WO2007134968A1 - Ethanolhaltige aerosolformulierung für die inhalation - Google Patents
Ethanolhaltige aerosolformulierung für die inhalation Download PDFInfo
- Publication number
- WO2007134968A1 WO2007134968A1 PCT/EP2007/054492 EP2007054492W WO2007134968A1 WO 2007134968 A1 WO2007134968 A1 WO 2007134968A1 EP 2007054492 W EP2007054492 W EP 2007054492W WO 2007134968 A1 WO2007134968 A1 WO 2007134968A1
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- WIPO (PCT)
- Prior art keywords
- propellant
- acid
- free
- formulations according
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- 239000000203 mixture Substances 0.000 title claims abstract description 80
- 238000009472 formulation Methods 0.000 title claims abstract description 74
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 239000000443 aerosol Substances 0.000 title abstract description 27
- 150000003839 salts Chemical class 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 22
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 claims description 12
- 239000000812 cholinergic antagonist Substances 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- 239000013011 aqueous formulation Substances 0.000 claims description 11
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 8
- 239000008139 complexing agent Substances 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 7
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- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 claims description 6
- 239000000808 adrenergic beta-agonist Substances 0.000 claims description 6
- 239000005557 antagonist Substances 0.000 claims description 6
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 6
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical group [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 6
- 230000003454 betamimetic effect Effects 0.000 claims description 6
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Classifications
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
Definitions
- the present invention relates to propellant-free, ethanol-containing aerosol formulations for inhalation with a defined particle size distribution.
- inhalative administration of drugs is not exclusively, but especially in the treatment of respiratory diseases such as asthma or COPD used.
- suitable pharmaceutical formulations are above all propellant-free aqueous or aqueous-alcoholic solutions of active ingredients.
- propellant-free solution formulations are known in the art.
- Ethanolic formulations are disclosed, for example, by WO 97/01329.
- Aqueous systems are described, for example, by WO 98/27959.
- aqueous formulations for inhalation can not be used if sufficient solubility of the drug constituents in water is not present.
- Formulation ingredients are increased by mixing the aqueous system with ethanol.
- ethanol concentration in an aqueous aerosol formulation significantly affects the particle size distribution of the aerosol generated by an inhaler.
- the present invention relates to propellant-free, aqueous formulations for inhalation, which contain ethanol in an amount of 10 to 50% (v / v) in addition to one or more active ingredients and excipients optionally contained.
- Particularly preferred according to the invention are the abovementioned formulations in which the ethanol content is more than 10%, preferably more than 20%, particularly preferably more than 30%. Particularly preferred are formulations in which the ethanol content is between 40 and 50%.
- the formulations according to the invention usually contain pharmacologically acceptable acids for adjusting the pH.
- the pH of the formulation according to the invention is preferably in the range from 2.0 to 6.5, preferably from 2.2 to 5.0, more preferably from about 2.5 to 4.5.
- inorganic or organic acids can be used as pharmacologically acceptable acids.
- preferred inorganic acids are selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid.
- particularly suitable organic acids are selected from the group consisting of ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and propionic acid.
- Preferred inorganic acids are hydrochloric acid and sulfuric acid, wherein the hydrochloric acid is of particular importance according to the invention.
- organic acids ascorbic acid, fumaric acid and citric acid are preferred, with citric acid being particularly preferred according to the invention.
- mixtures of said acids may also be employed, particularly in the case of acids which, in addition to their acidification properties, also possess other properties, e.g. as flavorants or antioxidants, such as citric acid or ascorbic acid.
- pharmacologically acceptable bases for accurate titration of the pH can be used. Suitable bases are, for example
- Alkali hydroxides and alkali carbonates Preferred alkali ion is sodium. If such bases are used, care must be taken that the resulting salts, which are then present in the finished pharmaceutical formulation, are also pharmacologically acceptable with the abovementioned acid.
- the formulations according to the invention may optionally contain other adjuvants in addition to the active ingredient components. Possible auxiliaries are preferably selected from preservatives and complexing agents.
- the formulations according to the invention may contain as further constituents in particular complexing agents or preservatives.
- complexing agents are understood to mean molecules capable of complexing. Cations, more preferably metallic cations, are preferably to be complexed by these compounds.
- the formulations according to the invention contain as complexing agents preferably editic acid (EDTA) or a known salt thereof, e.g. Sodium EDTA, or disodium EDTA. Preference is given to using disodium edetate, if appropriate in the form of its hydrates, particularly preferably in the form of its dihydrate.
- complexing agents are used in the context of the formulations according to the invention, their content is preferably in a range from 1 to 50 mg per 100 ml, more preferably in a range from 2 to 15 mg per 100 ml of the formulation according to the invention.
- the formulations according to the invention preferably contain a complexing agent in an amount of about 4 to 12 mg per 100 ml, particularly preferably about 10 mg per 100 ml of the formulation according to the invention.
- Analogous as stated above for disodium edetate also applies to possible additives which are comparable with EDTA or its salts and which have complex-forming properties and can be used instead, such as, for example, nitrilotriacetic acid and its salts.
- Preservatives may be used to protect the formulation from contamination with pathogenic germs. Suitable preservatives are those known in the art, in particular benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentrations known from the prior art.
- the formulation of the invention benzalkonium chloride is added.
