EP1919549A1 - Transcorneal system for delivery of a pharmaceutical agent - Google Patents
Transcorneal system for delivery of a pharmaceutical agentInfo
- Publication number
- EP1919549A1 EP1919549A1 EP06792966A EP06792966A EP1919549A1 EP 1919549 A1 EP1919549 A1 EP 1919549A1 EP 06792966 A EP06792966 A EP 06792966A EP 06792966 A EP06792966 A EP 06792966A EP 1919549 A1 EP1919549 A1 EP 1919549A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- amino
- phenyl
- quinazoline
- chloro
- matrix material
- 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- Withdrawn
Links
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
Definitions
- the invention relates to a transcorneal drug delivery system which is present in a matrix material forming a base plate, wherein the base plate for penetration of the stratum corneum of the skin is associated with a plurality of protrusions, and a method of preparation.
- EP 0 840 634 B1 discloses a transcorneal drug delivery system comprising a drug reservoir and a micro spiked device with capillary or microcutaneous apertures having a length of at least 10 ⁇ m and communicating with the drug via a fluid conducting compound - Servoir are connected, that an active transport of the drug from the reservoir through the micro spines or along the micro-cutting is possible.
- an integrated pump with electronic control is provided for active release of the active substance from the reservoir through the micro spines or along the micro-cutting. Due to the integrated pump with electronic control, this system has a complex and expensive construction.
- US Pat. No. 3,964,482 discloses a transcorneal drug delivery system comprising a drug reservoir in a base plate provided with needle-like elevations for penetrating the skin.
- the active ingredient diffuses from the active substance reservoir through the elevations and enters the skin, the active substance traversing a relatively long path, determined by the thickness of the base plate and the length of the elevations.
- the relatively large time delay, the so-called lag-time, until the drug his Effect as intended which is usually up to ten hours.
- transdermal system This is a system of needles made of a biodegradable polymer and applied to a plate. This plate has depressions in which the drug is located and can penetrate with the help of the needles into the skin.
- the active substance within the meaning of the invention may be a composition of different substances, in particular pharmaceutically active substances, or a placebo.
- the object is achieved in the system in that the elevations consist of the matrix material and include the active ingredient.
- the active substance present in the elevations comes directly into the layer of the skin below the stratum corneum, in which it can develop its effect, whereby the lag-time until onset of action over conventional systems is significantly shortened.
- the active ingredient is present not only within the elevations, but also on their outer surfaces, and its transport due to the permeation via fluids of the skin is rapid.
- the elevations are preferably formed integrally with the base plate and pyramid-shaped.
- the pyramidal shape also has a penetration of the stratum corneum with a low force result.
- the bumps are chosen in length so that they do not penetrate into the nerve-bearing tissue, thereby avoiding pain for the user of the system.
- the nerve-bearing tissue is about 200-500 microns below the Skin surface, which varies depending on the body region.
- the active ingredient is present in solid form, as a solution or gel in the matrix material.
- Suitable agents are, for example, agents for heart disease - such.
- B. thrombolytic substances for examplereteplase or tenecteplase
- Agents for stroke treatment - e.g. Dipyridamole, if necessary. in combination with other agents, such.
- B. acetylsalicylic acid antiviral agents, such as B. protease inhibitors, for example tipranavir; antidepressants; Inflammatory insufficiency - such. Meloxicam; Agents for the treatment of respiratory diseases, such. B. tiotropium, if necessary.
- Painkillers such as Morphine, naltrexone, fentanyl, oxymorphone
- Anti-Parkinson agents - such as L-Dopa, pramipexole
- Cardiovascular nitroglycerin, antihypertensive agents - such as. B. Telmisartan, if necessary. in combination with other agents and vasodilating diseases such as clonidine, nifidepine, verapamil, diltiazam; Anticoagulants, such as heparin, hirudin
- Long-term therapy for cancer and immune diseases - such as B. nevirapine for the treatment of autoimmune diseases; Long-term treatment for addiction therapy; peptides; ACE inhibitors; Neurokinin antagonists; Hormones, such as estradiol.
- 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 antihistamines, P AF Antagonists and PB kinase inhibitors.
- W represents a betamimetics combined with an anticholinergic, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists,
- W represents an anticholinergic agent 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, bitolertrol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharines, isoprenaline, levosalbutamol, mabuterol, meluadrine , Metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmefamol, salemetole, soterenol, sulphoneterol, terbutaline, tiaramide, toluubuterol, zinterol, CHF-1035, HOKU-81, KUL-1248 and
- the acid addition salts of the betamimetics 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 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, iodine, 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 an 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-Toluene sulfonate, preferably a singly negatively charged anion, more preferably an anion selected from the group consisting of fluoride, chloride, bromide, methanesulfonate and p-toluenesulfonate, most preferably bromide, optionally 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, acetate
- R is either methyl or ethyl and in which X ⁇ may have the abovementioned meanings.
- the compound of the formula AC-2 also 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
- Examples of possible salts and derivatives of the steroids may be: alkali metal salts, such as sodium or potassium salts, Sulfobenzoa- te, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
- compounds are preferably used which are selected from the group consisting of enprofylline, theophylline, roflumilast, A-riflo (cilomilast), tof ⁇ milast, pumafentrin, lirimilast, arofylline, atizoram, D-4418, bovine 198004, BY343, CP-325,366, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS
- the acid addition salts of the betamimetics are preferably selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrogen phosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate,
- Hydro fumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate are Hydro fumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
- Preferred LTD4 antagonists here are compounds which are selected from the group consisting of montelukast, pranlukast, zafirlukast,
- the acid addition salts of the betamimetics 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 ,
- Examples of salts or derivatives whose formation the LTD4 antagonists are capable of are: alkali metal salts, such as sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicoates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or also furoate.
- the EGFR inhibitors used are preferably compounds selected from the group consisting of cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and - 4 - [(3-chloro-4-fluorophenyl) amino] -6- ⁇ [4- (morpholin-4-yl) -1-oxo-2-butene-1-yl-amino ⁇ -7-cyclopropyl-methoxy-quinazoline
- the acid addition salts of the betamimetics 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 dopamine agonists are compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viozan, optionally in the form of their racemates , Enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.
- the acid addition salts of the betamimetics 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.
- the acid addition salts of the betamimetics are preferably selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate,
- the compound may be derived from the group of derivatives of ergot alkaloids, the triptans, the CGRP inhibitors, the 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 hydrates.
- the matrix material is a polymer or a salt.
- Such polymers or salts are suitable with which, on the one hand, a precise metering of the active substance into the skin is possible and, on the other hand, have such material properties, such as hardness and elasticity, that the elevations penetrate the stratum corneum.
- the polymer is biodegradable.
- the biodegradable polymer can be selected from a group consisting of poly-a-hydroxyester, poly-b-hydroxyester, polyanhydrides, polycyanoacrylates, cellulose, cellulose esters, polypeptides (polyaspartic acid), polylactones, polyglycols.
- Biodegradable polymers have the advantage that any remaining particles in the skin are degraded.
- the polymer is a copolymer of lactic and glycolic acid.
- Such copolymers also serve as raw materials for the preparation of active ingredient capsules for the controlled release of pharmaceutical active substances.
- a poly (L-lactide-co-D, L-lactide) 70:30 and especially a 50:50 poly (D, L-lactide-co-glycolide) is suitable as a matrix material.
- the matrix material and the elevations advantageously have channels in which the active ingredient is present.
- the channels are formed due to the mixing ratio of the matrix material and the drug due to local accumulations of the drug, which are favored by the very different molecular weights of the matrix material and the active ingredient. about These channels penetrate not only the existing in the surveys active ingredient in the skin, but also passes into the base plate present drug through the channels there, if already the drug was transported from the surveys into the skin.
- the length of the elevations or the microneedles is expediently dimensioned in such a way that they penetrate into the epidermis of the skin.
- the base plate is coated with a protective film.
- an adhesive surface for attachment to the skin is provided. Suitable adhesive surfaces and adhesives are well known to those skilled in the art.
- the object is achieved in the process for producing a transcorneal system for delivering a drug substance with a polymeric matrix material in that the powdery matrix material is mixed with the active ingredient, melted in an extruder and the composite material produced is shaped in a shaping process such, that a base plate with elevations for penetration of the Straumum corneum of the skin is present.
- a method which allows the production of a previously explained transcorneal system in large numbers and thus cost.
- the individual processing parameters such as temperature and pressure, are dependent on the polymeric matrix material and the active ingredient and are chosen such that material or active substance damage is ruled out.
- the volume percentage of the matrix material is set to the composite material less than or equal to the volume percentage of the active ingredient.
- the ratio of the matrix material to the active ingredient is For example, 20% by volume / 80% by volume, preferably 40% by volume / 60% by volume or 50% by volume / 50% by volume. If only small amounts of active ingredient are to be released, it goes without saying that the volume percentage of the matrix material on the composite material can be greater than the volume percentage of the active ingredient. The ratio is therefore arbitrary.
- the active ingredient in solid form is micronized prior to mixing with the melt.
- FIG. 1 is a schematic partial representation of a top view of a transcorneal system according to the invention
- FIG. 2 is a sectional view of the system according to the line H-II of FIG. 1,
- FIG. 3 is an enlarged view of a detail III of FIG. 2,
- the transcorneal system for delivering a drug substance comprises a base plate 1 made of a polymeric matrix material in which the active ingredient is present, wherein the base plate 1 is integrally connected to a plurality of pyramidal elevations 4 for penetration into the stratum corneum 2 of the skin 3 , which consist of the matrix material and also have the active ingredient.
- the ratio of the height to the base of the needle corresponds to about 2 parts height to 1 part base side. Per cm 2 of the base plate about 370 surveys are provided.
- the polymer of the base plate 1 and the bumps 4 is a biodegradable copolymer of lactic and glycolic acid, which is mixed with about 60% by volume of the micronized solid active ingredient and melted in an extruder.
- the contour of the system is made.
- the active ingredient separates out in phases, which leads to the formation of channels within the matrix material in which the active ingredient is present and which substantially promote permeation.
