CN101505798A - Aerosol formulation for the inhalation of beta agonists - Google Patents

Aerosol formulation for the inhalation of beta agonists Download PDF

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CN101505798A
CN101505798A CNA2007800307840A CN200780030784A CN101505798A CN 101505798 A CN101505798 A CN 101505798A CN A2007800307840 A CNA2007800307840 A CN A2007800307840A CN 200780030784 A CN200780030784 A CN 200780030784A CN 101505798 A CN101505798 A CN 101505798A
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acid
enantiomer
pharmaceutical preparation
active substance
hydroxyl
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柯尔斯滕·拉多
迈克尔·埃文
赖纳·韦策尔
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Boehringer Ingelheim International GmbH
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Boehringer Ingelheim International GmbH
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Abstract

The invention relates to an aerosol formulation for inhalation that is devoid of a propellant and contains one or more compounds of the general formula (1) and an additional active ingredient 2 and 3. In said formula, the groups R<1>, R<2>, R<3> and X<-> can be defined as cited in the claims and the description.

Description

Suck aerosol with beta-2-agonists
The present invention relates to the aerosol of inhalant no propellant, it contains one or more general formula 1 chemical compounds:
Figure A200780030784D00061
Radicals R wherein 1, R 2, R 3And X-can have the implication shown in claims and the description; And two kinds of other active substances 2 and 3.
Detailed Description Of The Invention
Pharmaceutical preparation of the present invention is the pharmaceutical preparation of no propellant, and it contains one or more general formula 1 chemical compounds as active substance:
Figure A200780030784D00062
Wherein:
R 1Expression hydrogen, C 1-4Alkyl, O-C 1-4Alkyl or halogen;
R 2Expression hydrogen, C 1-4Alkyl, O-C 1-4Alkyl or halogen;
R 3Expression hydrogen, C 1-4Alkyl, O-C 1-4Alkyl, halogen, OH ,-O-C 1-4Alkylidene-COOH or O-C 1-4Alkylidene-COO-C 1-4Alkyl;
X -Expression monovalence or multivalent anions are preferably the monovalence or the multivalent anions that are selected from chloride ion, bromide ion, iodide ion, sulfate radical, phosphate radical, methanesulfonate, nitrate anion, maleate, acetate, benzoate anion, citrate, salicylate, trifluoroacetic acid root, fumaric acid radical, tartrate anion, oxalate, amber acid radical, benzoate anion and p-methyl benzenesulfonic acid root;
Optional mixture, racemic modification, solvate or the hydrate forms that is its tautomeride isomer, enantiomer, enantiomer;
Active substance 2, it is selected from Budesonide (budesonide), beclometasone (beclomethasone), fluticasone (fluticasone), ciclesonide (ciclesonide) or its metabolite, optional mixture, racemic modification, solvate or the hydrate forms that is its tautomeride isomer, enantiomer, enantiomer;
Active substance 3, it is selected from tiotropium salt (tiotropium salt), oxygen holder ammonium salt (oxitropiumsalt), fluorine holder ammonium salt (flutropium salt), ipratropium salt (ipratropium salt), glycopyrronium salt (glycopyrronium salt) and Trospium cation salt (trospium salt), optional mixture, racemic modification, solvate or the hydrate forms that is its tautomeride isomer, enantiomer, enantiomer;
At least a pharmacology goes up acceptable acid, and optionally also contain other pharmacology and go up acceptable excipient, and as ethanol or the water and the alcoholic acid mixture of solvent.
Preferred drug substances is for containing above-mentioned active substance 2 and 3, and those pharmaceutical preparatioies of general formula 1 chemical compound, wherein:
R 1Expression hydrogen, methyl, ethyl, fluorine or chlorine;
R 2Expression hydrogen, methyl, ethyl, fluorine or chlorine;
R 3Expression hydrogen, methyl, ethyl, propyl group, OH, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, O-CH 2-COOH, O-CH 2-COO methyl or O-CH 2-COO ethyl ,-O-CH 2-CH 2COOH, O-CH 2-CH 2COO methyl or O-CH 2-CH 2The COO ethyl ,-O-CH 2-CH 2-CH 2COOH, O-CH 2-CH 2-CH 2The COO methyl or-O-CH 2-CH 2-CH 2The COO ethyl;
X -Expression monovalence or multivalent anions are preferably the monovalence or the multivalent anions that are selected from chloride ion, bromide ion, iodide ion, sulfate radical, phosphate radical, methanesulfonate, nitrate anion, maleate, acetate, benzoate anion, citrate, salicylate, trifluoroacetic acid root, fumaric acid radical, tartrate anion, oxalate, amber acid radical, benzoate anion and p-methyl benzenesulfonic acid root;
Optional mixture, racemic modification, solvate or the hydrate forms that is its tautomer, enantiomer, enantiomer.
Preferred drug substances is for containing above-mentioned active substance 2 and 3, and those pharmaceutical preparatioies of general formula 1 chemical compound, wherein:
R 1Expression hydrogen or methyl are preferably hydrogen;
R 2Expression hydrogen or methyl are preferably hydrogen;
R 3Expression methyl, OH, methoxyl group, fluorine, chlorine, bromine, O-CH 2-COOH or-O-CH 2-COO ethyl;
X -Expression is selected from the monovalence or the multivalent anions of chloride ion, bromide ion, sulfate radical, methanesulfonate, maleate, acetate, benzoate anion, citrate, salicylate, trifluoroacetic acid root, fumaric acid radical, tartrate anion and amber acid radical;
Optional mixture, racemic modification, solvate or the hydrate forms that is its tautomer, enantiomer, enantiomer.
Also preferably contain above-mentioned active substance 2 and 3, and the pharmaceutical preparation of general formula 1 chemical compound, wherein:
R 3Expression methoxyl group, ethyoxyl, fluorine, chlorine, bromine, O-CH 2-COOH ,-O-CH 2-COO methyl or O-CH 2-COO ethyl;
And R 1, R 2And X-can have above given implication, optional mixture, racemic modification, solvate or the hydrate forms that is its tautomer, enantiomer, enantiomer.
Also preferably contain above-mentioned active substance 2 and 3, and the pharmaceutical preparation of general formula 1 chemical compound, wherein:
R 1Expression hydrogen;
R 2Expression hydrogen;
R 3Expression OH, fluorine, chlorine, methoxyl group, ethyoxyl ,-O-CH 2-COOH is preferably OH, fluorine, chlorine, ethyoxyl or methoxyl group;
And X -Can have one of above given implication, optional mixture, racemic modification, solvate or the hydrate forms that is its tautomer, enantiomer, enantiomer.
Also preferably contain above-mentioned active substance 2 and 3, and the pharmaceutical preparation of general formula 1 chemical compound, described general formula 1 chemical compound is selected from:
6-hydroxyl-8-{1-hydroxyl-2-[2-(4-methoxyl group-phenyl)-1,1-dimethyl-ethylamino]-ethyl }-4H-benzo [1,4] oxazine-3-ketone;
6-hydroxyl-8-{1-hydroxyl-2-[2-(4-phenoxy group-ethyl acetate)-1,1-dimethyl-ethylamino]-ethyl }-4H-benzo [1,4] oxazine-3-ketone;
6-hydroxyl-8-{1-hydroxyl-2-[2-(4-phenoxy group-acetic acid)-1,1-dimethyl-ethylamino]-ethyl }-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[1,1-dimethyl-2-(2,4, the 6-trimethylphenyl)-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
6-hydroxyl-8-{1-hydroxyl-2-[2-(4-hydroxyl-phenyl)-1,1-dimethyl-ethylamino]-ethyl }-4H-benzo [1,4] oxazine-3-ketone;
6-hydroxyl-8-{1-hydroxyl-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]-ethyl }-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(4-fluoro-3-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(4-fluoro-2-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(2,4-two fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(3,5-two fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(4-ethyoxyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(3,5-dimethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
4-(4-{2-[2-hydroxyl-2-(6-hydroxyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-8-yl)-ethylamino]-2-methyl-propyl group }-phenoxy group)-butanoic acid;
8-{2-[2-(3,4-two fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(2-chloro-4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(4-chloro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(4-bromo-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(4-fluoro-3-methoxyl group-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(4-fluoro-2,6-dimethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(4-chloro-2-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(4-chloro-3-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(4-chloro-2-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(3-chloro-4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(2,6-two fluoro-4-methoxyl group-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(2,5-two fluoro-4-methoxyl group-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(4-fluoro-3,5-dimethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(3,5-two chloro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(4-chloro-3-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(3,4,5-three fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
8-{2-[2-(3-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone, and
8-{2-[2-(3,4-two chloro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone;
Be the acid-addition salts form that forms with sour HX under various situations, wherein X-can have one of above given implication, and optional mixture, racemic modification, solvate or the hydrate forms that is its tautomer, enantiomer, enantiomer.
In drug regimen of the present invention, active substance 2 is the steroid that are selected from budesonide, beclometasone, fluticasone, ciclesonide or its metabolite.Above-mentioned steroid can be chosen wantonly has the chiral carbon center.In this case, drug regimen of the present invention can contain the mixture that is its enantiomer, enantiomer or the steroid of racemic modification form, and the preferred steroid with high enantiomeric purity that uses.