- the amount of benzalkonium chloride is between 1 mg and 50 mg per 100 ml formulation, preferably about 2 to 15 mg per 100 ml, more preferably about 3 to 12 mg per 100 ml, more preferably about 4 to 10 mg per 100 ml of the inventive Formulation.
- Benzalkonium chloride can also be used according to the invention in admixture with other preservatives.
- the active substances which can be used in the context of the formulations according to the invention are preferably selected from the group consisting of anticholinergics, betamimetics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, dopamine agonists and HIV antihistamines, one or more of these active ingredients may be included.
- Anticholinergics which can be used as active ingredient in the drug combinations according to the invention are preferably selected from the group consisting of tiotropium salts, oxitropium salts, flutropium salts, ipratropium salts, glycopyrronium salts and trospium salts.
- the cations tiotropium, oxitropium, flutropium, ipratropium, glycopyrronium and trospium are the pharmacologically active ingredients. Any reference to the above salts naturally includes reference to the corresponding cations tiotropium, oxitropium, flutropium, ipratropium, glycopyrronium , Trospium.
- the salts are understood as meaning those compounds which, in addition to the cations tiotropium, oxitropium, flutropium, ipratropium, glycopyrronium and trospium as counterion (anion) chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, Fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulfonate, with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate are preferred as counterions.
- the chlorides, bromides, iodides and methanesulfonates are particularly preferred.
- drug combinations containing tiotropium salts, oxitropium salts or ipratropium salts are particularly important according to the invention.
- the tiotropium bromide is particularly important.
- the abovementioned salts can be present in the medicament combinations according to the invention optionally in the form of their solvates or hydrates, preferably in the form of their hydrates.
- the drug combinations according to the invention preferably contain this in the form of the crystalline tiotropium bromide monohydrate, which is known from WO 02/30928.
- the aforementioned anticholinergics have chiral carbon centers.
- the medicament combinations according to the invention may contain the anticholinergics in the form of their enantiomers, mixtures of the enantiomers or racemates, wherein preferably enantiomerically pure anticholinergics are used.
- the concentration of tiotropium cation in the medicament formulations according to the invention is preferably between 0.01 g per 100 g formulation and 0.06 g per 100 g formulation.
- Preferred is an amount of 0.015 g / 100 g to 0.055 g / 100 g, more preferred is an amount of 0.02 g / 100 g to 0.05 g / 100 g.
- Most preferred is an amount of 0.023 + 0.001 g per 100 g formulation up to 0.045 + 0.001 g per 100 g formulation.
- the concentration of ipratropium cation in the medicament formulations according to the invention is preferably between 0.20 g per 100 g formulation and 1.58 g per 100 g formulation. Preferred is an amount of 0.30 g / 100 g to 1.45 g / 100 g, more preferred is an amount of 0.40 g / 100 g to 1.32 g / 100 g. Most preferred is an amount of 0.46 + 0.02 g per 100 g formulation up to 0.92 + 0.02 g per 100 g formulation.
- the concentration of oxitropium cation in the medicament formulations according to the invention is preferably between 0.20 g per 100 g formulation and 1.58 g per 100 g formulation. Preferred is an amount of 0.30 g / 100 g to 1.45 g / 100 g, more preferred is an amount of 0.40 g / 100 g to 1.32 g / 100 g. Most preferred is an amount of 0.46 + 0.02 g per 100 g formulation up to 0.92 + 0.02 g per 100 g formulation.
- the anticholinergics contained in the preparations according to the invention are selected from the salts of the formula
- X - a singly negatively charged anion, preferably an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, Methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate, preferably bromide, optionally in the form of their racemates, enantiomers or hydrates.
- anion preferably an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, Methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate, preferably bromide, optionally in the form of their racemates,
- the concentration with which the above-mentioned anticholinergics are contained in the pharmaceutical preparations according to the invention is according to the invention at about 4 to 2000 mg per 100 g, preferably at about 8 to 1600 mg per 100 g.
- 100 g of the formulations according to the invention contain about 80 to about 1360 mg of the abovementioned anticholinergics (based on pharmacologically active cation).
- their concentration in the compositions according to the invention is usually about 5 to 2500 mg per 100 g, preferably about 10 to 2000 mg per 100 g of pharmaceutical preparation.
- 100 g of the formulations according to the invention contain about 100 to 1700 mg of one of the abovementioned bromides.
- the anticholinergics contained in the preparations according to the invention are selected from the group consisting of 2,2-diphenylpropionic acid tropol ester methobromide, 2,2-diphenylpropionic acid copophenate methobromide, 2-fluoro-2,2-diphenylacetic acid scopine ester methobromide, 2-fluoro-2,2-diphenylacetic acid tropol ester methobromide, 3,3 ', 4,4'-tetrafluorobenzylic acid, tropol ester methobromide, 3,3', 4,4'-tetrafluorobenzilic acid scopine ester methobromide, 4,4'-difluorobenzilic acid triester -methobromide, 4,4'-difluorobenzilic acid copolinester methobromide, 3,3'-difluorobenzylic acid triesterolate, 3,3'
- Tartrates, oxalates, succinates, benzoates or p-toluenesulfonates be included, but the bromides are of particular importance. If appropriate, the abovementioned compounds may be present in the form of their enantiomers, mixtures of their enantiomers or racemates, and, if appropriate, in the form of their hydrates and / or solvates.
