MX2008009323A - Pharmaceutical formulation for aerosols, comprising two or more active agents and at least one surfactant - Google Patents

Abstract

The invention relates to novel pharmaceutical formulations for aerosols, comprising at least two or more active agents and at least one surfactant and suitable for inhalative or nasal application. The invention particularly relates to pharmaceutical preparations for propellant-containing dosage aerosols containing a fluorohydrocarbon (HFA) as propellant, said preparations containing an active agent combination of at least two or more active agents, wherein at least one active agent is present in dissolved form and at least another active agent is present in the form of suspended particles in conjunction with at least one surfactant.

Description

PHARMACEUTICAL FORMULATION FOR AEROSOLS WITH TWO OR MORE ACTIVE PRINCIPLES AND AT LEAST ONE SURGICAL SUBSTANCE The present invention relates to new pharmaceutical formulations for aerosols with at least two or more active principles together with at least one surfactant substance for inhalation or nasal application. STATE OF THE ART In metered dose inhalers with propellants, the active ingredients can be formed as a solution or suspension. In most cases, aerosol formulations are prepared for metered dose inhalers, especially when the preparation contains more than one active ingredient. Solution formulations are used in only a small proportion. In these cases, the formulations usually contain only one active ingredient. In a suspension, in general, the chemical stability of the active ingredients is clearly higher than in solution. Additionally, the active principle can be concentrated more in a suspension than in a solution, so that the suspension formulation allows higher dosages. In suspension formulations it is very advantageous to store the suspended particles over time (eg, in storage) in large, more or less stable aggregates or to form, sediment or suspend loose flakes or, in the worst case, show particle growth. , which clearly worsens the pharmaceutical quality of the product. The size of the particles that are produced or the speed of the growth of the particles is influenced by the solution properties of the liquid phase. In this way, the penetration of moisture during storage or a The desired increase in polarity, for example by the addition of co-solvents, can have an adverse effect on the quality of the final medical product, especially when the suspended particles have polar structural elements. By the addition of surface-active substances, physical stabilization of the suspension can be achieved by reducing the harmful influence of moisture and / or growth of the particles and keeping the suspended particles in suspension for a longer time. Solution formulations are not naturally affected by the problems of increasing particle size or demixing processes, such as sedimentation or flocculation. However, in this case, there is a great danger produced by chemical processes of disintegration. Another disadvantage is that the limited solubility of the ingredients can avoid a high dose application. Particularly suitable solvents were chlorofluorinated hydrocarbons TG 11 (trichlorofluoromethane), TG 12 (dichlorodifluoromethane) and TG 114 (dichlorotetrafluoroethane) in the past. By adding cosolvents the solubility of the ingredients can be increased. In addition, most of the time additional measures must be taken in the solution formulations to chemically stabilize the dissolved components. CFCs such as, for example, the aforesaid TG 11, were used as propellant gases. But since CFCs are linked to the destruction of the ozone layer, their production and use are regulated gradually.

The use of special fluorinated hydrocarbons (HFA), which are less harmful to the ozone layer, are intended as inputs, but they also have completely different solubility properties. The toxicological profile and physicochemical properties such as, for example, vapor pressure determine which HFAs are suitable for aerosols for dosing. The most promising representatives at present are TG 134a (1, 1, 2,2-tetrafluoroethane) and TG 227 (1, 1, 1, 2,3,3,3-heptafluoropropane). For inhalation treatment, aerosol formulations with two or more active ingredient components may be desired. In this case, the active ingredients are formulated in the necessary concentration in a unitary form as a solution or as a unit suspension, which is often linked to problems regarding the chemical stability or the achievable