CN101384248A - Pharmaceutical formulation for aerosols, comprising two or more active agents and at least one surfactant - Google Patents
Pharmaceutical formulation for aerosols, comprising two or more active agents and at least one surfactant Download PDFInfo
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- CN101384248A CN101384248A CNA2007800051054A CN200780005105A CN101384248A CN 101384248 A CN101384248 A CN 101384248A CN A2007800051054 A CNA2007800051054 A CN A2007800051054A CN 200780005105 A CN200780005105 A CN 200780005105A CN 101384248 A CN101384248 A CN 101384248A
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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
The present invention relates to a kind of new being used to have at least two kinds or various active material and at least a surfactant through sucking or the pharmaceutical preparation of the aerosol that nose is used.
Prior art
In the metered dose inhaler of propellant actuated, active substance can be formulated as solution or suspension.In most cases, the aerosol formulation that is used for metered dose inhaler provides with the form of suspension, especially contains under the situation of more than one active substances at said preparation.Pharmaceutical solutions uses limited.In this case, said preparation only contains a kind of active substance usually.
In suspension, the chemical stability of active substance is significantly higher than its stability in solution usually.In addition, active substance is more concentrated in suspension than in solution, thereby makes the use suspension preparation can obtain higher dosage.
In suspension preparation, major defect be suspended particles in time (for example, when storing) gather to form more stable or more unsettled bigger aggregation or loose tablet, its sedimentation or floating, or under situation about more worsening, demonstrate the particle growth, thereby have a strong impact on the medical quality of product.The size of formed particle or particle growth rate are influenced by the solution feature of liquid phase.Therefore, the infiltration of moisture content or (for example) are had a mind to increase and can be produced harmful effect to the quality of medical end product because of adding polar due to the cosolvent in the storage process, especially have under the unitary situation of polar structure at suspended particles.By adding surfactant, might and make suspended particles can in suspended state, keep the physically stable that reaches suspension more of a specified duration because of the adverse effect that reduces the growth of moisture content and/or particle.
Pharmaceutical solutions is not subjected to the increase of particle size or certainly as the influence of the problem of the separation process of sedimentation or flocculation.Yet, in the case, have the serious risk that causes because of chemical decomposition process.Another shortcoming is that the limited solubility of composition can hinder the administration of high dose.Verified in the past specially suitable solvent comprises Chlorofluorocarbons (CFCs) TG 11 (Arcton 11), TG 12 (dichlorodifluoromethane) and TG 114 (dichlorotetra-fluoroethane).By adding cosolvent, might increase the dissolubility of composition.Simultaneously, in pharmaceutical solutions, other measure must be adopted usually so that dissolved component is chemically being stablized.
Employed so far propellant gas is generally CFC, as above-mentioned TG 11.Yet, because of CFC is associated with the destruction of ozone layer, so its manufacturing and use are just phased out.Need to use the specific fluorinated hydrocarbons (HFA) that does not more damage ozone layer and also have a diverse dissolving characteristic with CFC alternative.The toxicology overview reaches determines that as the physicochemical characteristics (for example) of vapour pressure which kind of HFA is suitable for metered aerosol.Current, the most promising TG 134a (1,1,2, the 2-tetrafluoroethane) and the TG 227 (1,1,1,2,3,3, the 3-heptafluoro-propane) of being represented as.
With regard to by sucking with regard to the treatment, it is desirable to contain the aerosol formulation of two kinds or various active material component.Thereby active substance will evenly be mixed with solution or the inhomogeneous suspension that is mixed with essential concentration, and can to reach the chemical stability problems of concentration relevant with single active substance usually for it.When can not suspending in this suspension preparation one of in the active substance or when unstable, or when being chemically unstable in pharmaceutical solutions one of in the active substance or can not dissolve the time, especially during as propellant, subject matter can appear at use HFA.
Therefore, the objective of the invention is to develop the preparation of the metered aerosol that is used to have two kinds or various active material and at least a surfactant, it has overcome above-mentioned shortcoming.
Summary of the invention
Surprisingly, have now found that two kinds or various active material can be formulated as solution and suspension and said preparation with at least a surfactant and have improved characteristics in a kind of preparation.
The present invention relates to contain the pharmaceutical preparation of stablizing the aerosol formulation form that is of fluorinated hydrocarbons (especially TG 134a and/or TG 227) as propellant gas, it is made up of two kinds or various active material, wherein at least a active substance is formulated as solution and at least a activating agent is formulated as suspension, and said preparation contains the characteristic of at least a surfactant with the improvement said preparation in addition.Pharmaceutical preparation according to the present invention is used for by sucking treatment, the especially disease of oral cavity and pharyngeal cavity and air flue, for example treatment of asthma disease and COPD.
The invention still further relates to the metered aerosol that contains with good grounds pharmaceutical preparation of the present invention.
Detailed Description Of The Invention
In one embodiment, the combination that medically is suitable for that is made of two kinds or various active material and at least a surfactant is used for by sucking or by the nose administration.
The pharmaceutically active substance, substance preparation or the mixture of substances that use can be any chemical compound that sucks, as the macromole that can suck, as disclosed among the EP 1 003 478.Preferably, the material of taking through suction, substance preparation or mixture of substances are used for the treatment of respiratory tract disease.
In this article, particularly preferred for to be selected from: anticholinergic, β simulant, steroid, phosphodiesterase IV inhibitors, LTD4-antagonist and EGFR-inhibitors of kinases, anti-allergic agent (antiallergics), peptide derivant, Qu Putan (triptanes), CGRP antagonist, phosphodiesterase-V inhibitor with following pharmaceutical composition, and the combination of this type of active substance, for example the β simulant adds anticholinergic, or the β simulant adds anti-allergic agent.Under the situation of combination, at least a active substance contains chemically combined water.The active substance that contains anticholinergic preferably uses with the preparation of single preparation or combination.