- the concentration with which the above-mentioned anticholinergics are contained in the pharmaceutical preparations according to the invention is according to the invention at about 4 to 2000 mg per 100 g, preferably at about 8 to 1600 mg per 100 g.
- 100 g of the formulations according to the invention contain about 80 to about 1360 mg of the abovementioned anticholinergics (based on pharmacologically active
- compositions according to the invention are usually about 5 to 2500 mg per 100 g, preferably about 10 to 2000 mg per 100 g of pharmaceutical preparation.
- 100 g of the formulations according to the invention contain about 100 to 1700 mg of one of the abovementioned bromides.
- Preferred betamimetics are compounds selected from the group consisting of albuterol, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharines, isoprenalines, levosalbutamol, mabuterol, meluadrins,
- the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate ,
- the concentration of the aforementioned betamimetics in the formulations according to the invention is usually about 0.1 to 1600 mg per 100 g, preferably about 0.5 to 1000 mg per 100 g, more preferably 0.75 to 200 mg per 100 g.
- 100 g of the formulations according to the invention contain from about 1 to about 100 mg of the abovementioned betamimetics (in each case based on the free base of the abovementioned compounds).
- Preferred corticosteroids are compounds selected from the group consisting of prednisolone, prednisone, butixocortepionate, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, betamethasone, defiazacort, RPR-106541, NS -126, ST-26, 6,9-difluoro-17 - [(2-furanylcarbonyl) oxy] -1-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionic acid (S.
- Etiprednol-dichloroacetate optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their salts and derivatives, their solvates and / or hydrates.
- Any reference to steroids includes reference to their optional salts or derivatives, hydrates or solvates.
- Examples of possible salts and derivatives of the steroids may be: alkali metal salts, for example sodium or potassium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or even furoates.
- Formulations are usually about 10 to 1800 mg per 100 g, preferably about 100 to 1500 mg per 100 g, more preferably 200 to 1000 mg per 100 g. Particularly preferably, 100 g of the formulations according to the invention contain from about 400 to about 700 mg of the abovementioned steroids.
- Preferred PDE4 inhibitors here are compounds selected from the group consisting of enprofylline, theophylline, roflumilast, ariflo (cilomilast), tof ⁇ milast, pumafentrin, lirimilast, arofylline, atizoram, D-4418, bay 198004, BY343, CP-325,366, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V- 11294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, N- (3,5-dichloro-1-oxo-pyridin-4-yl) -4-difluoromethoxy 3-cyclopropylmethoxybenzamide, (-) p - [(4 ⁇ R *, 10Z> S *)
- the acid addition salts of the PDE4 inhibitors are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate ,
- the concentration of the aforementioned PDE4 inhibitors in the formulations according to the invention is usually about 1 to 1500 mg per 100 g, preferably about 10 to 1200 mg per 100 g, more preferably 100 to 1000 mg per 100 g.
- 100 g of the formulations according to the invention contain about 150 to about 800 mg of the abovementioned PDE4 inhibitors (in each case based on the free base of the abovementioned compounds).
- Preferred LTD4 antagonists here are compounds selected from the group consisting of montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078 , VUF-K-8707, L- 733321, l - (((R) - (3- (2- (6,7-Difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2-hydroxy-2-propyl) phenyl) thio) methylcyclopropane-acetic acid, l - (((l (R) -3 (3- (2- (2,3-dichlorothieno [3,2-b] pyridin-5-yl) - (E) -ethenyl) -phenyl ) -3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) thi
- the acid addition salts of the LTD4 antagonists are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, Hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate
- salts or derivatives for their formation the LTD4-antagonists optionally in the L are for example understood: alkali metal salts, such as sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
- concentration of the aforementioned LTD4-antagonists in the formulations according to the invention is usually about 0.1 to 1600 mg per 100 g, preferably
- Preferred dopamine agonists are compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viozan, optionally in the form of their racemates, enantiomers , Diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.
- the acid addition salts of the dopamine agonists are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate ,
- concentration of the aforementioned dopamine agonists in the formulations according to the invention is usually about 0.1 to 1500 mg per 100 g, preferably about 1 to 1000 mg per 100 g, more preferably 5 to 750 mg per 100 g (in each case based on the free base of the above compounds).
- Hl antihistamines here are preferably compounds used, which are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, Mizo lastin, ketotifen, emedastine, dimetindene, clemastine, bamipine, Cexchlorpheniramin, pheniramine, doxylamine, Chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclocine, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.
- the acid addition salts of the Hl antihistamines are preferably selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate,
- Hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate are Hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
- the concentration of the abovementioned Hl antihistamines in the formulations according to the invention is usually about 1 to 1500 mg per 100 g, preferably about 10 to 1000 mg per 100 g, more preferably 20 to 800 mg per 100 g (in each case based on the free Base of the above compounds).
- a further aspect of the present invention relates to the use of the pharmaceutical formulations according to the invention for the preparation of a medicament for the treatment of respiratory diseases selected from the group consisting of obstructive pulmonary diseases of different origin, pulmonary emphysema of different origin, restrictive lung diseases, interstitial lung diseases, cystic fibrosis, bronchitis of different origin , Bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary edema.
