CN1984642A - Aerosol suspension formulations containing TG 227 ea or TG 134 a as a propellant - Google Patents

Abstract

The invention is directed to a propellant preparation containing at least a suspended active component, the propellant preparation comprises chemically bound water, water and propellant TG227 or TG134a.

Description

Comprise TG227ea or TG134a aerosol suspension formulations as propellant

Technical field that the present invention belongs to

The invention relates to the gas-pressurized preparation of dosing aerosols, wherein will be at TG227ea (1,1,1 as propellant, 2,3,3, the 3-heptafluoro-propane) or TG134a (1,1,1,2-tetrafluoroethane) a kind of medicament in is mixed with suspension, and is used to prepare the purposes of medicament about it.The present invention is preferably about a kind of imbedibility aerosol.

Prior art

Since people carry out open debate to some Chlorofluorocarbons (CFCs) that may destroy ozone, done a lot of work in the field of the alternative propellant that is used for medical dosing aerosols.Since nineteen ninety, known propellant gas TG227ea or TG134a can be used as alternative propellant gas and are used for aerosol.

Now be surprised to find,, then can stablize the active material particle that contains suspension and as the TG227ea of propellant or the propellant gas preparation of TG134a if contain a certain amount of water in propellant gas or the propellant gas mixture.

Detailed Description Of The Invention

Propellant formulation of the present invention uses TG227ea and/or TG134a as propellant gas, and it can be chosen wantonly with one or more other propellant gas and mix, and these other propellant gas are preferably selected from propane, butane, pentane, dimethyl ether, CHClF ₂, CH ₂F ₂, CF ₃CH ₃, iso-butane, isopentane and neopentane.

Preferred float of the present invention is that it only contains TG227ea or only contains the suspension of TG134a as propellant gas.

If suspension formulation of the present invention uses the mixture of propellant gas TG227ea and TG134a, then the part by weight of wherein employed these two kinds of propellant gas compositions can freely change, but wherein must have TG227ea.

(be selected from propane, butane, pentane, dimethyl ether, CHClF having one or more other propellant gas ₂, CH ₂F ₂, CF ₃CH ₃, iso-butane, isopentane and neopentane) mixture in, the component of this other propellant gas preferably is less than 60%, preferable be less than 40% and the best be less than 30%.

Employed active substance preferably mixes in its particle structure or in conjunction with the active substance of one or more hydrones.But water is not only that physical property is mixed with the particle of active substance.Preferably, active material particle is that crystal and this water are the bonded water of water of crystallization or complexation or with the bonded water of other chemical modes, for example hydrate.The form that this water mixes is also referred to as hereinafter with the bonded water of chemical mode.In this case, water also influences the crystalline texture of active substance molecule usually.

Preferably use, thereby suspension formulation of the present invention is preferably clearly used for sucking with the suction compounds effective.

In this case, particularly preferred relevant medicament is selected from following: the derivant of anticholinergic agent, betamimetics medicine (betamimetics), steroid, phosphodiesterase IV inhibitors, LTD4-antagonist and EGFR-inhibitors of kinases, antiallergic agent, ergotin, triptan medicine (triptanes), CGRP antagonist, phosphodiesterase-V inhibitor, and the compositions of these active substances, for example the betamimetics medicine adds anticholinergic agent or the betamimetics medicine adds antiallergic agent.If combining form, then at least a active substance is with the chemical mode bound water.The preferred active substance that contains anticholinergic agent that uses with unitary agent or combination preparation form.

Details are as follows for the instantiation of these active ingredients or its salt:

