NZ536030A - HFA-suspension formulation of crystalline tiotropium bromide anhydrate - Google Patents

HFA-suspension formulation of crystalline tiotropium bromide anhydrate

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Publication number
NZ536030A
NZ536030A NZ536030A NZ53603003A NZ536030A NZ 536030 A NZ536030 A NZ 536030A NZ 536030 A NZ536030 A NZ 536030A NZ 53603003 A NZ53603003 A NZ 53603003A NZ 536030 A NZ536030 A NZ 536030A
Authority
NZ
New Zealand
Prior art keywords
hfa
tiotropium bromide
acid
suspension
suspension according
Prior art date
Application number
NZ536030A
Inventor
Christel Schmelzer
Original Assignee
Boehringer Ingelheim Pharma
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim Pharma filed Critical Boehringer Ingelheim Pharma
Publication of NZ536030A publication Critical patent/NZ536030A/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dispersion Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Otolaryngology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

Disclosed is a suspension of crystalline tiotropium bromide anhydrate in the propellant gases HFA 227 and/or HFA 134a, optionally including one or more of the propellant gases propane, butane, pentane, dimethylether, CHClF2, CH2F2, CF3CH3, isobutene, isopentane and neopentane, wherein the tiotropium bromide anhydrate is characterised by the elementary cell a = 10.4336 A, b = 11.3297 A, c = 17.6332 A and alpha = 90degree , beta = 105.158degree and gamma = 90degree , and a cell volume of 2011.89 A2.