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Abstract
The invention relates to a transcorneal system for delivery of a pharmaceutical agent, made from a matrix material forming a baseplate (1), said baseplate (1) being connected to a number of projections (4) for penetration of the Stratum corneum of the skin, said projections (4) being made from the matrix material and comprising the agent.
Description
Transcorneales System zur Abgabe eines Arzneimittel- Wirkstoffes Transcorneal drug delivery system
Beschreibungdescription
Die Erfindung bezieht sich auf ein transcorneales System zur Abgabe eines Arzneimittel- Wirkstoffes, der in einem eine Basisplatte bildenden Matrixmaterial vorliegt, wobei die Basisplatte zur Penetration des Stratum corneum der Haut mit einer Vielzahl von Erhebungen verbunden ist, und ein Verfahren zur Herstellung.The invention relates to a transcorneal drug delivery system which is present in a matrix material forming a base plate, wherein the base plate for penetration of the stratum corneum of the skin is associated with a plurality of protrusions, and a method of preparation.
Die EP 0 840 634 Bl offenbart ein transcorneales System zur kontrollierten Freigabe von Arzneimitteln, das ein Wirkstoffreservoir und eine Vorrichtung mit Mikrostacheln mit kapillaren Öffnungen oder Mikroschneiden umfasst, die eine Länge von mindestens 10 μm aufweisen und die über eine Flüssigkeit leitende Verbindung derart mit dem Wirkstoffre- servoir verbunden sind, dass ein aktiver Transport des Wirkstoffes aus dem Reservoir durch die Mikrostacheln oder entlang der Mikroschneiden möglich ist. Zur aktiven Freigabe des Wirkstoffes aus dem Reservoir durch die Mikrostacheln oder entlang der Mikroschneiden ist eine integrierte Pumpe mit elektronischer Ansteuerung vorgesehen. Dieses System weist aufgrund der integrierten Pumpe mit elektronischer Ansteuerung einen auf- wendigen und teuren Aufbau auf.EP 0 840 634 B1 discloses a transcorneal drug delivery system comprising a drug reservoir and a micro spiked device with capillary or microcutaneous apertures having a length of at least 10 μm and communicating with the drug via a fluid conducting compound - Servoir are connected, that an active transport of the drug from the reservoir through the micro spines or along the micro-cutting is possible. For active release of the active substance from the reservoir through the micro spines or along the micro-cutting an integrated pump with electronic control is provided. Due to the integrated pump with electronic control, this system has a complex and expensive construction.
Im Weiteren ist aus der US-A-3 964 482 ein transcorneales System zur Abgabe eines Arzneimittel-Wirkstoffes bekannt, das ein Wirkstoffreservoir in einer Basisplatte aufweist, die mit nadelartigen Erhebungen zur Penetration der Haut versehen ist. Der Wirkstoff diffun- diert aus dem Wirkstoffreservoir durch die Erhebungen und gelangt in die Haut, wobei der Wirkstoff einen verhältnismäßig langen, durch die Dicke der Basisplatte und die Länge der Erhebungen bestimmten Weg zurücklegt. Als problematisch erweist sich bei diesem System die relativ große Zeitverzögerung, die so genannte lag-time, bis der Wirkstoff seine
Wirkung bestimmungsgemäß entfalten kann, die in der Regel bis zu zehn Stunden beträgt.Furthermore, US Pat. No. 3,964,482 discloses a transcorneal drug delivery system comprising a drug reservoir in a base plate provided with needle-like elevations for penetrating the skin. The active ingredient diffuses from the active substance reservoir through the elevations and enters the skin, the active substance traversing a relatively long path, determined by the thickness of the base plate and the length of the elevations. As problematic proves in this system, the relatively large time delay, the so-called lag-time, until the drug his Effect as intended, which is usually up to ten hours.
Im Journal of Controlled Release 104 (2005) Seiten 51-66 wird ebenfalls ein transdermales System beschrieben. Es handelt sich hier um ein System aus Nadeln, welche aus einem biologisch-abbaubaren Polymer hergestellt sind und auf eine Platte aufgebracht werden. Diese Platte besitzt Vertiefungen, in welchen sich der Wirkstoff befindet und mit Hilfe der Nadeln in die Haut eindringen kann.Journal of Controlled Release 104 (2005) pages 51-66 also describes a transdermal system. This is a system of needles made of a biodegradable polymer and applied to a plate. This plate has depressions in which the drug is located and can penetrate with the help of the needles into the skin.
Selbstverständlich kann es sich bei dem Wirkstoff im Sinne der Erfindung um eine Zu- sammensetzung unterschiedlicher Stoffe, insbesondere pharmazeutisch wirksamer Stoffe, oder um ein Placebo handeln.Of course, the active substance within the meaning of the invention may be a composition of different substances, in particular pharmaceutically active substances, or a placebo.
Es ist Aufgabe der Erfindung, ein transcorneales System der eingangs genannten Art zu schaffen, das bei seiner Wirkstoffabgabe eine kurze Zeitverzögerung aufweist und dabei kostengünstig aufgebaut ist und ein entsprechendes Verfahren zur Herstellung dieses Systems.It is an object of the invention to provide a transcorneales system of the type mentioned, which has a short time delay in its drug delivery and is constructed inexpensively and a corresponding method for producing this system.
Erfindungsgemäß wird die Aufgabe bei dem System dadurch gelöst, dass die Erhebungen aus dem Matrixmaterial bestehen und den Wirkstoff beinhalten.According to the invention, the object is achieved in the system in that the elevations consist of the matrix material and include the active ingredient.
Aufgrund dieser Maßnahmen kommt der in den Erhebungen vorhandene Wirkstoff direkt in die Schicht der Haut unterhalb des Stratum corneum, in der er seine Wirkung entfalten kann, wodurch die lag-time bis zum Einsetzen der Wirkung gegenüber herkömmlichen Systemen wesentlich verkürzt ist. Hierbei liegt der Wirkstoff nicht nur innerhalb der Erhe- bungen, sondern auch an deren Außenflächen vor und sein Transport aufgrund der Permea- tion über Fluide der Haut geht schnell vonstatten.Because of these measures, the active substance present in the elevations comes directly into the layer of the skin below the stratum corneum, in which it can develop its effect, whereby the lag-time until onset of action over conventional systems is significantly shortened. In this case, the active ingredient is present not only within the elevations, but also on their outer surfaces, and its transport due to the permeation via fluids of the skin is rapid.
Um eine verhältnismäßig große Fläche für den Stofftransport bereitzustellen, sind vorzugsweise die Erhebungen einstückig mit der Basisplatte und pyramidenförmig ausgebil- det. Die Pyramidenform hat auch ein Durchdringen des Stratum corneum bei einem geringen Kraftaufwand zur Folge. Die Erhebungen sind in ihrer Länge so gewählt, dass diese nicht in das nervenführende Gewebe eindringen, wodurch Schmerzen für den Benutzer des Systems vermieden werden. Das nervenführende Gewebe liegt etwa 200-500 μm unter der
Hautoberfläche, wobei dieses je nach Körperregion variiert.In order to provide a relatively large area for the mass transfer, the elevations are preferably formed integrally with the base plate and pyramid-shaped. The pyramidal shape also has a penetration of the stratum corneum with a low force result. The bumps are chosen in length so that they do not penetrate into the nerve-bearing tissue, thereby avoiding pain for the user of the system. The nerve-bearing tissue is about 200-500 microns below the Skin surface, which varies depending on the body region.
In Ausgestaltung liegt der Wirkstoff in fester Form, als Lösung oder Gel in dem Matrixmaterial vor. Geeignete Wirkstoffe sind beispielsweise Mittel gegen Herzerkrankungen - wie z. B. thrombolytische Substanzen, beispielsweise Alteplase oder Tenecteplase; Mittel zur Schlaganfallbehandlung - wie z.B. Dipyridamole, ggfls. in Kombination mit weiteren Mitteln, wie z. B. Acetylsalicylsäure; antivirale Mittel, wie z. B. Proteaseinhibitoren, beispielsweise Tipranavir; Antidepressiva; Entzündugnshemmer - wie z. B. Meloxicam; Mittel zur Behandlung von Atemwegserkrankungen, wie z. B. Tiotropium, ggfls. in Kombina- tion mit weiteren Mitteln; Schmerzmittel - wie z. B. Morphine, Naltrexon, Fentanyl, Oxymorphon; Anti-Parkinsonmittel - wie beispielsweise L-Dopa, Pramipexol; Herz- Kreislaufmittel, Nitroglycerin, Mittel gegen Bluthochdruck - wie z. B. Telmisartan, ggfls. in Kombination mit weiteren Mitteln und vasodilatorische Erkrankungen, wie beispielsweise Clonidin, Nifidepine, Verapamil, Diltiazam; Antikoagulantien, wie beispielsweise Heparin, Hirudin; Mittel zur Langzeittherapie bei Krebserkrankungen und Immunerkrankungen - wie z. B. Nevirapine zur Behandlung von Autoimmunerkrankungen; Mittel zur Langzeitbehandlung bei der Suchttherapie; Peptide; ACE-Hemmer; Neurokininantago- nisten; Hormone, wie beispielsweise Oestradiol.In an embodiment, the active ingredient is present in solid form, as a solution or gel in the matrix material. Suitable agents are, for example, agents for heart disease - such. B. thrombolytic substances, for example alteplase or tenecteplase; Agents for stroke treatment - e.g. Dipyridamole, if necessary. in combination with other agents, such. B. acetylsalicylic acid; antiviral agents, such as B. protease inhibitors, for example tipranavir; antidepressants; Inflammatory insufficiency - such. Meloxicam; Agents for the treatment of respiratory diseases, such. B. tiotropium, if necessary. in combination with other resources; Painkillers - such as Morphine, naltrexone, fentanyl, oxymorphone; Anti-Parkinson agents - such as L-Dopa, pramipexole; Cardiovascular, nitroglycerin, antihypertensive agents - such as. B. Telmisartan, if necessary. in combination with other agents and vasodilating diseases such as clonidine, nifidepine, verapamil, diltiazam; Anticoagulants, such as heparin, hirudin; Long-term therapy for cancer and immune diseases - such as B. nevirapine for the treatment of autoimmune diseases; Long-term treatment for addiction therapy; peptides; ACE inhibitors; Neurokinin antagonists; Hormones, such as estradiol.