Employed anticholinergic agent is preferably selected from tiotropium bromide (tiotropium bromide), oxitropium bromide (oxiotropium bromide), flutropium bromide (flutropium bromide), ipratropium bromide (ipratropiumbromide), glycopyrronium salt (glycopyrronium salts), spasmex (trospium chloride), tolterodine (tolterodine), 2,2-diphenyl-propionic acid tropine alcohol ester first bromine, 2,2-diphenyl-propionic acid Di(2-thienyl)glycolic acid scopine ester. first bromine, 2-fluoro-2,2-diphenyl acetic acid Di(2-thienyl)glycolic acid scopine ester. first bromine, 2-fluoro-2,2-diphenyl acetic acid tropine alcohol ester first bromine, 3,3 ', 4,4 ' tetrafluoro benzilic acid tropine alcohol ester first bromine, 3,3 ', 4,4 '-difluorodiphenyl base glycolic Di(2-thienyl)glycolic acid scopine ester. first bromine, 4,4 '-difluorodiphenyl base glycolic tropine alcohol ester first bromine, 4,4 '-difluorodiphenyl base glycolic Di(2-thienyl)glycolic acid scopine ester. first bromine, 3,3 '-difluorodiphenyl base glycolic tropine alcohol ester first bromine, 3,3 '-tetrafluoro benzilic acid Di(2-thienyl)glycolic acid scopine ester. first bromine, 9-hydroxyl-fluorenes-9-formic acid tropine alcohol ester first bromine, 9-fluoro-fluorenes-9-carboxylic acid tropine alcohol ester first bromine, 9-hydroxyl-fluorenes-9-carboxylic acid scopine alcohol ester first bromine, 9-fluoro-fluorenes-9-carboxylic acid Di(2-thienyl)glycolic acid scopine ester. first bromine, 9-methyl-fluorenes-9-carboxylic acid tropine alcohol ester first bromine, 9-methyl-fluorenes-9-carboxylic acid Di(2-thienyl)glycolic acid scopine ester. first bromine, benzilic acid cyclopropyl tropeine first bromine, 2,2-diphenyl-propionic acid cyclopropyl tropeine first bromine, 9-hydroxyl-xanthene-9-carboxylic acid cyclopropyl tropeine first bromine, 9-methyl-fluorenes-9-carboxylic acid cyclopropyl tropeine first bromine, 9-methyl-xanthene-9-carboxylic acid cyclopropyl tropeine first bromine, 9-hydroxyl-fluorenes-9-carboxylic acid cyclopropyl tropeine first bromine, 4,4 '-difluorodiphenyl base glycolic methyl ester cyclopropyl tropeine first bromine, 9-hydroxyl-xanthene-9-carboxylic acid tropine alcohol ester first bromine, 9-hydroxyl-xanthene-9-carboxylic acid Di(2-thienyl)glycolic acid scopine ester. first bromine, 9-methyl-cluck ton-9-carboxylic acid tropine alcohol ester first bromine, 9-methyl-xanthene-9-carboxylic acid Di(2-thienyl)glycolic acid scopine ester. first bromine, 9-ethyl-xanthene-9-carboxylic acid tropine alcohol ester first bromine, 9-difluoromethyl-xanthene-9-carboxylic acid tropine alcohol ester first bromine and 9-hydroxymethyl-xanthene-9-carboxylic acid Di(2-thienyl)glycolic acid scopine ester. first bromine, optional its raceme that is, enantiomer or diastereomeric form and optional its solvate and/or the hydrate forms of being.

Spendable betamimetics medicine is preferably selected from albuterol (albuterol); bambuterol (bambuterol); Bitolterol (bitolterol); special sieve (broxaterol) of bromine ; Bronsecur (carbuterol); clenbuterol (clenbuterol); fenoterol (fenoterol); formoterol (formoterol); hexoprenaline (hexoprenaline); terbutaline diisobutyrate (ibuterol); neoisuprel (isoetharine); isoproterenol (isoprenaline); Levalbuterol (1evosalbutamol); Mabuterol (mabuterol); meluadrine (meluadrine); orciprenaline (metaproterenol); alotec (orciprenaline); pirbuterol (pirbuterol); Meptin (procaterol); sharp sieve Pood (reproterol); rimiterol (rimiterol); ritodrine (ritodrine); salmaterol (salmeterol); salmefamol; MJ-1992 (soterenot); sulfonterol (sulphonterol); tiaramide (tiaramide); terbutaline; special sieve (tolubuterol) of holder infectious coryza; CHF-1035; HOKU-81; KUL-1248; 3-(4-{6-[2-hydroxyl-2-(4-hydroxyl-3-hydroxymethyl-phenyl)-ethylamino]-hexyl oxygen base }-butyl) benzene-sulfonamide; 5-[2-(5; 6-diethyl-dihydro indenes-2-base is amino)-l-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-benzoxazine-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-benzoxazine-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propyl group amino] ethanol; 1-[2H-5-hydroxyl-3-oxo-4H-1,4-benzoxazine-8-yl]-2-[3-(4-normal-butyl oxygen base phenyl)-2.Methyl-2-propyl group amino] ethanol, 1-[2H-5-hydroxyl-3-oxo-4H-1,4-benzoxazine-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-benzoxazine-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 its raceme that is, enantiomer or diastereomeric form and optional its pharmaceutically acceptable acid-addition salts that is, solvate and/or hydrate forms.