concentration of each of the active ingredients. Great difficulties arise when in a suspension formulation of this type one of the active ingredients is not suspended or is not consistent or when in a solution formulation one of the active ingredients is chemically unstable or does not dissolve, especially when using HFA as a propellant. Therefore, an object of the invention is to develop a formulation for aerosols for dosing with two or more active principles together with at least one surfactant substance that overcomes the aforementioned disadvantages. DESCRIPTION OF THE INVENTION Surprisingly it was found that two or more active principles can be formulated together with at least one surfactant substance in a formulation as a solution and as a suspension and this formulation has better properties. The invention relates to a pharmaceutical preparation in the form of stable aerosol formulations with fluorinated hydrocarbons as a propellant gas, especially TG 134a and / or TG 227, which is composed of two or more active principles, wherein at least one active ingredient is formulated as a solution and at least one active ingredient is formulated as a suspension and in addition the formulation contains at least one surfactant substance, to improve the properties of the formulation. In this case, the pharmaceutical preparation according to the invention serves for the treatment by inhalation, in particular of diseases of the mouth and tracheal area and of the airways, for example, asthmatic diseases and COPD. The invention also relates to aerosols for dosage containing the pharmaceutical preparation according to the invention. DETAILED DESCRIPTION OF THE INVENTION In one embodiment, a medically convenient combination of active ingredients of two or more active ingredients together with at least one surfactant substance for inhalation or nasal application is employed. As substances, formulations of substances or mixtures of substances of pharmaceutical efficacy all inhalable compounds are used, such as, for example, also inhalable macromolecules, as disclosed in EP 1 003 478. Preferably, substances, formulations of Substances or mixtures of substances for the treatment of pathological diseases areas that are used in the inhalation area. In this regard, drugs selected from the group consisting of anticholinergics, betamimetics, spheroids, phosphodiesterase IV inhibitors, LTD4 antagonists and EGFR kinase inhibitors, antiallergics, ergot alkaloid derivatives, are particularly preferred. triptans, CGRP antagonists, phosphodiesterase-V inhibitors, as well as combinations of active principles of this type, e.g. ex. betamimetics plus anticholinergics or betamimetics plus antiallergics. In the case of combinations, at least one of the active ingredients has chemically bound water. Preferably, active ingredients containing anticholinergics, in the form of monopreparated or in the form of combination preparations are used. In particular, as examples of the active components or their salts should be mentioned: The anticholinergics used are preferably selected from the group consisting of tiotropium bromide, oxitropium bromide, flutropium bromide, ipratropium bromide, glycopyrronium salts, trospium chloride , tolterodine, tropenic ester methobromide of 2,2-diphenylpropionic acid, 2,2-diphenylpropionic acid scopin ester metobromide, 2-fluoro-2,2-diphenylacetic acid scopinic ester metobromide, tropenic acid ester methobromide 2 -fluoro-2,2-diphenylacetic acid, tropenolic ester metobromide of S.S '^^' - tetrafluorobenzilic acid, scopic ester ester metobromide S.S '^^' - tetrafluorobenzyl, 4,4'-difluorbenzyl tropenic ester methobromide, 4,4-, -difluorobenzyl, scophenyl ester methobromide, 3,3'-difluorobenzyl tropenic acid methobromide, methobromide of 1,3,3-difluorobenzyl acid scopin ester, tropenolic ester methobromide of 9-hydroxy-fluoren-9-carboxylic acid, tropenic ester methobromide of 9-fluoro-fluoren-9-carboxylic acid, scopolamine ester methobromide of acid 9-hydroxy-fluoren-9-carboxylic acid, 9-fluoro-fluoren-9-carboxylic acid scopin ester ester, tropenic acid methobromide of 9-methyl-fluoren-9-carboxylic acid, ester methobromide 9-methyl-fluoren-9-carboxylic acid scopinic acid, benzyl acid cyclopropyl-proproline ester metobromide, 2,2-diphenylpropionic acid cyclopropyl-propionic ester methobromide, 9-hydroxy-xanthen-9-carboxylic acid cyclopropyl-proproline ester methobromide, ester 9-methyl-fluoren-9-carboxylic acid cyclopropylpyrin-9-methobromide, 9-methyl-xanten-9-carboxylic acid