- respiratory diseases selected from the group consisting of obstructive pulmonary diseases of different origin, pulmonary emphysema of different origin, restrictive lung diseases, interstitial lung diseases, cystic fibrosis, bronchitis of different origin , Bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary edema.
- the above-mentioned use is for the manufacture of a medicament for the treatment of obstructive lung diseases selected from the group consisting of bronchial asthma, pediatric asthma, severe asthma, acute asthma attack, chronic bronchitis, and chronic obstructive pulmonary disease (COPD) for the preparation of a medicament for the treatment of asthma bronchial or COPD according to the invention is particularly preferred.
- obstructive lung diseases selected from the group consisting of bronchial asthma, pediatric asthma, severe asthma, acute asthma attack, chronic bronchitis, and chronic obstructive pulmonary disease (COPD) for the preparation of a medicament for the treatment of asthma bronchial or COPD according to the invention is particularly preferred.
- COPD chronic obstructive pulmonary disease
- compositions of the invention for the manufacture of a medicament for the treatment of pulmonary emphysema originating in COPD (chronic obstructive pulmonary disease) or ⁇ l-proteinase inhibitor deficiency.
- restrictive lung diseases selected from the group consisting of allergic alveolitis, restrictive pulmonary diseases induced by occupational noxae, such as asbestosis or silicosis and restriction due to lung tumors such as lymphangiosis carcinomatosa. brochoalveolar carcinoma and lymphomas.
- interstitial lung diseases which are selected from the group consisting of infectious pneumonias, such as due to infection with viruses, bacteria, fungi, protozoa, helminths or other pathogens, pneumonitis due to different causes such as aspiration and left ventricular failure, radiation-induced pneumonitis or fibrosis, collagenoses such as lupus erythematosus, sytemic scleroderma or sarcoidosis, granulomatosis such as Boeck's disease, idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF).
- infectious pneumonias such as due to infection with viruses, bacteria, fungi, protozoa, helminths or other pathogens
- pneumonitis due to different causes such as aspiration and left ventricular failure
- radiation-induced pneumonitis or fibrosis such as lupus erythematosus, sytemic scleroderma or sarcoidos
- compositions according to the invention for the production of a medicament for the treatment of cystic fibrosis or cystic fibrosis.
- bronchitis such as, for example, bronchitis due to bacterial or viral infection, allergic bronchitis and toxic bronchitis.
- the pharmaceutical formulations according to the invention for the manufacture of a medicament for the treatment of pulmonary edema, for example toxic pulmonary edema after aspiration or inhalation of toxic substances and foreign substances.
- the present invention relates to the use of the pharmaceutical formulations of the invention for the manufacture of a medicament for the treatment of asthma or COPD.
- the manufacture of a medicament for once-daily treatment of inflammatory and obstructive airway diseases particularly preferably for the once-daily treatment of asthma or COPD.
- the present invention relates to a method for the treatment of the abovementioned diseases, characterized in that one or more of the abovementioned pharmaceutical formulations according to the invention are administered in therapeutically effective amounts.
- the present invention is concerned with inhalable liquid
- the formulations according to the invention can be inhaled orally or pernasally.
- a liquid, dispensing with propellant gases formulation by means of suitable inhalers offers.
- the inhalative administration of such a formulation can be carried out both orally and nasally.
- Particularly suitable are those inhalers which can nebulise a small amount of a liquid formulation in the therapeutically necessary dosage within a few seconds in a therapeutically inhalable aerosol.
- nebulizers in which an amount of less than 100 microliters, preferably less than 50 microliters, more preferably less than 25 microliters of active substance solution with preferably one stroke or two strokes, results in an aerosol with an average particle size (or Particle diameter) of less than 20 microns, preferably less than 10 microns, so can be atomized that the inhalable fraction of the aerosol already corresponds to the therapeutically effective amount.
- Such a device for the propellant-free administration of a metered amount of a liquid medicament for inhalation use, for example, in International Patent Application WO 91/14468 "Atomizing Device and Methods" and in WO 97/12687, there Figures 6a and 6b and the accompanying description , described in detail.
- a drug solution is transferred by means of high pressure of up to 500 bar in a respirable aerosol and sprayed.
- the solution formulations are stored in a reservoir. It is necessary that the active substance formulations used have a sufficient storage stability and at the same time are such that they can be applied directly for the medical purpose as far as possible without further manipulation. Furthermore, they must not contain components which may interact with the inhaler in such a way that the inhaler or the pharmaceutical grade of the solution or of the aerosol produced could be damaged.
- a special nozzle is used, as described, for example, WO 94/07607 or WO 99/16530. Both are hereby incorporated by reference.
- Drug formulations must also have sufficient pharmaceutical grade, i. they should be pharmaceutically stable over a shelf life of a few years, preferably at least one year, more preferably two years.
- These propellant-free solution formulations must also be able to be atomized under pressure by means of an inhaler, wherein the mass discharged in the generated aerosol is reproducibly within a defined range.
- compositions according to the invention are preferably used in an inhaler of the type described above in order to obtain therefrom the inventive produce propellant-free aerosols. For this reason, reference should again be made expressly to the patent documents described at the outset, to which reference is hereby incorporated by reference.