In drug regimen of the present invention, active substance 3 is the anticholinergic that are selected from tiotropium salt (3.1), oxygen holder ammonium salt (3.2), fluorine holder ammonium salt (3.3), ipratropium salt (3.4), glycopyrronium salt (3.5) and Trospium cation salt (3.6).Above-mentioned anticholinergic can be chosen wantonly has the chiral carbon center.In this case, drug regimen of the present invention can contain the mixture that is its enantiomer, enantiomer or the anticholinergic of racemic modification form, and the preferred anticholinergic with high enantiomeric purity that uses.
In above-mentioned salt 3.1 to 3.6, cation tiotropium, oxygen holder ammonium, fluorine holder ammonium, ipratropium, GLYCOPYRRONIUM and Trospium cation constitute the component of pharmacological activity.By using name 3.1 ' to the above-mentioned cation of 3.6 ' specific reference.Any above-mentioned salt 3.1 to 3.6 also comprises corresponding cation tiotropium (3.1 '), oxygen holder ammonium (3.2 '), fluorine holder ammonium (3.3 '), ipratropium (3.4 '), GLYCOPYRRONIUM (3.5 '), Trospium cation (3.6 ') naturally.
According to the present invention, salt 3.1 to 3.6 is meant decationize tiotropium (3.1 '), oxygen holder ammonium (3.2 '), fluorine holder ammonium (3.3 '), ipratropium (3.4 '), GLYCOPYRRONIUM (3.5 ') and Trospium cation (3.6 ') contain the chloride ion as equilibrium ion (anion) in addition, bromide ion, iodide ion, sulfate radical, phosphate radical, methanesulfonate, nitrate anion, maleate, acetate, citrate, fumaric acid radical, tartrate anion, oxalate, amber acid radical, those chemical compounds of benzoate anion or p-methyl benzenesulfonic acid root, and be preferably chloride ion, bromide ion, iodide ion, sulfate radical, methanesulfonate or p-methyl benzenesulfonic acid root are as equilibrium ion.In all salt, chloride, bromide, iodide and mesylate are especially preferred.
Under the situation of Trospium cation salt (3.6), chloride is especially preferred.Under the situation of other salt 3.2 to 3.6, mesylate and bromide are even more important.The particularly important is the drug regimen that contains tiotropium salt (3.1), oxygen holder ammonium salt (3.2) or ipratropium salt (3.4), and according to the present invention, bromide separately is even more important.Tiotropium bromide (tiotropium bromide) (3.1) is even more important.
Above-mentioned salt can be chosen wantonly with its solvate or hydrate forms, preferably it is stored in the drug regimen of the present invention with hydrate forms.Under the situation of tiotropium bromide, drug regimen of the present invention preferably contains the tiotropium bromide of crystallization tiotropium bromide monohydrate form, and it is known from WO02/30928.If tiotropium bromide uses in drug regimen of the present invention with anhydrous form, then preferably use the anhydrous crystal tiotropium bromide, it is known from WO 03/000265.
Employed term and definition
Term " C 1-4Alkyl " (be included as those C of the part of other group 1-4Alkyl) is meant side chain and straight chained alkyl with 1 to 4 carbon atom.Example comprises: methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or the tert-butyl group.Below abbreviation also can be chosen wantonly and be used for above-mentioned group: Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu etc.Except as otherwise noted, otherwise the definition of propyl group and butyl comprises that the institute of the group discussed might isomeric form.Therefore, for example, propyl group comprises n-pro-pyl and isopropyl, and butyl comprises isobutyl group, sec-butyl and the tert-butyl group etc.
Term " C 1-4Alkylidene " (be included as those C of the part of other group 1-4Alkylidene) is meant side chain and straight-chain alkyl-sub-with 1 to 4 carbon atom.Example comprises: methylene, ethylidene, propylidene, 1-methyl ethylidene, butylidene, 1-methyl propylidene, 1,1-dimethyl ethylidene or 1,2-dimethyl ethylidene.Except as otherwise noted, otherwise the definition of propylidene and butylidene comprises that the same carbon number purpose group institute of being discussed of having might isomeric form.Therefore, for example, propylidene also comprises 1-methyl ethylidene, and butylidene comprises 1-methyl propylidene, 1,1-dimethyl ethylidene, 1,2-dimethyl ethylidene.
Within the scope of the invention, " halogen " expression fluorine, chlorine, bromine or iodine.Unless opposite explanation is arranged, otherwise fluorine, chlorine and bromine are regarded as preferred halogen.
The acid-addition salts of going up acceptable acid formation with the pharmacology is meant that (for example) is selected from the salt of hydrochlorate, hydrobromate, hydriodate, sulfate, phosphate, mesylate, nitrate, maleate, acetate, benzoate, citrate, fumarate, tartrate, oxalates, succinate, benzoate and tosilate, is preferably hydrochlorate, hydrobromate, sulfate, phosphate, fumarate and mesylate.In above-mentioned acid-addition salts, according to the present invention, the salt of hydrochloric acid, methanesulfonic acid, benzoic acid and acetic acid is especially preferred.
Chemical compound with high enantiomeric purity is meant those chemical compounds that can be made up of two or more enantiomer, wherein a kind of enantiomer exists with excessive, this excessive 90% of gross mass that is preferably greater than, especially be preferably greater than gross mass 95% and special in 98% of gross mass.
For reaching purpose of the present invention, the metabolite of steroid is meant the steroid that is produced or reacted by metabolism in metabolism.Therefore, the steroid of pharmaceutical active in fact can be corresponding to the metabolite of employed steroid.If metabolite is a pharmaceutically stable, then it also can directly use.Therefore, for example, in the time of in being administered to lung, the metabolite of the pharmaceutical active of ciclesonide be the des-ciclesonide (D.Ukena, Pneumologie 2005; 59; 689-695).
Figure A200780030784D00131
Ciclesonide des-ciclesonide
Chemical compound of the present invention can prepare by being similar to method as known in the art.Appropriate preparation method is known from (for example) US 4460581, and its content is hereby incorporated by.
Formula 1 chemical compound can be chosen wantonly with its tautomeric forms and be present in the pharmaceutical preparation of the present invention.The term tautomerism is represented the phenomenon by the isocompound that σ key or π bond migration is formed and can poised state exist.The example of the possible tautomeric form of formula 1 chemical compound is
Figure A200780030784D00132
Also or
Figure A200780030784D00133
In another aspect, the present invention relates to contain the pharmaceutical preparation of above-mentioned formula 1 chemical compound of the mixture that is single optical isomer, single enantiomer or racemic modification form.Especially preferably contain the pharmaceutical preparation of above-mentioned formula 1 chemical compound that is compound form, and according to the present invention, the R-enantiomer of formula 1 chemical compound is important unusually with high enantiomeric purity.These R-enantiomers can be represented by general formula R-1:
Figure A200780030784D00141
Radicals R wherein 1, R 2, R 3And X-can have above given implication.
Within the scope of the invention, especially preferably use those formula 1 chemical compound, wherein X -Be selected from chloride ion, maleate, salicylate, fumaric acid radical or amber acid radical, optional its hydrate and the solvate form thereof of being.Within the scope of the invention, especially preferably contain X -Those preparations of formula 1 chemical compound of expression chloride ion.
Within the scope of the invention, formula 1 chemical compound comprises all possible amorphous and crystal habit of this chemical compound all the time.Within the scope of the invention, formula 1 chemical compound comprises that also from then on the institute of compound formation might solvate and hydrate.Within the scope of the invention, the pharmacology of any chemical compound 1 ' be regarded as following formula contained in the salt 1 goes up active free alkali:
Figure A200780030784D00142
Radicals R wherein 1, R 2And R 3And can have above given implication.
In another aspect, the present invention relates to contain the pharmaceutical preparation of following each thing: active substance 2 and 3, and formula 1 ' free alkali, wherein radicals R 1, R 2And R 3Can have above given implication, optional mixture, racemic modification, solvate or the hydrate forms that is its tautomer, enantiomer, enantiomer; At least a pharmacology goes up acceptable acid; Optional also contain other pharmacology and go up acceptable excipient, and as water, ethanol or water and the alcoholic acid mixture of solvent.
In another aspect, the present invention relates to pharmaceutical preparation of the present invention and be used for the treatment of purposes in the pharmaceutical composition of respiratory system disease in preparation, described respiratory system disease is selected from the pulmonary edema of bronchitis, bronchiectasis, ARDS (adult respiratory distress syndrome) and the form of ownership of emphysema, restrictive lung disease, interstitial lung disease, the cystic fibrosis of the obstructive pulmonary disease of multiple origin, multiple origin, multiple origin.
Preferably, use chemical compound to be used for the treatment of the pharmaceutical composition of the obstructive pulmonary disease that is selected from following each disease with preparation as mentioned above: bronchial asthma, infantile asthma, severe asthma, acute asthma outbreak, chronic bronchitis and chronic obstructive pulmonary disease (COPD), and according to the present invention, especially be preferably and use them to be used for the treatment of the pharmaceutical composition of bronchial asthma or COPD with preparation.
Also preferred use pharmaceutical preparation of the present invention is used for the treatment of the emophysematous medicine that has its COPD (chronic obstructive pulmonary disease) origin or lack Prolastin with preparation.
The also preferred pharmaceutical composition that uses pharmaceutical preparation of the present invention to be used for the treatment of the restrictive lung disease that is selected from following each disease with preparation: sequoiosis; The restrictive lung disease that the harmful substance of being correlated with by work causes is such as asbestosis or silicosis; And by the caused limited disease of lung tumor, such as lymphangiosarcoma, bronchovesicular tumor and lymphoma.
