EP2244686A1 - Method and device for filling capsules - Google Patents

Method and device for filling capsules

Info

Publication number
EP2244686A1
EP2244686A1 EP09708924A EP09708924A EP2244686A1 EP 2244686 A1 EP2244686 A1 EP 2244686A1 EP 09708924 A EP09708924 A EP 09708924A EP 09708924 A EP09708924 A EP 09708924A EP 2244686 A1 EP2244686 A1 EP 2244686A1
Authority
EP
European Patent Office
Prior art keywords
capsule
amino
quinazoline
phenyl
chloro
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.)
Withdrawn
Application number
EP09708924A
Other languages
German (de)
French (fr)
Inventor
Michael Spallek
Burkhard Metzger
Rolf Kuhn
Stefan Lustenberger
Hubert Hoelz
Torsten Kuehn
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Priority to EP09708924A priority Critical patent/EP2244686A1/en
Publication of EP2244686A1 publication Critical patent/EP2244686A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/07—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use
    • A61J3/071—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use into the form of telescopically engaged two-piece capsules
    • A61J3/074—Filling capsules; Related operations

Definitions

  • the invention relates to a method for filling a capsule with a pharmaceutical active ingredient formulation, wherein the capsule consists of two capsule parts (a capsule body and a capsule cap) and the two capsule parts telescopically without pre-locking in the unfilled state only after filling a capsule part with a pharmaceutical drug formulation be plugged together, as well as a device to do so.
  • Capsules with pharmaceutical preparations are widely used in the therapy and diagnosis of diseases.
  • the capsules may be administered orally or used in certain medical devices such as powder inhalers.
  • a capsule consists of two parts, namely a capsule body and a capsule cap, which are telescoped into one another.
  • the parts of the capsules are often made of gelatin, in particular hard gelatin, or of HPMC (hydroxypropylmethylcellulose).
  • HPMC hydroxypropylmethylcellulose
  • the parts of the capsules also consist of human-digestible, water-soluble plastics to release, for example, when administered orally, the active ingredient in certain compartments of the gastrointestinal tract.
  • EP 1 100 474 B1 discloses plastic capsules which are made of a capsule body and a capsule cap, both made of the same non-water-soluble, hydrophobic plastic material and connected to one another in such a way that a stable, closed cavity of defined volume is formed.
  • the plastic is polyethylene.
  • the capsules are intended for use in powder inhalers. As an example of such powder inhalers may be mentioned: HandiHaler ® , as he z. B.
  • DE 10 2005 001 332 A1 describes a two-part capsule with a complex geometry which allows a prefastening.
  • the two parts of the capsule are each made separately and pushed together in a releasable pre-locking position to prevent the ingress of foreign particles into the capsule before it is filled.
  • the pre-locking position in the capsule parts can consist of different structures in the capsule walls: for example, knobs or annular beads, which respectively engage in the depressions on the other capsule half.
  • capsules which have neither a preload position in the capsule body nor in the cap can also be stored in a pre-rest position. be brought to rest position. These capsules are then simply telescoped together before filling.
  • the pre-locked capsules with or without pre-locking position, are delivered to the bottler and placed in a filling device. After aligning the capsules in the device for filling the capsule body are non-destructively separated from the capsule caps. The separation can take place without disturbing the filling process only with the required speed, if a pre-locking force, ie the effective force between the capsule body and the capsule cap in the pre-locking position, is exactly adhered to, which is accompanied by the maintenance of small manufacturing tolerances in the manufacturing process.
  • a pre-locking force ie the effective force between the capsule body and the capsule cap in the pre-locking position
  • the pharmaceutical active substance formulation for example in the form of powder, pellets and / or microtablets, is introduced into the capsule body. Subsequently, the capsule body and the capsule cap are telescoped together and brought into a closed position. The force required to reach the locking position is greater than the pre-locking force.
  • the object is achieved in the method in that the capsule body and the capsule caps are placed separately in a device for filling, without first to lock the two capsule halves and separate again before filling each other.
  • the method achieves simple process control with reduced fine-tuning of the handling devices and handling forces during filling.
  • the cylindrical capsules have only one latching position (final latching position), which is defined in particular by a circumferential groove and a bead corresponding thereto.
  • final latching position which is defined in particular by a circumferential groove and a bead corresponding thereto.
  • This is accompanied by a simplified production and handling of the capsule body and the capsule caps.
  • the handling is simplified both in the manufacturer of the capsule body and capsule caps as well as in the bottler of the drug formulation.
  • the capsule manufacturer saves the formation of a Vorrastpositi- on in the two capsule parts and the Vorverrasten the two capsule parts during capsule production.
  • the filler saves the separation of the two capsule halves before filling. In total, 3 working steps are saved.
  • the capsule bodies and capsule caps of the lockable capsules consist of all conventional materials known to the person skilled in the art, in particular of injection-molded polymer material.
  • the capsules can serve any application form; They are designed especially for use in the above-mentioned inhalers and most preferably for the Handi- Haler ® as disclosed in EP 1,342,483th
  • capsule bodies and capsule caps are made, for example, from PP, PE or ABS and have an modulus of elasticity in the range from 200 to 3600 MPa, in particular in the range from 400 to 3000 MPa, the resulting stability leads to a disruption of the filling process leading deformation of the capsule body or capsule caps avoided.
  • An e-module Range between 600 and 1400 MPa has proven to be particularly advantageous.
  • the capsule elements are treated by means of ionizing gases after their preparation, electrostatic charges of the capsule bodies and, consequently, a particle load can be further reduced.
  • the separately present capsule cap and body can be easily subjected to a drying process or a flooding with dry gases, whereby a complete drying of the inner surface of the two capsule parts is ensured. This drying is required for the storage of the capsules and simplifies the filling of powdered drug formulations.
  • the capsule body and the capsule caps can be visually inspected immediately before filling. This can be done for example by means of image acquisition and processing systems automatically or by the operator. Thus, damage to or in the capsule parts can be detected early before filling and drug safety can be increased.
  • the object is achieved in a device for filling capsules with pharmaceutical active ingredient formulations for carrying out the method according to the invention in that the capsule delivery device receiving cavities for separate recording of capsule bodies and capsule caps and separate reservoir for capsule body and capsule caps has.
  • a Kapselabhelillvorraum is characterized by a simplified design and allows, compared to a filling device known from the prior art, to achieve an increased process speed, since no Vorverrastung the capsules to solve before filling.
  • the capsules can be filled with medicines of any kind.
  • the filling with medicaments takes place in powder form.
  • W is a pharmacologically active agent and (for example) selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, HIV antihistaminics, PAF antagonists and PI3 kinase inhibitors.
  • a pharmacologically active agent selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, HIV antihistaminics, PAF antagonists and PI3 kinase inhibitors.
  • two- or three-fold combinations of W can be combined and used for application in the device according to the invention. Exemplary combinations of W would be:
  • W represents a betamimetics combined with an anticholinergic, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists,
  • W represents an anticholinergic, combined with a betamimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists,
  • W represents a corticosteroid combined with a PDE4 inhibitor, EGFR inhibitor or LTD4 antagonist W represents a PDE4 inhibitor combined with an EGFR inhibitor or LTD4 antagonist
  • W represents an EGFR inhibitor combined with a LTD4 antagonist.
  • Preferred betamimetics for this purpose are compounds selected from the group consisting of albuterol, arformoterol, bambuterol, bitolterol, broxeterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharines, isoprenaline, levosalbutamol, mabuterol , Meluadrine, Metaproterenol, Orciprenaline, Pirbuterol, Procaterol, Reproterol, Rimiterol, Ritodrine, Salmefamol, Salmeterol, Soterenol, Sulphone terol, Terbutaline, Tiaramide, Tolubuterol, Zinterol, CHF-1035, HOKU-81, KUL-1248 and 3- (4- ⁇ 6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -hexyloxy ⁇
  • the acid addition salts of the betamimetics are preferably selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydroxides citrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
  • Preferred anticholinergic compounds are compounds which are selected from the group consisting of tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, glycopyrronium salts, preferably the bromide salt, trospium salts , preferably the chloride salt, tolterodine.
  • the cations are the pharmacologically active ingredients.
  • the abovementioned salts may preferably contain chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate , Succinate, benzoate or p-toluenesulfonate, with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate being preferred as counterions.
  • the chlorides, bromides, iodides and methanesulfonates are particularly preferred.
  • anticholinergics are selected from the salts of the formula AC-I
  • X - is a single negatively charged anion, preferably one Anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate, preferably a single negatively charged anion, particularly preferably an anion selected from the group consisting of fluoride, chloride, bromide, methanesulfonate and p-toluenesulfonate, particularly preferably bromide, if appropriate in the form of their racemates, enantiomers or hydrates.
  • Anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, a
  • X - may have the meanings given above.
  • Further preferred anticholinergics are selected from the salts of the formula AC-2
  • the compound of formula AC-2 may also be in the form of the free base AC-2-base.
  • Preferred corticosteroids are compounds selected from the group consisting of beclomethasone, betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone, RPR -106541, NS-126, ST-26 and 6,9-Difluoro-17- [(2-furanylcarbonyl) oxy] -ll-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionic acid (S) -fluoromethyl ester
  • any reference to steroids includes reference to their optional salts or derivatives, hydrates or solvates.
  • Examples of possible salts and derivatives of steroids may be: alkali metal salts, such as, for example, sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or even furoates.
  • Preferred PDE4 inhibitors used here are compounds selected from the group consisting of enprofylline, theophylline, roflumilast, ariflo (cillobast), tofimilast, pumafentrin, lirimilast, arofylline, atizoram, D-4418 198004, BY343, CP-325,366, D-4396 (Sch351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T- 2585, V-11294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and
  • the acid addition salts of the PDE4 inhibitors are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro p-toluenesulfonate.
  • Preferred LTD4 antagonists here are compounds selected from the group consisting of montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078 , VUF-K-8707, L-733321 and
  • these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofluorate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
  • salts or derivatives which the LTD4-antagonists are capable of forming include: alkali metal salts, such as, for example, sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates ,
  • alkali metal salts such as, for example, sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates ,
  • compounds which are preferably present as EGFR inhibitors for use selected from the group consisting of cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and
  • these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofluorate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
  • Preferred dopamine agonists are compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viozane, optionally in the form of their racemates, enantiomers , Diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.
  • these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate ,
  • Hl-antihistamines here preferably compounds are used, which are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipine, Cexchlorpheniramin, pheniramine, doxylamine, chlorphenoxamine , Dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclocine, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.
  • these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, tartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
  • substance formulations or substance mixtures all inhalable compounds are used, such as e.g. also inhalable macromolecules, as disclosed in EP 1 003 478.
  • substances, substance formulations or substance mixtures are used for the treatment of respiratory diseases, which are used in the inhalation area.
  • the compound may be derived from the group of derivatives of ergot alkaloids, triptans, CGRP inhibitors, phosphodiesterase V inhibitors, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, their solvates and / or or hydrates.
  • a device for gassing and / or drying the capsule body and capsule caps is arranged directly before the filling of one of the two capsule halves. This is followed by fumigation and / or drying of the capsule body and capsule caps, their filling and the closing of the capsules by latching the capsule body with the capsule caps immediately after one another.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

The invention relates to a method for filling a capsule with a pharmaceutical active-substance formulation. According to the method, the capsule consists of two capsule parts (a capsule body and a capsule cap) and the two capsule parts, without being previously interlocked when empty, are only fitted together in a telescopic manner once one capsule part has been filled with a pharmaceutical active-substance formulation. The invention also relates to a device for carrying out said method.