Below be the instantiation of active component or its salt:
Employed anticholinergic is preferably selected from: tiotropium bromide, oxitropium bromide, flutropium bromide, ipratropium bromide, glycopyrronium salt, trospium chloride, tolterodine, Tropenol (tropenol) 2,2-diphenylprop acid esters Methobromide, scopine (scopine) 2,2-diphenylprop acid esters Methobromide, scopine 2-fluoro-2,2-diphenyl acetic acid ester Methobromide, Tropenol 2-fluoro-2,2-diphenyl acetic acid ester Methobromide, Tropenol 3,3 ', 4,4 '-tetrafluoro benzilic acid ester Methobromide, scopine 3,3 ', 4,4 '-tetrafluoro benzilic acid ester Methobromide, Tropenol 4,4 '-difluorodiphenyl base ethyl glycolate Methobromide, scopin 4,4 '-difluorodiphenyl base glycolic Methobromide, Tropenol 3,3 '-difluorodiphenyl base ethyl glycolate Methobromide, scopine 3,3 '-difluorodiphenyl base ethyl glycolate Methobromide, Tropenol 9-hydroxyl-fluorenes-9-formic acid esters-Methobromide, Tropenol 9-fluoro-fluorenes-9-formic acid esters-Methobromide, scopine 9-hydroxyl-fluorenes-9-formic acid esters Methobromide, scopine 9-fluoro-fluorenes-9-formic acid esters Methobromide, Tropenol 9-methyl-fluorenes-9-formic acid esters Methobromide, scopine 9-methyl-fluorenes-9-formic acid esters Methobromide, cyclopropyl tropanol (cyclopropyltropine) benzilic acid ester Methobromide, cyclopropyl tropanol 2,2-diphenylprop acid esters Methobromide, cyclopropyl tropanol 9-hydroxyl-xanthene-9-formic acid esters Methobromide, cyclopropyl tropanol benzilic acid ester Methobromide, cyclopropyl tropanol 2,2-diphenylprop acid esters Methobromide, cyclopropyl tropanol 9-hydroxyl-xanthene-9-formic acid esters Methobromide, cyclopropyl tropanol 9-methyl-fluorenes-9-formic acid esters Methobromide, cyclopropyl tropanol 9-methyl-xanthene-9-formic acid esters Methobromide, cyclopropyl tropanol 9-hydroxyl-fluorenes-9-formic acid esters Methobromide, methyl cyclopropyl tropanol 4,4 '-difluorodiphenyl base ethyl glycolate methyl ester bromide, Tropenol 9-hydroxyl-xanthene-9-formic acid esters Methobromide, scopine 9-hydroxyl-xanthene-9-formic acid esters Methobromide, Tropenol 9-methyl-xanthene-9-formic acid esters Methobromide, scopine 9-methyl-xanthene-9-formic acid esters Methobromide, Tropenol 9-ethyl-xanthene-9-formic acid esters Methobromide, Tropenol 9-difluoromethyl-xanthene-9-formic acid esters Methobromide and scopine 9-hydroxymethyl-xanthene-9-formic acid esters Methobromide, optional with its racemic modification, enantiomer or diastereomeric form, and optional be its solvate and/or hydrate forms.
Spendable β simulant is preferably selected from: albuterol; bambuterol; bitolterol; broxaterol; carbuterol; clenbuterol; fenoterol; formoterol; hexoprenaline; ibuterol; because of reaching Quattro (indacaterol); isoetarine; isoproterenol; levosalbutamol; Mabuterol; meluadrine; alotec (metaproterenol); orciprenaline; pirbuterol; procaterol; reproterol; rimiterol; ritodrine; salmaterol; Salmefamol; Suo Tenuo (soterenot); special sieve (sulphonterol) of husky wind; tiaramide; terbutaline; Tuo Luteluo (tolubuterol); CHF-1035; HOKU-81; KUL-1248; 3-(4-{6-[2-hydroxyl-2-(4-hydroxyl-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy }-butyl)-benzsulfamide; 5-[2-(5; 6-diethyl-dihydroindene-2-base is amino)-1-hydroxyl-ethyl]-8-hydroxyl-1H-quinoline-2-one-; 4-hydroxyl-7-[2-{[2-{[3-(2-phenyl ethoxy) propyl group] sulfonyl } ethyl]-amino } ethyl]-2 (3H)-benzothiazolones; 1-(2-fluoro-4-hydroxy phenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butyl amino] ethanol; 1-[3-(4-methoxy-benzyl-amino)-4-hydroxy phenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butyl amino] ethanol; 1-[2H-5-hydroxyl-3-oxo-4H-1; 4-benzoxazinyl-8-yl]-2-[3-(4-N; the N-dimethylaminophenyl)-and 2-methyl-2-propyl group amino] ethanol; 1-[2H-5-hydroxyl-3-oxo-4H-1; 4-benzoxazinyl-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propyl group amino] ethanol; 1-[2H-5-hydroxyl-3-oxo-4H-1; 4-benzoxazinyl-8-yl]-2-[3-(4-n-butoxy phenyl)-2-methyl-2-propyl group amino] ethanol; 1-[2H-5-hydroxyl-3-oxo-4H-1; 4-benzoxazinyl-8-yl]-2-{4-[3-(4-methoxyphenyl)-1; 2; 4-triazole-3-yl]-2-methyl-2-butyl amino } ethanol; 5-hydroxyl-8-(the amino butyl of 1-hydroxyl-2-isopropyl)-2H-1; 4-benzoxazinyl-3-(4H)-ketone; 1-(4-amino-3-chloro-5-trifluoromethyl)-2-tert-butyl group amino) ethanol and 1-(4-ethoxy carbonyl amino-3-cyano group-5-fluorophenyl)-2-(tert-butyl group amino) ethanol; optional with its racemic modification; enantiomer or diastereomeric form, and optional be acceptable acid-addition salts on its pharmacology; solvate and/or hydrate forms.