Also preferred use preparation of pharmaceutical formulations according to the present invention is used for the treatment of the pharmaceutical composition that is selected from following interstitial lung disease: by infecting the pneumonia that (for example infection that is caused by virus, antibacterial, fungus, protozoacide, anthelmintic or other pathogen) causes; The pneumonia (for example air-breathing and left heart insufficiency) that causes by various factors; Radiation induced pneumonia or fibrosis; Collagenzation (for example lupus erythematosus, systemic scleroderma or sarcoidosis); (for example uncle restrains (Boeck) disease to granulomatosis; Idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF)).
The also preferred pharmaceutical composition that uses preparation of pharmaceutical formulations according to the present invention to be used for the treatment of cystic fibrosis or mucoviscidosis.
Also preferred use preparation of pharmaceutical formulations according to the present invention is used for the treatment of bronchitic pharmaceutical composition, the bronchitis that this bronchitis is for example caused by antibacterial or viral infection, allergic bronchitis and toxic bronchitis.
Also preferably preparation of pharmaceutical formulations according to the present invention is used for the treatment of bronchiectasic pharmaceutical composition.
The pharmaceutical composition that also preferably will preparation of pharmaceutical formulations according to the present invention be used for the treatment of ARDS (adult respiratory distress syndrome).
Also preferably will preparation of pharmaceutical formulations according to the present invention be used for the treatment of the pharmaceutical composition of pulmonary edema, this pulmonary edema is the toxic pulmonary edema behind toxicity on inhalation material and foreign substance for example.
Especially preferably, the present invention relates to pharmaceutical preparation according to the present invention and be used for the treatment of purposes in the pharmaceutical composition of asthma or COPD in preparation.What also be even more important is: be used for preparing and be used for treating once a day inflammatory and obstructive respiration disease, treat the such use of the pharmaceutical composition of asthma or COPD especially once a day.
In addition, according on the other hand, the present invention relates to pharmaceutical preparation of the present invention is used for stimulating the pharmaceutical composition of stem cell mobilization in preparation purposes.
The present invention also relates to be used for the treatment of the method for above-mentioned disease, it is characterized in that with treatment effective dose administration one or more said medicine preparations of the present invention.Especially need to prepare active substance preparation, it can be used in the treatment by once a day in (single dose) administration.Use medicine to have following advantage once a day: the patient can get used to relatively fast every day particular point in time take medicine regularly.
The present invention relates to and to satisfy high-quality standard through the liquid active substance preparation of these chemical compounds of inhalation according to liquid preparation of the present invention.But the approach according to preparation per os of the present invention or nose sucks.For making active substance reach best distribution in lung, suggestion uses the liquid preparation that does not contain propelling gas to use suitable inhaler administration.But but both also nasal route suctions of per os approach of this kind preparation.Especially the inhaler of Shi Heing is for can be in the several seconds becoming the inhaler of the aerosol that is suitable for treating suction to treat required dosage spraying small amount of liquid preparation.Within the scope of the invention, preferred aerosol apparatus is those following aerosol apparatus, wherein less than 100 microlitres, preferably less than 50 microlitres, most preferably less than the active substance solution of 25 microliter amount can be preferably with spraying or twice spraying ejection once form mean diameter less than 20 microns, preferably less than 10 microns aerosol, make the sucked part of aerosol corresponding to treating effective dose.This kind is used for being described in detail in (for example) international application WO 91/14468 " Atomizing Deviceand Methods " and WO 97/12687 (referring to Fig. 6 a and 6b and appended explanation) not containing under the propellant device of throwing with metered amount in order to the liquid pharmaceutical formulation that sucks.In this kind aerosol apparatus, drug solution passes on aerosol by means of the high pressure up to 500 crust or is sprayed in the lung.In the scope of this description, the full content of the above-mentioned document of specific reference.
In this kind inhaler, pharmaceutical solutions is stored in the apotheca.Thereby importantly, used active substance preparation is enough storage stabilities and while to be arranged according to goals of medicine, if possible without any other processing, and can directly offer medicine.In addition, its should not contain can with any composition of the medical quality of interactional infringement inhaler of inhaler or aerosol that solution produces.
For spray solution can use special nozzle described in (for example) WO 94/07607 or WO 99/16530.This two routine application case of specific reference herein.
The object of the present invention is to provide aqueous, ethanol or the aqueous-ethanol preparation of formula 1 chemical compound, it satisfies guarantees to use above-mentioned inhaler to make the required high standard of the best atomizing of solution.Active substance preparation of the present invention must have sufficiently high medicine quality, that is it is through several years, preferred at least ten two months, more preferably 18 months storage time should be pharmaceutically stable.The no propellant formulation of these of solution also must atomize by means of inhaler under pressure, and the compositions of being delivered in the aerosol that is produced simultaneously is in specified scope.
According to the present invention, preparation preferably contains active substance 2 and 3, and only a kind of chemical compound of formula 1.Yet said preparation also can contain the mixture of the different salt of formula 1.If pharmaceutical preparation according to the present invention contains the different salt of formula 1, preferred formulation then according to the present invention be those wherein some salt all be formula 1 ' the preparation of different salt of identical free alkali.
With the pharmacology in the pharmaceutical preparation according to the present invention go up effective free alkali 1 ' proportional meter, according to the present invention, formula 1 compound concentrations be every 100ml about 0.1 to 1000mg, preferred every 100ml about 0.5 is to 500mg, especially preferred every 100ml is 1 to 250mg.100ml preparation of the present invention especially preferably contain have an appointment 2 to about 100mg 1 '.
Pharmaceutical preparation Chinese style 2 compound concentrations of the present invention are about 10 to 6000mg/100ml, are preferably 10 to 5000mg/100ml, are preferably 50 to 5000mg/100ml, are preferably 50 to 3000mg/100ml, especially are preferably 75 to 3500mg/100ml.
According to the present invention, in the amount of the free cations of the active salt 3.1 of pharmacology in the pharmaceutical preparation of the present invention, formula 3 compound concentrations are about 0.1 to 2000mg/100ml, are preferably about 1 to 1000mg/100ml, especially are preferably 0.75 to 500mg/100ml.Especially preferably, 100ml preparation of the present invention contains the free cations of 5mg to the salt 3.1 of about 100mg of having an appointment.
Pharmaceutical preparation of the present invention contains the mixture as the straight alcohol of solvent or ethanol and water.If use ethanol-water mixture, then the ethanol percentage by volume is preferably 30% to 99% in this mixture, and is especially preferred in 40% to 97% scope.For reaching purpose of the present invention, the most especially preferred pharmaceutical preparation contains as the straight alcohol of solvent or contains 50% to 96% ethanol, especially preferred 67% to 95% ethanol, 67% to 93% alcoholic acid ethanol-water mixture especially.Except that ethanol and water, also can use other cosolvent and solubilizing agent, such as benzylalcohol, gamma-butyrolacton or carbiphene.Yet,, preferably do not use other solvent according to the present invention.
If chemical compound 1 and 2 is dissolved in the mixture of ethanol or ethanol and water, then according to the present invention, the pH value of preparation of the present invention preferably 2.0 to 6.5, preferably 2.5 to 5.5, especially preferably about 3.0 to 5.0, especially between 2.8 to 4.8.
PH value is gone up acceptable acid by the interpolation pharmacology and is regulated.For reaching this purpose, can use the pharmacology to go up acceptable mineral acid or organic acid.Preferred representative examples of mineral pigments is selected from hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and phosphoric acid.Especially the organic acid example of Shi Heing is selected from ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid, propanoic acid, sorbic acid, benzoic acid, methanesulfonic acid and benzenesulfonic acid.Preferred mineral acid is hydrochloric acid, phosphoric acid and sulphuric acid, and wherein according to the present invention, hydrochloric acid and phosphoric acid are even more important.In organic acid, ascorbic acid, fumaric acid, methanesulfonic acid and citric acid are preferred, and wherein according to the present invention, citric acid is especially preferred.In case of necessity, also can use the mixture of above-mentioned acid, especially except that its acidify characteristic, have under the situation of other characteristic, for example serve as those acid of flavoring agent or antioxidant, such as citric acid or ascorbic acid in acid.In case of necessity, also can use the pharmacology to go up acceptable alkali with accurate titration pH value.Suitable alkali comprises (for example) alkali metal hydroxide and alkali carbonate.Preferred alkali metal ion is a sodium.If use this type of alkali, then must carefully go up compatible with gained salt and the above-mentioned sour pharmacology who guarantees then to be contained in the pharmaceutical preparation of being finished.
In addition, pH value also can use the last acceptable buffer system of pharmacology to regulate.For this reason, can use the pharmacology to go up acceptable inorganic or organic buffer system.The example of preferred buffer system is selected from citrate buffer, acetate buffer and phosphate buffer.Especially be preferably phosphate buffer.
Preparation of the present invention can contain the chelating agent of going up acceptable excipient as other pharmacology.Within the scope of the invention, chelating agent is meant the molecule that can enter in the complex bonds.Preferably, these chemical compounds should have the effect with cation (most preferably being metal cation) complexation.Preparation of the present invention preferably contains ethylenediaminetetraacetic acid (EDTA) or its a kind of known salt (for example EDTA sodium or EDTA disodium) as chelating agent.Preferably, use disodiumedetate, optionally be its hydrate forms, more preferably be its dihydrate form.In addition, EDTA can its ethyl ester form be present in and contains in the alcoholic solution, and it can be mono ethyl ester, diethylester, triethyl or tetra-ethyl ester or its form of mixtures.