- WO 97/12687 a further developed embodiment of the preferred inhaler is disclosed in WO 97/12687 (see there in particular FIGS. 6a and 6b and the relevant parts of the description).
- This nebuliser (Respimat ®) can advantageously be used to produce the inhalable aerosols according to the invention. Due to its cylindrical shape and a handy size of less than 9 to 15 cm in length and 2 to 4 cm in width, this device can always be carried by the patient.
- the nebulizer sprays a defined volume of the drug formulation using high pressures through small nozzles to form inhalable aerosols.
- the preferred atomizer consists of an upper housing part, a
- Pump housing a nozzle, a locking mechanism, a spring housing, a spring and a reservoir, characterized by a pump housing which is fixed in the upper housing part, and which carries at one end a nozzle body with the nozzle or nozzle assembly, - a hollow piston with valve body, a Abtriebsfiansch, in which the hollow piston is fixed, and located in the
- Upper housing part is located, a locking body, which is located in the upper housing part, a spring housing with the spring therein, which is rotatably mounted on the upper housing part by means of a rotary bearing, a lower housing part, which is mounted on the spring housing in the axial direction.
- the hollow piston with valve body corresponds to a disclosed in WO 97/12687 devices. It partially protrudes into the cylinder of the pump housing and is arranged axially displaceably in the cylinder.
- the hollow piston with valve body exerts on its high pressure side at the time of release of the spring a pressure of 5 to 60 MPa (about 50 to 600 bar), preferably 10 to 60 MPa (about 100 to 600 bar) on the fluid, the measured Wirkstoffiösung.
- the valve body is preferably attached to the end of the hollow piston, which faces the nozzle body.
- the nozzle in the nozzle body is preferably microstructured, i. produced by microtechnology.
- Microstructured nozzle bodies are disclosed, for example, in WO-99/16530; This document is hereby incorporated by reference, in particular to the figure 1 and its description disclosed therein.
- the nozzle body consists e.g. of two fixed plates of glass and / or silicon, at least one plate of which has one or more microstructured channels connecting the nozzle inlet side to the nozzle outlet side.
- On the nozzle outlet side is at least one round or non-round aperture of 2 to 10 micrometers in depth and 5 to 15 micrometers in width, the depth being preferably 4.5 to 6.5 micrometers and the length 7 to 9 micrometers.
- the jet directions of the nozzles in the nozzle body can be parallel to one another or they are inclined towards one another in the direction of the nozzle opening.
- the jet directions may be inclined at an angle of 20 degrees to 160 degrees to each other, preferably an angle of 60 to 150 degrees, particularly preferably 80 to 100 °.
- the nozzle orifices are preferably located at a distance of 10 to 200 microns, more preferably at a distance of 10 to 100 microns, more preferably 30 to 70 microns. Most preferred are 50 microns.
- the liquid pharmaceutical formulation meets the nozzle body with an inlet pressure of up to 600 bar, preferably 200 to 300 bar, and is atomized via the nozzle openings into an inhalable aerosol.
- the preferred particle sizes of the aerosol are up to 20 microns, preferably 3 to 10 microns.
- the locking mechanism includes a spring, preferably a cylindrical helical compression spring, as a memory for the mechanical energy.
- the spring acts on the output flange as a jump piece whose movement through the position of a locking member is determined.
- the path of the output flange is precisely limited by an upper and a lower stop.
- the spring is preferably tensioned via a force-transmitting gear, for example a screw thrust gear, by an external torque which is generated when the housing upper part is rotated against the spring housing in the housing bottom part.
- the upper housing part and the output flange contain a single or multi-start wedge gear.
- the locking member with engaging locking surfaces is arranged annularly around the output flange.
- the ring is arranged in a plane perpendicular to the atomizer axis. After tensioning the spring, the locking surfaces of the locking member push in the path of the output flange and prevent the relaxation of the spring.
- the Sprerrglied is triggered by a button.
- the release button is connected or coupled to the locking member.
- the shutter button is parallel to the ring plane, and preferably in the atomizer, moved; while the deformable ring is deformed in the ring plane. Constructive details of the locking mechanism are described in WO 97/20590.
- the lower housing part is pushed in the axial direction over the spring housing and covers the storage, the drive of the spindle and the reservoir for the fluid.
- the upper housing part When actuating the atomizer, the upper housing part is rotated against the lower housing part, wherein the lower housing part entrains the spring housing.
- the spring is compressed and tensioned via the screw slide, and the lock engages automatically.
- the angle of rotation is preferably an integer fraction of 360 degrees, e.g. 180 degrees.
- the driven part Simultaneously with the tensioning of the spring, the driven part is displaced in the upper housing part by a predetermined path, the hollow piston is withdrawn within the cylinder in the pump housing, whereby a subset of the fluid from the reservoir is sucked into the high-pressure chamber in front of the nozzle.
- a plurality of interchangeable reservoirs containing the fluid to be atomized can be inserted and used successively in the atomizer.
- the storage container contains the aerosol preparation according to the invention.
- the sputtering process is initiated by lightly pressing the shutter button.
- the blocking mechanism clears the way for the stripping section.
- the tensioned spring pushes the piston into the cylinder of the pump housing.
- the fluid exits the nozzle of the atomizer in atomized form.
- the components of the atomizer are made of a functionally suitable material.