Description

P01-2345 FF Text Boehringer Ingelheim International GmbH P01-2345 FF Text Boehringer Ingelheim International GmbH
Verfahren und Vorrichtung zur Befüllung von KapselnMethod and device for filling capsules
Beschreibungdescription
Die Erfindung betrifft ein Verfahren zur Befüllung einer Kapsel mit einer pharmazeutischen Wirkstoffformulierung, wobei die Kapsel aus zwei Kapselteilen (einem Kapselkörper und einer Kapselkappe) besteht und die beiden Kapselteile ohne Vor- rastung im unbefüllten Zustand alleinig nach der Befüllung eines Kapselteils mit einer pharmazeutischen Wirkstoffformulierung teleskopartig zusammengesteckt werden, sowie eine Vorrichtung dazu.The invention relates to a method for filling a capsule with a pharmaceutical active ingredient formulation, wherein the capsule consists of two capsule parts (a capsule body and a capsule cap) and the two capsule parts telescopically without pre-locking in the unfilled state only after filling a capsule part with a pharmaceutical drug formulation be plugged together, as well as a device to do so.
Kapseln mit pharmazeutischen Zubereitungen werden vielfältig in der Therapie und Diagnose von Krankheiten eingesetzt. Die Kapseln können oral verabreicht werden oder kommen in bestimmten medizinischen Vorrichtungen wie Pulverinhalatoren zum Einsatz. In der Regel besteht eine Kapsel aus zwei Teilen, nämlich einem Kapselkörper und einer Kapselkappe, die teleskopartig ineinander geschoben werden. Die Teile der Kapseln sind häufig aus Gelatine, insbesondere Hartgelatine, o- der aus HPMC (Hydroxypropylmethylcellulose) gefertigt. Für einige Anwendungen bestehen die Teile der Kapseln auch aus für den Menschen gut verdaulichen, wasserlöslichen Kunststoffen, um, z.B. bei oraler Verabreichung, den Wirkstoff in bestimmten Kompartimenten des Magen-Darm-Trakts freizusetzen. Die EP 1 100 474 Bl offenbart Kunststoffkapseln, die aus einem Kapselkörper und einer Kapselkappe gefertigt sind, die beide aus dem gleichen, nicht-wasserlöslichen, hydrophoben Kunststoff bestehen und so miteinander verbunden werden, dass ein stabiler, abgeschlossener Hohlraum von definiertem Volumen gebildet ist. Insbesondere handelt es sich bei dem Kunststoff um Polyethylen. Die Kapseln sind zur Verwendung in Pulverinhalatoren bestimmt. Als Beispiel für derartige Pulverinhalatoren seien genannt: HandiHaler®, wie er z . B . in der EP 1342483 offenbart wurde, Spinhaler®, Rotahaler®, Aerolizer®, Flowcaps®, Turbospin®, AIR DPI®, Orbital® oder Directhaler® so wie Inhalatoren, die u.a. in den Schriften DE 3345722, EP 0591136, DE 4318455, WO91/02558, FR-A-2146202 , US-A-4069819 , EP 666085, EP 869079, US 3,991,761, WO99/45987, WO 200051672, Bell, J. Pharm. Sei. 60, 1559 (1971); Cox, Brit. Med. J. 2, 634 (1969), beschrieben sind.Capsules with pharmaceutical preparations are widely used in the therapy and diagnosis of diseases. The capsules may be administered orally or used in certain medical devices such as powder inhalers. In general, a capsule consists of two parts, namely a capsule body and a capsule cap, which are telescoped into one another. The parts of the capsules are often made of gelatin, in particular hard gelatin, or of HPMC (hydroxypropylmethylcellulose). For some applications, the parts of the capsules also consist of human-digestible, water-soluble plastics to release, for example, when administered orally, the active ingredient in certain compartments of the gastrointestinal tract. EP 1 100 474 B1 discloses plastic capsules which are made of a capsule body and a capsule cap, both made of the same non-water-soluble, hydrophobic plastic material and connected to one another in such a way that a stable, closed cavity of defined volume is formed. In particular, the plastic is polyethylene. The capsules are intended for use in powder inhalers. As an example of such powder inhalers may be mentioned: HandiHaler ® , as he z. B. has been disclosed in EP 1342483, Spinhaler ®, Rotahaler ®, Aerolizer ®, FlowCaps ®, Turbo Spin ®, AIR DPI ®, Orbital ® or Directhaler ® as inhalers, among others, in the documents DE 3345722, EP 0591136, DE 4318455, WO91 No. 02558, FR-A-2146202, US-A-4069819, EP 666085, EP 869079, US 3,991,761, WO99 / 45987, WO 200051672, Bell, J. Pharm. 60, 1559 (1971); Cox, Brit. Med. J. 2, 634 (1969).
Im Weiteren beschreibt die DE 10 2005 001 332 Al eine zweiteilige Kapsel mit einer komplexen Geometrie, die einen Vorverschluss ermöglicht. Die beiden Teile der Kapsel werden jeweils separat gefertigt und in eine lösbare Vorrastposition zusammen geschoben, um das Eindringen von Fremdpartikeln in die Kapsel vor ihrer Befüllung zu verhindern.In addition, DE 10 2005 001 332 A1 describes a two-part capsule with a complex geometry which allows a prefastening. The two parts of the capsule are each made separately and pushed together in a releasable pre-locking position to prevent the ingress of foreign particles into the capsule before it is filled.
Die Vorrastposition in den Kapselteilen kann aus verschiedenen Strukturen in den Kapselwandungen bestehen: beispielsweise Noppen oder ringförmige Wülste, die jeweils in die Vertiefungen auf der anderen Kapselhälfte eingreifen.The pre-locking position in the capsule parts can consist of different structures in the capsule walls: for example, knobs or annular beads, which respectively engage in the depressions on the other capsule half.
Grundsätzlich können auch Kapseln, die weder im Kapselkörper noch in der -kappe eine Vorrastposition haben , in eine Vor- rastposition gebracht werden. Diese Kapseln werden dann vor ihrem Befüllen einfach teleskopartig zusammengesteckt.In principle, capsules which have neither a preload position in the capsule body nor in the cap can also be stored in a pre-rest position. be brought to rest position. These capsules are then simply telescoped together before filling.
Die vorverrasteten Kapseln, mit oder ohne Vorrastposition, werden beim Abfüller angeliefert und in eine Vorrichtung zur Befüllung gegeben. Nach dem Ausrichten der Kapseln in der Vorrichtung zur Befüllung werden die Kapselkörper zerstörungsfrei von den Kapselkappen getrennt. Die Trennung kann ohne eine Störung des Abfüllprozesses nur dann mit der erforderlichen Geschwindigkeit erfolgen, wenn eine Vorrastkraft , also die wirksame Kraft zwischen dem Kapselkörper und der Kapselkappe in der Vorrastposition, genau eingehalten wird, womit das Einhalten kleiner Fertigungstoleranzen beim Her- stellprozess einhergeht.The pre-locked capsules, with or without pre-locking position, are delivered to the bottler and placed in a filling device. After aligning the capsules in the device for filling the capsule body are non-destructively separated from the capsule caps. The separation can take place without disturbing the filling process only with the required speed, if a pre-locking force, ie the effective force between the capsule body and the capsule cap in the pre-locking position, is exactly adhered to, which is accompanied by the maintenance of small manufacturing tolerances in the manufacturing process.
In den Kapselkörper wird die pharmazeutische Wirkstoffformu- lierung, beispielsweise in Form von Pulver, Pellets und/ oder Mikrotabletten, eingefüllt. Anschließend werden die Kapselkörper und die Kapselkappe teleskopartig zusammen geschoben und in eine Verschlusspositiongebracht . Die zum Erreichen der Verschlussposition benötigte Kraft ist größer als die Vorrastkraft.The pharmaceutical active substance formulation, for example in the form of powder, pellets and / or microtablets, is introduced into the capsule body. Subsequently, the capsule body and the capsule cap are telescoped together and brought into a closed position. The force required to reach the locking position is greater than the pre-locking force.
Bei diesem herkömmlichen Verfahren der Kapselbefüllung mit vorverrasteten Kapseln erweist sich die Vielzahl der Fertigungsschritte zum Befüllen der Kapseln als problematisch, da die Kapseln Schaden erleiden können. Insofern ist eine Reduzierung der Verfahrensschritte bis zur Befüllung und Verschließung der Kapsel wünschenswert. Darüber hinaus werden durch Reibungseffekte beim Vorverrasten der Kapseln und dem Öffnen der vorverrasteten Kapseln zusätzliche Partikel von Pulver, Pellets und/oder der Mikrotablette freigesetzt, die aufwendig zu beseitigen sind.In this conventional method of capsule filling with pre-locked capsules, the multiplicity of manufacturing steps for filling the capsules proves to be problematic since the capsules can be damaged. In this respect, a reduction of the process steps to the filling and sealing of the capsule is desirable. In addition, frictional effects in the pre-locking of the capsules and the opening of the pre-locked capsules additional particles of Powder, pellets and / or the micro-tablet released, which are consuming to eliminate.
Es ist Aufgabe der Erfindung, ein Verfahren zur Befüllung von Kapseln der eingangs genannten Art und eine Vorrichtung bereitzustellen, um ein schnelles und prozesssicheres Befüllen zu gewährleisten.It is an object of the invention to provide a method for filling capsules of the type mentioned and an apparatus to ensure a fast and reliable filling.
Die Aufgabe wird erfindungsgemäß bei dem Verfahren dadurch gelöst, dass die Kapselkörper und die Kapselkappen separat in eine Vorrichtung zur Befüllung eingelegt werden, ohne zuvor die beiden Kapselhälften zu verrasten und vor der Befüllung wieder voneinander zu trennen.The object is achieved in the method in that the capsule body and the capsule caps are placed separately in a device for filling, without first to lock the two capsule halves and separate again before filling each other.
Mit dem Verfahren ist eine einfache Prozessführung mit reduzierter Feinabstimmung der Handhabungseinrichtungen und Handhabungskräfte bei der Befüllung erzielt.The method achieves simple process control with reduced fine-tuning of the handling devices and handling forces during filling.
Die zylindrischen Kapseln weisen nur eine Rastposition (Endrastposition) auf, die insbesondere durch eine umlaufende Nut und einen dazu korrespondierenden Wulst definiert ist. Damit geht eine vereinfachte Fertigung und Handhabung der Kapsel- körper und der Kapselkappen einher. Durch das Entfallen der aus dem Stand der Technik bekannten Vorverrastung ist zum einen die Handhabung sowohl bei dem Hersteller der der Kapselkörper und der Kapselkappen als auch bei dem Abfüller der Wirkstoffformulierung vereinfacht. Der Kapselhersteller spart bei der Kapselherstellung die Ausbildung einer Vorrastpositi- on in den beiden Kapselteilen und das Vorverrasten der beiden Kapselteile. Der Abfüller spart die Trennung der beiden kap- selhälften vor der Befüllung. Insgesamt können 3 Arbeits- schritte eingespart werden.The cylindrical capsules have only one latching position (final latching position), which is defined in particular by a circumferential groove and a bead corresponding thereto. This is accompanied by a simplified production and handling of the capsule body and the capsule caps. By eliminating the Vorverrastung known from the prior art, on the one hand, the handling is simplified both in the manufacturer of the capsule body and capsule caps as well as in the bottler of the drug formulation. The capsule manufacturer saves the formation of a Vorrastpositi- on in the two capsule parts and the Vorverrasten the two capsule parts during capsule production. The filler saves the separation of the two capsule halves before filling. In total, 3 working steps are saved.