If disodiumedetate or EDTA-ethyl ester are as chelating agent in the scope of preparation of the present invention, then its content is preferably in the scope of 0.10 to 25mg/100ml preparation of the present invention, especially preferably in the scope of 0.15 to 15mg/100ml preparation of the present invention.Preferably, preparation of the present invention contains the chelating agent of 0.20 to 8mg/100ml the amount of having an appointment.
The argumentation of doing about disodiumedetate is also similar to be applicable to that other suitable with EDTA or its salt may additive, and these additives have complexation characteristic and alternative EDTA or its salt to be used, such as nitrilotriacetic acid(NTA) and salt thereof.
Also other pharmacology can be gone up acceptable excipient is added in the preparation of the present invention.In this case, adjuvant and additive be meant can accept on any pharmacology and therapeutics on useful material, itself and inert matter, but in the solvent that can on the pharmacology, be fit to together with active substance preparation with the quality of modified activity substance preparation.Preferably, treat in the situation, these materials do not have pharmacological action or do not have and obviously or at least do not have undesirable pharmacological action.Adjuvant and additive comprise that (for example) prolongs stabilizing agent, antioxidant and/or the antiseptic of the storage period of the pharmaceutical preparation of being finished, and flavoring agent, vitamin and/or other additive as known in the art.Additive comprises that also the pharmacology goes up acceptable salt, such as sodium chloride.
Preferred excipient comprises antioxidant, and such as ascorbic acid, its restrictive condition is not used to regulate pH value as yet for it; Propyl gallate; And natural and synthetic phenol antioxidant.Natural phenolic antioxidant comprises (for example) vitamin A; Tocopherol is such as vitamin E; And the similar vitamin or the rovitamin that produce in the human body.The Natural antioxidant also comprises the flavone compound that produces in the plant organism, such as naringenin (naringenin) and resveratrol (resveratrol).Synthetized oxidation preventive agent comprises (for example) BHA (Butylated hydroxyanisole), BHT (butylated hydroxytoluene), TBHQ (tert-butyl group hydroxyquinone), three (2,4-two-tert-butyl-phenyl) phosphite ester and four [methylene (3,5-two-tert-butyl group hydroxyl hydrogenated cinnamate)] methane (tetrakis[methylene (3,5-di-tert-butylhydroxyhydrocinnamate)] methane).Be preferably BHT or tocopherol, and BHT most preferably.
If use antioxidant in the scope of preparation of the present invention, then its content is preferably in 0.1 to 200mg/100ml scope.
Can add antiseptic and avoid the pathogenetic bacteria pollution with the protection preparation.Suitable antiseptic is known those antiseptic of prior art that are in the prior art concentration known, especially is benzalkonium chloride or benzoic acid or benzoate (such as sodium benzoate).Preferably, benzalkonium chloride is added in the preparation of the present invention.The amount of the benzalkonium chloride that is added is preferably about 2 to 15mg/100ml between 1mg and 50mg/100ml preparation, especially be preferably about 3 to 12mg/100ml, especially is preferably about 4 to 10mg/100ml preparations of the present invention.According to the present invention, also can use and the miscellaneous benzalkonium chloride of other antiseptic.
Under the situation of the ethanol/water mixture 50 to 93%V/V, without any need for other antiseptic, this is because this characteristic is present in the solvent mixture.
Preferred preparation only contains antioxidant and regulates the required acid of pH value beyond desolventizing water and ethanol, formula 1 chemical compound and active substance 2.Especially preferred preparation only contains BHT and regulates the required acid of pH value beyond desolventizing water and ethanol, formula 1 chemical compound and active substance 2 and 3.
Aerosol apparatus
The atomizing of the medicine that dissolves or suspend in water can be used compressed air or ultrasonic carrying out.Gained granule spectrum is passed to being better than propellant gas and powder aerosol aspect the lung thoroughly at it.This inhalation method is suitable for the situation of severe asthma, because the suction technology is simple, it also is suitable for regulating child and the patient who has problems on breathing.There are fixture and travelling dingus.Certainly all the time greater than MDI and DPI.Spendable pharmaceutical preparation is limited on the microbiology fully, aqueous, etc. open and pH value neutral solution or suspension.
The injecting type aerosol apparatus-for a long time, simple mechanism has been used to distribute solution, and wherein airflow is passed opening capillaceous, through its suction solution (perfume nebulizer principle).In the hand-hold atomization device of making by glass (aerosol apparatus), air communication overcompression ball or produce by pump (pump formula nebulizer).The fixture recently that is used for aerosol therapy is the aerosol apparatus by the compressed air operation, and it can produce and surpass 50% amount in optimum size scope (1-5 μ m).Compressed air makes solution disperse through the nozzle acceleration and through capillary tube delivery drug solution (Bernoulli effect (Bernoulli effect)) this moment.Be positioned at shock plate behind the nozzle in addition in order to smash solution.Special-purpose blocking-up member guarantees that only smallest particles is escaped, and flows back in the reservoir and can atomize once more than macroparticle.During sucking, sizable evaporation takes place, it is cold aerosol and concentrated active substance solution because of evaporative cooling produces.
Ultrasonic nebulizer-excite piezoquartz producing vibration by high-frequency alternating current, this vibration transfers to active substance solution and therefrom discharges the very fine drop of liquid but heat this liquid simultaneously through transfer medium.
Pharmaceutical preparation according to the present invention is preferred in the inhaler of the described type of preamble to produce according to the aerosol that does not contain propellant of the present invention.On this aspect, should clearly mention this paper aforementioned patent document once more, thereby it is incorporated in herein.As described in beginning, the example that further develops of preferred inhaler is disclosed among the WO 97/12687 explanation of Fig. 6 a and 6b and relevant paragraph (especially referring to).
This aerosol apparatus
Figure A200780030784D00201
But can be advantageously used in generation according to inhalation aerosol of the present invention.Because its cylindrical shape reaches less than 9 to 15cm long and 2 to 4cm wide light sizes, the patient can carry this device at any time.Under high pressure, aerosol apparatus is through the pharmaceutical preparation of small nozzle ejection defined volume, but to produce inhalation aerosol.Preferred aerosol apparatus is made up of upper case parts, pump case, nozzle, locking pliers, spring shell, spring and storage capsule basically, it is characterized by
-pump case, the nozzle body that it is fixed in the upper case parts and carrying at one end has nozzle or nozzle arrangement;
-hollow piston, it has valve body;
-drive flange, wherein fixedly hollow body and its are arranged in the upper case parts;
-locking pliers mechanism, it is arranged in the upper case parts;
-there is spring to be positioned at wherein spring shell, it is rotatably installed on the upper case parts by means of swivel bearing;
-be inserted into the lower case parts on the spring shell in the axial direction.
Hollow piston with valve body is corresponding to the device that is disclosed among the WO 97/12687.Its part protrude in the cylinder that enters pump case and in cylinder with arrangement that can be axially movable.Especially referring to the explanation of Fig. 1-4 in the above-mentioned international application (especially Fig. 3) and relevant paragraph.When spring discharged, the hollow piston with valve body applied the pressure of 5 to 60Mpa (about 50 to 600 crust), the pressure (fluid measures) of preferred 10 to 60Mpa (about 100 to 600 crust) at its high-pressure side on fluid.The volume that therefore each stroke activates 10 to 50 microlitres is preferred, and the volume of 10 to 20 microlitres is more preferably, and each stroke 10 to 17.5 microlitre volumes are especially preferred.
Valve body is preferably mounted at the hollow piston end that turns to nozzle body.
The micro structure that nozzle in the nozzle body preferred (for example) makes through little processing (micro-engineering), the nozzle body of micro structure is disclosed among (for example) WO 99/16530, quotes the content of this description, especially Fig. 1 and related description at this this paper.Nozzle body (for example) is made up of interconnective two sheet glass and/or silicon, and wherein a slice is to connect the micro structure passage that one or more connects the upstream side of the injector and nozzle exit end at least.At nozzle exit end, be at least one circle or non-circular openings, its from 2 to 10 microns dark and 5 to 15 microns wide, this degree of depth preferred 4.5 to 6.5 microns and length are 7 to 9 microns.If there are a plurality of nozzles, then the spray direction of preferred two nozzles can running parallel to each other or can be toward each other in tendency on the direction of nozzle opening in nozzle body.Have at the port of export under the situation of at least two nozzle openings at nozzle body, spray direction can be inclined with 20 degree to the angle of 160 degree toward each other mutually, preferably inclines mutually with the angle of 60 to 150 degree, and the best is inclined mutually with 80 to 100 °.Nozzle opening is preferably with 10 to 200 microns be spaced, more preferably with 10 to 100 microns be spaced, more preferably with 30 to 70 microns be spaced.50 microns best at interval.Therefore, spray direction is met in the nozzle opening district.
As described in, but liquid pharmaceutical formulation is applied to nozzle body and sprays inhalation aerosol through nozzle opening with the inlet pressure up to 600 crust, preferred 200 to 300 crust.The preferable particle size of aerosol is up to 20 microns, preferred maximum 10 microns.
Spring is contained in locking pliers mechanism, and preferred cylindric spiral type compression spring is with store mechanical energy.Serve as the springing member at driving flange upper spring, its motion is through the determining positions of locking component.Driving advancing of flange ends part and bottom and ends part and accurately limit through top.Spring is preferably strained through outer moment of torsion via step gear (for example helical form balladeur train), and this outer moment of torsion is to produce when the upper case parts rotate with respect to the spring shell in the case member of bottom.In the case, upper case parts and driving flange contain a single or multiple speed key gear.