Description

New Zealand Paient Spedficaiion for Paient Number 536030 536 80282pct.210 HFA-suspension formulation of an anhydrate The invention relates to propellant gas preparations for metered-dose aerosols with suspension formulations of the crystalline anhydrate of (1a,2p,4p,5a,7p)-7-[(hyd roxyd i-2-th ienylacety l)oxy]-9,9-d imethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane-bromide.
The compound (1 a,2p,4p,5a,7p)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane-bromide, is known from European Patent Application EP 418 716 A1 and has the following chemical structure: The compound has valuable pharmacological properties and is known by the name tiotropium bromide (BA679). Tiotropium bromide is a highly effective anticholinergic and can therefore provide therapeutic benefit in the treatment of asthma or COPD (chronic obstructive pulmonary disease).
Tiotropium bromide is preferably administered by inhalation.
The aim of the present invention is to prepare HFA-metered-dose aerosols containing tiotropium bromide as the sole active ingredient in suspended form.
It has been found that, depending on the choice of conditions which can be used when purifying the crude product obtained after industrial manufacture, tiotropium bromide occurs in various crystalline modifications.
Background to the invention Br (I) Detailed description of the invention 2 the process conditions used in the crystallisation process. One of these crystalline modifications is the crystalline monohydrate of tiotropium bromide.
It has now surprisingly been found that starting from this crystalline monohydrate of 5 tiotropium bromide which is not yet known in the art it is possible to obtain an anhydrous crystal modification of tiotropium bromide (tiotropium anhydrate) which is exceptionally suitable for the preparation of suspensions in the propellant gases HFA 227 and/or HFA 134a for administration by inhalation.
Accordingly, the present invention relates to suspensions of this crystalline tiotropium bromide anhydrate in the propellant gases HFA 227 and/or HFA 134a, optionally in admixture with one or more other propellant gases, preferably selected from the group consisting of propane, butane, pentane, dimethylether, CHCIF2, CH2F2, CF3CH3 isobutane, isopentane and neopentane.
Where reference is made within the scope of the present invention to crystalline tiotropium bromide anhydrate this should be taken as a reference to the anhydrous crystalline modification of tiotropium bromide which can be obtained by drying the crystalline tiotropium bromide monohydrate. This crystal modification is also 20 optionally known within the scope of the present invention as crystalline tiotropium bromide in anhydrous form.
Preferred suspensions according to the invention are those which contain as propellant gas HFA 227 on its own, a mixture of HFA 227 and HFA 134a or HFA 25 134a on its own.
If a mixture of propellant gases HFA 227 and HFA 134a is used in the suspension formulations according to the invention, the weight ratios in which these two propellant gas components are used may be freely selected.
If in the suspension formulations according to the invention one or more other 30 propellant gases are used in addition to the propellant gases HFA 227 and/or HFA 134a , selected from the group consisting of propane, butane, pentane, dimethylether, CHCIF2, CH2F2, CF3CH3 isobutane, isopentane and neopentane, the proportion of this other propellant gas component is preferably less than 50 %, preferably less than 40%, more preferably less than 30%.
The suspensions according to the invention preferably contain between 0.001 and 0.8% tiotropium. Suspensions which contain 0.08 to 0.5%, more preferably 0.2 to 0.4% tiotropium are preferred according to the invention. 3 By tiotropium is meant the free ammonium cation. The propellant gas suspensions according to the invention are characterised in that they contain tiotropium in the form of the crystalline tiotropium bromide anhydrate which is exceptionally suitable for this application. Accordingly, the present invention preferably relates to 5 suspensions which contain between 0.0012 and 96% crystalline tiotropium bromide anhydrate. Of particular interest according to the invention are suspensions which contain 0.096 to 0.6%, more preferably 0.24 to 0.48% crystalline tiotropium bromide anhydrate.
The percentages specified within the scope of the present invention are always percent by mass. If parts by mass of tiotropium are given in percent by mass, the corresponding values for the crystalline tiotropium bromide anhydrate which is preferably used within the scope of the present invention may be obtained by ^ multiplying by a conversion factor of 1.2036.
In some cases within the scope of the present invention the term suspension formulation may be used instead of the term suspension. The two terms are to be regarded as interchangeable within the scope of the present invention.
The propellant-containing inhalation aerosols or suspension formulations according to the invention may also contain other ingredients such as surface-active agents (surfactants), adjuvants, antioxidants or flavourings.
The surface-active agents (surfactants) which may be contained in the suspensions 25 according to the invention are preferably selected from among Polysorbate 20, Polysorbate 80, Myvacet 9-45, Myvacet 9-08, isopropylmyristate, oleic acid, ^ propyleneglycol, polyethyleneglycol, Brij, ethyloleate, glyceryl trioleate, glyceryl ^ monolaurate, glyceryl monooleate, glyceryl monosterate, glyceryl monoricinoleate, cetylalcohol, sterylalcohol, cetylpyridinium chloride, block polymers, natural oil, 30 ethanol and isopropanol. Of the abovementioned suspension adjuvants Polysorbate 20, Polysorbate 80, Myvacet 9-45, Myvacet 9-08 or isopropylmyristate are preferably used. Myvacet 9-45 or isopropylmyristate are particularly preferred.
Where the suspensions according to the invention contain surfactants, these are 35 preferably present in an amount of 0.0005 -1 %, more preferably 0.005 - 0.5 %.
The adjuvants optionally contained in the suspensions according to the invention are preferably selected from among alanine, albumin, ascorbic acid, aspartame, betaine, cysteine, phosphoric acid, nitric acid, hydrochloric acid, sulphuric acid and citric acid. 4 Of these, ascorbic acid, phosphoric acid, hydrochloric acid or citric acid are preferred, while hydrochloric acid or citric acid is more preferable.
Where the suspensions according to the invention contain adjuvants, these are 5 preferably present in an amount of 0.0001-1.0 %, preferably 0.0005-0.1 %, more preferably 0.001-0.01 %, while an amount of from 0.001-0.005 % is particularly preferred according to the invention.