Spendable steroid is preferably selected from prednisolone (prednisolone), prednisone (prednisone), propanoic acid butixocort (butixocortpropionate), RPR-106541,9-removes fluorine topsyne (flunisolide), beclometasone (beclomethasone), omcilon, budesonide (budesonide), Fluticasone (fluticasone), Mo Mitasong (mometasone), strop Maimonides (ciclesonide), sieve fluorine Maimonides (rofleponide), St-126, dexamethasone (dexamethasone), (S)-methyl fluoride 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-thiono acid esters, (S)-(2-oxo-tetrahydrochysene-furan-3S-yl) 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha--methyl-3-oxo-17 α-propionyl oxygen-androstane-1,4-diene-17 β-thiono acid esters reaches for general many alcohol (etiprednol)-dichloroacetic acid esters (BNP-166), optional its racemate that is, enantiomer or diastereomeric form and optional its salt and the derivant of being, solvate and/or hydrate forms.

Spendable PDE IV inhibitor be preferably selected from enprofylline (enprofyllin), aminophylline (theophyllin), roflumilast (roflumilast), cilomilast (ariflo) (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-two-fluorine methoxyl group-3-cyclo propyl methoxy Benzoylamide, NCS-613, Pu Mafenting (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 Benzoylamide, (R)-(+)-1-(4-Brombenzyl)-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 group-4-cyano group-4-(3-cyclo propyl methoxy-4-two-fluorine methoxyphenyl) cyclohexane extraction-1-ketone, along [4-cyano group-4-(3-cyclo propyl methoxy-4-difluoro-methoxy phenyl) cyclohexane extraction-1-alcohol], (R)-(+)-ethyl [4-(3-cyclopenta oxygen-4-methoxyphenyl) pyrrolidine-2-subunit] acetas, (S)-(-)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine-2-subunit] acetas, CDP840, Bay-198004, D-4418, PD-168787, T-440, T-2585, Bimbisara theophylline (arofyllin), Ah Ti assistant south (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 its racemate that is, enantiomer or diastereoisomer form and optional its pharmaceutically acceptable acid-addition salts that is, solvate and/or hydrate forms.

Spendable LTD4-antagonist is preferably selected from montelukast (Montelukast), 1 (((R)-((2-(6 for 3-, 7-two fluoro-2-quinolyls) phenyl vinyl))-and 3-(2-(2-hydroxyl-2-propyl group) phenyl) sulfo-) methyl cyclopropane-acetic acid, 1 (((1 (R)-((2-(2 for 3-, 3-dichloro-thiophene also [3,2-b] pyridine-5-yl)-(E)-and vinyl) phenyl)-3-(2-(1-hydroxyl-1-Methylethyl) phenyl) propyl group) sulfo-) methyl) cyclopropaneacetic acid, pranlukast (pranlukast), zafirlukast (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 its racemate that is, enantiomer or diastereomeric form, optional its pharmaceutically acceptable acid-addition salts form and optional its salt and the derivant of being of being, solvate and/or hydrate forms.

Spendable EGFR-inhibitors of kinases is preferably selected from western native Xidan anti-(cetuximab); Qu Sizuo monoclonal antibody (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-ethyoxyl-quinazoline; 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-oxo-morpholine-4-yl)-piperidines-1-yl]-ethyoxyl }-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluorophenyl) 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-methane sulfonyl amino-cyclohexane extraction-1-base oxygen base)-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluorophenyl) 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-acetyl-amino-ethyl)-piperidin-4-yl oxygen base]-7-methoxyl group-quinazoline; 4-[(3-chloro-4-fluoro-phenyl) amino]-6-(oxolane-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-(oxolane-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 its racemate that is; enantiomer or diastereomeric form, optional its pharmaceutically acceptable acid-addition salts that is; solvate and/or hydrate forms.