Locking component with engagement locking surface is to be configured in the cyclic configuration that drives flange.Its ring that is made of plastics or becket one (for example) is formed elastically deformable diametrically.This ring be disposed at aerosol apparatus the axle vertical plane on.Behind the locking spring, the locking surface of locking component slides in the path that drives flange and stops spring to discharge.Locking component is through press-button actuated.Actuation button connects or is bonded on the locking component.Be to activate the locking clamping mechanism, make actuation button be parallel to ring plain and move preferably and move in the aerosol apparatus, and this deformable loop and then in the planar annular internal strain.The structure of locking pliers mechanism is specified among the WO 97/20590.
The lower case parts are pushed on the spring shell vertically and cover bearing, axle driving and fluidic storage capsule.
When this aerosol apparatus of operation, the upper member of shell is with respect to the rotation of outer casing underpart parts, outer casing underpart parts band upper spring shell.Meanwhile, spring is compressed and tension through the helical form balladeur train, and clamping mechanism meshes automatically.The anglec of rotation is preferably the integer part of 360 degree, for example 180 degree.Simultaneously when spring through when tension, the driving flange component in the shell upper member moves with specified rate, in the cylinder of hollow piston through being returned to pump case, some fluids in the storage capsule suck in the altitude chamber that enters before the nozzle thus.
If need, then contain a plurality of replaceable storage capsule for the treatment of the spray flow body and can insert in the aerosol apparatus in succession and use subsequently.Storage capsule contains with good grounds aerosol formulation of the present invention.
Spray process is initial through the flicking actuation button.Clamping mechanism is opened the path that drives flange component subsequently.Spring through tension is pushed into piston in the cylinder in the pump case.Fluid sprays with Sprayable from the nozzle of aerosol apparatus.
Other details of this structure are disclosed in this is incorporated in herein PCT application case WO97/12683 and WO 97/20590.
The element of aerosol apparatus is made by suitable its materials with function.The shell of aerosol apparatus and (if function allows) miscellaneous part are equally preferably by the alert castable manufactured of plastics.For medical applications, use the physiology to go up acceptable material.
Fig. 6 a/b of WO 97/12687 shows
Figure A200780030784D00221
Aerosol apparatus, it helps sucking according to aqueous aerosol preparation of the present invention.The longitudinal cross-section with spring aerosol apparatus under tension is passed in Fig. 6 a displaying, and the longitudinal cross-section with spring aerosol apparatus under relaxing is passed in Fig. 6 b displaying.
Upper case parts (51) contain pump case (52), and the holder (53) of rose is installed on the pump case end.In holder nozzle body (54) and filter (55).Being fixed in hollow piston (57) part in the driving flange (56) of locking pliers mechanism protrudes and enters in the cylinder of pump case.At the hollow piston end, its biased valve main body (58).Hollow piston seals through sealing gasket (59).Exist in the upper case parts and end part (60), when relaxing of spring, the driving flange is still in this to be ended on the part.End part (61) and be positioned on the driving flange, when spring stretched, the driving flange is still in this to be ended on the part.After the spring tension, locking component (62) ends slip between part (61) and the support in the upper case parts (63).Actuation button (64) is through being connected on the locking component.The upper case parts at nozzle (65) but in end and move plug-in mounting protective cover (66) sealing.
Spring shell (67) with compression spring (68) is installed on the upper case parts with rotary type by means of attaching clamp (69) and swivel bearing.Lower case parts (70) are pushed on the spring shell.In spring shell, be the replaceable storage capsule (71) of fluid (72) to be sprayed.Only part (73) sealing of storage capsule warp, part hollow piston protrusion enters in the storage capsule and makes its terminal fluid interior (storage active substance solution) that immerses through only being somebody's turn to do.
The axle of mechanical counter (74) is installed on the outside of spring shell.Driving pinion (75) is positioned at the tip of the axis that turns to the upper case parts.It on axle saddle (76).
The above-mentioned aerosol apparatus aerosol that aerosol formulation according to the present invention is suitable for sucking with formation that is suitable for spraying.
If use above-mentioned technology
Figure A200780030784D00231
Spraying is according to preparation of the present invention, then whole strokes of inhaler or repeatedly the stroke operation make at least 97%, preferred at least 98% the output should be corresponding to the amount of defining, its margin of tolerance is no more than 25% of this amount, preferably is no more than 20%.Each stroke preferably between 5 to 30mg, more preferably 5 and 20mg between preparation as the amount of defining transmission.
Preparation of the present invention also can use the inhaler except that above-mentioned those inhalers to atomize, for example injection stream inhaler or drop inhaler.
The present invention also relates to by above-mentioned according to a kind of in the pharmaceutical preparation of the present invention and the suction test kit formed of the inhaler of this pharmaceutical preparation that is suitable for spraying.The present invention preferably relates to by above-mentioned a kind of and above-mentioned according in the pharmaceutical preparation of the present invention
Figure A200780030784D00232
The suction test kit that inhaler is formed.
If use above-mentioned
Figure A200780030784D00233
The device per nasal is thrown and preparation, and then this aerosol apparatus can possess adnexa on nozzle, and it is similar to a kind of cylindrical pyramid, promptly a kind of cone with circle or oval cross section; Or taper, circle or elliptic cylindrical.This adnexa inner for hollow and have two openings.Wherein an opening can be placed on the nozzle and another opening can be inserted in the ditch head hole at the tip.
Therefore, this adhering member preferably is the jet pipe form of conventional per nasal spraying.Adhering member can be through construction so that removably or non-dismountablely be connected to mouthpiece.The also alternative mouthpiece of this type of adhering member.
Can suck solution and be contained in the suitable close container of airtight and liquid, the capacity of this container is suitable for desirable purposes, and container is plasticity and irreversibly flattens and almost completely emptying shading to depress according to predetermined way thus.
This problem is to solve by the container that is used for medicinal fluid according to the present invention, and this container is airtight and liquid is close and be characterised in that:
Bag film, it is sealed at both ends and be out of shape because of external pressure when the pressure reduction that exists between internal tank and its environment less than 300hPa (300mbar) and flatten;
And intrinsic hard flange, it closely is connected to bag film and is constructed into and is used for container is installed on the element that removably connects on the moving nozzle;
And at least one weld seam, bag film is in spool substantially the meet at right angles extension of at least one end by the sealing of this weld seam and this weld seam and this bag;
And seal point, it is in this intrinsic hard flange;
And the liquid transfer point, it is in the zone of intrinsic hard flange.
In another embodiment, this can flatten bag film and can be out of shape and flatten because of being lower than 150hPa (150mbar) or being preferable over external pressure under the pressure reduction of 80hPa (80mbar).
Bag film can be sealed by the weld seam at two ends.In this case, intrinsic hard flange closely is soldered to the side of bag film, preferably approaches an end of bag film.Yet, this bag film also can be at one end by the weld seam tight seal and at the other end by intrinsic hard flange tight seal.In this case, an end of bag film is soldered to intrinsic hard flange, preferably in edge week of this intrinsic hard flange.Intrinsic hard flange can adopt various forms.If it is installed on the end of bag film, form the closure member of this bag film, then its rotary type symmetry and be suitable for the size of bag film end.Intrinsic hard flange can possess guiding channel, distributing nozzle introduce wherein and when container is in the appropriate location this distributing nozzle be positioned at wherein.The guiding channel that is pressed into counterpart that has around distributing nozzle can be provided aptly.This is pressed into the part that counterpart can be guiding channel, and its smooth internal walls by the internal diameter with the external diameter that only is different from distributing nozzle is slightly formed.In another embodiment, many projections can be provided on the inwall of a part of guiding channel.This projection can (for example) be three and extends axially and the protuberance of symmetric arrays and elongation.In addition, a plurality of protuberances that each interval arrangement vertically can be provided and on angular orientation, extend, its (for example) forms two rings, or is made up of many loop sections.In addition, the shape of these projections can be spiral type; It can be formed or be made up of greater than the spiral section of the girth of guiding channel a length by the many spiral sections on the inwall that is scattered in guiding channel.This is pressed into counterpart can make container be installed on the abundant stable base that is provided for intrinsic hard flange on the distributing nozzle and on this distributing nozzle.In addition, container can be sloughed distributing nozzle and can not destroy this distributing nozzle after emptying.
Intrinsic hard flange is made up of rubber, metal or plastic cement, preferably is made up of thermoplastic plastic's material.Can make intrinsic hard flange from bag film or bag film inside from its identical plastic cement of making aptly.
Weld seam in the bag film one or both ends can be U-shaped, V-arrangement or T shape; Its substantially with the axle stretching, extension that meets at right angles of this bag.It can extend on the direction of principal axis top of this bag, impels bag film generation regulation distortion when withdrawn fluid thus.
Seal point can be provided in the inside or an end of guiding channel.Sealing point can be made up of the ring that is arranged in the groove on the inwall that is formed at guiding channel.The cross section of this ring can be O shape or is substantially rectangle.This ring is chosen wantonly possesses sealing lip.This ring can be made up of elastomer, thermoplastic elastomer (TPE) or rubber.Seal point seals the internal tank that is installed on the distributing nozzle to surrounding air with airtight and the close mode of liquid.It allows empty to slough distributing nozzle.Under the inadequate situation of the sealing function that is pressed into counterpart, need seal point.
