MXPA04009338A - Hfa-suspension formulation of an anhydrate. - Google Patents
Hfa-suspension formulation of an anhydrate.Info
- Publication number
- MXPA04009338A MXPA04009338A MXPA04009338A MXPA04009338A MXPA04009338A MX PA04009338 A MXPA04009338 A MX PA04009338A MX PA04009338 A MXPA04009338 A MX PA04009338A MX PA04009338 A MXPA04009338 A MX PA04009338A MX PA04009338 A MXPA04009338 A MX PA04009338A
- Authority
- MX
- Mexico
- Prior art keywords
- acid
- hfa
- contain
- tiotropium
- suspensions
- Prior art date
Links
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
Abstract
The invention relates to propellant formulations containing suspensions of a crystalline anhydrate of (1 alpha, 2 beta,4 beta, 5 alpha, 7 beta)-7- [(hydroxydi-2- thienylacetyl)oxy] -9, 9-dimethyl -3-oxa-9 -azoniatricyclo [3.3.1.02,4] nonane bromide.alpha.
Description
FORMULATIONS OF AN ANHYDRATE IN SUSPENSION WITH HFA
FIELD OF THE INVENTION The invention relates to carrier gas preparations for dosing aerosols with suspension formulations of the crystalline bromide anhydrate of (1a.2.sub.4.sub.4.sub.5.sub.7.sub.β) -7- [(idroxydi-2-thienylacetyl) oxy]. ] -9, 9-dimethyl-3-oxa-9-azonia-tricyclo [3.3.1. O2-4] nonane. BACKGROUND OF THE INVENTION The compound bromide of (1a.2β.4.5a.7β) -7- [(hydroxydi-2-thienylacetyl) oxy] -9, -dimethyl-3-oxa-9-azoniatricyclo [3.3.1. O2'4] nonane is known from "European patent application EP 418 716 Al, and has the following chemical structure:
The compound possesses valuable REF: 157314 pharmacological properties, and is known by the name of tiotropium bromide (BA679). The tiotropium bromide is a very effective anticholinergic, and can therefore develop its therapeutic utility in the therapy of asthma or chronic obstructive pulmonary disease (COPD = chronic obstructive pulmonary disease). The administration of tiotropium bromide is preferably carried out by inhalation. An object of the present invention is to make available dosing aerosols with HFA, which contain tiotropium bromide as a single active substance in suspended form. DETAILED DESCRIPTION OF THE INVENTION It has been found that, depending on the choice of conditions that can be applied in the purification of the crude product obtained after the technical preparation, tiotropium bromide can be presented in different crystalline modifications. It has been found that these various modifications can be achieved at will by choosing the solvents used in the crystallization and choosing the process conditions during the crystallization process. One of these crystalline modifications is the crystalline monohydrate of tiotropium bromide. Surprisingly, it has been found that starting from this crystalline monohydrate of tiotropium bromide, which was also not known in the prior art, an anhydrous crystalline modification of tiotropium bromide (tiotropium anhydrate) can be obtained, which is extremely suitable for preparing suspensions in the carrier gases HFA 227 and / or HFA 134a which can be administered by inhalation. Accordingly, the present invention relates to suspensions of this crystalline anhydrate of tiotropium bromide in the carrier gases HFA 227 and / or HFA 134a, optionally mixed with one or more additional carrier gases, preferably selected from the group consisting of propane, butane, pentane, dimethyl ether, CHC1F2, CH2F2, CF3CH3) isobutane, isopentane and neopentane. If reference is made in the context of the present invention to "tiotropium bromide crystalline anhydrate", this should be considered as the reference name for the anhydrous crystalline modification of tiotropium bromide which can be obtained by drying the crystalline monohydrate of bromide of tiotropium Optionally, this crystalline modification can also be designated, within the framework of the present invention, crystalline tiotropium bromide in anhydrous form. According to the invention, suspensions containing as carrier gas only HFA 227, a "mixture of HFA 227 and HFA 134a, or only HFA 134a are preferred. In the suspension formulations according to the invention a mixture is used. of the carrier gases HFA 227 and HFA 134a, the proportions by weight in which both components of the carrier gas can be used are freely variable.If in the suspension formulations according to the invention are used, in addition to carrier gases HFA 227 and / or HFA 134a, one or more additional carrier gases selected from the group of propane, butane, pentane, dimethyl ether, CHC1F2, C¾F2, CF3CH3 (isobutane, isopentane