CN1642525A - HFA suspension formulations of an anhydrate - Google Patents
HFA suspension formulations of an anhydrate Download PDFInfo
- Publication number
- CN1642525A CN1642525A CNA038072475A CN03807247A CN1642525A CN 1642525 A CN1642525 A CN 1642525A CN A038072475 A CNA038072475 A CN A038072475A CN 03807247 A CN03807247 A CN 03807247A CN 1642525 A CN1642525 A CN 1642525A
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- Prior art keywords
- suspensoid
- acid
- tiotropium
- impelling
- present
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-
- 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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- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (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
The invention relates to propellant gas formulations containing suspensions of the 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[3.3.1.0<2,4>]nonane-bromide.
Description
The present invention relates to as contain (1 α, 2 β, 4 β, 5 α, 7 β)-7-[(hydroxyl two-the 2-thiophene acetyl) oxygen]-9,9-dimethyl-3-oxa--9-nitrogen three ring [3.3.1.0
2,4] the impelling gas preparation of metered aerosol of crystal anhydrous compound suspensoid of nonane bromide.
Background technology
Chemical compound (1 α, 2 β, 4 β, 5 α, 7 β)-7-[(hydroxyl is two-the 2-thiophene acetyl) and oxygen]-9,9-dimethyl-3-oxa--9-nitrogen three ring [3.3.1.0
2,4] the nonane bromide is to know from European patent application EP 418 716 A1, and following chemical constitution arranged:
This chemical compound has valuable pharmacological characteristics, and known with (BA679) name of tiotropium bromide (tiotropium bromide).Tiotropium bromide is an anticholinergic efficiently, and therefore asthma or COPD (chronic obstructive pulmonary disease) is had therapeutic effect.
Preferably by the inhalation tiotropium bromide.
The objective of the invention is to prepare the HFA-metered aerosol that contains tiotropium bromide, tiotropium bromide is the active component of unique suspendible form.
Detailed Description Of The Invention
Have been found that the condition difference of using when the natural prodcuts that obtain after the commercial production are carried out purification, tiotropium bromide can occur with the form of various crystal modification.
Have been found that by selection to be used for crystalline solvent, and the condition of using in the selective freezing process rightly, can on purpose prepare these different variants.The crystal sulfuric monohydrate of tiotropium bromide is a kind of in the described crystal modification.
We are surprised to find now, from this crystal sulfuric monohydrate also not known of tiotropium bromide in this area, may obtain a kind of anhydrous crystal variant (tiotropium anhydrous compound) of tiotropium bromide, that it is particularly suitable for preparing inhalation and be in suspensoid among impelling gas HFA 227 and/or the HFA134a.
Therefore, the present invention relates to be in the suspensoid of the crystal type tiotropium bromide anhydrous compound among impelling gas HFA227 and/or the HFA 134a, this impelling gas is optional to be mixed with one or more other impelling gases, described other impelling gases are preferably selected from propane, butane, pentane, dimethyl ether, CHClF
2,, CH
2F
2, CF
3CH
3, iso-butane, isopentane and neopentane.
According to the content that relates to crystal type tiotropium bromide anhydrous compound within the scope of the present invention, we can regard it as the anhydrous crystal variant of the tiotropium bromide that the monohydrate by drying crystalline type tiotropium bromide obtains.Within the scope of the present invention, this crystal modification also can be considered to the crystal type tiotropium bromide of anhydrous form.
The present invention's suspensoid preferably only contains HFA227, contains the mixture of HFA227 and HFA134a or only contains HFA134a itself as impelling gas.If the mixing impelling gas of HFA 227 and HFA 134a is used for the mixed suspension preparation according to the present invention, can optionally selects to the part by weight of these two kinds of impelling gas componants.Except HFA 227 and/or HFA 134a, if in mixed suspension preparation of the present invention, use one or more to be selected from propane, butane, pentane, dimethyl ether, CHClF
2,, CH
2F
2, CF
2CH
3, iso-butane, isopentane and neopentane other impelling gases, the ratio of these other impelling gases preferably is lower than 50%, preferably is lower than 40%, more preferably less than 30%.