cyclopropylpyrinic ester-methobromide, 9-hydroxy-fluoren-9-carboxylic acid cyclopropyl-thrombinic ester-metobromide, cyclopropyl-proproline ester methobromide of 4,4'-difluorobenzyl methyl ester, tropenolic ester methobromide of 9-hydroxy-xanthen-9-carboxylic acid, methobromide of 9-hydroxy-xanten-9-carboxylic acid scopin ester, tropenolic ester methobromide of 9-methyl-xanten-9-carboxylic acid, 9-methyl-xanthen-9-carboxylic acid scopin ester ester ester methobromide tropenolic acid 9-ethyl-xanthen-9-carboxylic acid, tropenolic ester metobromide of 9-difluoromethyl-xanthen-9-carboxylic acid and metochromide of 9-hydroxymethyl-xanthene-9-carboxylic acid, optionally in the form of their racemates, enantiomer or diastereomers and optionally in the form of their solvates and / or hydrates. The betamimetics used are preferably selected from the group consisting of albuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, indacaterol, isoetarin, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmeterol, salmefamol, soterenot, sulfonterol, thiaramide, terbutaline, tolubuterol, CHF-1035, HOKU-81, KUL-1248, 3- (4-. {6- [2-hydroxy-2- ( 4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -hexyloxy.] - butyl) -benzenesulfonamide, 5- [2- (5,6-diethyl-indan-2-ylamino) -1 - hydroxy-ethyl] -8-hydroxy-1 H -quinolin-2-one, 4-hydroxy-7- [2-. { [2-. { [3- (2-phenylethoxy) propyl] -sulfonyl} ethyl] -amino} ethyl] -2 (3H) -benzothiazolone, 1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1 - [3- (4 -methoxybenzyl amino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1 - [2H-5-hydroxy-3-oxo-4H-1, 4 -benzoxazin-8-yl] -2- [3- (4-NIN-dimethylaminophenyl) -2-methyl-2-propylaminohetanol, 1 - [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8 -yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol, 1 - [2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl] -2- [3- (4-n-Butyloxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] - 2-. { 4- [3- (4-methoxyphenyl) -1,2,4-triazol-3-yl] -2-methyl-2-butylamino} ethanol, 5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1, 4-benzoxazin-3- (4H) -one, 1- (4-amino-3-chloro-5-trifluoromethylphenyl) ) -2-tert-butylamino) ethanol and 1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert-butylamino) ethanol, optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of its salts by the addition of pharmacologically tolerated acids, solvates and / or hydrates. Steroids which are to be used are preferably selected from the group consisting of prednisolone, prednisone, butyclocort propionate, RPR-106541, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, ST-126, dexamethasone, ester ( S) -fluoromethyl acid 6a, 9a-difluoro-17a - [(2-furanylcarbonyl) oxy] -11β-hydroxy-16a-methyl-3-oxo-androsta-1,4-diene-17a-carbothionic acid, ester ( S) - (2-oxo-tetrahydro-furan-3S-H) of 6a, 9a-difluoro-11β-hydroxy-16a-methyl-3-oxo-17a-propionyloxy-androsta-1,4-dien-17ß-acid carbothionic and etipredone dichloroacetate (BNP-166), optionally in the form of their racemates, enantiomers or diastereoisomers and, optionally, in the form of their salts and derivatives, their solvates and / or their hydrates.

The PDE IV inhibitors used are preferably selected from the group consisting of enprophyllin, theophylline, roflumilast, ariflo (cilomilast), CP-325,366, BY343, D-4396 (Sch-351591), AWD-12-281 (GW-842470), N- (3,5-dichloro-1-oxo-pyridin-4-yl) -4-d-fluoro-methoxy-3-cyclopropylmethoxybenzamide, NCS-613, pumafentin, (-) p - [(4aR *, 10bS * ) -9-ethoxy-1, 2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo [s] [1,6] naphthyridin-6-yl] -N, N-diisopropylbenzamide, (R ) - (+) - 1- (4-bromobenzyl) -4 - [(3-cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone, 3- (cyclopentyloxy-4-methoxyphenyl) -1- (4-N'- [N-2-cyano-S-methyl-isothioureido] benzyl) -2-pyrrolidone, cis [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid], 2- carbomethoxy- 4-Cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -cyclohexan-1 -one, cis [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -cyclohexan-1-ol], (R) - ( +) - ethyl [4- (3-cyclopentyloxy-4-methoxy-phenol) pyrrolidin-2-ylidene] acetate, (S) - (-) - ethyl [4- (3-cyclopentyloxy-4-methoxy-phenyl) piiT Oldin-2-ylidene] acetate, CDP840, Bay-198004, D-4418, PD-168787, T-440, T-2585, arophylline, atizoram, V-11294A, CI-1018, CDC-801, CDC- 3052, D-22888, YM-58997, Z-15370, 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3,4-c] -1, 2 , 4-triazolo [4,3-a] pyridine and 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (tert-butyl) -9H-pyrazolo [3,4-c] -1) 2, 4-triazolo [4,3-a] pyridine, optionally in the form of its racemates, enantiomers or diastereomers and optionally in the form of its salts by the addition of pharmacologically tolerated acids, solvates and / or hydrates. The LTD4 antagonists used are preferably selected from the group consisting of montelukast, 1 - (((R) - (3- (2- (6,7-difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2-hydroxy-2-propyl) phenyl) thio) methylcyclopapanacetic acid, 1 - (((1 (R) -3 (3- (2- (2,3-dichlorothieno [3,2-b] pyridin-5- il) - (E) -ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropanacetic, pranlukast, zafiriukast, [2 - [[2- (4-tert-butyl-2-thiazolyl) -5-benzofuranyl] oxymethyl] phenyl] acetic acid, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507) ), VUF-5078, VUF-K-8707 and L-733321, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their salts by the addition of pharmacologically tolerated acids, as well as optionally in the form of their salts and derivatives , of its solvates and / or hydrates. The EGFR kinase inhibitors used are preferably selected from the group consisting of cetuximab, trastuzumab, ABX-EGF, Mab ICR-62, 4 - [(3-chloro-4-fluorophenyl) amino] -6-. { [4- (morpholin-4-yl) -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-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-. { [4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] -quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [2 - ((S) -6-methyl] -2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- (. {4- [N- (2- methoxy-ethyl) -N-methyl-amino] -1 -oxo-2-buten-1-yl.}. amino) -7-cyclopropylmethoxy-quinazoline, 4 - [(R) - (1-phenyl-ethyl) amino] ] -6- ( { 4- [N- (tetrahydropyran-4-yl) -N-methyl-amino] -1-oxo-2-buten-1-yl.}. Amino) -7-cyclopropylmethoxy-quinazoline , 4 - [(3-chloro-4-fluorophenyl) amino] -6- (. {4- [N- (2-methoxy-ethyl) -N-methyl-amino] -1 -oxo-2-buten- 1 -yl.}. Amino) -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6-. { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(R) - (tetrahydrofuran-2-yl) methoxy] -quinazoline, 4 - [(3-ethynyl-phenyl) amino] -6,7-bis- (2-methoxy-ethoxy) -quinazoline, - [(R) - (1-phenyl-ethyl) amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d-pyrimidine, 3-cyano-4 - [(3-chloro-4- fluorophenyl) amino] -6-. { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-ethoxy-quinoline, 4 - [(R) - (1-phenyl-ethyl) amino] -6-. { [4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1 -oxo-2-buten-1-yl] amino} -7-methoxy-quinazoline, 4 - [(3- chloro-4-fluorophenyl) amino] -6-. { [4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7- [(tetrahydrofuran-2-yl) methoxy] -quinazoline, 4 - [(3-ethynyl-phenyl) amino] -6-. { [4- (5,5-dimethyl-2-oxo-morpholin-4-yl) -1 -oxo-2-buten-1-yl-amino} - quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-. { 2- [4- (2-Oxo-morpholin-4-yl) -piperidin-1-yl] -ethoxy} -7-methoxy-quinazoline, 5 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (trans-4-amino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-Chloro-4-fluoro-phenyl) amino] -6- (trans-4-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (tetrahydropyran-3-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-. { 1 - [(Morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-or fluoro-phenyl) amino] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4 -fluoro-phenol) amino] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-. { trans-4 - [(morpholin-4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-. { 1 - [(piperidin-1 -5-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (cis-4- { N - [(morpholin-4-yl) carbonyl] -N-methyl -amino.}. -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (trans-4-ethanesulfonylamino-cyclohexan-1-yloxy ) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluoro-or phenyl) amino] -6- [1 - (2-methoxy-acetyl) -piperidin-4-yloxy] -7- (2-methoxy-ethoxy) -quinazoline, 4 - [(3-ethynyl-phenyl) amino] -6- (tetrahydropyran-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6 - (cis-4- { N - [(piperidin-1-yl) carbonyl] -N-methyl-amino.} - cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3- chloro-4-fluoro-phenyl) amino] -6- { cis-4- [(morpholin-4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [( 3-Chloro-4-fluoro-phenyl) amino] -6- { 1 - [2- (2-oxopinOlidin-1-yl) ethyl] -piperidin-4-yloxy} -7-methoxy- quinazoline, 4 - [(3-ethynyl-phenyl) amino] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) amino] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy- quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (1-methyl-piperidin-4-yloxy) -7 (2-methoxy-ethoxy) -quinazoline, 4 - [(3- ethynyl-phenyl) amino] -6-. { 1 - [(Morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-. { 1 - [(N-methyl-N-2-methoxyethyl-amino) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (1-ethyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3- chloro-4-fluoro-phenyl) amino] -6- [cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-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-chloro- 4-fluoro-phenyl) amino] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- ( trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (trans-4 {N - [( morpholin-4-yl) carbonyl] -N-methyl-amino.} - cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [2- (2,2-Dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline, 4 - [(3-chloro -4-fluoro-phenyl) amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline and 4 - [(3-chloro-4 -fluoro-phenyl) amino] -6-. { 1 - [(2-methoxyethyl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, optionally in the form of their racemates, enantiomers or diastereoisomers, optionally in the form of their salts by the addition of pharmacologically tolerable acids, their solvates and / or hydrates. By salts by the addition of pharmacologically compatible acids, for which formation the compounds are optionally suitable, it is understood, for example, salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethane sulphonate, hydronitrate, hydro-monoate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotrearate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydrometanesulfonate. As antiallergic: disodium cromoglycate, nedocromil. As derivatives of corn mother alkaloids: dihydroergotamine, ergotamine. For the inhalation, medications, formulations and pharmacological mixtures are taken into account with the active principles mentioned above, as well as their salts, esters, as well as the combination of these active principles, salts and esters. Which of the active ingredients listed above are formulated in the preparation according to the invention as a solution and which as suspension, depends on the corresponding active ingredient combinations and can be calculated relatively quickly by solution and suspension tests. In a preferred embodiment, one or more of the following active ingredients are suspended: budesonide, cromoglicinic acid, nedocromil, reproterol and / or salbutamol (albuterol) or esters, salts and / or solvates that are derived from these compounds and dissolve a or several of the following substances: beclomethasone, fenoterol, ipratropium bromide, orciprenaline and / or oxitropium bromide, N - [[2,2-dimethyl-4- (2-oxo-2H-pyridin-1-yl) -6 -trifluoromethyl-2H-1-benzopyran-3-yl] methyl] -N-hydroxy-acetamide or esters, salts and / or solvates which they are derived from these compounds. Embodiments with two different active ingredients are preferred. Preferably, the pharmaceutical preparation contains a combination of active ingredients from the group of the following active ingredients: beclomethasone, budesonide, cromoglicinic acid, fenoterol, flunisolide, fluticasone, ipratropium, nedocromil, orciprenaline, oxitropium bromide, reproterol, salbutamol, salmeterol (albuterol ), terbutaline, N - [[2,2-dimethyl-4- (2-oxo-2H-pyridin-1-yl) -6-trifluoromethyl-2H-1-benzopyran-3-yl] methyl] -N-hydroxy -acetamide, its esters, salts and / or solvates. A particularly preferred embodiment of the pharmaceutical preparation contains dissolved ipratropium bromide monohydrate, especially in combination with salbutamol sulphate (albuterol salt) as an active ingredient in suspension. __ In all embodiments, the active ingredients are used in a therapeutically effective amount, that is, in an amount that can produce the success of the treatment. In this case, the concentration of the active ingredients and the volume per shot is regulated in such a way that the medically necessary or recommended amount of the corresponding active ingredient is released through one or more shots. One embodiment relates to formulations in which the suspended particles are stabilized by the addition of surfactants. This has the advantage that the particle size also remains pharmaceutically stable and acceptable over a prolonged period, for example, during storage. Particle sizes of up to 20 μm are preferred, very especially particle sizes of between 5 and 15 μm, at best of cases, 10 μm maximum. The advantage of these particle