and neopentane, the proportion of these additional components of the carrier gas is preferably located below 50%, more preferably below 40%, and particularly preferably below 30%. The suspensions according to the invention preferably contain between 0.001 and 0.8% tiotropium. More preferred, according to the invention, are suspensions containing from 0.08 to 0.5%, particularly preferably 0.2 to 0.4% tiotropium. The free ammonium cation is to be understood as tiotropium. The suspensions in carrier gas according to the invention are characterized in that they contain tiotropium in the form of their crystalline anhydrate of tiotropium bromide, extraordinarily suitable for this administration. Therefore, the present invention preferably relates to suspensions containing between 0.0012 and 96% crystalline anhydrate of tiotropium bromide. Of special interest, according to the invention, are suspensions containing 0.096 to 0.6% of crystalline anhydrate of tiotropium bromide, particularly preferably 0.24 to 0.48% of crystalline anhydrate of tiotropium bromide. When, in the context of the present invention, percentage data are mentioned, it is always mass percentages. If the proportions by mass of tiotropium are expressed as percentages by mass, the corresponding values for the crystalline anhydrate of tiotropium bromide, which is preferably used within the framework of the present invention, can be obtained by multiplying by the calculation factor 1.2036. Eventually, in the context of the present invention, instead of the term "suspension", the expression "suspension formulation" is also used. It should be considered that both terms have the same meaning in the context of the present invention. Inhalation aerosols or suspension formulations containing carrier gas, according to the invention, may further contain other components such as surfactants, adjuvants, antioxidants or flavoring agents.
The surfactants which are present in the suspensions according to the invention are preferably selected from the group consisting of Polysorbate 20, Polysorbat 80, Myvacet 9-45, Myvacet 9-08, isopropyl myristate, oleic acid, propylene glycol, polyethylene glycol, Brij, ethyl oleate, glyceryl trioleate, glyceryl monolaurate, glyceryl mono-oleate, glyceryl monostearate, glyceryl monorricinoleate, cetyl alcohol, stearyl alcohol, cetylpyridinium chloride, block polymers, natural oil, ethanol and isopropanol. Of the excipients for suspensions mentioned above, Polysorbate 20, Polysorbate 80, Myvacet 9-45, Myvacet 9-08 or isopropyl myristate are preferably used. Particularly preferred are Myvacet 9-45 or isopropyl myristate. If the suspensions according to the invention contain surfactants, they are preferably used in a proportion of 0.0005-1%, particularly preferably 0.005-0.5%. The adjuvants optionally contained in the suspensions according to the invention are preferably selected from the group consisting of alanine, albumin, ascorbic acid, aspartame, betaine, cysteine, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid and citric acid. Preferably, ascorbic acid, phosphoric acid, hydrochloric acid or citric acid, especially hydrochloric acid or citric acid, are especially preferred. If the suspensions according to the invention contain adjuvants, they are preferably used in a proportion of 0.0001-1.0%, preferably 0.0005-0.1%, particularly preferably 0.001-0.01%, with a special importance according to the invention from 0.001-0.005%. The antioxidants optionally contained in the suspensions according to the invention are preferably selected from the group consisting of ascorbic acid, citric acid, sodium edetate, edetic acid, tocopherols, butylated hydroxytoluene, butylhydroxyanisole and ascorbyl palmitate, preferably being used tocopherols, butylated hydroxytoluene, butylhydroxyanisole or palmitate of ascorbyl The flavoring agents optionally contained in