Außerdem ist eine geringere Partikelbeladung durch beim Vor- verrasten und anschließendem Öffnen der Kapseln auftretende Reibungseffekte der Kapsel sichergestellt.In addition, lower particle loading is ensured by the capsule's frictional effects occurring during pre-locking and subsequent opening of the capsules.
In Versuchen hat sich gezeigt, dass die partikuläre Belastung der in dem erfindungsgemäßen Verfahren verwendeten Kapsel geringer ist als bei dem aus dem Stand der Technik bekannten Verfahren. So konnte beispielsweise in bestimmten Partikelgrößenklassen eine Reduktion bis um den Faktor 100 erreicht werden, was zum einen auch durch entsprechende Reinraumbedingungen beim Spritzgießen sowie der geringen Reibungsbelastung der Kapsel aufgrund der entfallenden Vorverrastung zu verdanken ist.Experiments have shown that the particulate loading of the capsule used in the method according to the invention is lower than in the method known from the prior art. Thus, for example, in certain particle size classes, a reduction of up to a factor of 100 can be achieved, which is partly due to the corresponding clean room conditions in injection molding and the low frictional load on the capsule due to the missing pre-locking.
Die Kapselkörper und Kapselkappen der verrastbaren Kapseln (mit oder ohne Vorrastposition) bestehen aus allen herkömmlichen und dem Fachmann bekannten Materialien, insbesondere aus spritzgegossenem Polymerwerkstoff .The capsule bodies and capsule caps of the lockable capsules (with or without pre-locking position) consist of all conventional materials known to the person skilled in the art, in particular of injection-molded polymer material.
Die Kapseln können jeder Applikationsform dienen; Sie sind insbesondere für den Einsatz in den zuvor aufgeführten Inhalatoren ausgelegt und ganz besonders bevorzugt für den Handi- Haler®, wie in EP 1342483 offenbart.The capsules can serve any application form; They are designed especially for use in the above-mentioned inhalers and most preferably for the Handi- Haler ® as disclosed in EP 1,342,483th
Sind die Kapselkörper und Kapselkappen beispielsweise aus PP, PE oder ABS gefertigt und weisen einen E-Modul im Bereich von 200 bis 3600 MPa, insbesondere im Bereich von 400 bis 3000 MPa, auf, ist aufgrund der daraus resultierenden Stabilität eine zu einer Störung des Abfüllprozesses führende Verformung der Kapselkörper bzw. Kapselkappen vermieden. Ein E-Modul- Bereich zwischen 600 und 1400 MPa hat sich als besonders vorteilhaft erwiesen.If the capsule bodies and capsule caps are made, for example, from PP, PE or ABS and have an modulus of elasticity in the range from 200 to 3600 MPa, in particular in the range from 400 to 3000 MPa, the resulting stability leads to a disruption of the filling process leading deformation of the capsule body or capsule caps avoided. An e-module Range between 600 and 1400 MPa has proven to be particularly advantageous.
Werden die Kapselelemente außerdem mittels ionisierender Gase nach ihrer Herstellung behandelt, können elektrostatische Aufladungen der Kapselkörper und damit einhergehend eine Partikelbeladung weiterhin reduziert werden.Furthermore, if the capsule elements are treated by means of ionizing gases after their preparation, electrostatic charges of the capsule bodies and, consequently, a particle load can be further reduced.
Weiterhin können die getrennt vorliegende Kapselkappe und - körper leicht einem Trocknungsprozess bzw. einer Flutung mit trockenen Gasen unterzogen werden, wodurch eine vollständige Trocknung der Innenoberfläche der beiden Kapselteile gewährleistet ist. Diese Trocknung ist für die Lagerung der Kapseln erforderlich und vereinfacht die Abfüllung von pulverförmigen Wirkstoffformulierungen .Furthermore, the separately present capsule cap and body can be easily subjected to a drying process or a flooding with dry gases, whereby a complete drying of the inner surface of the two capsule parts is ensured. This drying is required for the storage of the capsules and simplifies the filling of powdered drug formulations.
Außerdem lassen sich die Kapselkörper und die Kapselkappen unmittelbar vor dem Befüllen innen optisch inspizieren. Dies kann beispielsweise mittels Bilderfassungs- und Bearbeitungssystemen automatisch oder durch den Bedienpersonal erfolgen. Somit können Schäden an oder in den Kapselteilen vor dem Befüllen frühzeitig erkannt und die Arzneimittelsicherheit erhöht werden.In addition, the capsule body and the capsule caps can be visually inspected immediately before filling. This can be done for example by means of image acquisition and processing systems automatically or by the operator. Thus, damage to or in the capsule parts can be detected early before filling and drug safety can be increased.
Die Aufgabe wird bei einer Vorrichtung zur Befüllung von Kapseln mit pharmazeutischen Wirkstoffformulierungen zur Durchführung des Verfahrens erfindungsgemäß dadurch gelöst, dass die Kapselfördereinrichtung Aufnahmekavitäten zur separaten Aufnahme von Kapselkörpern und Kapselkappen sowie getrennte Vorratsbehälter für Kapselkörper und Kapselkappen aufweist. Eine derartige Kapselabfüllvorrichtung zeichnet sich durch eine vereinfachte Bauweise aus und gestattet es, gegenüber einer aus dem Stand der Technik bekannten Abfüllvorrichtung, eine erhöhte Prozessgeschwindigkeit zu erreichen, da keine Vorverrastung der Kapseln vor der Befüllung zu lösen ist.The object is achieved in a device for filling capsules with pharmaceutical active ingredient formulations for carrying out the method according to the invention in that the capsule delivery device receiving cavities for separate recording of capsule bodies and capsule caps and separate reservoir for capsule body and capsule caps has. Such a Kapselabfüllvorrichtung is characterized by a simplified design and allows, compared to a filling device known from the prior art, to achieve an increased process speed, since no Vorverrastung the capsules to solve before filling.
Die Kapseln können mit Arzneimitteln jeglicher Art befüllt werden. Vorzugsweise erfolgt die Befüllung mit Arzneimitteln in Pulverform.The capsules can be filled with medicines of any kind. Preferably, the filling with medicaments takes place in powder form.
Die unten genannten Verbindungen können allein oder in Kombination zur Anwendung in der erfindungsgemäßen Vorrichtung gelangen. In den unten genannten Verbindungen ist W einen pharmakologisch, aktiver Wirkstoff und (beispielsweise) ausgewählt aus der Gruppe bestehend aus Betamimetika, Anticholinergika, Corticosteroiden, PDE4-Inhibitoren, LTD4- Antagonisten, EGFR-Hemmern, Dopamin-Agonisten, Hl-Anti- histaminika, PAF-Antagonisten und PI3-Kinase Inhibitoren. Weiterhin können zwei- oder dreifach Kombinationen von W kombiniert werden und zur Anwendung in der erfindungsgemäßen Vorrichtung gelangen. Beispielhaft genannte Kombinationen von W wären :The compounds mentioned below can be used alone or in combination for use in the device according to the invention. In the compounds listed below, W is a pharmacologically active agent and (for example) selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, HIV antihistaminics, PAF antagonists and PI3 kinase inhibitors. Furthermore, two- or three-fold combinations of W can be combined and used for application in the device according to the invention. Exemplary combinations of W would be:
W stellt ein Betamimetika dar, kombiniert mit einem Anticholinergika, Corticosteroide, PDE4-Inhibitore, EGFR- Hemmern oder LTD4 -Antagonisten,W represents a betamimetics combined with an anticholinergic, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists,
W stellt ein Anticholinergika dar, kombiniert mit einem Betamimetika, Corticosteroiden, PDE4-Inhibitoren, EGFR- Hemmern oder LTD4-Antagonisten,W represents an anticholinergic, combined with a betamimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists,
W stellt ein Corticosteroiden dar, kombiniert mit einem PDE4-Inhibitoren, EGFR-Hemmern oder LTD4-Antagonisten W stellt ein PDE4-Inhibitoren dar, kombiniert mit einem EGFR-Hemmern oder LTD4-AntagonistenW represents a corticosteroid combined with a PDE4 inhibitor, EGFR inhibitor or LTD4 antagonist W represents a PDE4 inhibitor combined with an EGFR inhibitor or LTD4 antagonist
- W stellt ein EGFR-Hemmern dar, kombiniert mit einem LTD4- Antagonisten.W represents an EGFR inhibitor combined with a LTD4 antagonist.