- the housing of the atomizer and, as far as the function permits, other parts are preferably made of plastic, e.g. by injection molding. Physiologically harmless materials are used for medical purposes.
- FIGS. 6 a / b of WO 97/12687 describe the nebuliser (Respimat®) with which the aqueous aerosol preparations according to the invention can advantageously be inhaled.
- FIG. 6 a shows a longitudinal section through the atomizer with the spring tensioned
- FIG. 6 b shows a longitudinal section through the atomizer with the spring relaxed.
- the upper housing part (51) contains the pump housing (52), at the end of which the holder (53) for the atomizer nozzle is mounted. In the holder is the nozzle body (54) and a filter (55).
- the hollow piston (57) fastened in the output flange (56) of the locking mechanism projects partially into the cylinder of the pump housing. At its end, the hollow piston carries the valve body (58).
- the hollow piston is sealed by means of the seal (59).
- the stop (60) on which the output flange rests with a relaxed spring.
- the stop (61) On which the output flange rests when the spring is tensioned.
- the locking member (62) slides between the stop (61) and a support (63) in the upper housing part.
- the release button (64) is in communication with the locking member.
- the upper housing part ends in the mouthpiece (65) and is closed with the attachable protective cap (66).
- the spring housing (67) with compression spring (68) is rotatably supported by means of the snap lugs (69) and pivot bearing on the upper housing part.
- the lower housing part (70) is pushed.
- the replaceable reservoir (71) for the fluid (72) to be atomized Within the spring housing is the replaceable reservoir (71) for the fluid (72) to be atomized.
- the storage tank is closed with the stopper (73) through which the hollow piston protrudes into the reservoir and immersed with its end in the fluid (stock of drug solution).
- the spindle (74) for the mechanical counter is mounted in the lateral surface of the spring housing.
- the drive pinion (75) At the end of the spindle, which faces the upper housing part, there is the drive pinion (75). The rider (76) sits on the spindle.
- the nebulizer described above is suitable for nebulizing the aerosol preparations according to the invention to form an aerosol suitable for inhalation.
- the mass expelled in at least 97%, preferably at least 98% of all actuations of the inhaler (puffs) a defined quantity with a tolerance of not more than 25%, preferably from 20 % of this amount.
- a defined quantity with a tolerance of not more than 25%, preferably from 20 % of this amount.
- between 5 and 30 mg of formulation per stroke are applied as a defined mass, more preferably between 5 and 20 mg.
- the formulation according to the invention can also be nebulized by means of inhalers other than those described above, for example jet stream inhalers.
- inhalers other than those described above, for example jet stream inhalers.
- Formulations can be used. These are, for example, devices according to international patent applications WO 02/51466, WO 03/49792 and WO 04/22242 (Chrysalis), devices according to international patent applications WO 94/14543, WO 00/35524, WO 00/38770 and WO 00 / 64590 (Batgres / Ventaira), devices according to the publications US 20060048772, US 20050224076 and WO 05/42075 (Pari), devices according to the publications WO 94/16755, WO 94/16717, WO 96/13291, WO 96/13161, WO 98/22169, WO 98/33480, WO 98/48878 and WO 02/74375 (Aradigm) and devices according to the publication EP 1211628 (Canon).
- the present invention further relates to an inhalation kit consisting of one of the pharmaceutical preparations according to the invention described above and an inhaler suitable for the nebulization of this pharmaceutical formulation.
- the present invention preferably relates to an inhalation kit consisting of one of the pharmaceutical preparations according to the invention the inhaler described above and the Respimat ® described above.
- the formulation examples set forth below serve to further illustrate without limiting the subject matter of the present invention to the compositions exemplified.
- BAC stands for benzalkonium chloride
- EDTA disodium edetate dihydrate
- the particle size distribution or the mean volume diameter is determined by means of laser diffraction, particle size measuring device Fa. Sympatec, model Helos BF, at a volume flow of 28.3 l / min and the climatic conditions of about 23 ° C / about 100% relative humidity.
- a compressed air source is connected to a humidification apparatus which is filled with water. The compressed air flows through the humidifier filled with water and thus enriches a moisture.
- the outlet of the humidification apparatus is connected via a hose to a humidity sensor, which analyzes the current air humidity of the air flow.
- the humidity sensor is connected via a hose to the adapter for the Respimat® inhaler. This will be connected to the modified Sample Induction Port.
- the modified sample is determined by means of laser diffraction, particle size measuring device Fa. Sympatec, model Helos BF, at a volume flow of 28.3 l / min and the climatic conditions of about 23 ° C / about 100% relative humidity.
- the Induction Port is installed in the measuring zone of the particle size measuring device and represents the actual measuring chamber.
- the outlet of the modified Sample Induction Port is connected to a suction device via a suitable adapter, interposing a collecting device in which the sample is taken delivered dose is collected.
- the suction apparatus is connected to a vacuum source.
- the particle size measuring device is operated with an R3 lens, focal length 100 mm.
- the trigger condition for the measurement is an optical concentration of> 0.1% on channel 30.
- the MIE theory with the corresponding substance parameters is used.
- the Respimat® inhaler is cocked, the mouthpiece, union nut and nozzle wiped dry and then inserted into the adapter.