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 -Antihistaminika, P AF- Antagonisten und PB -Kinase Inhibitoren. Weiterhin können zwei- oder dreifach Kombinationen von W kombiniert werden und zur Anwendung in der erfmdungs- gemäßen Vorrichtung gelangen. Beispielhaft genannte Kombinationen von W wären: W stellt ein Betamimetika dar, kombiniert mit einem Anticholinergika, Corticosteroi- de, PDE4-Inhibitore, EGFR-Hemmern oder LTD4- Antagonisten,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 antihistamines, P AF Antagonists and PB kinase inhibitors. Furthermore, two or three combinations of W can be combined and used for application in the device according to the invention. Exemplary combinations of W are: 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 stellt ein Corticosteroiden dar, kombiniert mit einem PDE4-Inhibitoren, EGFR- Hemmern oder LTD4-AntagonistenW represents an anticholinergic agent 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 stellt ein PDE4-Inhibitoren dar, kombiniert mit einem EGFR-Hemmern oder LTD4- Antagonisten - W stellt ein EGFR-Hemmern dar, kombiniert mit einem LTD4-Antagonisten.W represents a PDE4 inhibitor combined with an EGFR inhibitor or LTD4 antagonist - 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, Bitolte- rol, Broxaterol, Carbuterol, Clenbuterol, Fenoterol, Formoterol, Hexoprenaline, Ibuterol, Isoetharine, Isoprenaline, Levosalbutamol, Mabuterol, Meluadrine, Metaproterenol, Or- ciprenaline, Pirbuterol, Procaterol, Reproterol, Rimiterol, Ritodrine, Salmefamol, Salmete- rol, Soterenol, Sulphonterol, Terbutaline, Tiaramide, Tolubuterol, Zinterol, CHF-1035, HOKU-81, KUL- 1248 undPreferred betamimetics for this purpose are compounds selected from the group consisting of albuterol, arformoterol, bambuterol, bitolertrol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharines, isoprenaline, levosalbutamol, mabuterol, meluadrine , Metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmefamol, salemetole, soterenol, sulphoneterol, terbutaline, tiaramide, toluubuterol, zinterol, CHF-1035, HOKU-81, KUL-1248 and
3-(4- {6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy} - butyl)-benzyl-sulfonamid3- (4- {6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethyl-amino] -hexyloxy} -butyl) -benzyl-sulfonamide
5-[2-(5,6-Diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-lH-quinolin-2-on5- [2- (5,6-diethyl-indan-2-ylamino) -l-hydroxy-ethyl] -8-hydroxy-lH-quinolin-2-one
4-Hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-4-hydroxy-7- [2 - {[2 - {[3- (2-phenylethoxy) propyl] sulphonyl} ethyl] -amino} ethyl] -
2(3H)-benzothiazolon l-(2-Fluor-4-hydroxyphenyl)-2-[4-(l-benzimidazolyl)-2-methyl-2-butylamino]ethanol - l-[3-(4-Methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(l-benzimidazolyl)-2-methyl-2 (3H) -benzothiazolone 1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol - 1- [3- (4-methoxybenzyl-amino ) -4-hydroxyphenyl] -2- [4- (l-benzimidazolyl) -2-methyl-
2-butylamino] ethano 12-butylamino] ethano 1
1 -[2H-5-hydroxy-3-oxo-4H- 1 ,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-1 - [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-N, N-dimethylaminophenyl) -
2-methyl-2-propylamino] ethano 12-methyl-2-propylamino] ethano 1
1 -[2H-5-hydroxy-3-oxo-4H- 1 ,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2- propylamino]ethanol1 - [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol
1 -[2H-5-hydroxy-3-oxo-4H- 1 ,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-1 - [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl]
2-propylamino]ethanol - l-[2H-5-hydroxy-3-oxo-4H-l,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)- 1,2,4- triazo 1-3 -yl] -2-methyl-2-butylamino } ethano 1 - 5-Hydroxy-8-(l -hydroxy-2-isopropylaminobutyl)-2H- 1 ,4-benzoxazin-3-(4H)-on2-propylamino] ethanol - 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -1,2, 4-triazo 1-3 -yl] -2-methyl-2-butylamino} ethano 1 - 5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1,4-benzoxazine-3- (4H) -one
1 -(4- Amino-3 -chlor-5 -trifluormethylphenyl)-2-tert. -butylamino)ethano 11 - (4-amino-3-chloro-5-trifluoromethylphenyl) -2-tert. -butylamino) ethano 1
6-Hydroxy-8- { 1 -hydroxy-2-[2-(4-methoxy-phenyl)- 1 , l-dimethyl-ethylamino]-ethyl} -6-hydroxy-8- {1-hydroxy-2- [2- (4-methoxyphenyl) -1,1-dimethyl-ethylamino] -ethyl} -
4H-benzo[l,4]oxazin-3-on
6-Hydroxy-8- { 1 -hydroxy-2-[2-(4-phenoxy-essigsäureethylester)- 1 , 1 -dimethyl- ethylamino]-ethyl} -4H-benzo[ 1 ,4]oxazin-3-on4H-benzo [l, 4] oxazin-3-one 6-Hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -l, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one
6-Hydroxy-8- { 1 -hydroxy-2-[2-(4-phenoxy-essigsäure)- 1 , 1 -dimethyl-ethylamino] - ethyl}-4H-benzo[l,4]oxazin-3-on - 8- {2-[ 1 , 1 -Dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]- 1 -hydroxy-ethyl} -6- hydroxy-4H-benzo[ 1 ,4]oxazin-3-on6-Hydroxy-8- {1-hydroxy-2- [2- (4-phenoxyacetic acid) -1,1-dimethylethylamino] ethyl} -4H-benzo [1,4-oxazin-3-one 8- {2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) -ethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3- on
6-Hydroxy-8- { 1 -hydroxy-2-[2-(4-hydroxy-phenyl)- 1 , 1 -dimethyl-ethylamino]-ethyl} -6-hydroxy-8- {1-hydroxy-2- [2- (4-hydroxyphenyl) -1,1-dimethyl-ethylamino] -ethyl} -
4H-benzo[l,4]oxazin-3-on4H-benzo [l, 4] oxazin-3-one
6-Hydroxy-8- { 1 -hydroxy-2-[2-(4-isopropyl-phenyl)- 1 , 1 dimethyl-ethylamino]-ethyl} - 4H-benzo[l,4]oxazin-3-on6-Hydroxy-8- {1-hydroxy-2- [2- (4-isopropyl-phenyl) -1,1-dimethyl-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[l,4]oxazin-3-on8- (2- [2- (4-ethylphenyl) -1,1-dimethylethylamino] -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[l,4]oxazin-3-on - 4-(4- {2-[2-Hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[l ,4]oxazin-8-yl)- ethylamino]-2-methyl-propyl}-phenoxy)-buttersäure8- (2- [2- (4-Ethoxy-phenyl) -l, 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 [l, 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-8- (2- [2- (3,4-difluorophenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy
4H-benzo[l,4]oxazin-3-on l-(4-Ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol - 2-Hydroxy-5-(l-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]- ethylamino } -ethyl)-benzaldehyd4H-benzo [l, 4] oxazin-3-one 1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert -butylamino) ethanol - 2-hydroxy-5- (1- hydroxy-2- {2- [4- (2-hydroxy-2-phenyl-ethylamino) -phenyl] -ethylamino} -ethyl) -benzaldehyde
N-[2-Hydroxy-5-(l-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]- ethylamino}-ethyl)-phenyl]-formamidN- [2-Hydroxy-5- (1-hydroxy-2- {2- [4- (2-hydroxy-2-phenyl-ethylamino) -phenyl] -ethylamino} -ethyl) -phenyl] -formamide
8-Hydroxy-5-(l-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]- ethylamino } -ethyl)- 1 H-quino lin-2-on8-Hydroxy-5- (1-hydroxy-2- {2- [4- (6-methoxy-biphenyl-3-ylamino) -phenyl] -ethylamino} -ethyl) -1 H-quinoline-2-one
8-Hydroxy-5 - [ 1 -hydroxy-2-(6-phenethylamino-hexylamino)-ethyl] - 1 H-quino lin-2-on 5-[2-(2- {4-[4-(2-Amino-2-methyl-propoxy)-phenylamino]-phenyl} -ethylamino)- 1 - hydroxy-ethyl]-8-hydroxy- 1 H-quino lin-2-on [3-(4- {6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy} - butyl)-5 -methyl-phenyl] -harnstoff8-hydroxy-5 - [1-hydroxy-2- (6-phenethylamino-hexylamino) -ethyl] -1 H-quino-lin-2-one 5- [2- (2- {4- [4- (2- Amino-2-methyl-propoxy) -phenylamino] -phenyl} -ethylamino) -1-hydroxyethyl] -8-hydroxy-1H-quino-lin-2-one [3- (4- {6- [2-] Hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -hexyloxy} -butyl) -5-methylphenyl] -urea
4-(2- {6-[2-(2,6-Dichloro-benzyloxy)-ethoxy]-hexylamino} - 1 -hydroxy-ethyl)-2- hy droxymethy 1-pheno 1
3-(4- {6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy} - butyl)-benzylsulfonamid4- (2- {6- [2- (2,6-dichloro-benzyloxy) -ethoxy] -hexylamino} -1-hydroxy-ethyl) -2-hydroxymethyl-1-pheno-1 3- (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)-benzylsulfonamid - 4-(2- {6-[4-(3-Cyclopentanesulfonyl-phenyl)-butoxy]-hexylamino} - 1 -hydroxy-ethyl)-2- hy droxymethy 1-pheno 13- (3- {7- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -heptyloxy} -propyl) -benzylsulfonamide 4- (2- {6- [4- (2- 3-cyclopentanesulfonyl-phenyl) -butoxy] -hexylamino} -1-hydroxy-ethyl) -2-hydroxymethyl-1-pheno-1
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, Diastereomere 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, Hyd- rophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, 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 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 Anticholinergika gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Tiotropiumsalzen, bevorzugt das Bromid- salz, Oxitropiumsalzen, bevorzugt das Bromidsalz, Flutropiumsalzen, bevorzugt das Bro- midsalz, 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, Bromid, Io- did, 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, iodine, 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-I