Spendable steroid is preferably selected from: prednisolone, prednisone, propanoic acid butixocort (butixocortpropionate), RPR-106541, flunisolide, beclometasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, ST-126, dexamethasone, 6 α, 9 α-two fluoro-, 17 α-[(2-furyl carbonyl) oxygen base]-11 beta-hydroxy-16 Alpha-Methyls-3-oxo-androstane-1,4-diene-17 β-thiocarboxylic acid (S)-fluorine methyl ester, 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha--methyl-3-oxo-17 α-propionyloxy-androstane-1,4-diene-17 β-thiocarboxylic acid (S)-(2-oxo-tetrahydrochysene-furan-3S-yl) ester and dust replace Po Nuo-dichloroacetic acid ester (etiprednol-dichloroacetate) (BNP-166), and optional is its racemic modification, enantiomer or diastereomeric form and optional be its salt and derivant, solvate and/or hydrate forms.
Spendable PDEIV inhibitor is preferably selected from: enprofylline, theophylline, roflumilast, A Fuluo (cilomilast), CP-325,366, BY343, D-4396 (Sch-351591), AWD-12-281 (GW-842470), N-(3,5-two chloro-1-oxo-pyridin-4-yls)-4-difluoro-methoxy-3-cyclo propyl methoxy benzyl amide, NCS-613, general Ma Fen spit of fland (pumafentine), (-) p-[(4aR
*, 10bS
*)-9-ethyoxyl-1; 2; 3; 4; 4a; 10b-six hydrogen-8-methoxyl group-2-methyl benzo [s] [1; 6] benzodiazine-6-yl]-N; N-diisopropyl benzyl amide; (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-the 4-methoxyphenyl]-2-Pyrrolidone; 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N '-[N-2-cyano group-S-methyl-isothiourea group] benzyl)-2-Pyrrolidone; along [4-cyano group-4-(3-cyclopentyloxy-4-methoxyphenyl) cyclohexane extraction-1-carboxylic acid]; 2-methoxycarbonyl base-4-cyano group-4-(3-cyclo propyl methoxy-4-difluoro-methoxy phenyl) cyclohexane extraction-1-ketone; along [4-cyano group-4-(3-cyclopropyl-methoxyl group-4-difluoro-methoxy phenyl) cyclohexane extraction-1-alcohol]; (R)-(+) [4-(3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine-2-subunit] acetic acid-ethyl ester; (S)-(-) ethyl acetate-[4-(3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine-2-subunit]; CDP-840; Bay-198004; D-4418; PD-168787; T-440; T-2585; arofylline (arofyllin); Ah Ti helps nurse (atizoram); V-11294A; C1-1018; CDC-801; CDC-3052; D-22888; YM-58997; Z-15370; 9-cyclopenta-5; 6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo [3; 4-c]-1; 2; 4-triazol [4; 3-a] pyridine and 9-cyclopenta-5; 6-dihydro-7-ethyl-3-(tert-butyl group)-9H-pyrazolo [3; 4-c]-1; 2; 4-triazol [4; 3-a] pyridine, optional is its racemic modification; enantiomer; diastereomeric form and optional be its pharmaceutically acceptable acid addition salts; solvate and/or hydrate forms.
Spendable LTD4-antagonist is preferably selected from: montelukast, (((R)-((2-(6 for 3-for 1-, 7-two fluoro-2-quinolyls) phenyl vinyl))-and 3-(2-(2-hydroxyl-2-propyl group) phenyl) sulfenyl) methyl cyclopropane-acetic acid, ((((2-(2 for 3-in (R)-3 for 1-, 3-dichloro-thiophene also [3,2-b] piperidines-5-yl)-(E)-and vinyl) phenyl)-3-(2-(1-hydroxyl-1-Methylethyl) phenyl) propyl group) sulfenyl)-methyl) cyclopropane-acetic acid, pranlukast, zafirlukast, [2-[[2-(the 4-tert-butyl group-2-thiazolyl)-5-benzofuranyl] oxygen ylmethyl] phenyl] acetic acid, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707 and L-733321, optional is its racemic modification, enantiomer or diastereomeric form, choosing wantonly to pharmaceutically acceptable acid addition salts form and choosing wantonly is its salt and derivant, solvate and/or hydrate forms.
Spendable EGFR-inhibitors of kinases is preferably selected from: Cetuximab; trastuzumab; ABX-EGF; Mab ICR-62; 4-[(3-chloro-4-fluorophenyl) amino]-6-{[4-(morpholine-4-yl)-1-oxo-2-butylene-1-yl]-amino }-7-cyclo propyl methoxy-quinazoline; 4-[(R)-(1-phenyl-ethyl) amino]-6-{[4-(morpholine-4-yl)-1-oxo-2-butylene-1-yl]-amino }-7-cyclopentyloxy-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1-oxo-2-butylene-1-yl] amino }-7-[(S)-(oxolane-3-yl) oxygen base]-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-[2-((S)-6-methyl-2-oxo-morpholine-4-yl)-ethyoxyl]-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluorophenyl) amino]-6-(4-[N-(2-methoxyl group-ethyl)-N-methyl-amino]-1-oxo-2-butylene-1-yl } amino)-7-cyclo propyl methoxy-quinazoline; 4-[(R)-(1-phenyl-ethyl) amino]-6-(4-[N-(tetrahydropyran-4-base)-N-methyl-amino]-1-oxo-2-butylene-1-yl } amino)-7-cyclo propyl methoxy-quinazoline; 4-[(3-chloro-4-fluorophenyl) amino]-6-{[4-[N-(2-methoxyl group-ethyl)-N-methyl-amino]-1-oxo-2-butylene-1-yl } amino)-7-cyclopentyloxy-quinazoline; 4-[(3-chloro-4-fluorophenyl) amino]-6-{[4-(N; the N-dimethylamino)-and 1-oxo-2-butylene-1-yl] amino }-7-[(R)-(oxolane-2-yl) methoxyl group]-quinazoline; 4-[(3-acetenyl-phenyl) amino]-6; 7-pair-(2-methoxyl group-ethyoxyl)-quinazoline; 4-[(R)-(1-phenyl-ethyl) amino]-6-(4-hydroxyl-phenyl)-7H-pyrrolo-[2; 3-d] pyrimidine; 3-cyano group-4-[(3-chloro-4-fluorophenyl) amino]-6-{[4-(N; the N-dimethylamino)-and 1-oxo-2-butylene-1-yl] amino }-7-ethoxy yl-quinoline; 4-[(R)-(1-phenyl-ethyl) amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1-oxo-2-butylene-1-yl] amino }-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluorophenyl) amino]-6-{[4-(morpholine-4-yl)-1-oxo-2-butylene-1-yl] amino }-7-[(oxolane-2-yl) methoxyl group]-quinazoline; 4-[(3-acetenyl-phenyl) amino]-6-{[4-(5; 5-dimethyl-2-oxo-morpholine-4-yl)-and 1-oxo-2-butylene-1-yl] amino }-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-{2-[4-(2-4-oxo-morpholine-4-yl)-piperidines-1-yl]-ethyoxyl }-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-(anti--4-amino-cyclohexane extraction-1-base oxygen base)-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-(anti--4-mesyl amino-cyclohexane extraction-1-base oxygen base)-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-(tetrahydropyran-3-base oxygen base)-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-{1-[(morpholine-4-yl) carbonyl]-piperidin-4-yl-oxygen base }-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-(piperidines-3-base oxygen base)-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-[1-(2-acetylaminohydroxyphenylarsonic acid ethyl)-piperidin-4-yl oxygen base)-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-(tetrahydropyran-4-base oxygen base)-7-ethyoxyl-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-{ is anti--4-[(morpholine-4-yl) and carbonylamino]-cyclohexane extraction-1-base oxygen base }-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-{1-[(piperidines-1-yl) carbonyl]-piperidin-4-yl oxygen base }-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-(suitable-4-{N-[(morpholine-4-yl) carbonyl]-N-methyl-amino }-cyclohexane extraction-1-base oxygen base)-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-(anti--4-ethylsulfonylamino-cyclohexane extraction-1-base oxygen base)-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-(1-mesyl-piperidin-4-yl oxygen base)-7-(2-methoxyl group-ethyoxyl)-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-[1-(2-methoxyl group-acetyl group)-piperidin-4-yl oxygen base]-7-(2-methoxyl group-ethyoxyl)-quinazoline; 4-[(3-acetenyl-phenyl) amino]-6-(tetrahydropyran-4-base oxygen base)-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-(suitable-4-{N-[(piperidines-1-yl) carbonyl]-N-methyl-amino }-cyclohexane extraction-1-base oxygen base)-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-{ is suitable-4-[(morpholine-4-yl) and carbonylamino]-cyclohexane extraction-1-base oxygen base }-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-{1-[2-(2-oxo-pyrrolidine-1-yl) ethyl]-piperidin-4-yl oxygen base }-7-methoxyl group-quinazoline; 4-[(3-acetenyl-phenyl) amino]-6-(1-acetyl group-piperidin-4-yl oxygen base)-7-methoxyl group-quinazoline; 4-[(3-acetenyl-phenyl) amino]-6-(1-methyl-piperidin-4-yl oxygen base)-7-methoxyl group-quinazoline; 4-[(3-acetenyl-phenyl) amino]-6-(1-mesyl-piperidin-4-yl oxygen base)-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-(1-methyl-piperidin-4-yl oxygen base)-7-(2-methoxyl group-ethyoxyl)-quinazoline; 4-[(3-acetenyl-phenyl) amino]-6-{1-[(morpholine-4-yl) carbonyl]-piperidin-4-yl oxygen base }-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-{1-[(N-methyl-N-2-methoxy ethyl-amino) carbonyl]-piperidin-4-yl oxygen base }-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-(1-ethyl-piperidin-4-yl oxygen base)-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-[is suitable-4-(N-mesyl-N-methyl-amino)-cyclohexane extraction-1-base oxygen base]-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-[is suitable-4-(N-acetyl group-N-methyl-amino)-cyclohexane extraction-1-base oxygen base]-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-(anti--4-methylamino-cyclohexane extraction-1-base oxygen base)-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-[is anti--4-(N-mesyl-N-methyl-amino)-cyclohexane extraction-1-base oxygen base]-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-(anti--4-dimethylamino-cyclohexane extraction-1-base oxygen base)-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-(anti--4-{N-[(morpholine-4-yl) carbonyl]-N-methyl-amino }-cyclohexane extraction-1-base oxygen base)-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-[2-(2; 2-dimethyl-6-oxo-morpholine-4-yl)-ethyoxyl]-7-[(S)-(oxolane-2-yl) methoxyl group]-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-(1-mesyl-piperidin-4-yl oxygen base)-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-(1-cyano group-piperidin-4-yl oxygen base)-7-methoxyl group-quinazoline and 4-[(3-chloro-4-fluoro-phenyl) amino]-the 6-{1-[(2-methoxy ethyl) carbonyl]-piperidin-4-yl oxygen base }-7-methoxyl group-quinazoline; optional is its racemic modification; enantiomer or diastereomeric form, optional is its pharmaceutically acceptable acid addition salts; its solvate and/or hydrate forms.
These chemical compounds and pharmacology go up the formed acid-addition salts of acceptable acid and are meant that (for example) is selected from following salt: hydrochlorate, hydrobromate, hydriodate, sulfate, phosphate, mesylate, nitrate, maleate, acetate, benzoate, citrate, fumarate, tartrate, oxalates, succinate, benzoate and right-toluene fulfonate are preferably hydrochlorate, hydrobromate, disulfate, hydrophosphate, fumarate and mesylate.
The example of anti-allergic agent is: disodium cromoglycate, nedocromil.
The example of peptide is: dihydroergotamine, Ergotamine.
The example of the suitable material that sucks has medicine, pharmaceutical preparation and contains the mixture of above-mentioned active substance, and the combination of salt and ester and these active substances, salt and ester.
In preparation according to the present invention, which is formulated as and is formulated as suspension above-mentioned active substance solution and which, and this depends on the combination of active substance, and can be relative with the suspension experiment definite apace by solution.