The antioxidants optionally contained in the suspensions according to the invention 10 are preferably selected from among ascorbic acid, citric acid, sodium edetate, editic acid, tocopherols, butylhydroxytoluene, butylhydroxyanisol and ascorbyl palmitate, of which tocopherols, butylhydroxytoluene, butylhydroxyanisol and ascorbyl palmitate are preferred. s o The flavourings which may be contained in the suspensions according to the invention are preferably selected from among peppermint, saccharine, Dentomint®, aspartame and ethereal oils (e.g. cinnamon, aniseed, menthol, camphor), of which peppermint or Dentomint® is particularly preferred.
For administration by inhalation it is necessary to prepare the active substance in finely divided form. The crystalline tiotropium bromide anhydrate which may be obtained as detailed in the experimental section is either ground (micronised or obtained in finely divided form by other technical methods known in principle in the art (such as precipitation and spray drying). Methods of micronising active 25 substances are known in the art. Preferably, after micronisation, the active substance has an average particle size of 0.5 to 10 |jm, preferably 1 to 6 pm, more preferably 1.5 to 5 pm. Preferably, at least 50%, more preferably at least 60%, most preferably at least 70% of the particles of active substance have a particle size which is within the ranges specified above. More preferably, at least 80%, most preferably 30 at least 90% of the particles of active substance have a particle size within the ranges specified above.
Surprisingly, it has been found that it is also possible to prepare suspensions which contain, apart from the abovementioned propellant gases, only the active substance 35 and no other additives. Accordingly, in another aspect, the present invention relates to suspensions which contain only the active substance and no other additives.
D .6 suspended in 4.4 kg of water, this mixture is added to the solution containing tiotropium bromide and rinsed with 4.3 kg of water. The mixture thus obtained is stirred for at least 15 min. at 80-90°C and then filtered through a heated filter into an apparatus which has been preheated to an outer temperature of 70°C. The filter is rinsed with 8.6 kg of water. The contents of the apparatus are cooled to a temperature of 20-25°C at a rate of 3-5°C every 20 minutes. Using cold water the apparatus is cooled further to 10-15°C and crystallisation is completed by stirring for at least another hour. The crystals are isolated using a suction filter drier, the crystal slurry isolated is washed with 9 L of cold water (10-15°C) and cold acetone (10-15°C). The crystals obtained are dried at 25°C for 2 hours in a nitrogen current. Yield: 13.4 kg of tiotropium bromide monohydrate (86 % of theory).
The tiotropium bromide monohydrate obtainable using the method described above was investigated by DSC (Differential Scanning Calorimetry). The DSC diagram shows two characteristic signals. The first, relatively broad, endothermic signal between 50-120°C can be attributed to the dehydration of the tiotropium bromide monohydrate into the anhydrous form. The second, relatively sharp, endothermic peak at 230 ± 5°C can be put down to the melting of the substance. This data was obtained using a Mettler DSC 821 and evaluated using the Mettler STAR software package. The data was recorded at a heating rate of 10 K/min.
The crystalline tiotropium bromide monohydrate was characterised by IR spectroscopy. The data was obtained using a Nicolet FTIR spectrometer and evaluated with the Nicolet OMNIC software package, version 3.1. The measurement was carried out with 2.5 pmol of tiotropium bromide monohydrate in 300 mg of KBr. The following Table shows some of the essential bands of the IR spectrum.
Wave number (cm"1) Attribution Type of oscillation 3570, 3410 O-H elongated oscillation 3105 Aryl C-H elongated oscillation 1730 C=0 elongated oscillation 1260 Epoxide C-0 elongated oscillation 1035 Ester C-OC elongated oscillation 720 Thiophene cyclic oscillation % 7 The monocrystal X-ray structural analysis carried out showed that the crystalline tiotropium bromide hydrate obtainable by the above process has a simple monoclinic cell with the following dimensions: a = 18.0774 A, b = 11.9711 A, c = 9.9321 A, p = 102.691°, V = 2096.96 A3. 5 These data were obtained using an AFC7R 4-circuit diffractometer (Rigaku) using monochromatic copper K* radiation. The structural resolution and refinement of the crystal structure were obtained by direct methods (SHELXS86 Program) and FMLQ-refinement (TeXsan Program). ^ Crystalline tiotropium bromide anhydrate: The anhydrous form is produced from the crystalline tiotropium bromide monohydrate obtained as described above by careful drying at 80 -100 °C under reduced pressure, preferably under high vacuum over a period of at least 30 minutes. Alternatively to the drying step at 80 - 100 °C in vacuo the anhydrous form may also be prepared by storing over dried silica gel at ambient temperature over a period of at least 24 hours.
The crystalline structure of the anhydrous tiotropium bromide was determined from high-resolution X-ray powder data (synchrotron radiation) by a real space mixture 20 using a so-called "simulating annealing" process. A final Rietveld analysis was carried out to refine the structural parameters. These investigations showed that the crystalline tiotropium bromide anhydrate which is used in the suspensions according to the invention is characterised by the elementary cell a = 10.4336(2)A, b = 11.3297(3)A, c= 17.6332(4) A and a = 90°, p = 105.158(2)° and y = 90° (cell volume = 2011.89(8) A3).
To prepare the suspensions according to the invention the crystalline tiotropium bromide anhydrate obtainable by the above process is micronised by methods known in the art, with the exclusion of moisture, to prepare the active substance in the form of the average particle size which corresponds to the specifications 35 according to the invention. 8 Examples of formulations Suspensions containing other ingredients in addition to active substance and propellant gas: a) 0.02 % Tiotropium* 0.20 % Polysorbate 20 99.78% HFA 227 b) 0.02 % Tiotropium* 1.00 % Isopropylmyristate 98.98% HFA 227 c) 0.02 % Tiotropium* 0.3% Myvacet 9-45 99.68% HFA 227 d) 0.04 % Tiotropium* 1.00 % Myvacet 9-08 98.96% HFA 227 e) 0.04 % Tiotropium* 0.04 % Polysorbate 80 99.92% HFA 227 f) 0.04 % Tiotropium* 0.005 % Oleic acid 99.955% HFA 227 g) 0.02 % Tiotropium* 0.1 % Myvacet 9-45 60.00% HFA 227 39.88% HFA 134a h) 0.02 % Tiotropium* 0.30 % Isopropylmyristate 20.00% HFA 227 79.68% HFA 134a i) 0.02 % Tiotropium* 0.01 % Oleic acid 60.00% HFA 227 39.97% HFA 134a *used in the form of the tiotropium bromide anhydrate (conversion factor 1.2036) 9 Suspensions containing only active substance and propellant gas: j) 0.02 % 99.98 % k) 0.02 % 99.98 % I) 0.04 % 99.96 % m) 0.04 % 99.96 % n) 0.02 % 20.00 % 79.98 % o) 0.02 % 60.00 % 39.98 % p) 0.04 % 40.00 % 59.96 % q) 0.04 % 80.00 % 19.96 % Tiotropium* HFA 227 Tiotropium* HFA 134a Tiotropium* HFA 227 Tiotropium* HFA 134a Tiotropium* HFA 227 HFA 134a Tiotropium* HFA 227 HFA 134a Tiotropium* HFA 227 HFA 134a Tiotropium* HFA 227 HFA 134a * used in the form of the tiotropium bromide anhydrate (conversion factor 1.2036)