Likewise 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-Toluol- sulfonat, bevorzugt ein einfach negativ geladenes Anion, besonders bevorzugt ein Anion ausgewählt aus der Gruppe bestehend aus Fluorid, Chlorid, Bromid, Methansulfonat 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 an 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-Toluene sulfonate, preferably a singly negatively charged anion, more preferably an anion selected from the group consisting of fluoride, chloride, bromide, methanesulfonate and p-toluenesulfonate, most preferably bromide, optionally 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-2contain, wherein X ~ can 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 Be- deutungen 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 in which X ~ may have the abovementioned meanings. In an alternative embodiment, the compound of the formula AC-2 also 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'-Tetrafiuorbenzilsäurescopinester-Methobromid 4,4'-Difluorbenzilsäuretropenolester-Methobromid 4,4'-Difluorbenzilsäurescopinester-Methobromid 3,3'-Difluorbenzilsäuretropenolester-Methobromid - 3,3'-Difluorbenzilsäurescopinester-Methobromid2,2-Diphenylpropionic acid-tropol ester-methobromide 2,2-diphenylpropionic acid copolester-methobromide 2-fluoro-2,2-diphenylacetic acid copoprene-methobromide 2-fluoro-2,2-diphenylacetic acid-tropol ester-methobromide - 3,3 ', 4,4'-tetrafluorobenzilic acid-tropol ester-methobromide 3,3 ', 4,4'-Tetrafluorobenzilic Acid Scopine Ester Methobromide 4,4'-Difluorobenzilic Acid Sterol Ester Methobromide 4,4'-Difluorobenzilic Acid Copoester Methobromide 3,3'-Difluorobenzilic Acid Sterol Ester Methobromide - 3,3'-Difluorobenzilic Acid Copoprene Methobromide
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-Methobromid9-Hydroxy-fluorene-9-carboxylic acid-tropol ester-methobromide 9-Fluoro-fluorene-9-carboxylic acid-tropol ester-methobromide 9-Hydroxy-fluorene-9-carboxylic acid-co-ester methobromide 9-fluoro-fluoren-9-carboxylic acid-co-ester methobromide - 9-methyl-fluorene 9-Carboxylic Acid Sterol Ester Methobromide 9-Methyl-Fluoren-9-Carboxylic Acid Copoester Methobromide Benzyl Acid Cyclopropyl Tropin Ester Methobromide - 2,2-Diphenylpropionic Acid Cyclopropyl Tropin Ester Methobromide
9-Hydroxy-xanthen-9-carbonsäurecyclopropyltropinester-Methobromid - 9-Methyl-fluoren-9-carbonsäurecyclopropyltropinester-Methobromid 9-Methyl-xanthen-9-carbonsäurecyclopropyltropinester-Methobromid 9-Hydroxy-fluoren-9-carbonsäurecyclopropyltropinester-Methobromid 4,4'-Difluorbenzilsäuremethylestercyclopropyltropinester-Methobromid
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-Methobromid9-Hydroxy-xanthene-9-carboxylic acid cyclopropyl-tropine ester methobromide - 9-methyl-fluorene-9-carboxylic acid cyclopropyl-tropine ester methobromide 9-methyl-xanthene-9-carboxylic acid cyclopropyl-tropine ester methobromide 9-hydroxy-fluorene-9-carboxylic acid cyclopropyl-tropine ester methobromide 4,4'- Difluorbenzilsäuremethylestercyclopropyltropinester methobromide 9-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-carbonsäuretropenolester methobromide
9-Difluormethyl-xanthen-9-carbonsäuretropenolester-Methobromid 9-Hydroxymethyl-xanthen-9-carbonsäurescopinester-Methobromid Die vorstehend genannten Verbindungen sind im Rahmen der vorliegenden Erfindung auch als Salze einsetzbar, in denen statt des Methobromids, die Salze Metho-X zur An- wendung gelangen, wobei X die vorstehend für X" genannten Bedeutungen haben kann.9-Difluoromethyl-xanthene-9-carboxylic acid-tropol ester-methobromide 9-hydroxymethyl-xanthene-9-carboxylic acid-co-ester methobromide 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 - Apply 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, Lo- teprednol, Mometason, Prednisolon, Prednison, Rofleponid, Triamcinolon, RPR- 106541, NS-126, ST-26 undPreferred 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-Difluor- 17-[(2-furanylcarbonyl)oxy]- 11 -hydroxy- 16-methyl-3-oxo-androsta- 1 ,4- dien- 17-carbothionsäure (S)-fluoromethylester6,9-Difluoro-17 - [(2-furanylcarbonyl) oxy] -11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionic acid (S) -fluoromethyl ester
6,9-Difluor- 11 -hydroxy- 16-methyl-3-oxo- 17-propionyloxy-androsta- 1 ,4-dien- 17- carbothionsäure (S)-(2-oxo-tetrahydro-furan-3S-yl)ester,6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionic acid (S) - (2-oxo-tetrahydrofuran-3S-yl) esters,
- 6α,9α-difluoro- 11 ß-hydroxy- 16α-methyl-3-oxo- 17α-(2,2,3 ,3-tertamethylcyclo- propylcarbonyl)oxy-androsta- 1 ,4-diene- 17ß-carbonsäure cyanomethyl ester gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere 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, Sulfobenzoa- te, Phosphate, Isonicotinate, Acetate, Dichloroacetate, Propionate, Dihydrogenphosphate, Palmitate, Pivalate oder auch Furoate.- 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α- (2,2,3,3-tertamethylcyclopropylcarbonyl) oxy-androsta-1,4-diene-17β-cyanomethyl cyanamide optionally 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 the steroids may be: alkali metal salts, such as sodium or potassium salts, Sulfobenzoa- te, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
Als PDE4-Inhibitoren gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Enprofyllin, Theophyllin, Roflumilast, A- riflo (Cilomilast), Tofϊmilast, Pumafentrin, Lirimilast, Arofyllin, Atizoram, D-4418, Bay-
198004, BY343, CP-325,366, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-As PDE4 inhibitors, compounds are preferably used which are selected from the group consisting of enprofylline, theophylline, roflumilast, A-riflo (cilomilast), tofϊmilast, pumafentrin, lirimilast, arofylline, atizoram, D-4418, bovine 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-801,613, CDP-840, D-4418, PD-168787, T-440, T-2585, V-11294A, CI-1018, CDC-801,
CDC-3052, D-22888, YM-58997, Z-15370 undCDC-3052, D-22888, YM-58997, Z-15370 and
N-(3,5-Dichloro-l-oxo-pyridin-4-yl)-4-difluormethoxy-3- 5 cyclopropylmethoxybenzamidN- (3,5-dichloro-1-oxopyridin-4-yl) -4-difluoromethoxy-3-5-cyclopropylmethoxybenzamide
. (-)p-[(4αR* , 1 OόS*)-9-Ethoxy- 1 ,2,3 ,4,4a, 10b-hexahydro-8-methoxy-2- methylbenzo[s] [ 1 ,6]naphthyridin-6-yl]-N,N-diisopropylbenzamid (R)-(+)- 1 -(4-Brombenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidon 3-(Cyclopentyloxy-4-methoxyphenyl)- 1 -(4-N'-[N-2-cyano-S-methyl- o isothioureido]benzyl)-2-pyrrolidon cis[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1 -carbonsäure] 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxy- phenyl)cyclohexan- 1 -on cis[4-Cyano-4-(3-cyclopropylmethoxy-4-difluormethoxyphenyl)cyclohexan- 1 -ol] 5 - (R)-(+)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden]acetat (S)-(-)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden]acetat, (-) p - [(4αR *, 1 OόS *) - 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-bromobenzyl) -4 - [(3-cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone 3- (cyclopentyloxy-4- methoxyphenyl) -1- (4-N '- [N-2-cyano-S-methyl-isothioureido] benzyl) -2-pyrrolidone cis [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane 1-carboxylic acid] 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane-1-one cis [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane] 1 -ol] 5 - (R) - (+) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene] acetate (S) - (-) - ethyl [4- (3-cyclopentyloxy-) 4-methoxyphenyl) pyrrolidin-2-ylidene] acetate
- 9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-l,2,4-triazolo[4,3- ajpyridin9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3,4-c] -1,4,4-triazolo [4,3-ajpyridine
- 9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-l,2,4- 0 triazolo[4,3-a]pyridin gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere 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, Hyd- 5 rophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat,9-cyclopentyl-5,6-dihydro-7-ethyl-3- (tert -butyl) -9H-pyrazolo [3,4-c] -1,4,4-0-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 betamimetics are preferably selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrogen phosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate,
Hydro fumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p- toluolsulfonat.Hydro fumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
Als LTD4-Antagonisten gelangen hierbei vorzugsweise Verbindungen zur Anwendung, 0 die ausgewählt sind aus der Gruppe bestehend aus Montelukast, Pranlukast, Zafirlukast,Preferred LTD4 antagonists here are compounds which are 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 und
- 1 -(((R)-(3-(2-(6,7-Difluor-2-quinolinyl)ethenyl)phenyl)-3-(2-(2- hydroxy-2- propyl)phenyl)thio)methylcyclopropan-essigsäure,MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321 and - 1 - (((R) - (3- (2- (6,7-Difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2-hydroxy-2-propyl) phenyl) thio) methylcyclopropane -acetic acid,
- l-(((l(R)-3(3-(2-(2,3-Dichlorthieno[3,2-b]pyridin-5-yI)-(E)-ethenyl)phenyl)-3-(2-(l- hydroxy-l-methylethyl)phenyl)propyl)thio)methyl)cyclopropanessigsäure - [2-[[2-(4-tert-Butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]essigsäure gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere 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, Hyd- rophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofumarat, 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, Isonico- tinate, 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, the acid addition salts of the betamimetics 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 , Examples of salts or derivatives whose formation the LTD4 antagonists are capable of are: alkali metal salts, such as sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicoates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or also furoate.
