |
| US10220163B2 (en) | 2012-04-13 | 2019-03-05 | Boehringer Ingelheim International Gmbh | Nebuliser with coding means |
| US10894134B2 (en) | 2013-08-09 | 2021-01-19 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10004857B2 (en) | 2013-08-09 | 2018-06-26 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US9744313B2 (en) | 2013-08-09 | 2017-08-29 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US11642476B2 (en) | 2013-08-09 | 2023-05-09 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10716905B2 (en) | 2014-02-23 | 2020-07-21 | Boehringer Lngelheim International Gmbh | Container, nebulizer and use |
| US10099022B2 (en) | 2014-05-07 | 2018-10-16 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10722666B2 (en) | 2014-05-07 | 2020-07-28 | Boehringer Ingelheim International Gmbh | Nebulizer with axially movable and lockable container and indicator |
| US10195374B2 (en) | 2014-05-07 | 2019-02-05 | Boehringer Ingelheim International Gmbh | Container, nebulizer and use |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2007141201A1 (en) | 2007-12-13 |
| DE102006025884A1 (en) | 2007-12-06 |
| JP2009538655A (en) | 2009-11-12 |
| EP2023990A1 (en) | 2009-02-18 |
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