Situation at these chemical compounds and the formed acid-addition salts of pharmaceutically acceptable acid, for example, be selected from the salt of following acid: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfate, phosphoric acid, Loprazolam, nitric acid, maleic acid, acetic acid, benzoic acid, citric acid, fumaric acid, tartaric acid, oxalic acid, succinic acid, benzoic acid and tosilate are preferably hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid, fumaric acid and Loprazolam.

The example of anti-allergic agent: disodium cromoglycate, nedocromil (nedocromil).

The example of ergotin is: dihydroergotamine, Ergotamine.

The example that is suitable for sucking is the pharmaceutical composition that contains the compositions of above-mentioned active substance and salt, ester and these active substances, its salt and ester.

The share of the suspended drug in the final preparation is between 0.001 and 5%, between preferred 0.005 to 3%, is in particular 0.01 to 2%.Add surfactant amount be 0.01 to 10%, preferred 0.05 to 5%, be in particular 0.05 to 3% (%=percentage by weight).

If the ipratropium bromide monohydrate, float then of the present invention preferably contains between 0.001 to 1%, special 0.005 to 0.5% ipratropium.Particularly preferably be the float that contains 0.01 to 0.1% ipratropium according to the present invention.

If albuterol and salt thereof, float then of the present invention preferably contain between 0.005 to 5% and 0.025 to 2.5% albuterol particularly.The particularly preferred float that contains 0.05 to 1% albuterol according to the present invention.

If tiotropium bromide monohydrate, float then of the present invention preferably contain between 0.001 to 1% and 0.0012 to 0.8% tiotropium particularly.Preferably contain 0.002 to 0.5% and the float of preferred especially 0.008 to 0.4% tiotropium according to the present invention.

All active substances, for example tiotropium or ipratropium are meant the free ammonium cation under each situation.The feature of propellant gas float of the present invention is that it contains tiotropium or the ipratropium that is the crystalline monohydrate form.Therefore, the present invention is preferably about containing the float of crystallization tiotropium bromide monohydrate or ipratropium bromide monohydrate.The tiotropium bromide monohydrate float that contains 0.001 to 0.62% and especially good 0.002 to 0.5 and especially most preferably 0.002 to 0.06 crystallization tiotropium bromide monohydrate attracts people's attention especially.

Described within the scope of the present invention degree is mass percent all the time.If the mass content of tiotropium is expressed with mass percent, then the respective value of the preferred crystallization tiotropium bromide monohydrate that uses obtains by multiply by conversion factor 1.2495 within the scope of the present invention.This is equally applicable to ipratropium.

If use anhydrous propellant gas, then can in anhydrous propellant gas, add low amounts of water according to the present invention.Yet, also can use moisture propellant gas according to the present invention, propellant gas has specific water content when it uses.The water that adds in the final suspension blender or exist one of be different from active substance or excipient with the bonded water of chemical mode.Within the scope of the present invention, non-chemically the bonded water of mode also refers to free water, to distinguish itself and active substance with molecule or chemically combined water.

Find that the suspended particles of active substance can change when low when water content is crossed.On the other hand, found that then particle diameter also changes if water content is too high.Can determine the optimum water concentration of every kind of material respectively.Find, generally speaking, propellant gas TG227ea or TG227ea and be selected from propane, butane, pentane, dimethyl ether, CHClF ₂, CH ₂F ₂, CF ₃CH ₃, iso-butane, isopentane and neopentane the mixture of propellant gas in preferred water content be generally 10 to 1000ppm, preferred especially 50 to 500ppm, especially most preferred water content is 100 to 450ppm.

If contain the preparation and the propellant gas TG227ea of ipratropium bromide monohydrate, then the optimum water concentration of said preparation be 20 and 500ppm between, and water content be preferably especially 50 and 350ppm between.

If the tiotropium bromide monohydrate, then the water content of preferred water content and ipratropium bromide monohydrate is suitable.Its optimum range be for 50 and 230ppm between.

Also find propellant gas TG134a or TG134a and be selected from propane, butane, pentane, dimethyl ether, CHClF ₂, CH ₂F ₂, CF ₃CH ₃, iso-butane, isopentane and neopentane the mixture of propellant gas in preferred water content be 30 and 4000ppm between, be preferably especially 150 and 2000ppm between and especially most preferably be 350 and 1700ppm between.

If contain the preparation of ipratropium monohydrate and propellant gas TG134a, then the optimum water concentration of said preparation be 70 and 1800ppm between, particularly, this water content be 180 and 1300ppm between.