Als EGFR-Hemmer gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Cetuximab, Trastuzumab, ABX-EGF, Mab ICR-62 und - 4-[(3-Chlor-4-fluorphenyl)amino]-6- {[4-(morpholin-4-yl)- 1 -oxo-2-buten- 1 -yljamino} - 7-cyclopropylmethoxy-chinazo linThe EGFR inhibitors used are preferably compounds selected from the group consisting of cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and - 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (morpholin-4-yl) -1-oxo-2-butene-1-yl-amino} -7-cyclopropyl-methoxy-quinazoline
4-[(3-Chlor-4-fluorphenyl)amino]-6- {[4-(N,N-diethylamino)- 1 -oxo-2-buten- 1 -yljamino } -7-cy clopropylmethoxy-chinazo lin 4-[(3-Chlor-4-fluorphenyl)amino]-6- {[4-(N,N-dimethylamino)- 1 -oxo-2-buten- 1 - yljamino} -7-cy clopropylmethoxy-chinazolin4 - [(3-Chloro-4-fluorophenyl) amino] -6- {[4- (N, N-diethylamino) -1-oxo-2-butene-1-yl-amino} -7-cyclopropylmethoxy-quinazoline 4 - [(3-Chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl-amino) -7-cyclopropylmethoxy-quinazoline
4-[(R)-( 1 -Phenyl-ethyl)amino]-6- { [4-(morpholin-4-yl)- 1 -oxo-2-buten- 1 -yl] amino} -7- cyclopentyloxy-chinazolin4 - [(R) - (1-phenylethyl) amino] -6- {[4- (morpholin-4-yl) -1-oxo-2-butene-1-yl] amino} -7-cyclopentyloxy quinazoline
4-[(3-Chlor-4-fiuor-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-l-oxo- 2-buten- 1 -yljamino} -7-cy clopropylmethoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6- {[4-((R)-6-methyl-2-oxo-morpholin-4-yl)- 1 -oxo- 2-buten- 1 -yljamino} -7-[(S)-(tetrahydrofuran-3-yl)oxy]-chinazo lin 4-[(3-Chlor-4-fiuor-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4- yl)- 1 -oxo-2-buten- 1 -yljamino} -7-cyclopropylmethoxy-chinazo lin
4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]- 7-methoxy-chinazolin4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -l-oxo-2-butene - 1 -ylamino} -7-cyclopropylmethoxy-quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [4 - ((R) -6-methyl-2-oxo-morpholine 4-yl) -1-oxo-2-buten-1-ylamino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] -quinazoline 4 - [(3-chloro-4-fluoro) phenyl) amino] -6 - {[4 - ((R) -2-methoxymethyl-6-oxomorpholin-4-yl) -1-oxo-2-butene-1-yl-amino} -7-cyclopropylmethoxy-quinazoline 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline
4-[(3-Chlor-4-fluorphenyl)amino]-6-( {4-[N-(2-methoxy-ethyl)-N-methyl-amino]- 1 - oxo-2-buten- 1 -yl} amino)-7-cyclopropylmethoxy-chinazolin - 4-[(3-Chlor-4-fluorphenyl)amino]-6- {[4-(N,N-dimethylamino)- 1 -oxo-2-buten- 1 - yljamino} ^-cyclopentyloxy-chinazo lin4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N- (2-methoxyethyl) -N-methylamino] -1-oxo-2-butene-1-yl } amino) -7-cyclopropylmethoxyquinazoline - 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yljamino } ^ -cyclopentyloxy-quinazoline
- 4-[(R)-(l-Phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-l-oxo-2- buten- 1 -yljamino} -7-cyclopropylmethoxy-chmazolm- 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - {[4- (N, N-bis (2-methoxy-ethyl) -amino] -l-oxo-2-butene 1 -ylamino} -7-cyclopropylmethoxy-chmazolm
- 4-[(R)-(I -Phenyl-ethyl)amino]-6-( {4-[N-(2-methoxy-ethyl)-N-ethyl-amino]- 1 -oxo-2- buten- 1 -yl} amino)-7-cyclopropylmethoxy-chinazolin4-[(R) - (1-phenylethyl) amino] -6- ({4- [N- (2-methoxy-ethyl) -N-ethylamino] -1-oxo-2-butene 1 -yl} amino) -7-cyclopropylmethoxy-quinazoline
4-[(R)-(I -Phenyl-ethyl)amino]-6-( {4-[N-(2-methoxy-ethyl)-N-methyl-amino]- 1 -oxo-2- buten- 1 -yl} amino)-7-cyclopropylmethoxy-chinazolin4 - [(R) - (1-Phenyl-ethyl) -amino] -6- ({4- [N- (2-methoxy-ethyl) -N-methyl-amino]-1-oxo-2-butene-1 -yl} amino) -7-cyclopropylmethoxy-quinazoline
4-[(R)-(I -Phenyl-ethyl)amino]-6-( {4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]- 1 - oxo-2-buten- 1 -yl} amino)-7-cyclopropylmethoxy-chinazolin - 4-[(3-Chlor-4-fluorphenyl)amino]-6- {[4-(N,N-dimethylamino)- 1 -oxo-2-buten- 1 - yljamino} -7-((R)-tetrahydrofuran-3-yloxy)-chinazolin4 - [(R) - (1-Phenyl-ethyl) -amino] -6- ({4- [N- (tetrahydropyran-4-yl) -N-methyl-amino]-1-oxo-2-butene-1 -yl} amino) -7-cyclopropylmethoxyquinazoline - 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-butene-1 - yljamino} -7 - ((R) -tetrahydrofuran-3-yloxy) quinazoline
4-[(3-Chlor-4-fluorphenyl)amino]-6- {[4-(N,N-dimethylamino)- 1 -oxo-2-buten- 1 - yljamino} -7-((S)-tetrahydrofuran-3-yloxy)-chinazolin4 - [(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]- 1 - oxo-2-buten- 1 -yl} amino)-7-cyclopentyloxy-chinazolin4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N- (2-methoxyethyl) -N-methylamino] -1-oxo-2-butene-1-yl } amino) -7-cyclopentyloxy-quinazoline
4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-l-oxo-2- buten- 1 -yljamino} -7-cyclopentyloxy-chinazolin4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-N-methyl-amino) -l-oxo-2-butene-1-yl-amino} -7-cyclopentyloxy quinazoline
4-[(3-Chlor-4-fluorphenyl)amino]-6- {[4-(N,N-dimethylamino)- 1 -oxo-2-buten- 1 - yljamino } -7- [(R)-(tetrahydrofuran-2-yl)methoxy] -chinazo lin - 4-[(3-Chlor-4-fluorphenyl)amino]-6- {[4-(N,N-dimethylamino)- 1 -oxo-2-buten- 1 - yljamino } -7- [(S)-(tetrahydrofuran-2-yl)methoxy] -chinazo lin4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yljamino} -7- [(R) - ( tetrahydrofuran-2-yl) methoxy] quinazoline - 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-butene-1 - yljamino} -7- [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline
4-[(3-Ethinyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-chinazolin4 - [(3-ethynyl-phenyl) amino] -6,7-bis- (2-methoxy-ethoxy) -quinazoline
4-[(3-Chlor-4-fluorphenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinyl- carbonyl)amino] -chinazo lin - 4-[(R)-(I -Phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin4 - [(3-Chloro-4-fluoro-phenyl) -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-3-Cyano-4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -l-oxo-2-butene
1 -yl] amino } -7-ethoxy-chino lin
4- {[3-Chlor-4-(3-fluor-benzyloxy)-phenyl]amino} -6-(5- {[(2-methansulfönyl- ethyl)amino]methyl}-furan-2-yl)chinazolin - 4-[(R)-(l-Phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-l-oxo-2- buten- 1 -yljamino} -7-methoxy-chinazolin - 4-[(3-Chlor-4-fluorphenyl)amino]-6- {[4-(morpholin-4-yl)- 1 -oxo-2-buten- 1 -yljamino} -1 -yl] amino} -7-ethoxy-quinoline 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-butene - 1 -ylamino} -7-methoxyquinazoline - 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (morpholin-4-yl) -1-oxo-2-butene-1 -yljamino} -
7- [(tetrahydrofuran-2-yl)methoxy] -chinazo lin7- [(tetrahydrofuran-2-yl) methoxy] quinazoline
4-[(3-Chlor-4-fluorphenyl)amino]-6-( {4-[N,N-bis-(2-methoxy-ethyl)-amino]- 1 -oxo-2- buten- 1 -yl} amino)-7-[(tetrahydrofuran-2-yl)methoxy]-chinazolin4 - [(3-Chloro-4-fluorophenyl) amino] -6- ({4- [N, N-bis (2-methoxy-ethyl) -amino] -1-oxo-2-butene-1-yl } amino) -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline
4-[(3-Ethinyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-l -oxo-2- buten- 1 -yljamino} -chinazo lin4 - [(3-ethynylphenyl) amino] -6 - {[4- (5,5-dimethyl-2-oxomorpholin-4-yl) -1-oxo-2-buten-1-ylamino] - chinazo lin
4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -
7-methoxy-chinazolin7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -
7- [(R)-(tetrahydrofuran-2-yl)methoxy] -chinazo lin - 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7- [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (2,2-dimethyl-6 oxo-morpholin-4-yl) -ethoxy] -
6- [(S)-(tetrahydro furan-2-yl)methoxy] -chinazo lin6- [(S) - (tetrahydro furan-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-chinazo lin4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {2- [4- (2-oxo-morpholin-4-yl) -piperidin-1-yl] -ethoxy} -7-methoxy -chinazo lin
4-[(3-Chlor-4-fluor-phenyl)amino]-6-[ 1 -(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7- methoxy-chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-amino-cyclohexan- 1 -yloxy)-7-methoxy- chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-amino-cyclohexan-1-ylxy) -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methansulfonylamino-cyclohexan- 1 - yloxy)-7-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazolin-4 - [(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-yl- oxy} -7-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6- { 1 -[(methoxymethyl)carbonyl]-piperidin-4-yl- oxy} -7-methoxy-chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl] -piperidin-4-yl-oxy} -7-methoxy-quinazoline-4- [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(methoxymethyl) -carbonyl] -piperidin-4-yl-oxy} -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-chinazolin
4-[(3-Chlor-4-fluor-phenyl)amino]-6-[ 1 -(2-acetylamino-ethyl)-piperidin-4-yloxy]-7- methoxy-chinazo lin4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy] -7-methoxy-quinazoline
4- [(3 -Chlor-4-fluor-phenyl)amino] -6-(tetrahydropyran-4-yloxy)-7-ethoxy-chinazo lin4- [(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-hydroxyquinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy- ethoxy)-chinazo lin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methoxyethoxy) quinazoline
4- [(3 -Chlor-4-fluor-phenyl)amino] -6- {trans-4- [(dimethylamino)sulfonylamino] - cyclo hexan- 1 -yloxy} -7-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6- {trans-4- [(morpholin-4-yl)carbonylamino]- cyclo hexan- 1 -yloxy} -7-methoxy-chinazolin4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- {trans-4- [(dimethylamino) -sulfonylamino] -cyclohexane-1-yl-oxy} -7-methoxy-quinazolin-4 - [(3 -Chloro-4-fluoro-phenyl) -amino] -6- {trans-4- [(morpholin-4-yl) -carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylamino]- cyclo hexan- 1 -yloxy} -7-methoxy-chinazolin4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(morpholin-4-yl) -sulfonylamino] -cyclohexane-1-yloxy} -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino- ethoxy)-chinazolin4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-acetylamino-ethoxy) -quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2- methansulfonylamino-ethoxy)-chinazolin4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylamino-ethoxy) -quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6- { 1 -[(piperidin- 1 -yl)carbonyl]-piperidin-4-yloxy} -4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(piperidine-1-yl) -carbonyl] -piperidin-4-yloxy} -