Transfer point preferably is constructed into puncture site.But membrana perforata can be provided in this puncture site place, and when being placed in container on the distributing nozzle this film is bored a hole.Between the fluid space of this film preferred arrangement in seal point and bag film.But membrana perforata can be provided in an end or the inside of guiding channel.It preferably directly is installed on the end of guiding channel or approaches this end towards fluid space.It can be the part of intrinsic hard flange or the part of bag film.If it is the part of intrinsic hard flange, then it can produce simultaneously with this intrinsic hard flange.It can be made by the plastic cement identical with intrinsic hard flange.But membrana perforata serves as the original seal of bag film inside.
In another embodiment, transfer point can seal by means of sealing film, and the sealing thin film was sloughed maybe before being placed in container on the distributing nozzle and is pierced when being placed in container on the distributing nozzle.
Intrinsic hard flange can divide a part or several portions.Many parts flange can preferably divide two parts.The exterior section of flange closely is connected to bag film.Exterior section contains the opening with the interior section tight seal.These two parts can be twisted in together by screw thread, or can be connected or be engaged in together by the ultrasound welding by snap fit.The single piece type flange is similar to two parts flange and forms but do not contain Connection Element.Intrinsic hard flange can be pressed into counterpart, be used for the groove of seal point and but membrana perforata produces simultaneously.
Bag film can be made up of the pipe that does not have the weld seam that extends on the axial direction of bag film.In addition, it can make and have one or two weld seam that extends in a longitudinal direction from thin film.The bag that it can be constructed into flat bag or have the side pleat.Bag with longitudinal extension weld seam is for preferred.
It is wide that weld seam on the bag film can be 0.7mm to 3mm; Its width is to select according to the demand of the sealing characteristics of this seam and durability.Indulging to being sewn on welding back on the bag film is flexible circular so that substantially near the outside of bag film and make this bag film only be slightly wider than the width of its not welding portion between weld seam.
Bag film can be made up of the metal or metal alloy paillon foil, is preferably become by aluminum, gold or copper group, or is made up of plastic film, preferred thermoplastic plastic film.In another embodiment, bag film can be made up of the laminated film of plastic cement and metal.Laminated film preferably is made up of the thin film that two or three are engaged in together.In addition, bag film can be made up of the plastic film that (for example) coated by vapour deposition on metal, glass or the ceramic layer.The thin film of plastic cement or metal is several micron thickness.Metal, glass or pottery through the thickness of the layer of vapour deposition in sub-micrometer range.
The laminated film that comprises two thin film can be made up of the tinsel and the plastic film that are engaged in together.This tinsel forms the inside or the outside of this laminated film.In another embodiment, laminated film is made up of two kinds of different plastic cement.
The laminated film that comprises three thin film preferably is made up of two plastic films, provides tinsel between these two plastic films.All three thin film are engaged in together.The alternative metals paillon foil can exist through glass or the ceramic layer of vapour deposition on plastic film, for example silicon oxide (SiOx).
In another embodiment, the inner membrance of laminated film is made up of copolymer (for example polyethylene and ethylene copolymers of ethylene-acrylic acid).For the outer plastic film of laminated film, preferably use plastic cement, polyethylene terephthalate for example, its melt temperature is higher than the melt temperature of inner membrance plastic cement.This makes and is easier to weld the inner membrance plastic cement to form seam when producing bag film.In laminated film, stick together promoting layer and can choose wantonly and be provided between two thin film.
Bag film can be made up of the thick plastic film of 20 μ m to 100 μ m.It also can be made up of the laminated film with the thick metal adventitia of thick plastic cement inner membrance of 20 μ m to 100 μ m and 8 μ m to 20 μ m.It also can be made up of the laminated film with the thick plastic cement adventitia of thick metal intermediate coat of the thick plastic cement inner membrance of 20 μ m to 100 μ m, 8 μ m to 20 μ m and 10 μ m to 40 μ m.
Pad between weld seam on the bag film and bag film and the intrinsic hard flange is that the known method (such as thermal weld, ultrasonic fusing or induction welding) by the laminated film that is used to have metal level produces, and pad preferably presses down at heated condition and is formed on together.These class methods are described among (for example) EP-0 111131 and the EP-0 130 239.
Can be attached to bag film by sulfuration by sticking together or choosing wantonly by rubber or metal intrinsic hard flange.
Container can be arranged in the intrinsic hard sleeve of metal or plastic cement, and this telescopic end is connected to intrinsic hard flange detachable or non-dismountablely, is sealed by pedestal and the other end is optional.Sleeve all sealings all around substantially.Yet it contains at least one opening or has the gap at the attachment point place with flange.In addition, sleeve can be constructed into the intrinsic hard basket with a plurality of openings.Container can be arranged in the intrinsic hard U-shaped carriage of instead of sleeve, and the end of every lower limb of this carriage is attached to intrinsic hard flange and these lower limbs are longer than bag film.The container that is arranged in sleeve only is attached to sleeve at intrinsic hard flange place.With the terminal of weld seam sealing or with two ends of the bag film of weld seam sealing and be not attached to sleeve.
When liquid when container marches in the distributing nozzle, bag film flattens into flat because of the external pressure effect.Opening or the gap through sleeve and intrinsic hard flange between and enter space sleeve and bag film between and thus make pressure be able to equilibrium of air in sleeve.Therefore, there are not needs in the valve in the bag film, and the liquid in the bag film does not contact with air.
Bag film for medical fluid and component thereof and for gas for non-proliferation.Select to be used for the material of bag film and the structure of optional laminated film thus.For reaching purpose of the present invention, non-proliferation is meant that the liquid because of spreading from container loses (measuring with ethanol at ambient temperature) less than 0.6 milligram/day, preferably less than 0.4 milligram/day, and most preferably less than 0.2 milligram/day, and especially less than 0.1 milligram/day.
The inner membrance of bag film or inside contact with the liquid of introducing wherein.This thin film is from not adhered to by liquid and the material that liquid does not have an adverse effect being made.This thin film is preferably through designing welding.
One of in the thin film that is coated with by vapour deposition or one deck (for example) diffuse out or diffuse into the diffusion barrier of bag film for preventing diffusion of liquid or its component and gas.Can protect diffusion barrier to avoid mechanical damage aptly by means of coating another plastic film on the diffusion barrier and when thin film is crooked, avoid tearing, to prevent the diffusion of liquid or gas for a long time.
When bag film is non-proliferation to gas, because of the decompression that removes in the caused bag film of liquid can not be compensated by the internal gas diffusion, and even when the still flattening reliably of bag film when container removes lentamente of the fluid utmost point.Liquid also can divide numerous a small amount of (for example 200 dosage) to remove from bag film, scatters through the long duration (for example three months).
Being arranged in substantially, the container of sealing sleeve is difficult to enter for the outside and can be not impaired when reaching between the storage life on being placed in distributing nozzle.Seal sleeve or be construed as the sleeve of basket or intrinsic hard carriage makes and is easier to store container with thin-walled bag film and handles when distributing nozzle removes empty when being placed in it on distributing nozzle or when being easier to substantially with a plurality of openings.
Distributing nozzle is used for the hollow piston of the nebulizer of medical fluid for (for example).This type of nebulizer is described among the DE-195 36 902.5 and reaches among the WO-97/12687 (especially wherein Fig. 6 a and 6b).The hollow piston of this nebulizer is constructed into the distributing nozzle that is used for medicinal fluid that is contained in the container of the present invention.Container is placed in preferably on the hollow piston of installing along the axle of nebulizer, and the end of this hollow piston thrusts in the distributing nozzle and thus and immerses in the medicinal fluid.Seal point in the intrinsic hard flange is from the outer wall tight seal internal tank of hollow piston.But be pressed into the container on the counterpart mechanical fasteners hollow piston.
Between alternate container and the distributing nozzle be pressed into counterpart (friction engagement is connected) or except that this is pressed into counterpart, between the intrinsic hard flange of container and distributor (for example nebulizer), provide applicatively can discharge, interlocking engagement is connected.This connection (connection of push-in type snap fit) can be made up of the carbine in a plurality of connecting elements that are installed in the distributor.When pushing container in the distributor, mesh in the dimple of carbine in flange, for example in annular groove or behind the edge of intrinsic hard flange.Snap fit lugs preferably is circle or oblique on the both direction that container moves, and therefore can be installed in the distributor by applying the removable empty of moderate force and expiring container.
But container of the present invention especially is fit to do the replaceable cartridge case of the inhalation agent solution in the no propellant atomization device.The capacity of container can be 0.5 to 5ml, is preferably 1 to 4ml, and especially is preferably 1 to 3ml or 2 to 4ml.These solution distribute with the dosage of 10 microlitre to 5 microlitres, preferred 15 microlitre to 20 microlitres in batches.
Sleeve diameter can be 10mm to 30mm, is preferably 12mm to 17mm.Comprise that the length from the container of the part of the outstanding intrinsic hard flange of sleeve can be 20mm to 60mm, is preferably 30mm to 50mm.
Hereinafter given example of formulations does not make purpose of the present invention be limited to the specific compound shown in the example in order to explanation the present invention.