Als Betamimetika gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Albuterol, Arformoterol, Bambuterol, Bitolterol, Broxate- rol, Carbuterol, Clenbuterol, Fenoterol, Formoterol, Hexopre- naline, Ibuterol, Isoetharine, Isoprenaline, Levosalbutamol , Mabuterol, Meluadrine, Metaproterenol , Orciprenaline, Pirbu- terol, Procaterol, Reproterol, Rimiterol, Ritodrine, Salmefa- mol, Salmeterol, Soterenol, Sulphonterol, Terbutaline, Tiara- mide, Tolubuterol, Zinterol, CHF-1035, HOKU-81, KUL-1248 und 3- (4- { 6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) - ethylamino] -hexyloxy} -butyl) -benzyl-sulfonamid 5- [2- (5 , 6-Diethyl-indan-2-ylamino) -1-hydroxy-ethyl] -8- hydroxy-lH-quinolin-2-onPreferred betamimetics for this purpose are compounds selected from the group consisting of albuterol, arformoterol, bambuterol, bitolterol, broxeterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharines, isoprenaline, levosalbutamol, mabuterol , Meluadrine, Metaproterenol, Orciprenaline, Pirbuterol, Procaterol, Reproterol, Rimiterol, Ritodrine, Salmefamol, Salmeterol, Soterenol, Sulphone terol, Terbutaline, Tiaramide, Tolubuterol, Zinterol, CHF-1035, HOKU-81, KUL-1248 and 3- (4- {6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -hexyloxy} -butyl) -benzylsulfonamide 5- [2- (5, 6- Diethyl-indan-2-ylamino) -1-hydroxy-ethyl] -8-hydroxy-1H-quinolin-2-one
- 4-Hydroxy-7- [2-{ [2-{ [3- (2- phenylethoxy) propyl] sulphonyl}ethyl] -amino}ethyl] -2 (3H) - benzothiazolon4-Hydroxy-7- [2- {[2- {[3- (2-phenylethoxy) propyl] sulphonyl} ethyl] amino} ethyl] -2 (3H) -benzothiazolone
1- (2-Fluor-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2- methyl-2-butylamino] ethanol1- (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] ethanol1- [3- (4-methoxybenzylamino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol
- 1- [2H-5-hydroxy-3-oxo-4H-l, 4-benzoxazin-8-yl] -2- [3- (4-N,N- dimethylaminophenyl) -2-methyl-2-propylamino] ethanol1- [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-l, 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-methoxyphenyl) -2-methyl-2-propylamino] ethanol
- 1- [2H-5-hydroxy-3-oxo-4H-l, 4-benzoxazin-8-yl] -2- [3- (4-n- butyloxyphenyl) -2-methyl-2-propylamino] ethanol 1- [2H-5-hydroxy-3-oxo-4H-l, 4-benzoxazin-8-yl] -2-{4- [3- (4- methoxyphenyl) -1,2, 4-triazol-3-yl] -2-methyl-2- butylamino } 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-triazole-3- yl] -2-methyl-2-butylamino} ethanol
5-Hydroxy-8- (l-hydroxy-2-isopropylaminobutyl) -2H-I14- benzoxazin-3- (4H) -on5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-I 1 4-benzoxazine-3- (4H) -one
1- (4-Amino-3-chlor-5-trifluormethylphenyl) -2-tert . - butylamino) ethanol1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-tert. - butylamino) ethanol
6-Hydroxy-8-{l-hydroxy-2- [2- (4-methoxy-phenyl) -1,1- dimethyl-ethylamino] -ethyl } -4H-benzo [1,4] oxazin-3-on6-Hydroxy-8- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one
6-Hydroxy-8- { l-hydroxy-2- [2- (4-phenoxy- essigsäureethylester ) -1 , 1-dimethyl-ethylamino] -ethyl} -4H- benzo [1,4] oxazin-3-on6-Hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -1, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one
6-Hydroxy-8- {l-hydroxy-2- [2- ( 4-phenoxy-essigsaure) -1,1- dimethyl-ethylamino] -ethyl} -4H-benzo [1,4] oxazin-3-on6-Hydroxy-8- {1-hydroxy-2- [2- (4-phenoxyacetic acid) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one
8-{2- [1, l-Dimethyl-2- (2,4, 6-trimethylphenyl) -ethylamino] -8- {2- [1,1-dimethyl-2- (2,4,6-trimethyl-phenyl) -ethyl-amino] -
1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-on1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one
6-Hydroxy-8- { 1-hydroxy-2 - [ 2- ( 4-hydroxy-pheny1 ) - 1 , 1- dimethyl-ethylamino] -ethyl} -4H-benzo [1 , 4] oxazin-3-on6-Hydroxy-8- {1-hydroxy-2 - [2- (4-hydroxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one
6-Hydroxy-8-{l-hydroxy-2- [2- (4-isopropyl-phenyl) -6-hydroxy-8- {1-hydroxy-2- [2- (4-isopropylphenyl) -
1, ldimethyl-ethylamino] -ethyl} -4H-benzo [1,4] oxazin-3-on1, ldimethyl-ethylamino] -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-on8- {2- [2- (4-ethylphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxyethyl} -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-on8- {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) -buttersäure4- (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-Difluor-phenyl) -1, 1-dimethyl-ethylamino] -1- hydroxy-ethyl}-6-hydroxy-4H-benzo[l, 4] oxazin-3-on8- {2- [2- (3,4-difluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4-oxazine-3-] on
1- (4-Ethoxy-carbonylamino-3-cyano-5-fluorophenyl) -2-1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2-
( tert . -butylamino ) ethanol - 2-Hydroxγ-5- (l-hydroxy-2- {2- [4- (2-hydroxy-2-phenyl- ethylamino) -phenyl] -ethylamino} -ethyl ) -benzaldehyd(tert -butylamino) ethanol 2-hydroxy-5- (1-hydroxy-2- {2- [4- (2-hydroxy-2-phenyl-ethylamino) -phenyl] -ethylamino} -ethyl) -benzaldehyde
- N- [2-Hydroxy-5- ( l-hydroxy-2- {2- [4- (2-hydroxy-2-phenyl- ethylamino) -phenyl] -ethylamino} -ethyl ) -phenyl] -formamid 8-Hydroxy-5- ( l-hydroxy-2- {2- [4- ( 6-methoxy-biphenyl-3- ylamino) -phenyl ] -ethylamino} -ethyl ) -lH-quinolin-2-on 8-Hydroxy-5- [l-hydroxy-2- ( 6-phenethylamino-hexylamino) - ethyl] -lH-quinolin-2-onN- [2-hydroxy-5- (1-hydroxy-2- {2- [4- (2-hydroxy-2-phenyl-ethylamino) -phenyl] -ethylamino} -ethyl) -phenyl] -formamide 8- Hydroxy-5- (1-hydroxy-2- {2- [4- (6-methoxy-biphenyl-3-ylamino) -phenyl] -ethylamino} -ethyl) -1H-quinolin-2-one 8-hydroxy-5 - [1-hydroxy-2- (6-phenethylamino-hexylamino) ethyl] -1H-quinolin-2-one
5- [2- (2-{4- [4- (2-Amino-2-methyl-propoxy) -phenylamino] - phenyl} -ethylamino) -1-hydroxy-ethyl] -8-hydroxy-lH- quinolin-2-on5- [2- (2- {4- [4- (2-Amino-2-methylpropoxy) -phenylamino] -phenyl} -ethylamino) -1-hydroxy-ethyl] -8-hydroxy-1H-quinoline 2-one
[3- (4- {6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl ) - ethylamino] -hexyloxy} -butyl) -5-methyl-phenyl] -harnstoff[3- (4- {6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -hexyloxy} -butyl) -5-methyl-phenyl] -urea
4- (2- { 6- [2- (2 , 6-Dichloro-benzyloxy) -ethoxy] -hexylamino} -1- hydroxy-ethyl) -2-hydroxymethyl-phenol4- (2- {6- [2- (2,6-dichloro-benzyloxy) -ethoxy] -hexylamino} -1-hydroxy-ethyl) -2-hydroxymethyl-phenol
3- (4- { 6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) - ethylamino] -hexyloxy} -butyl) -benzylsulfonamid3- (4- {6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -hexyloxy} -butyl) -benzylsulfonamide
3- (3- {7- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) - ethylamino] -heptyloxy} -propyl) -benzylsulfonamid3- (3- {7- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -heptyloxy} -propyl) -benzylsulfonamide
4- (2- {6- [4- ( 3 -Cyclopentanesulfonyl-phenyl) -butoxy] - hexylamino} -1-hydroxy-ethyl) -2-hydroxymethyl-phenol4- (2- {6- [4- (3-Cyclopentanesulfonyl-phenyl) -butoxy] -hexylamino} -1-hydroxy-ethyl) -2-hydroxymethyl-phenol
- N-Adamantan-2-yl-2- (3- {2- [2-hydroxy-2- (4-hydroxy-3- hydroxymethyl-phenyl) -ethylamino] -propyl} -phenyl ) -acetamidN-adamantan-2-yl-2- (3- {2- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -propyl} -phenyl) -acetamide
gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastere- omere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate. Erfindungsgemäß bevorzugt sind die Säureadditionssalze der Betamimetika ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat , Hydro- methansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydro- citrat, Hydrofumarat, Hydrotartrat , Hydrooxalat, Hydrosucci- nat, Hydrobenzoat und Hydro-p-toluolsulfonat .optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts of the betamimetics are preferably selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydroxides citrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
Als Anticholinergika gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Tiotropiumsalzen, bevorzugt das Bromidsalz, Oxitro- piumsalzen, bevorzugt das Bromidsalz, Flutropiumsalzen, bevorzugt das Bromidsalz, Ipratropiumsalzen, bevorzugt das Bromidsalz, Glycopyrroniumsalzen, bevorzugt das Bromidsalz, Trospiumsalzen, bevorzugt das Chloridsalz, Tolterodin. In den vorstehend genannten Salzen stellen die Kationen die pharmakologisch aktiven Bestandteile dar. Als Anionen können die vorstehend genannten Salze bevorzugt enthalten Chlorid, Bro- mid, Iodid, Sulfat, Phosphat, Methansulfonat , Nitrat, Maleat, Acetat, Citrat, Fumarat, Tartrat, Oxalat, Succinat, Benzoat oder p-Toluolsulfonat , wobei Chlorid, Bromid, Iodid, Sulfat, Methansulfonat oder p-Toluolsulfonat als Gegenionen bevorzugt sind. Von allen Salzen sind die Chloride, Bromide, Iodide und Methansulfonate besonders bevorzugt.Preferred anticholinergic compounds here are compounds which are selected from the group consisting of tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, glycopyrronium salts, preferably the bromide salt, trospium salts , preferably the chloride salt, tolterodine. In the salts mentioned above, the cations are the pharmacologically active ingredients. As anions, the abovementioned salts may preferably contain chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate , Succinate, benzoate or p-toluenesulfonate, with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate being preferred as counterions. Of all the salts, the chlorides, bromides, iodides and methanesulfonates are particularly preferred.
Ebenfalls bevorzugte Anticholinergika sind ausgewählt aus den Salzen der Formel AC-ILikewise preferred anticholinergics are selected from the salts of the formula AC-I
worin X - ein einfach negativ geladenes Anion, bevorzugt ein Anion ausgewählt aus der Gruppe bestehend aus Fluorid, Chlorid, Bromid, Iodid, Sulfat, Phosphat, Methansulfonat, Nitrat, Maleat, Acetat, Citrat, Fumarat, Tartrat, Oxalat, Succinat, Benzoat und p-Toluolsulfonat , bevorzugt ein einfach negativ geladenes Anion, besonders bevorzugt ein Anion ausgewählt aus der Gruppe bestehend aus Fluorid, Chlorid, Bromid, Methansul- fonat und p-Toluolsulfonat , insbesondere bevorzugt Bromid, bedeutet gegebenenfalls in Form ihrer Racemate, Enantiomere oder Hydrate. Von besonderer Bedeutung sind solche Arzneimittelkombinationen, die die Enantiomere der Formel AC-l-enwherein X - is a single negatively charged anion, preferably one Anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate, preferably a single negatively charged anion, particularly preferably an anion selected from the group consisting of fluoride, chloride, bromide, methanesulfonate and p-toluenesulfonate, particularly preferably bromide, if appropriate in the form of their racemates, enantiomers or hydrates. Of particular importance are those drug combinations which contain the enantiomers of the formula AC-I-ene
enthalten, worin X - die vorstehend genannten Bedeutungen aufweisen kann. Weiterhin bevorzugte Anticholinergika sind ausgewählt aus den Salzen der Formel AC-2in which X - may have the meanings given above. Further preferred anticholinergics are selected from the salts of the formula AC-2
worin R entweder Methyl oder Ethyl bedeuten und worin X - die vorstehend genannte Bedeutungen aufweisen kann. In einer alternativen Ausführungsform kann die Verbindung der Formel AC- 2 auch in Form der freien Base AC-2-base vorliegen. wherein R is either methyl or ethyl and wherein X - may have the meanings given above. In an alternative embodiment, the compound of formula AC-2 may also be in the form of the free base AC-2-base.