7-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-aminocarbonylmethyl-piperidin-4-yloxy)-7- methoxy-chinazo lin7-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} -cyclohexane-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} -cyclohexane-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-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-ethansulfonylamino-cyclo hexan- 1 - yloxy)-7-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-methansulfonyl-piperidin-4-yloxy)-7-ethoxy- chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-ethanesulfonylamino-cyclo-hexan-1-yloxy) -7-methoxy-quinazoline-4 - [(3-chloro-4- fluorophenyl) amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-ethoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-methansulfonyl-piperidin-4-yloxy)-7-(2- methoxy-ethoxy)-chinazo lin
4-[(3-Chlor-4-fluor-phenyl)amino]-6-[ 1 -(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2- methoxy-ethoxy)-chinazo lin4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxyethoxy) quinazoline 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7- (2-methoxy-ethoxy) -quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan- 1 -yloxy)-7- methoxy-chinazo lin - 4-[(3-Ethinyl-phenyl)amino]-6-[ 1 -(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7- methoxy-chinazo lin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-acetylamino-cyclohexane-1-yloxy) -7-methoxy-quinazolin-4 - [(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-ethynyl-phenyl) amino] -6- (tetrahydropyran-4-yloxy] -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4- {N-[(piperidin- 1 -yl)carbonyl]-N-methyl- amino} -cyclo hexan- 1 -yloxy)-7-methoxy-chinazolin - 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 - [(piperidine-1-yl) carbonyl] -N-methyl-amino} -cyclohexane 1 - yloxy) -7-methoxy-quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(4-methylpiperazin-1-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-oxy) -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] -cyclohexane-1-yloxy} -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6- { 1 -[2-(2-oxopyrrolidin- 1 -yl)ethyl]-piperidin-4- yloxy} -7-methoxy-chinazolin4 - [(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-methoxyethoxy) - quinazoline
4-[(3-Ethinyl-phenyl)amino]-6-(l-acetyl-piperidin-4-yloxy)-7-methoxy-chinazolin4 - [(3-ethynyl-phenyl) amino] -6- (l-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline
4-[(3-Ethinyl-phenyl)amino]-6-(l-methyl-piperidin-4-yloxy)-7-methoxy-chinazolin - 4-[(3-Ethinyl-phenyl)amino]-6-(l-methansulfonyl-piperidin-4-yloxy)-7-methoxy- chinazolin4 - [(3-Ethynylphenyl) amino] -6- (1-methylpiperidin-4-yloxy) -7-methoxyquinazoline-4 - [(3-ethynylphenyl) amino] -6- (1 -methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-methyl-piperidin-4-yloxy)-7(2-methoxy- ethoxy)-chinazo lin4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methyl-piperidin-4-yloxy) -7 (2-methoxy-ethoxy) -quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-isopropyloxycarbonyl-piperidin-4-yloxy)-7- methoxy-chinazolin- 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-isopropyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-methylamino-cyclo hexan- 1 -yloxy)-7- methoxy-chinazo lin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-methylamino-cyclohexane-1-ylxy) -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-chinazolin - 4-[(3-Ethinyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4- [N- (2-methoxy-acetyl) -N-methyl-amino] -cyclohexane-1-yloxy} -7 -methoxy-quinazoline - 4 - [(3-ethynyl-phenyl) -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-chinazo lin4 - [(3-ethynylphenyl) amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7-methoxy-quinazoline 4 - [(3-ethynylphenyl) amino] -6- {1 - [(morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6- { 1 -[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]- piperidin-4-yloxy} -7-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6- { 1 -[(2-methyl-morpholin-4-yl)carbonyl]- piperidin-4-yloxy} -7-methoxy-chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(cis-2,6-dimethyl-morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7- methoxy-quinazoline - 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-Chlor-4-fluor-phenyl)amino]-6- { 1 -[(N-methyl-N-2-methoxyethyl- amino)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-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-piperidm-4-yloxy)-7-methoxy- chinazolin4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-ethyl-piperidm-4-yloxy) -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6- { 1 -[(2-methoxyethyl)carbonyl]-piperidin-4- yloxy} -7-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6- { 1 -[(3-methoxypropyl-amino)-carbonyl]- piperidin-4-yloxy} -7-methoxy-chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2-methoxyethyl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline-4 - [(3 Chloro-4-fluoro-phenyl) amino] -6- {1 - [(3-methoxy-propyl-amino) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-methansulfonyl-N-methyl-amino)- cyclohexan- 1 -yloxy]-7-methoxy-chinazolin 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan- 1 - yloxy]-7-methoxy-chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexane-1-yloxy] -7-methoxy-quinazoline 4- [(3-chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-acetyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methylamino-cyclohexan- 1 -yloxy)-7- methoxy-chinazo lin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methylamino-cyclohexane-1-yloxy) -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-[trans-4-(N-methansulfonyl-N-methyl-amino)- cyclohexan- 1 -yloxy]-7-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan- 1 -yloxy)-7- methoxy-chinazo lin4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexane-1-yloxy] -7-methoxy-quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-dimethylamino-cyclohexane-1-yloxy) -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N- methyl-amino} -cyclohexan- 1 -yloxy)-7-methoxy-chinazolin 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]- 7- [(S)-(tetrahydro furan-2-yl)methoxy] -chinazo lin4 - [(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-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] - 7- [(S) - (tetrahydro furan-2-yl) methoxy] quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-methansulfonyl-piperidin-4-yloxy)-7- methoxy-chinazo lin
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-cyano-piperidin-4-yloxy)-7-methoxy- chinazolin gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere 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, Hyd- rophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p- toluolsulfonat.4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline 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 the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts of the betamimetics 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 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, Tergu- rid und Viozan, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere 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, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p-toluolsulfonat.Preferred dopamine agonists are compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viozan, 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 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, Fexofena- din, Levocabastin, Loratadin, Mizo lastin, 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 die Säureadditionssalze der Betamimetika ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat,Compounds which are preferably selected from the group consisting of epinastin, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizoastin, ketotifen, emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine, are preferably used as HIV antihistamines. 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, the acid addition salts of the betamimetics are preferably selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate,
Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p-toluolsulfonat.
Außerdem können inhalierbare Makromoleküle verwendet werden, wie in EP 1 003 478 offenbart.Hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate. In addition, inhalable macromolecules can be used as disclosed in EP 1 003 478.
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, the triptans, the CGRP inhibitors, the 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 hydrates.
Als Derivate der Mutterkornalkaloide: Dihydroergotamin, Ergotamin.As derivatives of ergot alkaloids: dihydroergotamine, ergotamine.
Zweckmäßigerweise ist das Matrixmaterial ein Polymer oder ein Salz. Geeignet sind derartige Polymere bzw. Salze, mit denen zum einen eine genaue Dosierung des Wirkstoffes in die Haut möglich ist und die zum anderen derartige Materialeigenschaften, wie Härte und Elastizität, aufweisen, dass die Erhebungen das Stratum corneum durchdringen.Conveniently, the matrix material is a polymer or a salt. Such polymers or salts are suitable with which, on the one hand, a precise metering of the active substance into the skin is possible and, on the other hand, have such material properties, such as hardness and elasticity, that the elevations penetrate the stratum corneum.
Vorteilhafterweise ist das Polymer biologisch abbaubar. Das bioabbaubare Polymer kann aus einer Gruppe, bestehend aus Poly-a-hydroxyester, Poly-b-hydroxyester, Polyanhydri- de, Polycyanacrylate, Cellulose, Celluloseester, Polypeptide (Polyasparaginsäure), Polylac- tone, Polyglycole, ausgewählt werden. Biologisch abbaubare Polymere haben den Vorteil, dass eventuell in der Haut zurückbleibende Partikel abgebaut werden.Advantageously, the polymer is biodegradable. The biodegradable polymer can be selected from a group consisting of poly-a-hydroxyester, poly-b-hydroxyester, polyanhydrides, polycyanoacrylates, cellulose, cellulose esters, polypeptides (polyaspartic acid), polylactones, polyglycols. Biodegradable polymers have the advantage that any remaining particles in the skin are degraded.