The suspensions according to the invention are preferably selected from the group consisting of peppermint, saccharin, Dentomint, aspartame and essential oils (for example cinnamon, anise, menthol, camphor), with, for example, mint or Dentomint® being especially preferred. . With a view to administration by inhalation it is necessary to prepare the active substance in finely divided form. For this, either the crystalline anhydrate of tiotropium bromide which can be obtained as explained in detail in the experimental part is milled (micronized) or obtained in finely divided form by means of other technical procedures ( example precipitation, spray drying) known in principle in the state of the art. In the state of the art, methods for micronizing active substances are known. After micronization, the active substance preferably has an average particle size of 0.5 to 10 μt, more preferably 1 to 6 μt, particularly preferably 1.5 to 5 μt. Preferably at least 50% of the particles of active substance, more preferably at least 60% of the particles of active substance, and particularly preferably at least 70% of the particles of active substance, have a particle size which lies within of the aforementioned size range. Particularly preferably at least 80%, and most preferably at least 90% of the particles of active substance have their particle size within the aforementioned ranges. Surprisingly, it has been found that suspensions containing exclusively can also be prepared, apart from the carrier gases mentioned, the active substance and no other additive. Accordingly, a further aspect of the present invention relates to suspensions containing exclusively the active substance, without other additives. To prepare the suspensions according to the invention, it is possible to proceed according to processes known in the state of the art. For this, the components of the formulation are mixed with the carrier gas or the carrier gases (possibly at low temperatures) and packaged in suitable containers. The suspensions containing carrier gas, according to the invention, mentioned above, can be administered by inhalers known in the state of the art (metered dose inhalers pMDIs = = pressurized metered dose inhalers). Therefore, a further aspect of the present invention relates to medicaments in the form of suspensions as described above, together with one or more suitable inhalers for administering these suspensions. The present invention also relates to inhalers characterized in that they contain suspensions containing carrier gas, according to the invention, described above. The present invention further relates to containers (cartridges) which, provided with an appropriate valve, can be used in a suitable inhaler, and which contain one of the "suspension containing carrier gas, according to the invention, described in what In the prior art, suitable containers (cartridges) are known, and methods for filling these cartridges with the suspensions containing carrier gas, according to the invention By virtue of the pharmaceutical activity of tiotropium, the present invention relates to , in addition, to the use of the suspensions according to the invention for preparing a medicament administrable by inhalation or nasally, preferably for preparing a medicament intended for the treatment by inhalation or nasally of diseases in which anticholinergics can develop a usefulness The invention is particularly preferably directed to the use of the - of the suspensions according to the invention for preparing a medicament intended for the treatment by inhalation of diseases of
The respiratory tract, preferably asthma or COPD. The following examples serve to illustrate in a broad and exemplary manner the present invention, without limiting it to the content thereof. Starting materials Tiotropium bromide crystalline monohydrate: To prepare the crystalline monohydrate of tiotropium bromide, the tiotropium bromide obtainable according to EP 418 716 A1 can be used. This can then be reacted in the manner described then. In a suitable reaction vessel, 15.0 kg of tiotropium bromide are added to 25.7 kg of water. The mixture is heated to 80-90 ° C and stirred, maintaining the temperature, until a clear solution is obtained. Active carbon (0.8 kg), wet water, is suspended in 4.4 kg of water, this mixture is incorporated into the solution containing tiotropium, and rinsed with 4.3 kg of water. The mixture thus obtained is stirred for at least 15 minutes at 80-90 ° C, and is then filtered through a heated filter to a previously heated apparatus at a jacket temperature of 70 ° C. The filter is washed 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. Then the apparatus is continued cooling to 10-15 ° C by cooling with cold water, and the crystallization is complete by stirring for at least one more hour. The crystallization is isolated by means of a Nutsche funnel, the crystalline cake isolated is washed with 9 liters of cold water (at 10-15 ° C) and with cold acetone (at 10-15 ° C). The crystals obtained were dried at 25 ° C for 2 hours in a stream of nitrogen.
Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theoretical) The crystalline monohydrate of tiotropium bromide, which can be obtained according to the procedure described above, was subjected to an analysis by DSC (differential scanning calorimetry, acronyms) English of Differential Scanning Calorxmetry). The DSC diagram presents two characteristic signals. The first endothermic signal, relatively broad, between 50 and 120 ° C, is attributable to the dehydration of tiotropium bromide monohydrate to give the anhydrous form. The second endothermic maximum at 230 ± 5 ° C, relatively acute, has to be assigned to the fusion of the substance. These data were obtained with a Mettler DSC 821 device, and were evaluated with the Mettler STAR program package. The data was recorded at a heating rate of 10 K / minute. The crystalline monohydrate of tiotropium bromide was characterized by IR spectroscopy. The data were obtained by means of a Nicolet FTIR spectrophotometer, and were evaluated using the OMNIC software package, version 3.1, of Nicolet. The measurement was carried out with 2.5 μt ??? of tiotropium bromide monohydrate in 300 mg of KBr.
The following table summarizes some of the special bands of the IR spectrum.
Wave number (was "1) Assignment Type of vibration 3570, 3410 O-H voltage vibration
3105 C-H arylic tension vibration
1730 C = 0 tension vibration
1260 C-0 of epoxy tension vibration
1035 C-OC of ester vibration of tension
720 thiophene ring vibration
The crystalline monohydrate of tiotropium bromide which can be obtained according to the procedure described above, presents in the single-crystal X-ray analysis a single monoclinic cell with the following dimensions: a = 18.0774 A, b = 11.9711 A, c = 9.9321 A, ß = 102.691 °, V = 2096.96 Á3. These data were obtained by means of a four-circle diffractometer APC7 (igaku), using Ka radiation from monochromatized copper. The structural resolution and the refinement of the crystalline structure were carried out by direct methods (SHELXS86 program) and FMLQ refinement (TeXsan program). Crystalline tiotropium bromide anhydrate: From the crystalline monohydrate of tiotropium bromide obtained in the manner described above, the anhydrous form is produced by careful drying at 80-100 ° C under reduced pressure., preferably in high vacuum, and for a period of at least 30 minutes. As an alternative to this drying step at 80-100 ° C in vacuum, the anhydrous form can also be prepared by keeping on dried silica gel, at room temperature, for a period of time of at least 24 hours. The crystal structure of anhydrous tiotropium bromide has been determined by high resolution powder X-ray spectrometry (synchrotron radiation) by a real-space arrangement through a so-called "simulated quenching procedure" (in English: " simulated annealing "). Then a Rietveld analysis was carried out to refine the structural parameters. These analyzes indicated that the crystalline anhydrate of tiotropium bromide which is used in the suspensions according to the invention is characterized by the elementary cell: a = 10.4336 (2) Á, b = 11.3297 (3) Áf c = 17.6332 (4) Á, y = 90 °, ß = 105.158 (2) °, and? = 90 ° (cell volume = 2011.89 (8) Á3). To prepare the suspensions according to the invention, the crystalline anhydride of tiotropium bromide which can be obtained according to the preceding process is micronized by methods known per se in the state of the art, excluding moisture, in order to obtain the active substance in a form with average particle size corresponding to the specifications according to the invention. Formulation examples Suspensions containing, in addition to active substance and carrier gas, other components: 0.02% tiotropium * 0.20% polysorbate 20 99.78% HFA 227 0.02 tiotropium * 1.00% isopropyl myristate 0.02% tiotropium * 0.3 % of yvacet 9-45 99.68 of HFA 227 0.04 ¾. of tiotropium * 1.00% of Myvacet 9-08 98.96 of HFA 227 0.04% of tiotropium * 0.04% of Polysorbat 80 99.92% of HFA 227 0.04% of tiotropium * 0.005% of oleic acid 99.955% of HFA 227 g) - 0.02% of tiotropium * 0.1% Myvacet 9-45 60.00 HFA 227 39.88% HFA 134a h) 0.02% tiotropium * 0.30% isopropyl myristate 20.00% HFA 227 79.68% HFA 134a i) 0.02% tiotropium * 0.01% of oleic acid 60.00% of HFA 227 39.97% of HFA 134a
* used in the form of tiotropium bromide anhydrate (conversion factor 1.2036) Suspensions containing only the vat substance and carrier gas:
j) 0.02% tiotropium * 99.98% HFA 227 k) 0.02% tiotropium * 99.98% HFA 134a 1) 0.04% tiotropium * 99.96% HFA 227 m) 0.04% tiotropium * 99.96% HFA 134a n) 0.02% tiotropium * 20.00% HFA 227 79.98% HFA 134a o) 0.02% tiotropium * 60.00 ¾ HFA 227 39.98% HFA 134a
P) 0.04% tiotropium * 40.00% HFA 227 59.96% HFA 134a
q) 0.04% tiotropium * 80.00% HFA 227 19.96% HFA 134a
* used in the form of tiotropium bromide anhydrate (conversion factor 1.2036) It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from this description of the invention.