Embodiment
As mentioning, formula 1 chemical compound can prepare by known way.Mention and preferred within the scope of the invention chemical compound is following lists with example.Therefore, preferred drug substances is for containing two kinds of active substances 2 and 3, and those pharmaceutical preparatioies of general formula 1 chemical compound, and described general formula 1 chemical compound is selected from:
Embodiment 1:6-hydroxyl-8-{1-hydroxyl-2-[2-(4-hydroxyl-2,6-dimethyl-phenyl)-1,1-dimethyl-ethylamino]-ethyl }-4H-benzo [1,4] oxazine-3-ketone-mesylate
Embodiment 2:8-{2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [acid-addition salts of 1,4] oxazine-3-ketone
Embodiment 3:6-hydroxyl-8-{1-hydroxyl-2-[2-(4-methoxyl group-phenyl)-1,1-dimethyl-ethylamino]-ethyl }-4H-benzo [1,4] oxazine-3-ketone-hydrochlorate
Embodiment 4:6-hydroxyl-8-{1-hydroxyl-2-[2-(4-phenoxy group-ethyl acetate)-1,1-dimethyl-ethylamino]-ethyl }-4H-benzo [1,4] oxazine-3-ketone-hydrochlorate
Embodiment 5:6-hydroxyl-8-{1-hydroxyl-2-[2-(4-phenoxy group-acetic acid)-1,1-dimethyl-ethylamino]-ethyl }-4H-benzo [1,4] oxazine-3-ketone-hydrochlorate
Embodiment 6:8-{2-[1,1-dimethyl-2-(2,4, the 6-trimethylphenyl)-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone-hydrochlorate
Embodiment 7:6-hydroxyl-8-{1-hydroxyl-2-[2-(4-hydroxyl-phenyl)-1,1-dimethyl-ethylamino]-ethyl }-4H-benzo [1,4] oxazine-3-ketone-hydrochlorate
Embodiment 8:6-hydroxyl-8-{1-hydroxyl-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]-ethyl }-4H-benzo [1,4] oxazine-3-ketone-hydrochlorate
Embodiment 9:8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone-hydrochlorate
Embodiment 10:8-{2-[2-(4-fluoro-3-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone-hydrochlorate
Embodiment 11:8-{2-[2-(4-fluoro-2-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone-hydrochlorate
Embodiment 12:8-{2-[2-(2,4-two fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone-hydrochlorate
Embodiment 13:8-{2-[2-(3,5-two fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone-hydrochlorate
Embodiment 14:8-{2-[2-(4-ethyoxyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone-hydrochlorate
Embodiment 15:8-{2-[2-(3,5-dimethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone-hydrochlorate
Embodiment 16:4-(4-{2-[2-hydroxyl-2-(6-hydroxyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-8-yl)-ethylamino]-2-methyl-propyl group }-phenoxy group)-butyro-acid-addition salts
Embodiment 17:8-{2-[2-(3,4-two fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone-trifluoroacetate
Embodiment 18:8-{2-[2-(2-chloro-4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone-trifluoroacetate
Embodiment 19:8-{2-[2-(4-chloro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [acid-addition salts of 1,4] oxazine-3-ketone
Embodiment 20:8-{2-[2-(4-bromo-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [acid-addition salts of 1,4] oxazine-3-ketone
Embodiment 21:8-{2-[2-(3-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [acid-addition salts of 1,4] oxazine-3-ketone
Embodiment 22:8-{2-[2-(4-fluoro-3-methoxyl group-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [acid-addition salts of 1,4] oxazine-3-ketone
Embodiment 23:8-{2-[2-(4-fluoro-2,6-dimethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [acid-addition salts of 1,4] oxazine-3-ketone
Embodiment 24:8-{2-[2-(4-chloro-2-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [acid-addition salts of 1,4] oxazine-3-ketone
Embodiment 25:8-{2-[2-(4-chloro-3-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [acid-addition salts of 1,4] oxazine-3-ketone
Embodiment 26:8-{2-[2-(4-chloro-2-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [acid-addition salts of 1,4] oxazine-3-ketone
Embodiment 27:8-{2-[2-(3-chloro-4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [acid-addition salts of 1,4] oxazine-3-ketone
Embodiment 28:8-{2-[2-(2,6-two fluoro-4-methoxyl group-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-acid-addition salts of 6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone
Embodiment 29:8-{2-[2-(2,5-two fluoro-4-methoxyl group-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-acid-addition salts of 6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone
Embodiment 30:8-{2-[2-(4-fluoro-3,5-dimethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [acid-addition salts of 1,4] oxazine-3-ketone
Embodiment 31:8-{2-[2-(3,5-two chloro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-acid-addition salts of 6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone
Embodiment 32:8-{2-[2-(4-chloro-3-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-6-hydroxyl-4H-benzo [acid-addition salts of 1,4] oxazine-3-ketone
Embodiment 33:8-{2-[2-(3,4,5-three fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-acid-addition salts of 6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone
Embodiment 34:8-{2-[2-(3,4-two chloro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyl-ethyl }-acid-addition salts of 6-hydroxyl-4H-benzo [1,4] oxazine-3-ketone
Choose the acid-addition salts form that is with sour HX wantonly, wherein X -Can have one of above given implication, and optional mixture, racemic modification, solvate or the hydrate forms that is its tautomer, enantiomer, enantiomer.
Following table has demonstrated the compilation of example of formulations of the present invention.Abbreviation EDTA represents edta disodium dihydrate, and BHA represents that Butylated hydroxyanisole and BHT represent butylated hydroxytoluene.
Specified active substance 1,2 and 3.1 optional uses with its salt and/or hydrate forms, but it provides with the quality about the free cations of 1 free alkali and 3.1 herein.Chemical compound 1 uses in following examples with hydrochlorate, tetrafluoro acetate (hydrotetrafluoroacetate) or mesylate (hydromethanesulphonate) form, and chemical compound 3 uses with the monohydrate form of bromide.
A) following table demonstrates the embodiment of preparation of the present invention of R-enantiomer, active substance 2 and the active substance 3.1 of the chemical compound of the embodiment 1 that is alkali and cationic form.100ml pharmaceutical preparation contains:
Figure A200780030784D00321
B) following table demonstrates the embodiment of preparation of the present invention of R-enantiomer, active substance 2 and the active substance 3.1 of the chemical compound of the embodiment 3 that is alkali and cationic form.100ml pharmaceutical preparation contains:
Figure A200780030784D00331
C) following table demonstrates the embodiment of preparation of the present invention of R-enantiomer, active substance 2 and the active substance 3.1 of the chemical compound of the embodiment 7 that is alkali and cationic form.100ml pharmaceutical preparation contains:
D) following table demonstrates the embodiment of preparation of the present invention of R-enantiomer, active substance 2 and the active substance 3.1 of the chemical compound of the embodiment 9 that is alkali and cationic form.100ml pharmaceutical preparation contains:
Figure A200780030784D00351
E) following table demonstrates the embodiment of preparation of the present invention of R-enantiomer, active substance 2 and the active substance 3.1 of the chemical compound of the embodiment 14 that is alkali and cationic form.100ml pharmaceutical preparation contains:
Figure A200780030784D00361
F) following table demonstrates the embodiment of preparation of the present invention of R-enantiomer, active substance 2 and the active substance 3.1 of the chemical compound of the embodiment 17 that is alkali and cationic form.100ml pharmaceutical preparation contains:
Figure A200780030784D00371
G) following table demonstrates the embodiment of preparation of the present invention of R-enantiomer, active substance 2 and the active substance 3.1 of the chemical compound of the embodiment 1 that is alkali and cationic form.100ml pharmaceutical preparation contains:
Figure A200780030784D00381
H) following table demonstrates the embodiment of preparation of the present invention of R-enantiomer, active substance 2 and the active substance 3.1 of the chemical compound of the embodiment 3 that is alkali and cationic form.100ml pharmaceutical preparation contains:
Figure A200780030784D00391
I) following table demonstrates the embodiment of preparation of the present invention of R-enantiomer, active substance 2 and the active substance 3.1 of the chemical compound of the embodiment 7 that is alkali and cationic form.100ml pharmaceutical preparation contains:
Figure A200780030784D00401
J) following table demonstrates the embodiment of preparation of the present invention of R-enantiomer, active substance 2 and the active substance 3.1 of the chemical compound of the embodiment 9 that is alkali and cationic form.100ml pharmaceutical preparation contains:
K) following table demonstrates the embodiment of preparation of the present invention of R-enantiomer, active substance 2 and the active substance 3.1 of the chemical compound of the embodiment 14 that is alkali and cationic form.100ml pharmaceutical preparation contains:
Figure A200780030784D00421
L) following table demonstrates the embodiment of preparation of the present invention of R-enantiomer, active substance 2 and the active substance 3.1 of the chemical compound of the embodiment 17 that is alkali and cationic form.100ml pharmaceutical preparation contains:
M) following table demonstrates the embodiment of preparation of the present invention of R-enantiomer, active substance 2 and the active substance 3.1 of the chemical compound of the embodiment 1 that is alkali and cationic form.100ml pharmaceutical preparation contains:
Figure A200780030784D00441
N) following table demonstrates the embodiment of preparation of the present invention of R-enantiomer, active substance 2 and the active substance 3.1 of the chemical compound of the embodiment 3 that is alkali and cationic form.100ml pharmaceutical preparation contains:
O) following table demonstrates the embodiment of preparation of the present invention of R-enantiomer, active substance 2 and the active substance 3.1 of the chemical compound of the embodiment 7 that is alkali and cationic form.100ml pharmaceutical preparation contains:
Figure A200780030784D00461
P) following table demonstrates the embodiment of preparation of the present invention of R-enantiomer, active substance 2 and the active substance 3.1 of the chemical compound of the embodiment 9 that is alkali and cationic form.100ml pharmaceutical preparation contains:
Figure A200780030784D00471
Q) following table demonstrates the embodiment of preparation of the present invention of R-enantiomer, active substance 2 and the active substance 3.1 of the chemical compound of the embodiment 14 that is alkali and cationic form.100ml pharmaceutical preparation contains:
Figure A200780030784D00481
R) following table demonstrates the embodiment of preparation of the present invention of R-enantiomer, active substance 2 and the active substance 3.1 of the chemical compound of the embodiment 17 that is alkali and cationic form.100ml pharmaceutical preparation contains:

Claims (21)

1. pharmaceutical preparation, it contains one or more general formula 1 chemical compounds as active substance:
Figure A200780030784C00021
Wherein:
R 1Expression hydrogen, C 1-4Alkyl, O-C 1-4Alkyl or halogen;
R 2Expression hydrogen, C 1-4Alkyl, O-C 1-4Alkyl or halogen;
R 3Expression hydrogen, C 1-4Alkyl, O-C 1-4Alkyl, halogen, OH ,-O-C 1-4Alkylidene-COOH or O-C 1-4Alkylidene-COO-C 1-4Alkyl;
X -Expression monovalence or multivalent anions are preferably the monovalence or the multivalent anions that are selected from chloride ion, bromide ion, iodide ion, sulfate radical, phosphate radical, methanesulfonate, nitrate anion, maleate, acetate, benzoate anion, citrate, salicylate, trifluoroacetic acid root, fumaric acid radical, tartrate anion, oxalate, amber acid radical, benzoate anion and p-methyl benzenesulfonic acid root;
Optional mixture, racemic modification, solvate or the hydrate forms that is its tautomeride isomer, enantiomer, enantiomer;
Active substance 2, it is selected from Budesonide, beclometasone, fluticasone, ciclesonide or its metabolite, optional mixture, racemic modification, solvate or the hydrate forms that is its tautomeride isomer, enantiomer, enantiomer;
Active substance 3, it is selected from tiotropium salt, oxygen holder ammonium salt, fluorine holder ammonium salt, ipratropium salt, glycopyrronium salt and Trospium cation salt, optional mixture, racemic modification, solvate or the hydrate forms that is its tautomeride isomer, enantiomer, enantiomer;
At least a pharmacology goes up acceptable acid, and optionally also contain other pharmacology and go up acceptable excipient, and as ethanol or the water and the alcoholic acid mixture of solvent.