In a preferred embodiment, one or more following active substances are suspended: budesonide, cromoglicic acid, nedocromil, reproterol and/or albuterol (salbutamol) (Aerolin (albuterol)), or by the ester of these compound derivings, salt and/or solvate, and with one or more following substance dissolves: beclometasone, fenoterol, ipratropium bromide, orciprenaline and/or oxitropium bromide, N-[[2,2-dimethyl-4-(oxo-2H-pyridine-1-yl)-6-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-yl] methyl]-N-hydroxyl-acetamide or by the ester of these compound derivings, salt and/or solvate.With the embodiment that contains two kinds of different activities materials serves as preferred.
Preferably, pharmaceutical preparation contains the combination that is selected from following active substance: beclometasone, budesonide, cromoglicic acid, fenoterol, flunisolide, fluticasone, ipratropium, nedocromil orciprenaline (nedocromil orciprenaline), oxitropium bromide, reproterol, albuterol, salmaterol (Aerolin), terbutaline, N-[[2,2-dimethyl-4-(2-oxo-2H-pyridine-1-yl)-6-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-yl] methyl]-N-hydroxyl-acetamide, its ester, salt and/or solvate.
A particularly preferred embodiment of pharmaceutical preparation comprises dissolved ipratropium bromide monohydrate, and especially the salbutamol sulfate (salbutamol sulphate) (Salbutamol (albuterol sulphate)) with conduct suspension active substance makes up.
In all embodiments, active substance is with the treatment effective dose, that is uses with the amount that successfully treatment can be provided.Adjust the concentration of active substance and spray the volume that is discharged at every turn so that once or only spray the described active substance of the amount that discharges the essential or recommendation of institute pharmaceutically several times.
An embodiment relates to preparation, and wherein suspended particles are stablized by adding surfactant.Even its advantage that has is that through long term (for example, between the storage life) it is pharmaceutically stable and acceptable that particle diameter still keeps.With the particle diameter that is at most 20 μ m serves as preferred, and the particle diameter between 5 μ m and the 15 μ m is especially preferred, and the best is no more than 10 μ m.The advantage of this particle diameter is that particle is enough little deep to lung to permeate, but can not be little of breathing out once more with the air of exchange.
Suitable surfactant comprises that all pharmacologys with lipophilic hydrocarbon and one or more hydrophilic functional groups go up acceptable material.That especially suitable is C
5-20-aliphatic alcohol, C
5-20-fatty acid, C
5-20-fatty acid ester, lecithin, glyceride, propylene glycol ester, polyoxyethylene, polysorbate, Isosorbide Dinitrate and/or sugar.Be preferably C
5-20-fatty acid, C
5-20The propylene glycol diesters of-fatty acid and/or triglyceride and/or Isosorbide Dinitrate, and especially be preferably C
5-20The sodium salt of-fatty acid or potassium salt, oleic acid and anhydro sorbitol list, two or trioleate, polyvinylpyrrolidone, polyvinyl alcohol, Sorbitan ethoxylate, polyoxyethylene glyceride, polyoxyethylene fatty acid ester, polyoxypropylene fatty acid ester, polyoxyethylene/polyoxypropylene block copolymers, alkyl polyglycoside, benzalkonium chloride and/or cetylpyridinium chloride.
Especially the best is polyvinylpyrrolidone K25 (Povidone
), the combination of polyoxyethylene-20-Arlacel-20, polyoxyethylene triolein or these surfactants.According to of the present invention especially preferred be polyoxyethylene-20-Arlacel-20 and polyoxyethylene triolein, it is commercially available and with brand name Tween
20 and Tagat
TO V can obtain.
Preferably with 0.001% to 5% (m/m), the concentration that especially is preferably 0.01% to 3% (m/m) exists this surfactant in preparation according to the present invention.
In particularly preferred embodiment of the present invention, one or more in the above-mentioned surfactant, preferred a kind of is with 0.02% to 0.2% (m/m), preferred 0.05% to 0.15% (m/m), the especially concentration of 0.1% (m/m) exist.
In another preferred alternate embodiment of the present invention, in the above-mentioned surfactant one or more, preferred a kind of is with 0.3% to 2.5% (m/m), preferred 0.4% to 2% (m/m), especially preferred 0.5% to 1.5% (m/m), more preferably 0.75% to 1.25% (m/m), the especially concentration of 1.0% (m/m) exist.
Another advantage of described surfactant is that it also can be used as valve lubricants.Therefore, an embodiment relates to preparation, wherein adds described surfactant as valve lubricants.
In another embodiment, the dissolubility for the treatment of dissolving active increases because of adding cosolvent.Its advantage that has is to treat the concentration preparation that dissolving active can be higher.The interpolation of cosolvent must not make liquid phase surpass critical polarity thresholds, surpasses this value, and then the active agent particle of Xuan Fuing one of can suffer in the above-mentioned shortcoming.
Suitable cosolvent is gone up acceptable alcohol such as ethanol, ester or water for the pharmacology, or its mixture; With ethanol is preferred.In total preparation, the concentration of cosolvent can be 0.0001% to 50% (m/m), is preferably 0.01% to 25% (m/m).In preferred embodiments, the concentration of cosolvent is 1% to 20% (m/m), is preferably 5% to 15% (m/m).The most particularly preferred those wherein the concentration of cosolvent be 8% to 12% (m/m), especially enclose 10% (m/m) according to preparation of the present invention.
The concentration of defined is based on the mass percent [%mm] of the quality of total preparation in the scope of the present invention.
In another embodiment, propellant gas other is commonly used is added in the HFA propellant gas.Except that other fluorinated hydrocarbons, the propellant gas that this type of added can be the saturated lower hydrocarbon as propane, butane, iso-butane or pentane, and its condition goes up safety for this mixture for the pharmacology.