Claims (9)
1. Suspensions of the crystalline anhydrate of tiotropium bromide in the carrier gases HFA 227 and / or HFA 134a, characterized in that they are optionally mixed with one or more additional carrier gases selected from the group consisting of propane, butane, pentane, dimethyl ether, CHC1F2, CH2F2, CF3CH3 , isobutane, isopentane and neopentane.
2. Suspensions according to claim 1, characterized in that they contain between 0.001 and 0.8% tiotropium.
3. Suspensions according to claim 1 or 2, characterized in that they contain, as additional components, surfactants, adjuvants, antioxidants and / or flavoring agents.
4. Suspensions according to claim 3, characterized in that they contain as one surfactant one or several compounds selected from the group consisting of Polysorbate 20, Polysorbate 80, Myvacet 9-45, Myvacet 9-08, isopropyl myristate, oleic acid, .propylene glycol , polyethylene glycol, Brij, ethyl oleate, glyceryl trioleate, glyceryl monolaurate, glyceryl mono-oleate, glyceryl monostearate, glyceryl monorricinoleate, cetyl alcohol, stearyl alcohol, cetylpyridinium chloride, block polymers, natural oil, ethanol and isopropanol
5. Suspensions according to claim 3, characterized in that they contain as one adjuvant one or several compounds selected from the group consisting of alanine, albumin, ascorbic acid, aspartame, betaine, cysteine, phosphoric acid, nitric acid, hydrochloric acid, acid. sulfuric acid and citric acid.
6. Suspensions according to claim 3, characterized in that they contain as one antioxidant one or more compounds selected from the group consisting of ascorbic acid, citric acid, sodium edetate, edetic acid, tocopherols, butylhydroxytoluene, butylhydroxyanisole and ascorbyl palmitate.
7. Suspensions according to claim 1 or 2, characterized in that, apart from the active substance and the carrier gas or the carrier gases, they do not contain any other component.
8. Use of a suspension according to one of claims 1 to 7 for preparing a medicament, preferably for preparing a medicament intended for the treatment by inhalation or nasally of diseases in which the anticholinergists can develop a therapeutic utility.
9. Use according to claim 8, wherein the diseases are diseases of the respiratory tract, preferably asthma or COPD.
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 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA04009338A true MXPA04009338A (en) | 2005-01-25 |
Family
ID=28050990
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
MXPA04009338A MXPA04009338A (en) | 2002-03-28 | 2003-03-20 | Hfa-suspension formulation of an anhydrate. |
Country Status (21)
Country | Link |
---|---|
EP (1) | EP1492498A2 (en) |
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) |
ZA (1) | ZA200405637B (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2606549A1 (en) * | 2005-05-02 | 2006-11-09 | Boehringer Ingelheim International Gmbh | Crystalline forms of tiotropium bromide |
KR20080007656A (en) * | 2005-05-02 | 2008-01-22 | 베링거 인겔하임 인터내셔날 게엠베하 | Novel crystalline forms of tiotropium bromide |
CA2763941A1 (en) * | 2009-05-29 | 2010-12-02 | Pearl Therapeutics, Inc. | Compositions, methods & systems for respiratory delivery of two or more active agents |
AU2015201037C1 (en) * | 2009-05-29 | 2017-07-27 | Pearl Therapeutics, Inc. | Respiratory delivery of active agents |
US8815258B2 (en) | 2009-05-29 | 2014-08-26 | Pearl Therapeutics, Inc. | Compositions, methods and systems for respiratory delivery of two or more active agents |