If the tiotropium monohydrate, then preferred water content is similar to the preferable water content of ipratropium bromide.Optimum range be 180 and 900ppm between.

If use the mixture of propellant gas TG134a and TG227ea, then preferred water content can obtain by the blending ratio of these two kinds of propellant gas.

According to the present invention, have only active substance not have other any water (free water) as propellant gas, propellant gas mixture or preparation with the bonded water of chemical mode, then in propellant gas or final aerosol suspension thing, add the water of this amount.In this method, can before the drug suspension preparation, in propellant gas, sneak into water, or can use anhydrous propellant gas or propellant gas mixture to prepare drug suspension earlier, sneak into the water of respective amount then.

The amount that provides with ppm is as the reference amount according to liquefied propellant.

Within the scope of the present invention, the term suspension formulation can use the term float.Two terms can be considered and are equal within the scope of the present invention.

Imbedibility aerosol or the suspension formulation that contains propellant gas of the present invention also can contain other compositions, for example surfactant (surfactant), adjuvant, antioxidant or flavoring agent.

Choose wantonly and be that surfactant contained in the float of the present invention is preferably selected from following material: polysorbate ester 20, polysorbate80, Myvacet9-45, Myvacet9-08, isopropyl myristate, oleic acid, propylene glycol, Polyethylene Glycol, Brij (Brij), ethyl oleate, glycerol trioleate, glyceryl monolaurate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, oleic acid oleic alcohol ester, stearyl alcohol, cetylpyridinium chloride , block polymer, natural oil, ethanol and isopropyl alcohol.Preferred polysorbate20, polysorbate80, Myvacet9-45, Myvacet9-08 or the isopropyl myristate of using in the above-mentioned suspension adjuvant.Best Myvacet9-45 or the isopropyl myristate of using.

If float of the present invention contains surfactant, then the consumption of these surfactants is preferred 0.0005 to 1%, especially preferably 0.005 to 0.5%.

The optional adjuvant that contains is preferably selected from following material in the float of the present invention: alanine, albumin, ascorbic acid, aspartame, betanin, aminothiopropionic acid, phosphoric acid, nitric acid, hydrochloric acid, sulphuric acid and citric acid.Preferred ascorbic acid, phosphoric acid, hydrochloric acid or the citric acid of using, best hydrochloric acid or the citric acid of using.

As containing adjuvant in the float of the present invention, then the consumption of these adjuvants is preferably 0.0001 to 1.0%, and is preferred 0.0005 to 0.1%, preferred especially 0.001 to 0.01%, and the amount that is even more important according to the present invention is 0.001 to 0.005%.

The optional antioxidant that contains is preferably selected from following material in the float of the present invention: ascorbic acid, citric acid, sodium ethylene diamine tetracetate, ethylenediaminetetraacetic acid, tocopherol, fourth hydroxy-methylbenzene, BHA and ascorbic palmitate, preferably use tocopherol, fourth hydroxy-methylbenzene, BHA or ascorbic palmitate.

The optional flavoring agent that contains is preferably selected from Herba Menthae, glucide, Dentomint , aspartame and etherificate oil (for example Cortex Cinnamomi, Fructus Anisi Stellati, menthol, Camphora) in the float of the present invention, particularly preferably is Herba Menthae or Dentomint .

For with the suction dispenser, importantly provide the active substance that is atomic thin form.For reaching this purpose, both can also can use additive method well known in the prior art (for example precipitating spray drying) to obtain to be the active substance of fine form by grinding (micronization).The method of micronization active substance is well known in the prior art.This active substance preferably has 0.5 to 10 micron mean diameter behind the micronization, preferable 1 to 6 micron, is preferably 1.5 to 5 microns especially.Preferably at least 50%, preferably at least 60%, preferred at least 70% active material particle has the particle diameter that is in above-mentioned particle size range especially.Especially preferably at least 80%, most preferably at least 90% active material particle has the particle diameter that is in above-mentioned particle size range.

Be surprised to find and also can prepare the float that except above-mentioned propellant gas, only contains one or more active substances and do not contain other additives.Therefore, another aspect of the present invention is about only containing one or more active substances and not having the float of other additives.

Can use method well known in the prior art to prepare float of the present invention.For this reason, the component of this prescription is mixed with one or more propellant gas (choosing wantonly under low temperature) and the appropriate vessel of packing in.