2. pharmaceutical preparation as claimed in claim 1 is characterized in that it contains active substance 2 and active substance 3, and one or more formula 1 chemical compounds, wherein:
R 1Expression hydrogen, methyl, ethyl, fluorine or chlorine;
R 2Expression hydrogen, methyl, ethyl, fluorine or chlorine;
R 3Expression hydrogen, methyl, ethyl, propyl group, OH, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, O-CH 2-COOH, O-CH 2-COO methyl or O-CH 2-COO ethyl ,-O-CH 2-CH 2COOH, O-CH 2-CH 2COO methyl or O-CH 2-CH 2The COO ethyl ,-O-CH 2-CH 2-CH 2COOH, O-CH 2-CH 2-CH 2The COO methyl or-O-CH 2-CH 2-CH 2The COO ethyl;
X -Expression monovalence or multivalent anions are preferably the monovalence or the multivalent anions that are selected from chloride ion, bromide ion, iodide ion, sulfate radical, phosphate radical, methanesulfonate, nitrate anion, maleate, acetate, benzoate anion, citrate, salicylate, trifluoroacetic acid root, fumaric acid radical, tartrate anion, oxalate, amber acid radical, benzoate anion and p-methyl benzenesulfonic acid root;
Optional mixture, racemic modification, solvate or the hydrate forms that is its tautomer, enantiomer, enantiomer.
3. pharmaceutical preparation as claimed in claim 1 is characterized in that it contains active substance 2 and active substance 3, and one or more formula 1 chemical compounds, wherein:
R 1Expression hydrogen or methyl are preferably hydrogen;
R 2Expression hydrogen or methyl are preferably hydrogen;
R 3Expression methyl, OH, methoxyl group, fluorine, chlorine, bromine, O-CH 2-COOH or-O-CH 2-COO ethyl;
X -Expression is selected from the monovalence or the multivalent anions of chloride ion, bromide ion, sulfate radical, methanesulfonate, maleate, acetate, benzoate anion, citrate, salicylate, trifluoroacetic acid root, fumaric acid radical, tartrate anion and amber acid radical;
Optional mixture, racemic modification, solvate or the hydrate forms that is its tautomer, enantiomer, enantiomer.
4. as one of in the claim 1 to 3 described pharmaceutical preparation, wherein this active substance 2 is selected from budesonide, ciclesonide or its metabolite, optional mixture, racemic modification, solvate or the hydrate forms that is its tautomer, enantiomer, enantiomer.
5. as one of in the claim 1 to 3 described pharmaceutical preparation, wherein this active substance 3 is selected from tiotropium bromide, oxitropium bromide or ipratropium bromide, optional mixture, racemic modification, solvate or the hydrate forms that is its tautomeride isomer, enantiomer, enantiomer.
6. as one of in the claim 1 to 4 described pharmaceutical preparation, wherein this pharmacology goes up acceptable acid and is selected from mineral acid hydrochloric acid, phosphoric acid, hydrobromic acid, nitric acid and sulphuric acid, or is selected from organic acid ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid, propanoic acid, sorbic acid, benzoic acid, methanesulfonic acid and benzenesulfonic acid.
7. as one of in the claim 1 to 5 described pharmaceutical preparation, it is characterized in that pH value is 2.0 to 6.5.
8. as one of in the claim 1 to 7 described pharmaceutical preparation, it is characterized in that under various situations 1 ', 2 and 3.1 ' content be about 0.5 to 6000mg/100ml solution independently of one another.
9. as one of in the claim 1 to 9 described pharmaceutical preparation, it is characterized in that it contains the chelating agent of going up acceptable excipient as other pharmacology.
10. pharmaceutical preparation as claimed in claim 9, the content that it is characterized in that chelating agent are 0.1 to 200mg/100ml solution.
11., it is characterized in that it contains the antioxidant of going up acceptable excipient as other pharmacology as one of in the claim 1 to 10 described pharmaceutical preparation.
12. as one of in the claim 1 to 11 described pharmaceutical preparation, it is characterized in that it contains the antioxidant of going up acceptable excipient as other pharmacology, this antioxidant is selected from ascorbic acid, propyl gallate, Butylated hydroxyanisole, butylated hydroxytoluene, tert-butyl group hydroxyquinone, three (2,4-two-tert-butyl-phenyl) phosphite ester and four [methylene (3,4-two-tert-butyl group hydroxyl-hydrogenated cinnamate)] methane, tocopherol, naringenin and resveratrol.
13., it is characterized in that it contains water and alcoholic acid mixture as solvent as one of in the claim 1 to 12 described pharmaceutical preparation.
14., it is characterized in that it contains benzylalcohol, gamma-butyrolacton or carbiphene as cosolvent as one of in the claim 1 to 13 described pharmaceutical preparation.
15. pharmaceutical preparation as claimed in claim 13 is characterized in that it contains water and alcoholic acid mixture as solvent, wherein the ethanol percentage by volume is 30% to 99%.
16. pharmaceutical preparation, it contains the formula 1 ' free alkali as active substance:
Figure A200780030784C00051
Radicals R wherein 1, R 2And R 3Can have the given implication of claim 1 to 3, optional mixture, racemic modification, solvate or the hydrate forms that is its tautomer, enantiomer, enantiomer;
Active substance 2, it is selected from budesonide, beclometasone, fluticasone, ciclesonide or its metabolite, optional mixture, racemic modification, solvate or the hydrate forms that is its tautomer, enantiomer, enantiomer;
Active substance 3, it is selected from tiotropium salt, oxygen holder ammonium salt, fluorine holder ammonium salt, ipratropium salt, glycopyrronium salt and Trospium cation salt, optional mixture, racemic modification, solvate or the hydrate forms that is its tautomer, enantiomer, enantiomer;
At least a pharmacology goes up acceptable acid, and optionally also contain other pharmacology and go up acceptable excipient, and as ethanol or the water and the alcoholic acid mixture of solvent.
17. pharmaceutical preparation as claimed in claim 16, wherein this active substance 2 is selected from budesonide, ciclesonide or its metabolite, optional mixture, racemic modification, solvate or the hydrate forms that is its tautomer, enantiomer, enantiomer.
18. pharmaceutical preparation as claimed in claim 16, wherein this active substance 3 is selected from tiotropium bromide, oxitropium bromide or ipratropium bromide, optional mixture, racemic modification, solvate or the hydrate forms that is its tautomer, enantiomer, enantiomer.
19. be used for the treatment of purposes in the pharmaceutical composition of respiratory system disease in preparation as one of in the claim 1 to 18 described pharmaceutical preparation.
20. the suction test kit, it is by as one of in the claim 1 to 18 described pharmaceutical preparation and be suitable for the inhaler of this pharmaceutical preparation atomizing is formed.
21. suction test kit as claimed in claim 20, wherein this inhaler is
Figure A200780030784C00052
CNA2007800307840A 2006-08-18 2007-08-16 Aerosol formulation for the inhalation of beta agonists Pending CN101505798A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107362140A (en) * 2016-05-11 2017-11-21 广东东阳光药业有限公司 Spray and spray assembly
CN108883079A (en) * 2016-03-15 2018-11-23 广东东阳光药业有限公司 Spray, spraying device and spray assembly

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108883079A (en) * 2016-03-15 2018-11-23 广东东阳光药业有限公司 Spray, spraying device and spray assembly
CN107362140A (en) * 2016-05-11 2017-11-21 广东东阳光药业有限公司 Spray and spray assembly

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