Bevorzugt ist das Polymer ein Copolymer aus Milch- und Glycolsäure. Solche Copolymere dienen auch als Rohstoffe für die Herstellung von Wirkstoffkapseln zur kontrollierten Frei- Setzung pharmazeutischer Wirksubstanzen. Beispielsweise eignet sich ein Poly(L-lactide- co-D,L-lactide) 70:30 und insbesondere ein Poly(D,L-lactide-co-glycolide) 50:50 als Matrixmaterial.Preferably, the polymer is a copolymer of lactic and glycolic acid. Such copolymers also serve as raw materials for the preparation of active ingredient capsules for the controlled release of pharmaceutical active substances. For example, a poly (L-lactide-co-D, L-lactide) 70:30 and especially a 50:50 poly (D, L-lactide-co-glycolide) is suitable as a matrix material.
Zur Erzielung eines schnellen Transportes des Wirkstoffes weisen vorteilhafterweise das Matrixmaterial und die Erhebungen Kanäle auf, in denen der Wirkstoff vorliegt. Die Kanäle bilden sich aufgrund des Mischungsverhältnisses des Matrixmaterials und des Wirkstoffes aufgrund lokaler Ansammlungen des Wirkstoffes aus, die durch die sehr unterschiedlichen Molekulargewichte des Matrixmaterials und des Wirkstoffes begünstigt sind. Über
diese Kanäle dringt nicht nur der in den Erhebungen vorhandene Wirkstoff in die Haut, vielmehr gelangt auch in der Basisplatte vorliegender Wirkstoff über die Kanäle dorthin, wenn bereits der Wirkstoff aus den Erhebungen in die Haut transportiert wurde.To achieve a rapid transport of the active ingredient, the matrix material and the elevations advantageously have channels in which the active ingredient is present. The channels are formed due to the mixing ratio of the matrix material and the drug due to local accumulations of the drug, which are favored by the very different molecular weights of the matrix material and the active ingredient. about These channels penetrate not only the existing in the surveys active ingredient in the skin, but also passes into the base plate present drug through the channels there, if already the drug was transported from the surveys into the skin.
Damit der Wirkstoff in die Epidermis der Haut gelangt, ist zweckmäßigerweise die Länge der Erhebungen oder der Mikronadeln derart bemessen, dass sie in die Epidermis der Haut eindringen.In order for the active ingredient to enter the epidermis of the skin, the length of the elevations or the microneedles is expediently dimensioned in such a way that they penetrate into the epidermis of the skin.
Um den Wirkstoff des Systems vor Umgebungseinflüssen zu schützen, ist vorzugsweise die Basisplatte mit einer Schutzfolie überzogen.In order to protect the active ingredient of the system from environmental influences, preferably the base plate is coated with a protective film.
Für die Fixierung des Systems während der Behandlungsdauer ist eine Klebefiäche zur Befestigung auf der Haut vorgesehen. Geeignete Klebefiächen und Klebstoffe sind dem Fachmann aus dem Stand der Technik hinlänglich bekannt.For the fixation of the system during the treatment period an adhesive surface for attachment to the skin is provided. Suitable adhesive surfaces and adhesives are well known to those skilled in the art.
Die Aufgabe wird bei dem Verfahren zur Herstellung eines transcornealen Systems zur Abgabe eines Arzneimittel- Wirkstoffes mit einem polymeren Matrixmaterial dadurch gelöst, dass das pulverförmige Matrixmaterial mit dem Wirkstoff vermischt, in einem Extruder aufgeschmolzen und das hergestellte Kompositmaterial in einem Formgebungsverfah- ren derart geformt wird, dass eine Basisplatte mit Erhebungen zur Durchdringung des Stra- tum corneum der Haut vorliegt.The object is achieved in the process for producing a transcorneal system for delivering a drug substance with a polymeric matrix material in that the powdery matrix material is mixed with the active ingredient, melted in an extruder and the composite material produced is shaped in a shaping process such, that a base plate with elevations for penetration of the Straumum corneum of the skin is present.
Demnach ist ein Verfahren geschaffen, das die Herstellung eines zuvor erläuterten transcornealen Systems in großer Stückzahl und damit kostengünstig ermöglicht. Die einzelnen Verarbeitungsparameter, wie Temperatur und Druck, sind abhängig von dem polymeren Matrixmaterial sowie dem Wirkstoff und werden derart gewählt, dass eine Material- bzw. Wirkstoffschädigung ausgeschlossen ist.Accordingly, a method is provided which allows the production of a previously explained transcorneal system in large numbers and thus cost. The individual processing parameters, such as temperature and pressure, are dependent on the polymeric matrix material and the active ingredient and are chosen such that material or active substance damage is ruled out.
Nach einer Weiterbildung wird der Volumenprozentanteil des Matrixmaterials an dem Kompositmaterial kleiner oder gleich dem Volumenprozentanteil des Wirkstoffes eingestellt. Damit ist bei einem entsprechenden Unterschied des Molekulargewichtes des Matrixmaterials und des Wirkstoffes ein Ausscheiden des Wirkstoffes in Phasen in dem Matrixmaterial gewährleistet. Das Verhältnis des Matrixmaterials zu dem Wirkstoff beträgt
beispielsweise 20 Vol-% / 80 Vol-%, vorzugsweise 40 Vol-% / 60 Vol-% oder 50 Vol-% / 50 Vol-%. Sollen nur geringe Wirkstoffmengen freigesetzt werden, kann selbstverständlich der Volumenprozentanteil des Matrixmaterials an dem Kompositmaterial größer als der Volumenprozentanteil des Wirkstoffes sein. Das Verhältnis ist demnach beliebig wählbar.According to a development of the volume percentage of the matrix material is set to the composite material less than or equal to the volume percentage of the active ingredient. Thus, with a corresponding difference in the molecular weight of the matrix material and the active ingredient, a separation of the active ingredient into phases in the matrix material is ensured. The ratio of the matrix material to the active ingredient is For example, 20% by volume / 80% by volume, preferably 40% by volume / 60% by volume or 50% by volume / 50% by volume. If only small amounts of active ingredient are to be released, it goes without saying that the volume percentage of the matrix material on the composite material can be greater than the volume percentage of the active ingredient. The ratio is therefore arbitrary.
Zweckmäßigerweise wird der in fester Form vorliegende Wirkstoff vor dem Vermischen mit der Schmelze mikronisiert.Conveniently, the active ingredient in solid form is micronized prior to mixing with the melt.
Es versteht sich, dass die vorstehend genannten und nachstehend noch zu erläuternden Merkmale nicht nur in der jeweils angegebenen Kombination, sondern auch in anderen Kombinationen verwendbar sind. Der Rahmen der vorliegenden Erfindung ist nur durch die Ansprüche definiert.It goes without saying that the features mentioned above and those yet to be explained below can be used not only in the respectively specified combination but also in other combinations. The scope of the present invention is defined only by the claims.
Die Erfindung wird im Folgenden anhand zweier Ausführungsbeispiele unter Bezugnahme auf die zugehörigen Zeichnungen näher erläutert. Es zeigt:The invention will be explained in more detail below with reference to two exemplary embodiments with reference to the accompanying drawings. It shows:
Fig.l eine schematische Teildarstellung einer Draufsicht auf ein erfindungsgemäßes transcorneales System,1 is a schematic partial representation of a top view of a transcorneal system according to the invention,
Fig.2 eine Schnittdarstellung des Systems gemäß der Linie H-II nach Fig. 1,2 is a sectional view of the system according to the line H-II of FIG. 1,
Fig.3 eine vergrößerte Darstellung einer Einzelheit III nach Fig. 2,3 is an enlarged view of a detail III of FIG. 2,
Fig.4 eine schematische Darstellung einer bestimmungsgemäßen Anwendung desA schematic representation of a proper application of
Systems nach Fig. 1.Systems according to FIG. 1.
Das transcorneale System zur Abgabe eines Arzneimittel- Wirkstoffes umfasst eine Basisplatte 1 aus einem polymeren Matrixmaterial, in dem der Wirkstoff vorliegt, wobei die Ba- sisplatte 1 zur Penetration in das Stratum corneum 2 der Haut 3 mit einer Vielzahl von pyramidenförmigen Erhebungen 4 einstückig verbunden ist, die aus dem Matrixmaterial bestehen und ebenfalls den Wirkstoff aufweisen. Das Verhältnis der Höhe zur Grundseite der Nadel entspricht etwa 2 Anteile Höhe zu 1 Anteil Grundseite. Pro cm2 der Basisplatte sind etwa 370 Erhebungen vorgesehen.
Das Polymer der Basisplatte 1 und der Erhebungen 4 ist ein bioabbaubares Copolymer aus Milch- und Glycolsäure, das mit etwa 60 Vol-% des mikronisierten festen Wirkstoffes gemischt und in einem Extruder aufgeschmolzen wird. In einem anschließenden Formgebungsverfahren wird die Kontur des Systems gefertigt. Hierbei scheidet der Wirkstoff aufgrund des Unterschiedes des Molekulargewichtes des Matrixmaterials und des Wirkstoffes in Phasen aus, weshalb Kanäle innerhalb des Matrixmaterials entstehen, in denen der Wirkstoff vorliegt und die die Permeation wesentlich begünstigen.
The transcorneal system for delivering a drug substance comprises a base plate 1 made of a polymeric matrix material in which the active ingredient is present, wherein the base plate 1 is integrally connected to a plurality of pyramidal elevations 4 for penetration into the stratum corneum 2 of the skin 3 , which consist of the matrix material and also have the active ingredient. The ratio of the height to the base of the needle corresponds to about 2 parts height to 1 part base side. Per cm 2 of the base plate about 370 surveys are provided. The polymer of the base plate 1 and the bumps 4 is a biodegradable copolymer of lactic and glycolic acid, which is mixed with about 60% by volume of the micronized solid active ingredient and melted in an extruder. In a subsequent molding process, the contour of the system is made. In this case, due to the difference in the molecular weight of the matrix material and the active ingredient, the active ingredient separates out in phases, which leads to the formation of channels within the matrix material in which the active ingredient is present and which substantially promote permeation.