In one embodiment, stabilizing agent is added in the preparation, even through long term (for example, between the storage life), it also advantageously influences the medicine stability of active substance.In the context of the present invention, the term stabilizing agent is meant by preventing or postponing indivedual compositions, especially active substance, but also refer to other additive, thus for example because of side reaction or the chemical change due to decomposing grow the property and the effect duration or prevent the material that biological pollution is prolonged for a long time late of pharmaceutical preparation.Under this meaning, preferred stabilizing agent influences the stabilizing agent of liquid phase as acid and/or its salt pH value for those.Especially suitable acid is hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, ascorbic acid, citric acid and salt thereof.The example of suitable antibacterial, antifungal etc. comprises benzalkonium chloride and disodium salt salt.Most preferably be citric acid.The concentration of aforementioned stable agent is preferably in the scope of 0.0001% to 0.02% (m/m), more preferably in the scope of 0.0005% to 0.01% (m/m).Especially preferred preparation according to the present invention contains the aforementioned stable agent that concentration is 0.001% to 0.008% (m/m), and the content of 0.002% to 0.006% (m/m), especially about 0.004% (m/m) is even more important according to the present invention.
Especially preferred embodiment comprises the salbutamol sulfate (salbutamol sulfate (albuterolsulphate)) of suspension, and dissolved ipratropium bromide is as the ethanol of cosolvent with as the citric acid of stabilizing agent.The concentration that these especially preferred preparations according to the present invention preferably contain the active substance salbutamol sulfate is 0.1% to 0.3% (m/m), especially is preferably 0.15% to 0.25% (m/m), more preferably 0.18% to 0.22% (m/m).The concentration that these especially preferred preparations according to the present invention also contain the ipratropium bromide monohydrate is preferably 0.02% to 0.05% (m/m), especially is preferably 0.03% to 0.04% (m/m).Be preferably especially according to those compositionss of the present invention, wherein the ratio of the above-mentioned concentration of two kinds of active substance salbutamol sulfates and ipratropium bromide monohydrate in the scope of 5:1 to 6:1, especially preferred in the scope of 5.5:1 to 5.9:1.Especially preferably the ratio of concentration that wherein is two kinds of active substance salbutamol sulfates and ipratropium bromide monohydrate in the scope of 5.60:1 to 5.85:1, especially in the scope of 5.70:1 to 5.80:1 according to compositions of the present invention.
In all embodiments, preparation is transferred to the suitable canister that is used for metered aerosol: canister is sealed with suitable metering valve.The example of suitable canister comprises Presspart Manufacturing Ltd., the rustless steel single measuring tank (DIN1.4539) that Blackburn UK makes, and its nominal volume is 17ml.Suitable metering valve for example comprises by Bespak Europe Ltd., King ' s Lynn, BK 357 or BK 361 that UK makes.
Preferably comprise pharmaceutical preparation according to metered aerosol of the present invention, this medicine comprises the combination that is selected from following active substance: beclometasone, budesonide, cromoglicic acid, fenoterol, flunisolide, fluticasone, ipratropium, nedocromil orciprenaline, oxitropium bromide, reproterol, albuterol, salmaterol (Aerolin), terbutaline, N-[[2,2-dimethyl-4-(2-oxo-2H-pyridine-1-yl)-6-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-yl] methyl]-N-hydroxyl-acetamide, its ester, salt and/or solvate.
The most particularly preferably, metered aerosol according to the present invention comprises pharmaceutical preparation, and this pharmaceutical preparation comprises the combination of active substance salbutamol sulfate (Salbutamol) and ipratropium bromide monohydrate.
Embodiment
Embodiment 1:
| Component | Quality/container [g] | Concentration [%m/m] |
| Salbutamol sulfate | 0.0312 | 0.210 |
| The ipratropium bromide monohydrate | 0.0055 | 0.037 |
| Dehydrated alcohol | 1.4824 | 10.000 |
| Polyoxyethylene-20-Arlacel-20 | 0.0741 | 0.500 |
| Anhydrous citric acid | 0.0006 | 0.004 |
| 1,1,1,2-tetrafluoroethane (HFA 134a) | 13.2302 | 89.249 |
| Amount to | 14.8240 | 100.00 |
Embodiment 2:
| Component | Quality/container [g] | Concentration [%m/m] |
| Salbutamol sulfate | 0.0312 | 0.211 |
| The ipratropium bromide monohydrate | 0.0055 | 0.037 |
| Dehydrated alcohol | 1.4818 | 10.000 |
| Polyoxyethylene-20-Arlacel-20 | 0.1482 | 1.000 |
| Anhydrous citric acid | 0.0006 | 0.004 |
| 1,1,1,2-tetrafluoroethane (HFA 134a) | 13.1508 | 88.749 |
| Amount to | 14.81800 | 100.000 |
Embodiment 3:
| Component | Quality/container [g] | Concentration [%m/m] |
| Salbutamol sulfate | 0.0312 | 0.211 |
| The ipratropium bromide monohydrate | 0.0055 | 0.037 |
| Dehydrated alcohol | 1.4805 | 10.000 |
| Polyoxyethylene-20-Arlacel-20 | 0.2961 | 2.000 |
| Anhydrous citric acid | 0.0006 | 0.004 |
| 1,1,1,2-tetrafluoroethane (HFA 134a) | 12.9912 | 87.748 |
| Amount to | 14.8050 | 100.000 |
Embodiment 4:
| Component | Quality/container [g] | Concentration [%m/m] |
| Salbutamol sulfate | 0.0312 | 0.185 |