Suspensoid of the present invention preferably comprises the tiotropium of 0.001-0.8%.The present invention preferably comprises 0.08-0.5%, more preferably the suspensoid of 0.2-0.4%tiotropium.
Tiotropium refers to free ammonium cation.Impelling gas suspensoid of the present invention is characterised in that: suspensoid comprises the tiotropium that the tiotropium bromide anhydrous compound form with crystal type exists, and it is particularly suitable for this application.Therefore, the present invention preferably relates to the suspensoid of the crystal type tiotropium bromide anhydrous compound that comprises 0.0012-96%.According to the present invention, useful especially is to comprise 0.096-0.6%, the more preferably suspensoid of 0.24-0.48% crystal type tiotropium bromide anhydrous compound.
Gui Ding percentage rate all is a quality percentage in the present invention.If the mass parts of tiotropium is to provide with quality percentage, can be by being multiplied by the value that conversion factor 1.2036 obtains to be preferred for accordingly the anhydrous compound of crystal type tiotropium bromide of the present invention.
Under the certain situation in the present invention, can use the term mixed suspension preparation to come the alternative terms suspensoid.For the present invention, these two kinds of terms can exchange.
Inhalation aerosol or the mixed suspension preparation that comprises propellant of the present invention can also contain other compositions, such as surface-active reagent (surfactant), adjuvant, antioxidant or flavoring agent.
Can be included in surfactant in the suspensoid of the present invention is preferably and is selected from polysorbate20, polysorbate80, Myvacet 9-45, Myvacet 9-08, isopropyl myristate, oleic acid, propylene glycol, Polyethylene Glycol, Brij, ethyl oleate, glycerol trioleate, glyceryl monolaurate, glyceryl monooleate, glyceryl monostearate, single castor oil acid glyceride, spermol, sterol (sterylalcohol), cetylpyridinium chloride, block copolymer, natural oil, ethanol and isopropyl alcohol.In the above-mentioned suspendible adjuvant, preferably use polysorbate20, polysorbate80, Myvacet 9-45, Myvacet 9-08, isopropyl myristate.Especially preferably use Myvacet9-45 or isopropyl myristate.
When suspensoid of the present invention comprised surfactant, the content of surfactant was 0.0005-1%, is preferably 0.005-0.5%.
The optional adjuvant that is included in the suspensoid of the present invention is preferably selected from following material: alanine, albumin, ascorbic acid, aspartyl-phenylalanine methyl ester, betanin, cysteine, phosphoric acid, nitric acid, hydrochloric acid, sulphuric acid or citric acid.Wherein, preferred ascorbic acid, phosphoric acid, hydrochloric acid, citric acid, and, more preferably hydrochloric acid, citric acid.
Comprise at suspensoid of the present invention under the situation of adjuvant, adjuvant content is preferably 0.0001-1.0%, preferred 0.0005-0.1%, and more preferably 0.001-0.01%, yet, according to the present invention, preferred especially 0.001-0.005%.
The optional antioxidant that is included in the suspendible of the present invention is preferably selected from following material: ascorbic acid, citric acid, edetate sodium, edetic acid, vitamin E, butylated hydroxytoluene, butylated hydroxyanisole (BHA) and ascorbic palmitate, wherein preferred butylated hydroxytoluene, butylated hydroxyanisole (BHA) and ascorbic palmitate.
The optional flavoring agent that is included in the suspendible of the present invention is preferably selected from following material: Herba Menthae, glucide, Dentomint
, aspartyl-phenylalanine methyl ester, volatile oil (for example: Cortex Cinnamomi, anisum fruit, menthol, Camphora), wherein, preferred especially Oleum menthae or Dentomint
In order to carry out administration, must prepare the active substance of segmentation by suction.The crystal type tiotropium bromide anhydrous compound that the scheme that describes in detail as experiment part can be made grinds (micronization), or the form that obtains segmenting by known substantially other technologies method in this area (such as separating out and spray drying).It is well known in the art making the micronized method of active substance.Behind the micronization, the particle mean size of active substance is preferably 0.5-10 μ m, preferred 1-6 μ m, more preferably 1.5-5 μ m.Preferably, at least 50%, more preferably at least 60%, most preferably the granularity of at least 70% active substance is in above-mentioned scope.Preferably, at least 80%, most preferably the granularity of at least 90% active substance is in above-mentioned scope.