Can use inhaler well known in the prior art (dose inhaler that pMDI=is pressurised metered) administration the invention described above to contain the float of propellant gas.Therefore, another aspect of the present invention be about as be suitable for the pharmaceutical composition that is aerosol form mentioned above of inhalers combination of these float with one or more.In addition, the present invention relates to inhaler, it is characterized in that it contains the float that contains propellant gas of the present invention mentioned above.

The invention still further relates to the container (for example medicine box) that is equipped with valve suitable and that regulate according to water content before use.This container can be used in the suitable inhaler and contains a kind of above-mentioned float that contains propellant gas of the present invention.Suitable container (for example medicine box) and load the method for this medicine box by known in the state of the art with the float that contains propellant gas of the present invention.

Medicinal activity in view of anticholinergic agent, the invention still further relates to the purposes of float of the present invention in the pharmaceutical composition of preparation suction-type or nose administration, preferably be used for the purposes of imbedibility treatment or per nasal medicine compositions in preparation, wherein anticholinergic agent can produce therapeutic effect.

Especially preferably, the present invention also is used for imbedibility treatment respiratory tract disease (preferred asthma or COPD), mucoviscidosis, Cystic fibrosis about float of the present invention in preparation; And the purposes in the pharmaceutical composition of systemic disease (for example pain, migraine, hypertension, erection problem).

Below executing example is used for explaining the present invention in more detail with way of example but not limit the invention to its content.

The embodiment of preparation

1.

-ipratropium bromide monohydrate 0.03 weight %

-Ipratropine 0.07 weight %

-Myvacet type 9-08 (acetylated monoglyceride) 0.4 weight %

-TG227ea 99.5 weight %

Total amount 100 weight % (15.9 gram)

2.

-ipratropium bromide monohydrate 0.03 weight %

-Ipratropine 0.07 weight %

-isopropyl myristate 0.4 weight %

-TG227ea 99.5 weight %

Total amount 100 weight % (15.9 gram)

3.

-ipratropium bromide monohydrate 0.03 weight %

-Ipratropine 0.07 weight %

-Tween20 0.4 weight %

-TG227ea 99.5 weight %

Total amount 100 weight % (15.9 gram)

4.

-ipratropium bromide monohydrate 0.03 weight %

-Ipratropine 0.07 weight %

-Tween80 0.4 weight %

-TG227ea 99.5 weight %

Total amount 100 weight % (15.9 gram)

5.

-ipratropium bromide monohydrate 0.03 weight %

-Ipratropine 0.07 weight %

-isopropyl myristate 10.00 weight %

-TG227ea 89.90 weight %

Total amount 100 weight % (15.9 gram)

6.

-ipratropium bromide monohydrate 0.03 weight %

-Ipratropine 0.07 weight %

-isopropyl myristate 10.00 weight %

-soybean lecithin 0.004 weight %

-TG227ea 89.9 weight %

Total amount 100 weight % (15.9 gram)

7.

-ipratropium bromide monohydrate 0.03 weight %

-salbutamol sulfate 0.19 weight %

-Tween20 0.4 weight %

-TG227ea 99.38 weight %

Total amount 100 weight % (15.9 gram)

8.

-ipratropium bromide monohydrate 0.03 weight %

-salbutamol sulfate 0.19 weight %

-TG227ea 99.78 weight %

Total amount 100 weight % (15.9 gram)

The water that example of formulations 1 to 8 preferably contains between 50 to 300ppm.

9.

-ipratropium bromide monohydrate 0.04 weight %

-salbutamol sulfate 0.21 weight %

-TG134a 99.75 weight %

Total amount 100 weight % (14.8 gram)

Example of formulations 9 can contain the water yield between 200 to 1000ppm.

Claims (18)

1. the aerosol suspension thing that contains propellant, it contains the active material particle that has with the bonded water of chemical mode, the TG227ea of at least 85 weight % and/or the propellant gas of TG134a, described propellant gas can mix with at least a other propellant gas, and these at least a other propellant gas are selected from propane, butane, pentane, dimethyl ether, CHClF ₂, CH ₂F ₂, CF ₃CH ₃, iso-butane, isopentane and neopentane, it is characterized in that this aerosol suspension thing except contain with this active substance also to contain free water the bonded water of chemical mode.