Claims (13)

WHAT WE CLAIM IS:
1) A suspension of crystalline tiotropium bromide anhydrate in the propellant gases HFA 227 and/or HFA 134a, optionally in admixture with one or more other propellant gases selected from the group consisting of propane, butane, pentane, dimethylether, CHCIF2, CH2F2, CF3CH3i isobutane, isopentane and neopentane, wherein the tiotropium bromide anhydrate is characterised by the elementary cell a = 10.4336(2)A, b = 11.3297(3)A, c = 17.6332(4)A and a = 90°, fi = 105.158(2)° and y = 90° and a cell volume = 2011.89(8)A3.
2) A suspension according to claim 1, comprising between 0.001 and 0.8% tiotropium bromide anhydrate.
3) A suspension according to claims 1 or 2, comprising as other ingredients surface-active agents (surfactants), adjuvants, antioxidants and/or flavourings.
4) A suspension according to claim 3, comprising as surface-active agents (surfactants) one or more compounds selected from the group consisting of Polysorbate 20, Polysorbate 80, Myvacet 9-45, Myvacet 9-08, isopropylmyristate, oleic acid, propyleneglycol, polyethyleneglycol, Brij, ethyl oleate, glyceryl trioleate, glyceryl monolaurate, glyceryl monooleate, glyceryl monosterate, glyceryl monoricinoleate, cetylalcohol, sterylalcohol, cetylpyridinium chloride, block polymers, natural oil, ethanol and isopropanol.
5) A suspension according to claims 3 or 4, comprising as adjuvants one or more compounds selected from the group consisting of alanine, albumin, ascorbic acid, aspartame, betaine, cysteine, phosphoric acid, nitric acid, hydrochloric acid, sulphuric acid and citric acid.
6) A suspension according to any one of claims 3 to 5, comprising as antioxidants one or more compounds selected from the group consisting of ascorbic acid, citric acid, sodium edetate, editic acid, tocopherols, butylhydroxytoluene, butylhydroxyanisol and ascorbyl palmitate.
7) A suspension according to claim 1 or 2, comprising no other ingredients apart from the active substance and the propellant gas or gases. 11
8) Use of a suspension according to any one of claims 1 to 7 for preparing a pharmaceutical composition.
9) Use according to claim 8, for preparing a pharmaceutical composition for the treatment by inhalation or nasal route of diseases which anticholinergics may confer a therapeutic benefit.
10) Use according to claim 9, wherein the diseases are respiratory complaints.
11) Use according to claim 9 or 10, wherein the diseases are asthma or COPD.
12) A suspension as claimed in any one of claims 1 to 7 substantially as described herein with reference to the Examples.
13) The use as claimed in any one of claims 8 to 11 substantially as described herein with reference to the Examples. BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG
NZ536030A 2002-03-28 2003-03-20 HFA-suspension formulation of crystalline tiotropium bromide anhydrate NZ536030A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10214264A DE10214264A1 (en) 2002-03-28 2002-03-28 HFA suspension formulations of an anhydrate
PCT/EP2003/002899 WO2003082244A2 (en) 2002-03-28 2003-03-20 Hfa-suspension formulation of an anhydrate