sizes is that the particles are small enough to penetrate deep into the lungs, but not so small as to be removed again with the replacement air. Suitable surfactants are all pharmacologically tolerated substances, which have a lipophilic hydrocarbon radical and one or more functional hydrophilic groups, C5-20 fatty alcohols are particularly suitable. Cs-20 fatty acids, esters of C5-20 fatty acids, lecithin, glycerides, propylene glycol esters, polyoxyethylenes, polysorbates, sorbitan esters and / or carbohydrates. Preference is given to fatty acids 05-20, propylene glycol diesters and / or triglycerides and / or sorbitans of the C5-20 fatty acids, particularly preferred are the sodium or potassium salts of a C5.20 fatty acid, an oleic acid and a mono-, di- or trioleate of sorbitan, a polyvinylpyrrolidone, a polyvinyl alcohol, a sorbitan ester of polyoxyethylene, a polyoxyethylene glycerol ester, a fatty acid ester of polyoxyethylene, a fatty acid ester of polyoxypropylene, a block copolymer of polyoxyethylenepolyoxypropylene, an alkyl polyglucoside, a benzalkonium chloride and / or a cetylpyridinium chloride. Especially preferred are polyvinyl pyrrolidone K25 (Povidon 25®), polyoxyethylene-20-sorbitan monolaurate, polyoxyethylene glycerol trioleate or a combination of these surfactants. Particularly preferred according to the invention are polyoxyethylene-20-sorbitan monolaurate and polyoxyethylene glycerol trioleate, which are known and commercially available under the trademarks Tween®20 and Tagat® TO V. Surfactants are contained in the formulations according to the invention preferably in a concentration of 0.001 to 5% (m / m), with special preference of 0.01 to 3% (m / m). In one embodiment of the invention, which is particularly preferred according to the invention, one or several are present, preferably one of the surfactants mentioned above in a concentration of 0.02 to 0.2% (m / m), preferably 0.05 to 0.15% (m / m), especially 0.1% (m / m). In an alternative embodiment of the invention also preferred according to the invention, one or more are present, preferably one of the aforementioned surfactants in a concentration of 0.3 to 2.5% (m / m), preferably 0.4 to 2% ( m / m), with special preference from 0.5 to 1.5% (m / m), also preferably from 0.75 to 1.25% (m / m), especially 1.0% (m / m). Another advantage of the aforementioned surfactants is that they can also be used as valve lubricants. Therefore, one embodiment refers to formulations in which surfactants are added as valve lubricants. In another embodiment, the solubility of the active ingredient (s) to be dissolved is increased by the addition of cosolvents. This has the advantage that the active ingredient (s) to be dissolved can be formulated in a high concentration. In this case, the addition of a cosolvent must not exceed the critical threshold of the polarity of the liquid phase, from which one of the disadvantages described above for the suspended particles of active principle appears. Pharmacologically tolerated alcohols such as ethanol, esters or water or mixtures thereof, are suitable as co-solvents. ethanol preference. The concentration of the cosolvent referred to the entire formulation is from 0.0001 to 50% (m / m), preferably from 0.01 to 25% (m / m). In a preferred embodiment, the concentration of the cosolvent is from 1 to 20% (m / m), preferably from 5 to 15% (m / m). Especially preferred are those formulations according to the invention in which the concentration of the cosolvent is from 8 to 12% (m / m), especially 10% (m / m). In the case of the concentrations indicated in the framework of the present invention, it is always the mass percentage [% m / m] with respect to the mass of the total formulation. In another embodiment, other conventional propellant gases are added to the HFA propellant gas. These added propellant gases can also be, in addition to other fluorinated hydrocarbons, saturated lower hydrocarbons such as propane, butane, isobutane or pentane, provided that there is a pharmacological safety for the mixture. In one embodiment, they are added to the stabilizing formulation, which advantageously influences the pharmaceutical stability of the active ingredients also over a prolonged period, for example, during storage. In the context of the invention, stabilizers are understood to be those substances that prolong the duration and the use capacity of the pharmaceutical preparation, by avoiding or delaying the chemical alterations of each of the ingredients, especially of the active