2. aerosol suspension thing as claimed in claim 1 is characterized in that it contains the active substance crystalline particle, and described active substance crystalline particle combines with the water that is water of crystallization, hydrate water or complex water form.

3. aerosol suspension thing as claimed in claim 1 or 2, it is characterized in that this active substance is selected from the combination of betamimetics medicine, anticholinergic agent, steroid, antiallergic agent, ergoline derivatives, triptan medicine, CGRP antagonist, phosphodiesterase-V inhibitor, phosphodiesterase-IV inhibitor, LTD4-antagonist, EGFR-inhibitors of kinases and these active substances.

4. aerosol suspension thing as claimed in claim 3, it is characterized in that, this float contains the anticholinergic agent as active substance, this cholilytic drug is preferably ipratropium salt or tiotropium salt, be more preferred from ipratropium bromide or tiotropium bromide, be preferably ipratropium bromide monohydrate or tiotropium bromide monohydrate especially.

5. as one of above-mentioned claim described aerosol suspension thing, it is characterized in that the consumption of this active substance is 0.001 to 5%, be preferably 0.002 to 3%, be preferably 0.002 to 2%.

6. as one of above-mentioned claim described aerosol suspension thing, it is characterized in that, for propellant gas TG227ea or with the mixture of this propellant gas, its water content be 10 and 1000ppm between, be preferably 50 and 500ppm between and especially be preferably 100 to 450ppm.

7. as one of above-mentioned claim described aerosol suspension thing, it is characterized in that, for propellant gas TG134a or with the mixture of this propellant gas, its water content is 30 to 4000ppm, is preferably 150 to 2000ppm and especially be preferably 350 to 1700ppm.

8. as one of above-mentioned claim described aerosol suspension thing, it is characterized in that it contains surfactant, adjuvant, antioxidant and/or flavoring agent as other compositions.

9. as one of above-mentioned claim described aerosol suspension thing, it is characterized in that it contains one or more and is selected from following chemical compound as surfactant (surfactant): polysorbate20, polysorbate80, Myvacet 9-45, Myvacet 9-08, isopropyl myristate, oleic acid, propylene glycol, Polyethylene Glycol, Brij, ethyl oleate, glycerol trioleate, glyceryl monolaurate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, oleic acid oil base fat, stearyl alcohol, cetylpyridinium chloride , block polymer, natural oil, ethanol and isopropyl alcohol.

10. as one of above-mentioned claim described aerosol suspension thing, it is characterized in that it contains one or more and is selected from following chemical compound as adjuvant: alanine, albumin, ascorbic acid, aspartame, betanin, aminothiopropionic acid, phosphoric acid, nitric acid, hydrochloric acid, sulphuric acid and citric acid.

11. as one of above-mentioned claim described aerosol suspension thing, it is characterized in that it contains one or more and is selected from following compounds as antioxidant: ascorbic acid, citric acid, sodium ethylene diamine tetracetate, ethylenediaminetetraacetic acid, tocopherol, butylated hydroxytoluene, Butylated hydroxyanisole and ascorbyl palmitate.

12., it is characterized in that except this active substance, water and one or more propellant gas, it does not contain other compositions as one of above-mentioned claim described aerosol suspension thing.

Treat the purposes of pharmaceutical composition that cholilytic drug wherein can produce the disease of curative effect 13. in pharmaceutical compositions and preferably be used for imbedibility or optional nasal route in preparation as each described aerosol suspension thing in the claim 1 to 12.

14. purposes as claimed in claim 13 is characterized in that, these diseases are respiratory tract diseases, are preferably asthma, COPD, mucoviscidosis or Cystic fibrosis.

15., it is characterized in that this disease is a kind of systemic disease, preferably pain, migraine, hypertension or erection problem as one in the claim 1～13 or multinomial described purposes.

16. a method for preparing as each described aerosol suspension thing in the claim 1 to 12 is characterized in that using moisture propellant gas or propellant gas mixture to prepare this aerosol suspension thing.

17. a method for preparing as each described aerosol suspension thing in the claim 1 to 12 is characterized in that using anhydrous propellant gas or propellant gas mixture to prepare the aerosol suspension thing, adds entry then.

18. be used for loading one or the multinomial described aerocolloidal container that contains propellant, it is characterized in that this container contains the suitable valve of regulating according to its water content before use as claim 1 to 12.