| The ipratropium bromide monohydrate | 0.0055 | 0.032 |
| Dehydrated alcohol | 1.6874 | 10.000 |
| Polyoxyethylene-20-Arlacel-20 | 0.0844 | 0.500 |
| Anhydrous citric acid | 0.0007 | 0.004 |
| 1,1,1,2,3,3,3-heptafluoro-propane (HFA 227) | 15.0649 | 89.279 |
| Amount to | 16.87400 | 100.000 |
Embodiment 5:
| Component | Quality/container [g] | Concentration [%m/m] |
| Salbutamol sulfate | 0.0312 | 0.185 |
| The ipratropium bromide monohydrate | 0.0055 | 0.032 |
| Dehydrated alcohol | 1.6853 | 10.000 |
| Polyoxyethylene-20-Arlacel-20 | 0.1685 | 1.000 |
| Anhydrous citric acid | 0.0007 | 0.004 |
| 1,1,1,2,3,3,3-heptafluoro-propane (HFA 227) | 14.9618 | 88.778 |
| Amount to | 16.85300 | 100.000 |
Embodiment 6:
| Component | Quality/container [g] | Concentration [%m/m] |
| Salbutamol sulfate | 0.0312 | 0.186 |
| The ipratropium bromide monohydrate | 0.0055 | 0.032 |
| Dehydrated alcohol | 1.6810 | 10.000 |
| Polyoxyethylene-20-Arlacel-20 | 0.3362 | 2.000 |
| Anhydrous citric acid | 0.0007 | 0.004 |
| 1,1,1,2,3,3,3-heptafluoro-propane (HFA 227) | 14.7555 | 87.778 |
| Amount to | 16.81000 | 100.000 |
Embodiment 7:
| Component | Quality/container [g] | Concentration [%m/m] |
| Salbutamol sulfate | 0.0312 | 0.210 |
| The ipratropium bromide monohydrate | 0.0055 | 0.037 |
| Dehydrated alcohol | 1.4824 | 10.000 |
| The polyoxyethylene triolein | 0.0741 | 0.500 |
| Anhydrous citric acid | 0.0006 | 0.004 |
| 1,1,1,2-tetrafluoroethane (HFA 134a) | 13.2302 | 89.249 |
| Amount to | 14.8240 | 100.000 |
Embodiment 8:
| Component | Quality/container [g] | Concentration [%m/m] |
| Salbutamol sulfate | 0.0312 | 0.211 |
| The ipratropium bromide monohydrate | 0.0055 | 0.037 |
| Dehydrated alcohol | 1.4818 | 10.000 |
| The polyoxyethylene triolein | 0.1482 | 1.000 |
| Anhydrous citric acid | 0.0006 | 0.004 |
| 1,1,1,2-tetrafluoroethane (HFA 134a) | 13.1508 | 88.749 |
| Amount to | 14.81800 | 100.000 |
Embodiment 9:
| Component | Quality/container [g] | Concentration [%m/m] |
| Salbutamol sulfate | 0.0312 | 0.211 |
| The ipratropium bromide monohydrate | 0.0055 | 0.037 |
| Dehydrated alcohol | 1.4805 | 10.000 |
| The polyoxyethylene triolein | 0.2961 | 2.000 |
| Anhydrous citric acid | 0.0006 | 0.004 |
| 1,1,1,2-tetrafluoroethane (HFA 134a) | 12.9912 | 87.748 |
| Amount to | 14.8050 | 100.000 |
Embodiment 10:
| Component | Quality/container [g] | Concentration [%m/m] |
| Salbutamol sulfate | 0.0312 | 0.185 |
| The ipratropium bromide monohydrate | 0.0055 | 0.032 |
| Dehydrated alcohol | 1.6874 | 10.000 |
| The polyoxyethylene triolein | 0.0844 | 0.500 |
| Anhydrous citric acid | 0.0007 | 0.004 |
| 1,1,1,2,3,3,3-heptafluoro-propane (HFA 227) | 15.0649 | 89.279 |
| Amount to | 16.87400 | 100.000 |
Embodiment 11:
| Component | Quality/container [g] | Concentration [%m/m] |
| Salbutamol sulfate | 0.0312 | 0.185 |
| The ipratropium bromide monohydrate | 0.0055 | 0.032 |
| Dehydrated alcohol | 1.6853 | 10.000 |
| The polyoxyethylene triolein | 0.1685 | 1.000 |
| Anhydrous citric acid | 0.0007 | 0.004 |
| 1,1,1,2,3,3,3-heptafluoro-propane (HFA 227) | 14.9618 | 88.778 |
| Amount to | 16.85300 | 100.000 |
Embodiment 12:
| Component | Quality/container [g] | Concentration [%m/m] |
| Salbutamol sulfate | 0.0312 | 0.186 |
| The ipratropium bromide monohydrate | 0.0055 | 0.032 |
| Dehydrated alcohol | 1.6810 | 10.000 |
| The polyoxyethylene triolein | 0.3362 | 2.000 |
| Anhydrous citric acid | 0.0007 | 0.004 |
| 1,1,1,2,3,3,3-heptafluoro-propane (HFA 227) | 14.7555 | 87.778 |
| Amount to | 16.81000 | 100.000 |
Claims (24)
1. be used to have the pharmaceutical preparation of fluorinated hydrocarbons (HFA) as the metered aerosol of the propellant actuated of propellant, it contains the combination and at least a surfactant of two kinds or various active material, and it is characterized in that at least a active substance is is to exist with the suspended particles form with dissolved form and at least a other active substance.
2. the pharmaceutical preparation of claim 1 is characterized in that described active substance combination is made up of two kinds of active substances.
3. the pharmaceutical preparation one of in the aforementioned claim is characterized in that described propellant is TG134a and/or TG227.
4. the pharmaceutical preparation one of in the aforementioned claim is characterized in that described preparation contains cosolvent.
5. the pharmaceutical preparation of claim 4 is characterized in that described cosolvent contains one or more pharmacologys and goes up acceptable alcohol, the last acceptable ester of pharmacology, water or its mixture.
6. the pharmaceutical preparation of claim 4 is characterized in that described cosolvent is an ethanol.
7. claim 4,5 or 6 pharmaceutical preparation is characterized in that, in total preparation, described cosolvent is that the concentration with 0.0001% to 50% (m/m) exists.
8. the pharmaceutical preparation of claim 7 is characterized in that, in total preparation, described cosolvent is with 5% to 15% (m/m), and the concentration of preferred 8% to 12% (m/m) exists.
9. the pharmaceutical preparation one of in the claim 1 to 8 is characterized in that described preparation is undertaken stable by stabilizing agent.
10. the pharmaceutical preparation of claim 9 is characterized in that described stabilizing agent comprises one or more acid and/or its salt.