Weiterhin genannte Verbindungen sind:Further named compounds are:
2 , 2 -Diphenylpropionsäuretropenolester-Methobromid 2 , 2 -Diphenylpropionsäurescopinester-Methobromid 2-Fluor-2 , 2-Diphenylessigsäurescopinester-Methobromid 2-Fluor-2 , 2-Diphenylessigsäuretropenolester-Methobromid 3 , 3 ' , 4 , 4 ' -Tetrafluorbenzilsäuretropenolester-Methobromid 3 , 3 ' , 4 , 4 ' -Tetrafluorbenzilsäurescopinester-Methobromid 4,4' -Difluorbenzilsäuretropenolester-Methobromid 4,4' -Difluorbenzilsäurescopinester-Methobromid 3,3' -Difluorbenzilsäuretropenolester-Methobromid 3,3' -Difluorbenzilsäurescopinester-Methobromid 9 -Hydroxy-fluoren-9-carbonsäuretropenolester-Methobromid 9 -Fluor- fluoren-9-carbonsäuretropenolester-Methobromid 9-Hydroxy-fluoren-9-carbonsäurescopinester-Methobromid 9-Fluor- fluoren-9-carbonsäurescopinester-Methobromid 9-Methyl- fluoren-9-carbonsäuretropenolester-Methobromid 9 -Methyl-fluoren-9-carbonsäurescopinester-Methobromid Benzilsäurecyclopropyltropinester-Methobromid 2, 2-Diphenylpropionsäurecyclopropyltropinester-Methobromid 9-Hydroxy-xanthen- 9-carbonsäurecyclopropyltropinester- Methobromid2, 2-Diphenylpropionic acid-tropol ester-methobromide 2, 2-diphenylpropionic acid copoprene-methobromide 2-fluoro-2, 2-diphenylacetic acid-co-ester methobromide 2-fluoro-2, 2-diphenylacetic acid-tropol ester-methobromide 3, 3 ', 4, 4'-tetrafluorobenzilic acid-tropol ester-methobromide 3 , 3 ', 4, 4' -Tetrafluorobenzilatecopine ester methobromide 4,4'-difluorobenzylic acid tropol ester methobromide 4,4'-difluorobenzylic acid copolester methobromide 3,3'-difluorobenzylic acid, tropol ester methobromide 3,3 '-difluorobenzylic acid copopriester methobromide 9 -hydroxyfluorene 9-Carboxylic Acid Sterol Esters-Methobromide 9 -Fluorofluoren-9-Carboxylic Acid-Sterol Ester-Methobromide 9-Hydroxy-Fluoren-9-Carboxylic Acidcopine Ester Methobromide 9-Fluoro-Fluoren-9-Carboxylic Acidcopinester-Methobromide 9-Methyl-Fluoren-9-Carboxylic Acid-Sterol Ester-Methobromide 9 Methyl fluorene-9-carboxylic acid copo-ester methobromide Benzylic acid cyclopropyl tropine ester methobromide 2, 2-Diphenylpropionsäurecyclopropyltropinester Methobro 9-hydroxy-xanthene-9-carboxylic acid cyclopropyltropic ester methobromide
9-Methyl-fluoren-9 -carbonsäurecyclopropyltropinester- Methobromid 9-Methyl-xanthen-9-carbonsäurecyclopropyltropinester- Methobromid9-Methyl-fluorene-9-carboxylic acid cyclopropyl-tropine ester methobromide 9-methyl-xanthene-9-carboxylic acid cyclopropyltropic ester methobromide
9-Hydroxy-fluoren-9-carbonsäurecyclopropyltropinester- Methobromid9-Hydroxy-fluorene-9-carboxylic acid cyclopropyltropic ester methobromide
4,4' -Difluorbenzilsäuremethylestercyclopropyltropinester- Methobromid4,4'-Difluorobenzilate methylcyclopropyltropine ester methobromide
9-Hydroxy-xanthen-9-carbonsäuretropenolester-Methobromid 9-Hydroxy-xanthen-9-carbonsäurescopinester-Methobromid 9-Methyl-xanthen-9-carbonsäuretropenolester-Methobromid 9-Methyl-xanthen-9-carbonsäurescopinester-Methobromid 9-Ethyl-xanthen- 9-carbonsäuretropenolester-Methobromid 9-Difluormethyl-xanthen-9-carbonsäuretropenolester- Methobromid9-Hydroxy-xanthene-9-carboxylic acid-tropol ester-methobromide 9-hydroxy-xanthene-9-carboxylic acid-co-ester methobromide 9-methyl-xanthene-9-carboxylic acid-tropol ester-methobromide 9-methyl-xanthene-9-carboxylic acid-co-ester methobromide 9-ethyl-xanthene 9-Carboxylic Acid Sterol Ester Methobromide 9-Difluoromethyl-xanthene-9-carboxylic Acid Sterol Ester Methobromide
9-Hydroxymethyl-xanthen-9 -carbonsäurescopinester- Methobromid9-hydroxymethyl-xanthene-9-carboxylic acid copo-ester methobromide
Die vorstehend genannten Verbindungen sind im Rahmen der vorliegenden Erfindung auch als Salze einsetzbar, in denen statt des Methobromids , die Salze Metho-X zur Anwendung gelangen, wobei X die vorstehend für X- genannten Bedeutungen haben kann.The abovementioned compounds can also be used in the context of the present invention as salts in which, instead of the methobromide, the salts Metho-X are used, where X may have the meanings given above for X-.
Als Corticosteroide gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Beclomethason, Betamethason, Budesonid, Butixocort, Ciclesonid, Deflazacort, Dexamethason, Etiprednol, Flunisolid, Fluticason, Loteprednol, Mometason, Prednisolon, Prednison, Rofleponid, Triamcinolon, RPR-106541, NS-126, ST-26 und 6 , 9-Difluor-17- [ (2-furanylcarbonyl) oxy] -ll-hydroxy-16- methyl-3-oxo-androsta-l, 4-dien-17-carbothionsäure (S) - fluoromethylesterPreferred corticosteroids here are compounds selected from the group consisting of beclomethasone, betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone, RPR -106541, NS-126, ST-26 and 6,9-Difluoro-17- [(2-furanylcarbonyl) oxy] -ll-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionic acid (S) -fluoromethyl ester
6, 9-Difluor-ll-hydroxy-16-methyl-3-oxo-17-propionyloxy- androsta-1, 4-dien-17-carbothionsäure (S) - (2-oxo- tetrahydro-furan-3S-yl) ester, - 6D, 9D-difluoro-HD-hydroxy-16D-methyl-3-oxo-17D- (2,2,3,3- tertamethylcyclopropylcarbonyl ) oxy-androsta-1 , 4-diene-17D- carbonsäure cyanomethyl ester gegebenenfalls in Form ihrer Racemate, Enantiomere oder Di- astereomere und gegebenenfalls in Form ihrer Salze und Derivate, ihrer Solvate und/oder Hydrate. Jede Bezugnahme auf Steroide schließt eine Bezugnahme auf deren gegebenenfalls existierende Salze oder Derivate, Hydrate oder Solvate mit ein. Beispiele möglicher Salze und Derivate der Steroide können sein: Alkalisalze, wie beispielsweise Natrium- oder Kaliumsalze, Sulfobenzoate, Phosphate, Isonicotinate, Acetate, Dichloroacetate, Propionate, Dihydrogenphosphate, Palmitate, Pivalate oder auch Furoate.6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxyandrosta-1,4-diene-17-carbothionic acid (S) - (2-oxotetrahydrofuran-3S-yl) esters, - 6D, 9D-difluoro-HD-hydroxy-16D-methyl-3-oxo-17D- (2,2,3,3-tertamethylcyclopropylcarbonyl) oxy-androsta-1,4-diene-17D-cyanomethyl carboxylic acid, if appropriate in the form of their racemates, enantiomers or diastereomers, and optionally in the form of their salts and derivatives, their solvates and / or hydrates. Any reference to steroids includes reference to their optional salts or derivatives, hydrates or solvates. Examples of possible salts and derivatives of steroids may be: alkali metal salts, such as, for example, sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or even furoates.
Als PDE4-Inhibitoren gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Enprofyllin, Theophyllin, Roflumilast, Ariflo (CiIo- milast) , Tofimilast, Pumafentrin, Lirimilast, Arofyllin, Ati- zoram, D-4418, Bay-198004, BY343, CP-325,366, D-4396 (Sch- 351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V-11294A, Cl-1018, CDC-801, CDC- 3052, D-22888, YM-58997, Z-15370 undPreferred PDE4 inhibitors used here are compounds selected from the group consisting of enprofylline, theophylline, roflumilast, ariflo (cillobast), tofimilast, pumafentrin, lirimilast, arofylline, atizoram, D-4418 198004, BY343, CP-325,366, D-4396 (Sch351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T- 2585, V-11294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and
N- (3 , 5-Dichloro-l-oxo-pyridin-4-yl) -4-difluormethoxy-3- cyclopropylmethoxybenzamid - (-)p- [ (4aR*, 10bS*)-9-Ethoxy-l,2,3,4,4a,10b-hexahydro-8- methoxy-2-methylbenzo [s] [1,6] naphthyridin-6-yl] -N, N- diisopropylbenzamidN- (3,5-dichloro-1-oxopyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide - (-) p- [(4aR *, 10bS *) - 9-ethoxy-1,2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo [s] [1,6] naphthyridine 6-yl] -N, N-diisopropylbenzamide
(R) - ( + ) -1- (4-Brombenzyl) -4- [ (3-cyclopentyloxy) -4- methoxyphenyl ] -2-pyrrolidon(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-pyrrolidon eis [4-Cyano-4- (3-cyclopentyloxy-4- methoxyphenyl ) eyelohexan-1-carbonsäure] 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4- difluoromethoxyphenyl ) cyclohexan-1-on eis [4-Cyano-4- (3-cyclopropylmethoxy-4- difluormethoxyphenyl) cyclohexan-1-ol]3- (cyclopentyloxy-4-methoxyphenyl) -1- (4-N '- [N-2-cyano-S-methyl-isothioureido] benzyl) -2-pyrrolidone eis [4-cyano-4- (3-cyclopentyloxy-) 4-methoxyphenyl) eyelohexane-1-carboxylic acid] 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one Ice [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl ) cyclohexan-1-ol]
(R) - ( + ) -Ethyl [4- (3-cyclopentyloxy-4- methoxyphenyl)pyrrolidin-2-yliden] acetat(R) - (+) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene] acetate
(S) - (-) -Ethyl [4- (3-cyclopentyloxy-4- methoxyphenyl ) pyrrolidin-2-yliden] acetat(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]-l,2, 4-triazolo [4, 3-a]pyridin- 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]-l,2, 4-triazolo [4, 3-a]pyridin gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastere- omere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate. Erfindungsgemäß bevorzugt sind die Säureadditionssalze der PDE4- Inhibitoren ausgewählt aus der Gruppe bestehend aus Hydro- chlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat , Hydromethansulfonat , Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofumarat, Hydrotartrat , Hydrooxalat, Hydro- succinat, Hydrobenzoat und Hydro-p-toluolsulfonat . Als LTD4 -Antagonisten gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Montelukast, Pranlukast, Zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321 und- 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 their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts of the PDE4 inhibitors are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro p-toluenesulfonate. Preferred LTD4 antagonists here are compounds selected from the group consisting of 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-Difluor-2-quinolinyl) ethenyl) phenyl ) -3- (2- (2- hydroxy-2-propyl) phenyl) thio)methylcyclopropan- essigsäure,- 1- (((R) - (3- (2- (6,7-Difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2-hydroxy-2-propyl) phenyl) thio) methylcyclopropane - acetic acid,