ingredients, for example , by subsequent reactions or disintegration, or by avoiding biological impurities. Preferred stabilizers in this sense are those which influence the pH value of the liquid phase, such as, for example, acids and / or their salts. Hydrochloric acid, sulfuric acid, nitric acid, acid are particularly suitable phosphoric acid, ascorbic acid, citric acid and its salts. As bactericides, fungicides, etc. further preferred are benzalkonium chloride or ethylenediamine tetraacetate. The most preferred is citric acid. The concentration of the aforementioned stabilizers is preferably in a range of 0.0001 to 0.02% (m / m), preferably in a range of 0.0005 to 0.01% (m / m). The formulations of particular preference according to the invention contain the aforementioned stabilizers in a concentration of 0.001 to 0.008% (m / m), where a content of 0.002 to 0.006% (m / m), especially about 0.004% (m / m), is particularly important according to the invention. A particularly preferred embodiment contains salbutamol sulphate in suspension (albuterol sulfate), dissolved ipratropium bromide, ethanol as a cosolvent and citric acid as a stabilizer. These formulations of particular preference according to the invention contain the active substance salbutamol sulphate preferably in a concentration of 0.1 to 0.3% (m / m), with special preference of 0.15 to 0.25% (m / m), with special preference of 0.18 to 0. 22% (m / m). These particularly preferred formulations according to the invention also contain ipratropium bromide hydrate in a concentration of preferably 0.02 to 0.05% (m / m), with a special preference of 0.03 to 0.04% (m / m). Particular preference is given to those compositions according to the invention in which the ratio of the previously mentioned concentrations of both active principles salbutamol sulphate and ipratropium bromide monohydrate is in a range of 5: 1 to 6: 1, with particular preference for a range of 5.5: 1 to 5.9: 1. The compositions according to the invention, wherein the ratio of the concentrations of both principles active salbutamol sulfate and ipratropium bromide monohydrate is in a range of 5.60: 1 to 5.85: 1, especially in a range of 5.70: 1 to 5.80: 1. In all embodiments, the formulations are packaged in metal containers Suitable for dosing aerosols: Metal containers are closed with appropriate dosing valves. Suitable metallic containers are, for example, stainless steel monobloc cans (DIN 1.4539) from Presspart Manufacturing Ltd., Blackburn, United Kingdom, with a nominal volume of 17 ml. Suitable metering valves are, for example, BK 357 or BK 361 from Bespak Europe Ltd., King's Lynn, United Kingdom. The dosage aerosol of the invention preferably contains a pharmaceutical preparation with a combination of active ingredients of the following group: beclomethasone, budesonide, cromoglicinic acid, fenoterol, flunisolide, fluticasone, ipratropium, nedocromil, orciprenaline, oxitropium bromide, reproterol, salbutamol, salmeterol (albuterol), terbutaline, N - [[2,2-dimethyl-4- (2-oxo-2H-pyridin-1-yl) -6-trifluoromethyl-2H-1-benzopyran-3-yl] methyl] -N -hydroxy-acetamide, its esters, salts and / or solvates. The dosage aerosol contains, with very particular preference, a pharmaceutical preparation containing the combination of active principles salbutamol sulphate (albuterol sulfate) and ipratropium bromide monohydrate. EXAMPLES Example 1 Example 4 Example 5: Example 6: Example 7: Example 8: Example 11: Example 12:

Claims (4)

CLAIMS 1.- Pharmaceutical preparation for aerosols for dosing operated with propellant gas with a fluorinated hydrocarbon (HFA) as a propellant containing a combination of active ingredients of two or more active ingredients 5 and characterized in that at least one active ingredient is present in dissolved form in addition to another active principle in the form of suspended particles together with at least one surfactant substance. 2. Pharmaceutical preparation according to claim 1, characterized in that the combination of active ingredients is composed of two or active ingredients. 3. Pharmaceutical preparation according to one of the preceding claims, characterized in that the propellant is TG 134a and / or TG 227. 4.- Pharmaceutical preparation according to one of the preceding claims, characterized in that the preparation contains a cosolvent. 5. Pharmaceutical preparation according to claim 4, characterized in that the cosolvent contains one or more pharmacologically tolerated alcohols, an ester of pharmacological tolerance, water or mixtures thereof. 