- the moisture supply is connected, and at a constant air humidity of approx. 100% r.F. carried out a reference measurement.
- the aerosol is generated by pressing the release button on the Respimat® inhaler.
- the emitted aerosol is detected by the particle size measuring device and calculated its particle size distribution or the average volume diameter.
- H D (v; 50) means: Average volume diameter
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- Animal Behavior & Ethology (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Epidemiology (AREA)
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- Dispersion Chemistry (AREA)
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Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002653111A CA2653111A1 (en) | 2006-05-20 | 2007-05-09 | Inhalant aerosol formulations containing ethanol |
JP2009511448A JP2009537587A (ja) | 2006-05-20 | 2007-05-09 | エタノールを含んだ吸入エアロゾル製剤 |
US12/301,291 US20090202447A1 (en) | 2006-05-20 | 2007-05-09 | Inhalant aerosol formulations containing ethanol |
EP07728944A EP2026762A1 (de) | 2006-05-20 | 2007-05-09 | Ethanolhaltige aerosolformulierung für die inhalation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102006023756.0 | 2006-05-20 | ||
DE102006023756A DE102006023756A1 (de) | 2006-05-20 | 2006-05-20 | Ethanolhaltige Aerosolformulierung für die Inhalation |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2007134968A1 true WO2007134968A1 (de) | 2007-11-29 |
Family
ID=38290151
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2007/054492 WO2007134968A1 (de) | 2006-05-20 | 2007-05-09 | Ethanolhaltige aerosolformulierung für die inhalation |
Country Status (6)
Country | Link |
---|---|
US (1) | US20090202447A1 (de) |
EP (1) | EP2026762A1 (de) |
JP (1) | JP2009537587A (de) |
CA (1) | CA2653111A1 (de) |
DE (1) | DE102006023756A1 (de) |
WO (1) | WO2007134968A1 (de) |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9545487B2 (en) | 2012-04-13 | 2017-01-17 | Boehringer Ingelheim International Gmbh | Dispenser with encoding means |
US9682202B2 (en) | 2009-05-18 | 2017-06-20 | Boehringer Ingelheim International Gmbh | Adapter, inhalation device, and atomizer |
US9724482B2 (en) | 2009-11-25 | 2017-08-08 | Boehringer Ingelheim International Gmbh | Nebulizer |
US9744313B2 (en) | 2013-08-09 | 2017-08-29 | Boehringer Ingelheim International Gmbh | Nebulizer |
US9757750B2 (en) | 2011-04-01 | 2017-09-12 | Boehringer Ingelheim International Gmbh | Medicinal device with container |
US9827384B2 (en) | 2011-05-23 | 2017-11-28 | Boehringer Ingelheim International Gmbh | Nebulizer |
US9943654B2 (en) | 2010-06-24 | 2018-04-17 | Boehringer Ingelheim International Gmbh | Nebulizer |
US10004857B2 (en) | 2013-08-09 | 2018-06-26 | Boehringer Ingelheim International Gmbh | Nebulizer |
US10011906B2 (en) | 2009-03-31 | 2018-07-03 | Beohringer Ingelheim International Gmbh | Method for coating a surface of a component |
US10016568B2 (en) | 2009-11-25 | 2018-07-10 | Boehringer Ingelheim International Gmbh | Nebulizer |
US10099022B2 (en) | 2014-05-07 | 2018-10-16 | Boehringer Ingelheim International Gmbh | Nebulizer |
US10124129B2 (en) | 2008-01-02 | 2018-11-13 | Boehringer Ingelheim International Gmbh | Dispensing device, storage device and method for dispensing a formulation |
US10124125B2 (en) | 2009-11-25 | 2018-11-13 | Boehringer Ingelheim International Gmbh | Nebulizer |
US10195374B2 (en) | 2014-05-07 | 2019-02-05 | Boehringer Ingelheim International Gmbh | Container, nebulizer and use |
US10722666B2 (en) | 2014-05-07 | 2020-07-28 | Boehringer Ingelheim International Gmbh | Nebulizer with axially movable and lockable container and indicator |
WO2022023515A1 (en) | 2020-07-31 | 2022-02-03 | Chemo Research , S.L. | Combination therapy for inhalation administration |
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DE19625027A1 (de) * | 1995-06-27 | 1997-01-02 | Boehringer Ingelheim Kg | Neue stabile Arzneimittelzubereitung zur Erzeugung treibgasfreier Aerosole |
DE19653969A1 (de) * | 1996-12-20 | 1998-06-25 | Boehringer Ingelheim Kg | Neue wässrige Arzneimittelzubereitung zur Erzeugung treibgasfreier Aerosole |
WO2000023065A2 (de) * | 1998-10-17 | 2000-04-27 | Boehringer Ingelheim Pharma Kg | Lagerfähiges wirkstoffkonzentrat mit formoterol |
DE10104367A1 (de) * | 2001-02-01 | 2002-08-08 | Boehringer Ingelheim Pharma | Betamimetika enthaltende Arzneimittelkompositionen mit geringeren Nebenwirkungen |