- l-( ( (l(R) -3 (3-(2-(2,3-Dichlorthieno[3,2-b]pyridin-5-yI)- (E) -ethenyl) phenyl) -3- (2- ( 1-hydroxy-1-methyIethyl) phenyl) - propyl) thio)methyl) cyclopropanessigsäure [2- [ [2- (4-tert-Butyl-2-thiazolyl) -5- benzofuranyl ] oxymethyl ] phenyl ] essigsaure gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastere- omere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate. Erfindungsgemäß bevorzugt sind diese Säureadditionssalze ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat , Hydromethansulfonat , Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofu- marat, Hydrotartrat, Hydrooxalat, Hydrosuccinat , Hydrobenzoat und Hydro-p-toluolsulfonat . Unter Salzen oder Derivaten zu deren Bildung die LTD4-Antagonisten gegebenenfalls in der Lage sind, werden beispielsweise verstanden: Alkalisalze, wie beispielsweise Natrium- oder Kaliumsalze, Erdalkalisalze, Sulfobenzoate, Phosphate, Isonicotinate, Acetate, Propionate, Dihydrogenphosphate, Palmitate, Pivalate oder auch Furoate.- l - (((l (R) -3 (3- (2- (2,3-dichlorothieno [3,2-b] pyridin-5-yl) - (E) -ethenyl) phenyl) -3- ( 2- (1-hydroxy-1-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 their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofluorate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate. Examples of salts or derivatives which the LTD4-antagonists are capable of forming include: alkali metal salts, such as, for example, sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates ,
Als EGFR-Hemmer gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Cetuximab, Trastuzumab, ABX-EGF, Mab ICR- 62 undIn this case, compounds which are preferably present as EGFR inhibitors for use, selected from the group consisting of cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and
- 4- [ (3-Chlor-4-fluorphenyl)amino] -6-{ [4- (morpholin-4-yl) -1- oxo-2-buten-l-yl ] amino} -V-cyclopropylmethoxy-chinazolin- 4- [(3-chloro-4-fluorophenyl) amino] -6- {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -V-cyclopropylmethoxyquinazoline
4- [ (3-Chlor-4-fluorphenyl) amino] -6-{ [4- (N, N-diethylamino) - l-oxo-2-buten-l-yl ] amino} -7-cyclopropylmethoxy-chinazolin4- [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline
- 4- [ ( 3 -Chlor-4-fluorphenyl) amino] -6-{ [4- (N, N- dimethylamino) -l-oxo-2-buten-l-yl] amino} -7- cyclopropylmethoxy-chinazolin- 4- [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline
4- [ (R) - (1-Phenyl-ethyl) amino] -6-{ [4- (morpholin-4-yl) - l-oxo-2-buten-l-yl ] amino} -7-cyclopentyloxy-chinazolin4- [(R) - (1-phenylethyl) amino] -6- {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy quinazoline
- 4- [ (3-Chlor-4-fluor-phenyl) amino] -6-{ [4- ( (R) -6-methyl- 2-oxo-morpholin-4-yl) -l-oxo-2-buten-l-yl] amino} -7- cyclopropylmethoxy-chinazolin4- [(3-chloro-4-fluoro-phenyl) -amino] -6- {[4- ((R) -6-methyl-2-oxo-morpholin-4-yl) -l-oxo-2-ol] butene-1-yl] amino} -7-cyclopropylmethoxy-quinazoline
- 4- [ (3-Chlor-4-fluor-phenyl) amino] -6-{ [4- ( (R) -6-methyl- 2-oxo-morpholin-4-yl) -l-oxo-2-buten-l-yl] amino} -7- [ (S) - ( tetrahydrofuran-3-yl) oxy] -chinazolin4- [(3-chloro-4-fluoro-phenyl) -amino] -6- {[4- ((R) -6-methyl-2-oxo-morpholin-4-yl) -l-oxo-2-ol] buten-1-yl] amino} -7- [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline
- 4- [ (3-Chlor-4-fluor-phenyl) amino] -6-{ [4- ( (R) -2- methoxymethyl-6-oxo-morpholin-4-yl) -l-oxo-2-buten-l- yl] amino} -7-cyclopropylmethoxy-chinazolin4- [(3-chloro-4-fluoro-phenyl) -amino] -6- {[4- ((R) -2-methoxymethyl-6-oxo-morpholin-4-yl) -l-oxo-2-one] butene-1-yl] amino} -7-cyclopropylmethoxy-quinazoline
- 4- [ (3-Chlor-4-fluor-phenyl) amino] -6- [2- ( (S) -6-methyl-2- oxo-morpholin-4-yl) -ethoxy] -7-methoxy-chinazolin4- [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy quinazoline
4- [ (3-Chlor-4-fluorphenyl) amino] -6- ( {4- [N- (2-methoxy- ethyl) -N-methyl-amino] -l-oxo-2-buten-l-yl}amino) -7- cyclopropylmethoxy-chinazolin4- [(3-Chloro-4-fluorophenyl) amino] -6- ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -l-oxo-2-buten-1-yl } amino) -7-cyclopropylmethoxy-quinazoline
- 4- [ (3-Chlor-4-fluorphenyl) amino] -β-{ [4- (N, N- dimethylamino) -l-oxo-2-buten-l-yl] amino} -7-cyclopentyloxy- chinazolin- 4- [(3-chloro-4-fluorophenyl) amino] -β- {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline
- 4- [ (R) - (1-Phenyl-ethyl) amino] -6-{ [4- (N,N-bis- (2-methoxy- ethyl) -amino) -l-oxo-2-buten-l-yl] amino} -7- cyclopropylmethoxy-chinazolin - 4- [ (R) - (1-Phenyl-ethyl) amino] -6- ( {4- [N- (2-methoxy-ethyl ) - N-ethyl-amino] -l-oxo-2-buten-l-yl}amino) -7- cyclopropylmethoxy-chinazolin4- [(R) - (1-phenylethyl) amino] -6- {[4- (N, N-bis (2-methoxyethyl) amino] -1-oxo-2-butene 1-yl] amino} -7-cyclopropylmethoxyquinazoline 4- [(R) - (1-phenylethyl) amino] -6- ({4- [N- (2-methoxyethyl) -N-ethyl-amino] -l-oxo-2-butene l-yl} amino) -7-cyclopropylmethoxy-quinazoline
- 4- [ (R) - (1-Phenyl-ethyl) amino] -6- ( {4- [N- (2-methoxy-ethyl) - N-methyl-amino] -l-oxo-2-buten-l-yl}amino) -7- cyclopropylmethoxy-chinazolin4- [(R) - (1-phenylethyl) amino] -6- ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -l-oxo-2-butene l-yl} amino) -7-cyclopropylmethoxy-quinazoline
4- [ (R) - (1-Phenyl-ethyl) amino] -6- ( {4- [N- ( tetrahydropyran-4- yl) -N-methyl-amino] -l-oxo-2-buten-l-yl}amino) -7- cyclopropylmethoxy-chinazolin4- [(R) - (1-phenylethyl) amino] -6- ({4- [N- (tetrahydropyran-4-yl) -N-methyl-amino] -l-oxo-2-butene-1 -yl} amino) -7-cyclopropylmethoxy-quinazoline
- 4- [ (3-Chlor-4-fluorphenyl)amino] -6-{ [4- (N7N- dimethylamino) -l-oxo-2-buten-l-yl] amino} -7- ( (R) - tetrahydrofuran-3-yloxy) -chinazolin- 4- [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N 7 N- dimethylamino) -l-oxo-2-buten-l-yl] amino} -7- ((R ) - tetrahydrofuran-3-yloxy) quinazoline
- 4- [ (3-Chlor-4-fluorphenyl)amino] -6-{ [4- (N, N- dimethylamino) -l-oxo-2-buten-l-yl] amino} -7- ( (S) - tetrahydrofuran-3-yloxy) -chinazolin- 4- [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- ((S. ) - tetrahydrofuran-3-yloxy) quinazoline
4- [ (3-Chlor-4-fluorphenyl) amino] -6- ( {4- [N- (2-methoxy- ethyl) -N-methyl-amino] -l-oxo-2-buten-l-yl}amino) -7- cyclopentyloxy-chinazolin4- [(3-Chloro-4-fluorophenyl) amino] -6- ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -l-oxo-2-buten-1-yl } amino) -7-cyclopentyloxy-quinazoline
4- [ ( 3 -Chlor-4-fluorphenyl) amino] -6- { [4- (N-cyclopropyl-N- methyl-amino) -l-oxo-2-buten-l-yl] amino} -7-cyclopentyloxy- chinazolin4- [(3-Chloro-4-fluorophenyl) amino] -6- {[4- (N-cyclopropyl-N-methyl-amino) -l-oxo-2-buten-1-yl] -amino} -7- cyclopentyloxy-quinazoline
- 4- [ (3-Chlor-4-fluorphenyl) amino] -6-{ [4- (N7N- dimethylamino) -l-oxo-2-buten-l-yl] amino} -7- [ (R) - ( tetrahydrofuran-2-yl ) methoxy] -chinazolin- 4- [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N 7 N- dimethylamino) -l-oxo-2-buten-l-yl] amino} -7- [(R ) - (tetrahydrofuran-2-yl) methoxy] quinazoline
- 4-[ (3-Chlor-4-fluorphenyl) amino] -6-{ [4- (N7N- dimethylamino) -l-oxo-2-buten-l-yl] amino} -7- [ (S) - ( tetrahydrofuran-2 -yl ) methoxy] -chinazolin- 4- [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N 7 N- dimethylamino) -l-oxo-2-buten-l-yl] amino} -7- [(S ) - (tetrahydrofuran-2-yl) methoxy] quinazoline
4- [ (3-Ethinyl-phenyl) amino] -6, 7 -bis- (2 -methoxy-ethoxy) - chinazolin4- [(3-ethynylphenyl) amino] -6, 7-bis (2-methoxy-ethoxy) -quinazoline
4- [ (3-Chlor-4-fluorphenyl) amino] -7- [3- (morpholin-4-yl) - propyloxy] -6- [ (vinylcarbonyl) amino] -chinazolin 4- [ (R) - (1-Phenyl-ethyl) amino] -6- (4-hydroxy-phenyl) -7H- pyrrolo [2 , 3-d] pyrimidin4- [(3-Chloro-4-fluorophenyl) amino] -7- [3- (morpholin-4-yl) -propyloxy] -6- [(vinylcarbonyl) amino] -quinazoline 4- [(R) - (1-phenylethyl) amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine
3-Cyano-4- [ (3-chlor-4-fluorphenyl) amino] -6- { [4- (N, N- dimethylamino) -l-oxo-2-buten-l-yl] amino} -7-ethoxy-chinolin3-cyano-4- [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- ethoxy-quinoline
- 4- { [3-Chlor-4- (3-fluor-benzyloxy) -phenyl] amino} -6- (5- { [ (2- methansulfonyl-ethyl) amino] methyl} -furan-2-yl) chinazolin- 4- {[3-Chloro-4- (3-fluoro-benzyloxy) -phenyl] -amino} -6- (5- {[(2-methanesulfonyl-ethyl) -amino] -methyl} -furan-2-yl) -quinazoline
- 4- [ (R) - (1-Phenyl-ethyl) amino] -6-{ [4- ( (R) -6-methyl-2-oxo- morpholin-4-yl) -l-oxo-2-buten-l-yl] amino} -7-methoxy- chinazolin4- [(R) - (1-phenylethyl) amino] -6- {[4- ((R) -6-methyl-2-oxomorpholin-4-yl) -l-oxo-2-one buten-1-yl] amino} -7-methoxy-quinazoline
- 4- [ (3-Chlor-4-fluorphenyl) amino] -6- { [4- (morpholin-4-yl) -1- oxo-2-buten-l-yl ] amino} -7- [ ( tetrahydrofuran-2-yl ) methoxy] - chinazolin- 4- [(3-chloro-4-fluorophenyl) amino] -6- {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7- [(tetrahydrofuran -2-yl) methoxy] - quinazoline
- 4- [ (3-Chlor-4-fluorphenyl) amino] -6- ( {4- [N,N-bis- (2- methoxy-ethyl ) -amino] -l-oxo-2-buten-l-yl} amino) -7-4- [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N, N-bis (2-methoxy-ethyl) -amino] -l-oxo-2-buten-1-one yl} amino) -7-
[ (tetrahydrofuran-2-yl) methoxy] -chinazolin[(tetrahydrofuran-2-yl) methoxy] quinazoline
4- [ (3-Ethinyl-phenyl) amino] -6-{ [4- (5, 5-dimethyl-2-oxo-mor- pholin-4-yl) -l-oxo-2-buten-l-yl] amino} -chinazolin4- [(3-ethynylphenyl) amino] -6- {[4- (5,5-dimethyl-2-oxo-morphol-4-yl) -1-oxo-2-buten-1-yl ] amino} quinazoline
- 4- [ (3-Chlor-4-fluor-phenyl)amino]-6- [2- (2, 2-dimethyl-6- oxo-morpholin-4-yl) -ethoxy] -7-methoxy-chinazolin- 4- [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline
- 4- [ (3-Chlor-4-fluor-phenyl) amino] -6- [2- (2, 2-dimethyl-6- oxo-morpholin-4-yl) -ethoxy] -7- [ (R) - ( tetrahydrofuran-2- yl) methoxy] -chinazolin4- [(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-Chlor-4-fluor-phenyl) amino] -7- [2- (2, 2-dimethyl-6- oxo-morpholin-4-yl) -ethoxy] -6- [ (S) - ( tetrahydrofuran-2- yl) methoxy] -chinazolin- 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-Chlor-4-fluor-phenyl) amino] -6-{2- [4- (2-oxo- morpholin-4-yl ) -piperidin-1-yl ] -ethoxy} -7-methoxy- chinazolin4- [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [4- (2-oxomorpholin-4-yl) -piperidin-1-yl] -ethoxy} -7- methoxyquinazoline
- 4- [ ( 3 -Chlor-4-fluor-phenyl) amino] -6- [1- (tert . - butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-chinazolin 4- [ (3-Chlor-4-fluor-phenyl) amino] -6- ( trans-4-amino- cyclohexan-1-yloxy) -7-methoxy-chinazolin 4- [ (3-Chlor-4-fluor-phenyl) amino] -6- (trans-4- methansulfonylamino-cyclohexan-1-yloxy) -7-methoxy- chinazolin- 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-1-yloxy) -7-methoxy-quinazoline 4- [(3-chloro-4-fluoro) phenyl) amino] -6- (trans-4-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline
4- [ ( 3 -Chlor-4-fluor-phenyl) amino] -6- ( tetrahydropyran-3- yloxy) -7-methoxy-chinazolin4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-3-yloxy) -7-methoxy-quinazoline
4- [ (3-Chlor-4-fluor-phenyl) amino] -6- (l-methyl-piperidin-4- yloxy) -7-methoxy-chinazolin4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline
4- [ (3 -Chlor-4-fluor-phenyl) amino] -6- { 1- [ (morpholin-4- yl ) carbonyl ] -piperidin-4-yloxy} -7-methoxy-chinazolin 4- [ (3-Chlor-4-fluor-phenyl) amino] -6-{l-4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1- [(morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline 4- [(3 -Chloro-4-fluoro-phenyl) amino] -6- {l-
[ (methoxymethyl) carbonyl] -piperidin-4-yloxy} -7-methoxy- chinazolin[(methoxymethyl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline
4- [ (3 -Chlor-4-fluor-phenyl) amino] -6- (piperidin-3-yloxy) -7- methoxy-chinazolin4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline
4- [ (3-Chlor-4-fluor-phenyl) amino] -6- [1- (2-acetylamino- ethyl) -piperidin-4-yloxy] -7-methoxy-chinazolin 4- [ (3-Chlor-4-fluor-phenyl) amino] -6- ( tetrahydropyran-4- yloxy) -7-ethoxy-chinazolin4- [(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-Chlor-4-fluor-phenyl) amino] -6- ( (S) -tetrahydrofuran- 3-yloxy) -7-hydroxy-chinazolin4- [(3-chloro-4-fluoro-phenyl) -amino] -6- ((S) -tetrahydrofuran-3-yloxy) -7-hydroxy-quinazoline
4- [ (3-Chlor-4-fluor-phenyl) amino] -6- ( tetrahydropyran-4- yloxy) -7- (2-methoxy-ethoxy) -chinazolin 4- [ (3 -Chlor-4-fluor-phenyl) amino] -6- { trans-4- [ (dimethylamino) sulfonylamino] -cyclohexan-1-yloxy} -7- methoxy-chinazolin4- [(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) sulfonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline
4- [ (3 -Chlor-4-fluor-phenyl) amino] -6- { trans-4- [ (morpholin- 4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy- chinazolin 4- [ (3-Chlor-4-fluor-phenyl) amino] -6- { trans-4- [ (morpholin- 4-yl ) sulfonylamino] -cyclohexan-1-yloxy} -7-methoxy- chinazolin4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- {trans-4- [(morpholin-4-yl) -carbonyl-amino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline 4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- {trans-4- [(morpholin-4-yl) -sulfonyl-amino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline
4- [ ( 3 -Chlor-4-fluor-phenyl) amino] -6- ( tetrahydropyran-4- yloxy) -7- (2-acetylamino-ethoxy) -chinazolin 4- [ (3 -Chlor-4-fluor-phenyl) amino] -6- ( tetrahydropyran-4- yloxy) -7- ( 2 -methansulfonylamino-ethoxy) -chinazolin 4- [ (3 -Chlor-4-fluor-phenyl) amino] -6- {1- [ (piperidin-1- yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-chinazolin 4- [ (3-Chlor-4-fluor-phenyl) amino] -6- (1- aminocarbonylmethyl-piperidin-4-yloxy) -7-methoxy- chinazolin4- [(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-methanesulfonylamino-ethoxy) quinazoline 4- [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [( piperidin-1-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-Chlor-4-fluor-phenyl) amino] -6- (cis-4-{N- [ ( tetrahydropyran-4-yl ) carbonyl] -N-methyl-amino} - cyclohexan-1-yloxy) -7-methoxy-chinazolin4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(tetrahydropyran-4-yl) -carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy ) -7-methoxy-quinazoline
4- [ (3 -Chlor-4-fluor-phenyl) amino] -6-(cis-4-{N-[ (morpholin- 4-yl ) carbonyl ] -N-methyl-amino} -cyclohexan-1-yloxy) -7- methoxy-chinazolin4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy ) -7-methoxy-quinazoline
4- [ (3 -Chlor-4-fluor-phenyl) amino] -6- (cis-4-{N- [ (morpholin- 4-yl ) sulfonyl ] -N-methyl-amino} -cyclohexan-1-yloxy) -7- methoxy- chinazolin4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -sulfonyl] -N-methyl-amino} -cyclohexan-1-yloxy ) -7-methoxyquinazoline
4- [ (3-Chlor-4-fluor-phenyl) amino] -6- ( trans-4- ethansulfonylamino-cyclohexan-1-yloxy) -7-methoxy- chinazolin4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- (trans-4-ethanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline
4- [ ( 3-Chlor-4-fluor-phenyl ) amino] -6- ( 1-methansulfonyl- piperidin-4-yloxy) -7-ethoxy-chinazolin4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-ethoxy-quinazoline
4- [ (3-Chlor-4-fluor-phenyl) amino] -6- (1-methansulfonyl- piperidin-4-yloxy) -7- ( 2 -methoxy-ethoxy) -chinazolin 4- [ ( 3-Chlor-4-fluor-phenyl ) amino] -6- [1- ( 2-methoxy-acetyl ) - piperidin-4-yloxy] -7- (2-methoxy-ethoxy) -chinazolin 4- [ (3-Chlor-4-fluor-phenyl) amino] -6- (cis-4-acetylamino- cyclohexan-1-yloxy) -7-methoxy-chinazolin4- [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline 4- [(3-chloro-4-yl) 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-1-yloxy) -7-methoxy-quinazoline
4- [ (3-Ethinyl-phenyl)amino] -6- [1- (tert . -butyloxycarbonyl ) - piperidin-4-yloxy] -7-methoxy-chinazolin4- [(3-Ethynyl-phenyl) -amino] -6- [1- (tert -butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline
4- [ (3-Ethinyl-phenyl) amino] -6- ( tetrahydropyran-4-yloxy] -7- methoxy-chinazolin4- [(3-ethynylphenyl) amino] -6- (tetrahydropyran-4-yloxy) -7-methoxy-quinazoline
4- [ (3-Chlor-4-fluor-phenyl) amino] -6- (cis-4-{N- [ (piperidin-4- [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N- [(piperidine)
1-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7- methoxy-chinazolin1-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline
4- [ ( 3-Chlor-4-fluor-phenyl) amino] -6- (cis-4-{N- [ (4-methyl- piperazin-1-yl ) carbonyl ] -N-methyl-amino} -cyclohexan-1- yloxy) -7-methoxy-chinazolin4- [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(4-methylpiperazin-1-yl) -carbonyl] -N-methyl-amino} -cyclohexane -1-yloxy) -7-methoxy-quinazoline
4- [ (3 -Chlor-4-fluor-phenyl) amino] -6-{cis-4- [ (morpholin-4- yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-chinazolin4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- {cis-4- [(morpholin-4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline
- 4- [ (3 -Chlor-4-fluor-phenyl) amino] -6-{l-[2- (2- oxopyrrolidin-1-yl ) ethyl ] -piperidin-4-yloxy} -7-methoxy- chinazolin- 4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1- [2- (2-oxopyrrolidin-1-yl) -ethyl] -piperidin-4-yloxy} -7-methoxy-quinazoline
4- [ (3 -Chlor-4-fluor-phenyl) amino] -6- {1- [ (morpholin-4- yl) carbonyl] -piperidin-4-yloxy} -7- (2-methoxy-ethoxy) - chinazolin4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1- [(morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7- (2-methoxy-ethoxy) - quinazoline
4- [ (3-Ethinyl-phenyl) amino] -6- (l-acetyl-piperidin-4- yloxy) -7-methoxy-chinazolin4- [(3-Ethynylphenyl) amino] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline
4- [ (3-Ethinyl-phenyl ) amino] -6- ( l-methyl-piperidin-4- yloxy) -7-methoxy-chinazolin4- [(3-Ethynylphenyl) amino] -6- (1-methylpiperidin-4-yloxy) -7-methoxyquinazoline
4- [ (3-Ethinyl-phenyl ) amino] -6- (1-methansulfonyl-piperidin- 4-yloxy) -7-methoxy-chinazolin4- [(3-ethynylphenyl) amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline
4- [ (3-Chlor-4-fluor-phenyl) amino] -6- (l-methyl-piperidin-4- ylöxy) -7 (2-methoxy-ethoxy) -chinazolin4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methylpiperidin-4-yloxy) -7 (2-methoxy-ethoxy) -quinazoline
- 4- [ (3-Chlor-4-fluor-phenyl) amino] -6- (1- isopropyloxycarbonyl-piperidin-4-yloxy) -7-methoxy- chinazolin 4- [ (3-Chlor-4-fluor-phenyl ) amino] -6- (cis-4-methylamino- cyclohexan-1-yloxy) -7-methoxy-chinazolin- 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-1-yloxy) -7-methoxy-quinazoline
4- [ ( 3 -Chlor-4-fluor-phenyl) amino] -6-{cis-4- [N- (2-methoxy- acetyl) -N-methyl-amino] -cyclohexan-1-yloxy} -7-methoxy- chinazolin4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- {cis-4- [N- (2-methoxy-acetyl) -N-methyl-amino] -cyclohexan-1-yloxy} -7 -methoxy-quinazoline
4- [ (3-Ethinyl-phenyl) amino] -6- (piperidin-4-yloxy) -7- methoxy-chinazolin4- [(3-ethynylphenyl) amino] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline
4- [ (3-Ethinyl-phenyl) amino] -6- [1- (2-methoxy-acetyl) - piperidin-4-yloxy] -7-methoxy-chinazolin 4- [ (3-Ethinyl-phenyl) amino] -6- { 1- [ (morpholin-4- yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-chinazolin 4- [ (3-Chlor-4-fluor-phenyl) amino] -6-{l- [ (cis-2 , 6-dimethyl- morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy- chinazolin4- [(3-Ethynylphenyl) 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- {l - [(cis -2,6-dimethyl-morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline
- 4- [ (3 -Chlor-4-fluor-phenyl) amino] -6-{l- [ (2-methyl- morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy- chinazolin- 4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1- [(2-methyl-morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline
- 4- [ (3 -Chlor-4-fluor-phenyl) amino] -6-{l-[(S,S)- (2-oxa-5- aza-bicyclo [2.2.1] hept-5-yl) carbonyl] -piperidin-4-yloxy} - 7-methoxy-chinazolin- 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-Chlor-4-fluor-phenyl) amino] -6-{l- [ (N-methyl-N-2- methoxyethyl-amino) carbonyl ] -piperidin-4-yloxy} -7-methoxy- chinazolin- 4- [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [(N-methyl-N-2-methoxyethyl-amino) -carbonyl] -piperidin-4-yloxy} -7-methoxy - quinazoline
4- [ (3-Chlor-4-fluor-phenyl) amino] -6- (l-ethyl-piperidin-4- yloxy) -7-methoxy-chinazolin4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-ethyl-piperidin-4-yloxy) -7-methoxy-quinazoline
- 4- [ (3-Chlor-4-fluor-phenyl) amino] -6-{l- [ (2- methoxyethyl) carbonyl] -piperidin-4-yloxy} -7-methoxy- chinazolin- 4- [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [(2-methoxy-ethyl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline
4- [ (3-Chlor-4-fluor-phenyl) amino] -6-{l- [ (3-methoxypropyl- amino) -carbonyl ] -piperidin-4-yloxy} -7-methoxy-chinazolin 4- [ (3-Chlor-4-fluor-phenyl) amino] -6- [cis-4- (N- methansulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7- methoxy-chinazolin4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1- [(3-methoxy-propyl-amino) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline 4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline
4- [ (3-Chlor-4-fluor-phenyl) amino] -6- [cis-4- (N-acetyl-N- methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-chinazolin 4- [ ( 3 -Chlor-4-fluor-phenyl) amino] -6- ( trans-4-methylamino- cyclohexan-1-yloxy) -7-methoxy-chinazolin 4- [ (3-Chlor-4-fluor-phenyl) amino] -6- [trans-4- (N- methansulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7- methoxy-chinazolin4- [(3-chloro-4-fluoro-phenyl) -amino] -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-1-yloxy) -7-methoxy-quinazoline 4- [(3-chloro-4-fluoro-phenyl) amino] -6- [trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline
4- [ (3-Chlor-4-fluor-phenyl) amino] -6- ( trans-4- dimethylamino-cyclohexan-1-yloxy) -7-methoxy-chinazolin 4- [ (3-Chlor-4-fluor-phenyl) amino] -6- (trans-4- {N- [ (morpholin-4-yl ) carbonyl ] -N-methyl-amino} -cyclohexan-1- yloxy) -7-methoxy-chinazolin4- [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline 4- [(3-chloro-4-fluoro) phenyl) amino] -6- (trans-4- {N- [(morpholin-4-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline
- 4- [ (3-Chlor-4-fluor-phenyl) amino] -6- [2- (2 , 2-dimethyl-6- oxo-morpholin-4-yl) -ethoxy] -7- [ (S) - ( tetrahydrofuran-2- yl)methoxy] -chinazolin4- [(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 -Chlor-4-fluor-phenyl) amino] -6- (1-methansulfonyl- piperidin-4-yloxy) -7-methoxy-chinazolin4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline
4- [ (3-Chlor-4-fluor-phenyl) amino] -6- (l-cyano-piperidin-4- yloxy) -7-methoxy-chinazolin gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastere- omere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate. Erfindungsgemäß bevorzugt sind diese Säureadditionssalze ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat , Hydromethansulfonat , Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofu- marat, Hydrotartrat , Hydrooxalat, Hydrosuccinat , Hydrobenzoat und Hydro-p-toluolsulfonat . Als Dopamin-Agonisten gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Bromocriptin, Cabergolin, Alpha- Dihydroergocryptin, Lisurid, Pergolid, Pramipexol, Roxindol, Ropinirol, Talipexol, Tergurid und Viozan, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate. Erfindungsgemäß bevorzugt sind diese Säureadditionssalze ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosul- fat, Hydrophosphat , Hydromethansulfonat , Hydronitrat, Hydro- maleat, Hydroacetat, Hydrocitrat, Hydrofumarat , Hydrotartrat , Hydrooxalat, Hydrosuccinat , Hydrobenzoat und Hydro-p- toluolsulfonat .4- [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline, optionally in the form of their racemates, enantiomers, diastereomers and optionally in Form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofluorate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate. Preferred dopamine agonists are compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viozane, optionally in the form of their racemates, enantiomers , Diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate ,
Als Hl-Antihistaminika gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Epinastin, Cetirizin, Azelastin, Fexofenadin, Levocabastin, Loratadin, Mizolastin, Ketotifen, Emedastin, Dimetinden, Clemastin, Bamipin, Cexchlorpheniramin, Pheniramin, Doxylamin, Chlorphenoxamin, Dimenhydrinat, Diphenhydramin, Promethazin, Ebastin, Desloratidin und Meclozin, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate. Erfindungsgemäß bevorzugt sind diese Säureadditionssalze ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofumarat, Hydro- tartrat, Hydrooxalat, Hydrosuccinat , Hydrobenzoat und Hydro- p-toluolsulfonat .As Hl-antihistamines here preferably compounds are used, which are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipine, Cexchlorpheniramin, pheniramine, doxylamine, chlorphenoxamine , Dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclocine, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, tartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
Als pharmazeutisch wirksame Substanzen, Substanzformulierungen oder Substanzmischungen werden alle inhalierbaren Verbindungen eingesetzt, wie z.B. auch inhalierbare Makromoleküle, wie in EP 1 003 478 offenbart. Vorzugsweise werden Substanzen, Substanzformulierungen oder Substanzmischungen zur Behandlung von Atemwegserkrankungen eingesetzt, die im inhalativen Bereich Verwendung finden.As pharmaceutically active substances, substance formulations or substance mixtures, all inhalable compounds are used, such as e.g. also inhalable macromolecules, as disclosed in EP 1 003 478. Preferably, substances, substance formulations or substance mixtures are used for the treatment of respiratory diseases, which are used in the inhalation area.
Weiterhin kann die Verbindung aus der Gruppe der Derivate von Mutterkornalkaloiden, der Triptane, der CGRP-Hemmern, der Phosphodiesterase-V-Hemmer stammen, gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere, gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, ihrer Solvate und/oder Hydrate.Furthermore, the compound may be derived from the group of derivatives of ergot alkaloids, triptans, CGRP inhibitors, phosphodiesterase V inhibitors, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, their solvates and / or or hydrates.
Als Derivate der Mutterkornalkaloide : Dihydroergotamin, Ergotamin. As derivatives of ergot alkaloids: dihydroergotamine, ergotamine.
Vorzugsweise ist eine Einrichtung zur Begasung und/oder Trocknung der Kapselkörper und Kapselkappen direkt vor der Befüllung einer der beiden Kapselhälften angeordnet. Damit erfolgt eine Begasung und/oder eine Trocknung der Kapselkörper und Kapselkappen, deren Befüllung und das Schließen der Kapseln durch ein Verrasten der Kapselkörper mit den Kapselkappen unmittelbar nacheinander.Preferably, a device for gassing and / or drying the capsule body and capsule caps is arranged directly before the filling of one of the two capsule halves. This is followed by fumigation and / or drying of the capsule body and capsule caps, their filling and the closing of the capsules by latching the capsule body with the capsule caps immediately after one another.
Es versteht sich, dass die vorstehend genannten Merkmale nicht nur in der jeweils angegebenen Kombination, sondern auch in anderen Kombinationen verwendbar sind. Der Rahmen der Erfindung ist nur durch die Ansprüche definiert. Vorzugsweise wird das zuvor erläuterte Verfahren an Kapseln aus Polyethylen durchgeführt. It is understood that the above-mentioned features can be used not only in the combination specified, but also in other combinations. The scope of the invention is defined only by the claims. Preferably, the method described above is performed on polyethylene capsules.

Claims

P01-2345 FF Text Boehringer Ingelheim International GmbHPatentansprüche P01-2345 FF Text Boehringer Ingelheim International GmbHPatent claims
1. Verfahren zur Befüllung jeweils aus einem Kapselkörper und einer Kapselkappe bestehenden Kapsel mit einer pharmazeutischen Wirkstoffformulierung, wobei der Kapselkörper und die Kapselkappe nach der Befüllung mit einer definierten Kraft über ihre Öffnungen teleskopartig zusammengesteckt werden, dadurch gekennzeichnet, dass der Kapselkörper und die Kapselkappe vor der Befüllung nicht vorverrastet sind und separat in eine Vorrichtung zur Befüllung eingelegt werden.1. A method for filling each consisting of a capsule body and a capsule capsule capsule with a pharmaceutical active ingredient formulation, wherein the capsule body and the capsule cap are telescoped after filling with a defined force through their openings, characterized in that the capsule body and the capsule cap before the Filling are not pre-locked and are placed separately in a device for filling.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass der Kapselkörper und die Kapselkappe vor der Befüllung mittels ionisierender Gase behandelt werden.2. The method according to claim 1, characterized in that the capsule body and the capsule cap are treated before filling by means of ionizing gases.
3. Verfahren nach Anspruch 1 oder 2 , dadurch gekennzeichnet, dass der Kapselkörper und die Kapselkappe getrocknet oder mit einem trockenen Gasoder Gasgemisch geflutet werden .3. The method according to claim 1 or 2, characterized in that the capsule body and the capsule cap are dried or flooded with a dry gas or gas mixture.
4. Vorrichtung zur Befüllung von Kapseln mit pharmazeutischen Wirkstoffformulierungen zur Durchführung des Verfahrens nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass die Kapselfördereinrichtung Aufnahme- kavitäten zur separaten Aufnahme von Kapselkörpern und Kapselkappen sowie getrennte Vorratsbehälter für Kapselkörper und Kapselkappen aufweist. 4. A device for filling capsules with pharmaceutical active ingredient formulations for carrying out the method according to one of claims 1 to 3, characterized in that the capsule delivery device receiving cavities for separate receiving capsule bodies and capsule caps and separate reservoir for capsule body and capsule caps.
5. Vorrichtung nach Anspruch 6, dadurch gekennzeichnet, dass eine Einrichtung zur Begasung und/oder Trocknung des Kapselkörpers und der Kapselkappe vor der Befüllung angeordnet ist.5. Apparatus according to claim 6, characterized in that a device for gassing and / or drying of the capsule body and the capsule cap is arranged prior to filling.
6. Verwendung der nach dem Verfahren nach einem der Ansprüche 1 bis 3 befüllten Kapseln zur Aufnahme von Inhalativen. 6. Use of the filled according to the method of any one of claims 1 to 3 capsules for receiving inhalants.
EP09708924A 2008-02-08 2009-02-07 Method and device for filling capsules Withdrawn EP2244686A1 (en)

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EP08151224 2008-02-08
PCT/EP2009/000863 WO2009098083A1 (en) 2008-02-08 2009-02-07 Method and device for filling capsules
EP09708924A EP2244686A1 (en) 2008-02-08 2009-02-07 Method and device for filling capsules

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CN101829022B (en) * 2010-05-04 2013-01-23 浙江飞云科技有限公司 High-yield capsule filling machine
KR102642847B1 (en) * 2017-07-10 2024-03-04 젤 캡 테크놀로지스 엘엘씨 Dual release dosage form capsules and methods, devices and systems for manufacturing the same

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GB818365A (en) * 1955-06-16 1959-08-12 Scherer Corp R P Improvements in or relating to method of making capsules and capsules resulting fromsaid method
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