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JP (1) JP5147158B2 (en)
KR (1) KR101005717B1 (en)
CN (1) CN1642525A (en)
AU (1) AU2003221509B2 (en)
BR (1) BR0308709A (en)
CA (1) CA2479638C (en)
DE (1) DE10214264A1 (en)
EA (1) EA008610B1 (en)
EC (1) ECSP045322A (en)
HR (1) HRP20040890A2 (en)
IL (1) IL163696A0 (en)
ME (1) ME00246B (en)
MX (1) MXPA04009338A (en)
NO (1) NO20044004L (en)
NZ (1) NZ536030A (en)
PL (1) PL371295A1 (en)
RS (1) RS52481B (en)
UA (1) UA79776C2 (en)
WO (1) WO2003082244A2 (en)
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AU2006243239A1 (en) * 2005-05-02 2006-11-09 Boehringer Ingelheim International Gmbh Crystalline forms of tiotropium bromide
WO2006117299A2 (en) * 2005-05-02 2006-11-09 Boehringer Ingelheim International Gmbh Novel crystalline forms of tiotropium bromide
AU2015201037C1 (en) * 2009-05-29 2017-07-27 Pearl Therapeutics, Inc. Respiratory delivery of active agents
PL3106149T3 (en) * 2009-05-29 2020-06-01 Pearl Therapeutics, Inc. Compositions for pulmonary delivery of long-acting muscarinic antagonists and long-acting beta-2 adrenergic receptor agonists and associated methods and systems
US8815258B2 (en) 2009-05-29 2014-08-26 Pearl Therapeutics, Inc. Compositions, methods and systems for respiratory delivery of two or more active agents
ES2712988T5 (en) 2013-03-15 2022-10-21 Pearl Therapeutics Inc Methods and systems for conditioning particulate crystalline materials
WO2018051132A1 (en) * 2016-09-19 2018-03-22 Mexichem Fluor S.A. De C.V. Pharmaceutical composition

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DE3931041C2 (en) * 1989-09-16 2000-04-06 Boehringer Ingelheim Kg Esters of thienyl carboxylic acids with amino alcohols, their quaternization products, processes for their preparation and medicaments containing them
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GB0009605D0 (en) * 2000-04-18 2000-06-07 Glaxo Group Ltd Medicaments
GB0009592D0 (en) * 2000-04-18 2000-06-07 Glaxo Group Ltd Respiratory combinations
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EP1341538B1 (en) * 2000-10-31 2009-12-23 Boehringer Ingelheim Pharma GmbH & Co.KG Medicament compositions with salts of tiotropium and epinastin for the therapy of respiratory diseases
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DE10113366A1 (en) * 2001-03-20 2002-09-26 Boehringer Ingelheim Pharma Medicament for treating inflammatory or obstructive respiratory diseases, e.g. asthma or chronic obstructive pulmonary disease, containing synergistic combination of anticholinergic agent and endothelin antagonist

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KR101005717B1 (en) 2011-01-05
AU2003221509A1 (en) 2003-10-13
RS52481B (en) 2013-02-28
EA008610B1 (en) 2007-06-29
NO20044004L (en) 2004-10-05
CN1642525A (en) 2005-07-20
EA200401159A1 (en) 2005-04-28
MXPA04009338A (en) 2005-01-25
IL163696A0 (en) 2005-12-18
UA79776C2 (en) 2007-07-25
ZA200405637B (en) 2005-07-27
CA2479638A1 (en) 2003-10-09
EP1492498A2 (en) 2005-01-05
KR20040098022A (en) 2004-11-18
MEP47308A (en) 2011-02-10
ME00246B (en) 2011-05-10
WO2003082244A3 (en) 2004-02-05
HRP20040890A2 (en) 2005-06-30
WO2003082244A2 (en) 2003-10-09
JP5147158B2 (en) 2013-02-20
DE10214264A1 (en) 2003-10-16
ECSP045322A (en) 2005-01-28
JP2005527550A (en) 2005-09-15
BR0308709A (en) 2005-01-04
AU2003221509B2 (en) 2008-01-24
CA2479638C (en) 2011-01-04
YU86004A (en) 2006-08-17
PL371295A1 (en) 2005-06-13

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