Claims
1. Transcorneales System zur Abgabe eines Arzneimittel- Wirkstoffes, der in einem eine Basisplatte (1) bildenden Matrixmaterial vorliegt, wobei die Basisplatte (1) zur Penetration des Stratum corneum der Haut mit einer Vielzahl von Erhebungen (4) verbunden ist, dadurch gekennzeichnet, dass die Erhebungen (4) aus dem Matrixmaterial bestehen und den Wirkstoff aufweisen.A transcorneal drug delivery system provided in a matrix material forming a base plate (1), the base plate (1) being connected to a plurality of protrusions (4) for penetrating the stratum corneum of the skin, characterized that the elevations (4) consist of the matrix material and have the active ingredient.
2. System nach Anspruch 1, dadurch gekennzeichnet, dass die Erhebungen (4) einstückig mit der Basisplatte (1) und pyramidenförmig ausgebildet sind.2. System according to claim 1, characterized in that the elevations (4) are formed integrally with the base plate (1) and pyramid-shaped.
3. System nach einem der Ansprüche 1 und 2, dadurch gekennzeichnet, dass der Wirkstoff in fester Form, als Lösung oder Gel in dem Matrixmaterial vorliegt.3. System according to any one of claims 1 and 2, characterized in that the active ingredient is in solid form, as a solution or gel in the matrix material.
4. System nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass das Matrixmaterial ein Polymer oder ein Salz ist.4. System according to one of claims 1 to 3, characterized in that the matrix material is a polymer or a salt.
5. System nach Anspruch 4, dadurch gekennzeichnet, dass das Polymer biologisch abbaubar ist.5. System according to claim 4, characterized in that the polymer is biodegradable.
6. System nach Anspruch 4 oder 5, dadurch gekennzeichnet, dass das Polymer ein Copolymer aus Milch- und Glycolsäure ist.6. System according to claim 4 or 5, characterized in that the polymer is a copolymer of lactic and glycolic acid.
7. System nach einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, dass das7. System according to one of claims 1 to 6, characterized in that the
Matrixmaterial und die Erhebungen (4) Kanäle aufweisen, in denen der Wirkstoff vorliegt.Matrix material and the surveys (4) have channels in which the active ingredient is present.
8. System nach einem der Ansprüche 1 bis 7, dadurch gekennzeichnet, dass die Länge der Erhebungen (6) oder der Mikronadeln (6) derart bemessen ist, dass sie in die Epidermis der Haut (3) eindringen.8. System according to any one of claims 1 to 7, characterized in that the length of the elevations (6) or the microneedles (6) is dimensioned such that they penetrate into the epidermis of the skin (3).
9. System nach einem der Ansprüche 1 bis 8, dadurch gekennzeichnet, dass die Basisplatte (1) mit einer Schutzfolie überzogen ist.9. System according to one of claims 1 to 8, characterized in that the base plate (1) is coated with a protective film.
10. System nach einem der Ansprüche 1 bis 9, dadurch gekennzeichnet, dass eine Klebefläche zur Befestigung auf der Haut (3) vorgesehen ist.10. System according to one of claims 1 to 9, characterized in that a Adhesive surface for attachment to the skin (3) is provided.
11. Verfahren zur Herstellung eines transcornealen System zur Abgabe eines Arzneimittel-Wirkstoffes mit einem polymeren Matrixmaterial, dadurch gekennzeichnet, dass das pulverförmige Matrixmaterial mit dem Wirkstoff vermischt, in einem11. A process for producing a transcorneal system for delivering a drug substance with a polymeric matrix material, characterized in that the powdery matrix material mixed with the active ingredient, in one
5 Extruder aufgeschmolzen und das hergestellte Kompositmaterial in einem Formgebungsverfahren derart geformt wird, dass eine Basisplatte (1) mit Erhebungen (4) zur Durchdringung des Stratum corneum der Haut vorliegt.5 extruder melted and the composite material produced is formed in a molding process such that a base plate (1) with protrusions (4) for penetrating the stratum corneum of the skin is present.
12. Verfahren nach Anspruch 11, dadurch gekennzeichnet, dass der Volumenprozentanteil des Matrixmaterials an dem Kompositmaterial kleiner oder gleich dem Vo- l o lumenprozentanteil des Wirkstoffes eingestellt wird.12. The method according to claim 11, characterized in that the volume percentage of the matrix material is set to the composite material less than or equal to the vol lol percentage of the active ingredient.
13. Verfahren nach Anspruch 11 oder 12, dadurch gekennzeichnet, dass der in fester Form vorliegende Wirkstoff vor dem Vermischen mit der Schmelze mikronisiert wird. 13. The method according to claim 11 or 12, characterized in that the active substance present in solid form is micronized before mixing with the melt.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE102005040251A DE102005040251A1 (en) | 2005-08-24 | 2005-08-24 | Transcorneal drug delivery system |
PCT/EP2006/065585 WO2007023167A1 (en) | 2005-08-24 | 2006-08-23 | Transcorneal system for delivery of a pharmaceutical agent |
Publications (1)
Publication Number | Publication Date |
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EP1919549A1 true EP1919549A1 (en) | 2008-05-14 |
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EP06792966A Withdrawn EP1919549A1 (en) | 2005-08-24 | 2006-08-23 | Transcorneal system for delivery of a pharmaceutical agent |
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US (1) | US20090011026A1 (en) |
EP (1) | EP1919549A1 (en) |
JP (1) | JP5198268B2 (en) |
CA (1) | CA2619041C (en) |
DE (1) | DE102005040251A1 (en) |
WO (1) | WO2007023167A1 (en) |
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US8136034B2 (en) * | 2007-12-18 | 2012-03-13 | Aaron Stanton | System and method for analyzing and categorizing text |
FR2973237A1 (en) | 2011-03-31 | 2012-10-05 | Oreal | FRACTIONAL COSMETIC TREATMENT PROCESS USING LASER OR MICRO-NEEDLES |
CN106166326A (en) * | 2016-08-19 | 2016-11-30 | 王子元 | A kind of non-intervention introduction method |
FR3122826A1 (en) | 2021-05-12 | 2022-11-18 | L'oreal | METHODS AND COMPOSITIONS FOR IMPROVING SKIN |
FR3124952A1 (en) | 2021-07-09 | 2023-01-13 | L'oreal | Methods and compositions for improving the skin |
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US3964482A (en) * | 1971-05-17 | 1976-06-22 | Alza Corporation | Drug delivery device |
US4919939A (en) * | 1986-04-29 | 1990-04-24 | Pharmetrix Corporation | Periodontal disease treatment system |
US5230897A (en) * | 1991-10-31 | 1993-07-27 | G. D. Searle & Co. | Transdermal pentamidine |
DE19525607A1 (en) * | 1995-07-14 | 1997-01-16 | Boehringer Ingelheim Kg | Transcorneal drug delivery system |
JP2002517300A (en) * | 1998-06-10 | 2002-06-18 | ジョージア テック リサーチ コーポレイション | Microneedle devices and methods of manufacture and uses thereof |
US7226469B2 (en) * | 1999-02-02 | 2007-06-05 | Arthrex, Inc. | Insert molded suture anchor |
US6689103B1 (en) * | 1999-05-07 | 2004-02-10 | Scimed Life System, Inc. | Injection array apparatus and method |
US6256533B1 (en) * | 1999-06-09 | 2001-07-03 | The Procter & Gamble Company | Apparatus and method for using an intracutaneous microneedle array |
GB0017999D0 (en) * | 2000-07-21 | 2000-09-13 | Smithkline Beecham Biolog | Novel device |
US7108681B2 (en) * | 2000-10-16 | 2006-09-19 | Corium International, Inc. | Microstructures for delivering a composition cutaneously to skin |
WO2002064193A2 (en) * | 2000-12-14 | 2002-08-22 | Georgia Tech Research Corporation | Microneedle devices and production thereof |
US20050202090A1 (en) * | 2002-01-03 | 2005-09-15 | Clarke Allan J. | Novel pharmaceutical dosage forms and method for producing same |
US7318944B2 (en) * | 2003-08-07 | 2008-01-15 | Medtronic Vascular, Inc. | Extrusion process for coating stents |
WO2005020912A2 (en) * | 2003-08-25 | 2005-03-10 | 3M Innovative Properties Company | Delivery of immune response modifier compounds |
AU2004311977A1 (en) * | 2003-12-29 | 2005-07-21 | 3M Innovative Properties Company | Medical devices and kits including same |
JP2007517042A (en) * | 2003-12-30 | 2007-06-28 | デュレクト コーポレーション | Polymer implant for the controlled release of an active substance, preferably GNRH, preferably containing a mixture of PEG and PLG |
US8551391B2 (en) * | 2004-02-17 | 2013-10-08 | Avery Dennison Corporation | Method of making microneedles |
-
2005
- 2005-08-24 DE DE102005040251A patent/DE102005040251A1/en not_active Withdrawn
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2006
- 2006-08-23 CA CA2619041A patent/CA2619041C/en not_active Expired - Fee Related
- 2006-08-23 JP JP2008527467A patent/JP5198268B2/en not_active Expired - Fee Related
- 2006-08-23 US US12/063,876 patent/US20090011026A1/en not_active Abandoned
- 2006-08-23 WO PCT/EP2006/065585 patent/WO2007023167A1/en active Application Filing
- 2006-08-23 EP EP06792966A patent/EP1919549A1/en not_active Withdrawn
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See references of WO2007023167A1 * |
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JP5198268B2 (en) | 2013-05-15 |
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US20090011026A1 (en) | 2009-01-08 |
JP2009506013A (en) | 2009-02-12 |
WO2007023167A1 (en) | 2007-03-01 |
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