11. the pharmaceutical preparation of claim 9 is characterized in that described stabilizer package is hydrochloric, sulphuric acid, nitric acid, phosphoric acid, ascorbic acid, citric acid, benzalkonium chloride and/or disodium salt, and/or its salt.
12. the pharmaceutical preparation of claim 9 is characterized in that described stabilizing agent is a citric acid.
13. the pharmaceutical preparation one of in the claim 9,10,11 or 12 is characterized in that in total preparation, described stabilizing agent is with 0.0001% to 0.02% (m/m), the concentration of preferred 0.0005% to 0.01% (m/m) exists.
14. the pharmaceutical preparation of claim 13 is characterized in that, in total preparation, described stabilizing agent is with 0.0001% to 0.008% (m/m), and the concentration of preferred 0.002% to 0.006% (m/m) exists.
15. the pharmaceutical preparation one of among the aforementioned claim 1-14 is characterized in that described preparation contains at least a surfactant.
16. the pharmaceutical preparation of claim 15 is characterized in that described surfactant is C
5-20The sodium salt of-fatty acid or potassium salt, oleic acid, polyvinylpyrrolidone, polyvinyl alcohol, Sorbitan ethoxylate, polyoxyethylene glyceride, polyoxyethylene fatty acid ester, polyoxypropylene fatty acid ester, polyoxyethylene/polyoxypropylene block copolymers, alkyl polyglycoside, benzalkonium chloride or cetylpyridinium chloride, or the combination of these surfactants.
17. the pharmaceutical preparation of claim 15 is characterized in that described surfactant is polyvinylpyrrolidone K25, polyoxyethylene-20-Arlacel-20 or polyoxyethylene triolein, or the combination of these surfactants.
18. claim 15,16 or 17 pharmaceutical preparation is characterized in that described surfactant with between 0.001% and 5% (m/m), preferably exists with the concentration between 0.01% to 3% (m/m).
19. the pharmaceutical preparation of claim 18 is characterized in that described surfactant is with between 0.02% to 0.2% (m/m), preferably exist with the concentration between 0.05% to 0.15% (m/m).
20. the pharmaceutical preparation of claim 18 is characterized in that described surfactant is with 0.3% to 2.5% (m/m), preferred 0.4% to 2% (m/m), and preferred especially 0.5% to 1.5% (m/m), more preferably the concentration of 0.75% to 1.25% (m/m) exists.
21. the pharmaceutical preparation one of in the aforementioned claim is characterized in that described active substance combination comprises that one or more are selected from following active substance: anticholinergic, β simulant, steroid, phosphodiesterase IV inhibitors, LTD4-antagonist, EGFR-inhibitors of kinases, anti-allergic agent, peptide derivant, Qu Putan, CGRP antagonist and phosphodiesterase-V inhibitor.
22. the pharmaceutical preparation one of in the aforementioned claim, it is characterized in that described active substance combination comprises beclometasone, budesonide, cromoglicic acid, fenoterol, flunisolide, fluticasone, ipratropium, nedocromil orciprenaline, oxitropium bromide, reproterol, albuterol, salmaterol (Aerolin), terbutaline, N-[[2,2-dimethyl-4-(oxo-2H-pyridine-1-yl)-6-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-yl] methyl]-N-hydroxyl-acetamide, its ester, salt and/or solvate.
23. the pharmaceutical preparation one of in the claim is characterized in that as described above, it contains the active substance combination of salbutamol sulfate (Salbutamol) and ipratropium bromide monohydrate.
24. metered aerosol, it contains the pharmaceutical preparation just like one of among the claim 1-23.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102006006207 | 2006-02-09 | ||
| DE102006006207.8 | 2006-02-09 | ||
| DE102006053374.7 | 2006-11-10 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210380794XA Division CN102861339A (en) | 2006-02-09 | 2007-02-06 | Pharmaceutical composition for aerosols with two or more active substances and at least one surfactant |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101384248A true CN101384248A (en) | 2009-03-11 |
Family
ID=40463718
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800051054A Pending CN101384248A (en) | 2006-02-09 | 2007-02-06 | Pharmaceutical formulation for aerosols, comprising two or more active agents and at least one surfactant |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN101384248A (en) |
| UA (1) | UA93540C2 (en) |
| ZA (1) | ZA200805938B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670505A (en) * | 2011-03-17 | 2012-09-19 | 益得生物科技股份有限公司 | Process for preparing quantitative spray inhalant for treating respiratory diseases |
| CN103655473A (en) * | 2011-10-27 | 2014-03-26 | 江苏长风药业有限公司 | Budesonide aerosol preparation with hydrofluoroalkane used as propellant |
| CN106038489A (en) * | 2016-05-25 | 2016-10-26 | 华润双鹤药业股份有限公司 | Ipratropium bromide aerosol |
-
2007
- 2007-02-06 CN CNA2007800051054A patent/CN101384248A/en active Pending
- 2007-02-06 UA UAA200810893A patent/UA93540C2/en unknown
-
2008
- 2008-07-08 ZA ZA200805938A patent/ZA200805938B/en unknown
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670505A (en) * | 2011-03-17 | 2012-09-19 | 益得生物科技股份有限公司 | Process for preparing quantitative spray inhalant for treating respiratory diseases |
| CN102670505B (en) * | 2011-03-17 | 2017-05-24 | 益得生物科技股份有限公司 | Process for preparing quantitative spray inhalant for treating respiratory diseases |
| CN103655473A (en) * | 2011-10-27 | 2014-03-26 | 江苏长风药业有限公司 | Budesonide aerosol preparation with hydrofluoroalkane used as propellant |
| CN106038489A (en) * | 2016-05-25 | 2016-10-26 | 华润双鹤药业股份有限公司 | Ipratropium bromide aerosol |
| CN106038489B (en) * | 2016-05-25 | 2018-11-02 | 华润双鹤药业股份有限公司 | Ipratropium Bromide aerosol |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200805938B (en) | 2009-06-24 |
| UA93540C2 (en) | 2011-02-25 |
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