6. Pharmaceutical preparation according to claim 4, or characterized in that the cosolvent is ethanol. 7. Pharmaceutical preparation according to claim 4, 5 or 6, characterized in that the cosolvent is present in a concentration of 0.0001 to 50% (m / m) based on the total formulation. 8. Pharmaceutical preparation according to claim 7, characterized in that the cosolvent is present in a concentration of 5 to 15% (m / m), preferably from 8 to 12% (m / m) based on the entire formulation. 9. Pharmaceutical preparation according to one of claims 1 to 8, characterized in that the preparation is stabilized by means of a stabilizer. 10. Pharmaceutical preparation according to claim 9, characterized in that the stabilizer contains one or more acids and / or its salts. 11. - Pharmaceutical preparation according to claim 9, characterized in that the stabilizer (s) contain hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, ascorbic acid, citric acid, benzalkonium chloride and / or ethylenediamine tetraacetate and / or a salt of they. 12. Pharmaceutical preparation according to claim 9, characterized in that the stabilizer is citric acid. 13. Pharmaceutical preparation according to one of the preceding claims 9, 10, 11 or 12, characterized in that the stabilizer is contained in a concentration of 0.0001 to 0.02% (m / m), preferably 0.0005 to 0.01% (m / m) referred to the entire formulation. 14. Pharmaceutical preparation according to claim 13, characterized in that the cosolvent is present in a concentration of 0.001 to 0.008% (m / m), preferably 0.002 to 0.006% (m / m) based on the entire formulation. 15. Pharmaceutical preparation according to one of the preceding claims 1 to 14, characterized in that the preparation contains at least one surfactant substance. 16. Pharmaceutical preparation according to claim 15, characterized in that the surfactant substance is a sodium or potassium salt of a Cs-20 fatty acid, an oleic acid, a polyvinylpyrrolidone, a polyvinyl alcohol, a polyoxyethylene sorbitan ester, a polyoxyethylene glycerol ester, a polyoxyethylene fatty acid ester, a polyoxypropylene fatty acid ester, a block copolymer of polyoxyethylenepolyoxypropylene, an alkyl polyglycoside, a benzalkonium chloride or a cetylpyridinium chloride or a combination of these surfactant substances. 17. Pharmaceutical preparation according to claim 15, characterized in that the surfactant substance is polyvinyl pyrrolidone K25, polyoxyethylene-20-sorbitan monolaurate or polyoxyethylene glycerol trioleate or a combination of these surfactants. 18. Pharmaceutical preparation according to claim 15, 16 or 17, characterized in that the surfactant substance is present in a concentration between 0.001 and 5% (m / m), preferably between 0.01 and 3% (m / m). 19. Pharmaceutical preparation according to claim 18, characterized in that the surfactant substance is present in a concentration between 0.02 and 0.2% (m / m), preferably between 0.05 and 0.15% (m / m). 20.- Pharmaceutical preparation according to claim 18, characterized in that the surfactant substance is contained in a concentration of 0.3 to 2.5% (m / m), preferably 0.4 to 2% (m / m), with special preference of the 0.5 to 1.5% (m / m), more preferably 0.75 to

1. 25% (m / m). 21. Pharmaceutical preparation according to one of the preceding claims, characterized in that the combination of active ingredients contains one or more active ingredients from the group of anticholinergics, betamimetics, spheroids, phosphodiesterase IV inhibitors, LTD4 antagonists, EGFR kinase inhibitors, antiallergics, maternal alkaloid derivatives, triptans, CGRP antagonists and phosphodiesterase inhibitors . 2

2. Pharmaceutical preparation according to one of the preceding claims, characterized in that the combination of active ingredients contains beclomethasone, budesonide, cromoglicinic acid, fenoterol, flunisolide, fluticasone, ipratropium, nedocromil, orciprenaline, oxitropium bromide, reproterol, salbutamol, salmeterol (albuterol), terbutaline, N - [[2,2-dimethyl-4- (2-oxo-2H-pyridin-1-yl) -6-trifluoromethyl-2H-1-benzopyran-3-yl] methyl] -N -hydroxy-acetamide, its esters, salts and / or solvates. 2

3. Pharmaceutical preparation according to one of the preceding claims, characterized in that it contains the combination of active principles salbutamol sulfate (albuterol sulfate) and ipratropium bromide monohydrate. 2

4. Aerosols for dosage containing a pharmaceutical preparation according to one of the preceding claims 1-23.