BR112015022784B1 (en) | 2013-03-15 | 2023-02-14 | Pearl Therapeutics, Inc | MICRONIZED CRYSTALLINE MATERIAL CONDITIONING METHOD AND CONDITIONING SYSTEMS |
EP3515439B1 (en) * | 2016-09-19 | 2021-12-15 | Mexichem Fluor S.A. de C.V. | Pharmaceutical composition comprising tiotropium bromide |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
CN1150890C (en) * | 1998-08-04 | 2004-05-26 | 杰格研究股份公司 | Medicinal aerosol formulations |
GB0009605D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Medicaments |
GB0009606D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Therapeutic combinations |
GB0009592D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Respiratory combinations |
GB0009583D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Respiratory formulations |
DE10111058A1 (en) * | 2001-03-08 | 2002-09-12 | Boehringer Ingelheim Pharma | New drug compositions based on anticholinergics and NK¶1¶ receptor antagonists |
CA2436537C (en) * | 2000-10-31 | 2009-05-26 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions comprising tiotropium salts and antihistamines |
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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2002
- 2002-03-28 DE DE10214264A patent/DE10214264A1/en not_active Withdrawn
-
2003
- 2003-03-20 ME MEP-2008-473A patent/ME00246B/en unknown
- 2003-03-20 KR KR1020047015174A patent/KR101005717B1/en active IP Right Grant
- 2003-03-20 CN CNA038072475A patent/CN1642525A/en active Pending
- 2003-03-20 UA UA20041008758A patent/UA79776C2/en unknown
- 2003-03-20 RS YU86004A patent/RS52481B/en unknown
- 2003-03-20 EA EA200401159A patent/EA008610B1/en unknown
- 2003-03-20 IL IL16369603A patent/IL163696A0/en unknown
- 2003-03-20 NZ NZ536030A patent/NZ536030A/en not_active IP Right Cessation
- 2003-03-20 BR BR0308709-3A patent/BR0308709A/en active Pending
- 2003-03-20 MX MXPA04009338A patent/MXPA04009338A/en active IP Right Grant
- 2003-03-20 AU AU2003221509A patent/AU2003221509B2/en not_active Expired
- 2003-03-20 WO PCT/EP2003/002899 patent/WO2003082244A2/en active Application Filing
- 2003-03-20 CA CA2479638A patent/CA2479638C/en not_active Expired - Fee Related
- 2003-03-20 JP JP2003579782A patent/JP5147158B2/en not_active Expired - Lifetime
- 2003-03-20 EP EP03717219A patent/EP1492498A2/en not_active Withdrawn
- 2003-03-20 PL PL03371295A patent/PL371295A1/en not_active Application Discontinuation
-
2004
- 2004-07-15 ZA ZA2004/05637A patent/ZA200405637B/en unknown
- 2004-09-23 NO NO20044004A patent/NO20044004L/en not_active Application Discontinuation
- 2004-09-27 HR HR20040890A patent/HRP20040890A2/en not_active Application Discontinuation
- 2004-09-28 EC EC2004005322A patent/ECSP045322A/en unknown
Also Published As
Publication number | Publication date |
---|---|
IL163696A0 (en) | 2005-12-18 |
AU2003221509A1 (en) | 2003-10-13 |
BR0308709A (en) | 2005-01-04 |
NO20044004L (en) | 2004-10-05 |
UA79776C2 (en) | 2007-07-25 |
EP1492498A2 (en) | 2005-01-05 |
NZ536030A (en) | 2006-07-28 |
KR20040098022A (en) | 2004-11-18 |
AU2003221509B2 (en) | 2008-01-24 |
JP2005527550A (en) | 2005-09-15 |
WO2003082244A2 (en) | 2003-10-09 |
CA2479638C (en) | 2011-01-04 |
EA008610B1 (en) | 2007-06-29 |
MEP47308A (en) | 2011-02-10 |
KR101005717B1 (en) | 2011-01-05 |
JP5147158B2 (en) | 2013-02-20 |
RS52481B (en) | 2013-02-28 |
EA200401159A1 (en) | 2005-04-28 |
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