US20020111363A1 (en) * | 2000-10-31 | 2002-08-15 | Karin Drechsel | Inhalable formulation of a solution containing a tiotropium salt |
US20020137764A1 (en) * | 2000-10-31 | 2002-09-26 | Karin Drechsel | Inhalable formulation of a solution containing a tiotropium salt |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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DE102006023770A1 (de) * | 2006-05-20 | 2007-11-22 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Treibgasfreie Aerosolformulierung für die Inhalation |
-
2006
- 2006-05-20 DE DE102006023756A patent/DE102006023756A1/de not_active Withdrawn
-
2007
- 2007-05-09 US US12/301,291 patent/US20090202447A1/en not_active Abandoned
- 2007-05-09 WO PCT/EP2007/054492 patent/WO2007134968A1/de active Application Filing
- 2007-05-09 EP EP07728944A patent/EP2026762A1/de not_active Withdrawn
- 2007-05-09 JP JP2009511448A patent/JP2009537587A/ja active Pending
- 2007-05-09 CA CA002653111A patent/CA2653111A1/en not_active Abandoned
Patent Citations (6)
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DE19625027A1 (de) * | 1995-06-27 | 1997-01-02 | Boehringer Ingelheim Kg | Neue stabile Arzneimittelzubereitung zur Erzeugung treibgasfreier Aerosole |
DE19653969A1 (de) * | 1996-12-20 | 1998-06-25 | Boehringer Ingelheim Kg | Neue wässrige Arzneimittelzubereitung zur Erzeugung treibgasfreier Aerosole |
WO2000023065A2 (de) * | 1998-10-17 | 2000-04-27 | Boehringer Ingelheim Pharma Kg | Lagerfähiges wirkstoffkonzentrat mit formoterol |
US20020111363A1 (en) * | 2000-10-31 | 2002-08-15 | Karin Drechsel | Inhalable formulation of a solution containing a tiotropium salt |
US20020137764A1 (en) * | 2000-10-31 | 2002-09-26 | Karin Drechsel | Inhalable formulation of a solution containing a tiotropium salt |
DE10104367A1 (de) * | 2001-02-01 | 2002-08-08 | Boehringer Ingelheim Pharma | Betamimetika enthaltende Arzneimittelkompositionen mit geringeren Nebenwirkungen |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10124129B2 (en) | 2008-01-02 | 2018-11-13 | Boehringer Ingelheim International Gmbh | Dispensing device, storage device and method for dispensing a formulation |
US10011906B2 (en) | 2009-03-31 | 2018-07-03 | Beohringer Ingelheim International Gmbh | Method for coating a surface of a component |
US9682202B2 (en) | 2009-05-18 | 2017-06-20 | Boehringer Ingelheim International Gmbh | Adapter, inhalation device, and atomizer |
US9724482B2 (en) | 2009-11-25 | 2017-08-08 | Boehringer Ingelheim International Gmbh | Nebulizer |
US10124125B2 (en) | 2009-11-25 | 2018-11-13 | Boehringer Ingelheim International Gmbh | Nebulizer |
US10016568B2 (en) | 2009-11-25 | 2018-07-10 | Boehringer Ingelheim International Gmbh | Nebulizer |
US9943654B2 (en) | 2010-06-24 | 2018-04-17 | Boehringer Ingelheim International Gmbh | Nebulizer |
US9757750B2 (en) | 2011-04-01 | 2017-09-12 | Boehringer Ingelheim International Gmbh | Medicinal device with container |
US9827384B2 (en) | 2011-05-23 | 2017-11-28 | Boehringer Ingelheim International Gmbh | Nebulizer |
US9545487B2 (en) | 2012-04-13 | 2017-01-17 | Boehringer Ingelheim International Gmbh | Dispenser with encoding means |
US10220163B2 (en) | 2012-04-13 | 2019-03-05 | Boehringer Ingelheim International Gmbh | Nebuliser with coding means |
US10004857B2 (en) | 2013-08-09 | 2018-06-26 | Boehringer Ingelheim International Gmbh | Nebulizer |
US11642476B2 (en) | 2013-08-09 | 2023-05-09 | Boehringer Ingelheim International Gmbh | Nebulizer |
US9744313B2 (en) | 2013-08-09 | 2017-08-29 | Boehringer Ingelheim International Gmbh | Nebulizer |
US10894134B2 (en) | 2013-08-09 | 2021-01-19 | Boehringer Ingelheim International Gmbh | Nebulizer |
US10716905B2 (en) | 2014-02-23 | 2020-07-21 | Boehringer Lngelheim International Gmbh | Container, nebulizer and use |
US10722666B2 (en) | 2014-05-07 | 2020-07-28 | Boehringer Ingelheim International Gmbh | Nebulizer with axially movable and lockable container and indicator |
US10195374B2 (en) | 2014-05-07 | 2019-02-05 | Boehringer Ingelheim International Gmbh | Container, nebulizer and use |
US10099022B2 (en) | 2014-05-07 | 2018-10-16 | Boehringer Ingelheim International Gmbh | Nebulizer |
WO2022023515A1 (en) | 2020-07-31 | 2022-02-03 | Chemo Research , S.L. | Combination therapy for inhalation administration |
Also Published As
Publication number | Publication date |
---|---|
JP2009537587A (ja) | 2009-10-29 |
EP2026762A1 (de) | 2009-02-25 |
US20090202447A1 (en) | 2009-08-13 |
DE102006023756A1 (de) | 2007-11-29 |
CA2653111A1 (en) | 2007-11-29 |
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