Also be surprised to find, also can prepare, except above-mentioned impelling gas, only comprise active substance and do not have the suspensoid of other additives.Therefore, the present invention relates to the suspensoid that only comprises active substance and do not have other additives on the other hand.Can prepare suspensoid of the present invention by methods known in the art.The composition of preparation and one or more impelling gases (can at low temperatures) be mixed, transfer in the suitable containers then.
The above-mentioned suspensoid that contains impelling gas of the present invention can carry out administration (pMDIs=pressurised metered dose inhalers) by inhaler well known in the art.Therefore, the present invention relates to the pharmaceutical composition of above-mentioned suspensoid form on the other hand, and the inhaler that this pharmaceutical composition and one or more are suitable for using these suspensoids combines.In addition, the present invention relates to inhaler, it is characterized in that: contain the above-mentioned suspensoid that contains impelling gas.The present invention also relates to container (cartridge case), this container is equipped with suitable valve, can be used in suitable inhaler, and simultaneously, container comprises the above-mentioned suspensoid that contains impelling gas of a kind of the present invention.Suitable containers (cartridge case) and the suspensoid of the present invention that will contain impelling gas are filled the method for these cartridge cases, can be from knowing in the prior art.
With regard to the pharmaceutically active of tiotropium, the invention further relates to the application of suspensoid in the medicine that preparation is used by suction or nasal passage, preferably the application in preparing the medicine for the treatment of those diseases that can treat with anti-gallbladder energy alkali medicine by suction or nasal passage.
More preferably, the invention further relates to suspensoid is preparing by sucking the application in the pharmaceutical composition for the treatment of respiratory disorder, particularly asthma or COPD.
Following embodiment illustrates more fully to the present invention, and the present invention is not limited only to its content.
Raw material
The crystal type tiotropium bromide monohydrate:
The tiotropium that obtains according to EP418 716 A1 can be used to prepare the crystal type tiotropium bromide monohydrate.Preparation process is carried out following reaction.In suitable reaction vessel, in the water of 25.7kg, add the tiotropium bromide of 15.0kg.Mixture heated to 80-90 ℃, and is stirred under constant temperature, up to forming settled solution.Water-moistened activated carbon (0.8kg) is suspended in the 4.4kg water, this mixture is added in the solution that contains tiotropium bromide, and wash with 4.3kg water.The mixture that obtains was stirred 15 minutes at least at 80-90 ℃, by a filter that heated, it is filled in the device of the external temperature that is heated to 70 ℃ in advance then.Water washing and filtering device with 8.6kg.With per 20 minutes decline 3-5 ℃ speed, the inclusions in the device is cooled to 20-25 °.By using cold water, will install and further be cooled to 10-15 ℃.By stirring at least 1 hour, thereby finish crystallization.With sucking filtration exsiccator isolation of crystalline, with the cold water (10-15 ℃) of 9L and cold acetone (10-15 ℃) wash crystallization serosity.Under 25 ℃, with the crystal that obtains in nitrogen current dry 2 hours.
Output: 13.4kg tiotropium bromide monohydrate (theoretical value 86%)
Utilize DSC (differential scanning calorimetry), to detecting by the available tiotropium bromide monohydrate of said method.DSC figure shows two kinds of characteristic signals.The first, because the monohydrate of tiotropium bromide is dehydrated into anhydrous form, thereby form the wide relatively endothermic signal between 50-120 ℃.The second because the fusing of material, thereby form point, be positioned at 230 ± 5 ℃ of endothermic peaks.These data are to use Mettler DSC 821 and obtain, and use Mettler STAR software kit to be assessed.Data are noted with the rate of heat addition that 10K/ divides.
Crystal type tiotropium bromide monohydrate can characterize with IR spectroscopy characteristic.Data are to utilize Nicolet FTIR spectrometer to obtain, and utilize the Nicolet OMNIC software kit of 3.1 versions to assess.Measurement contains in 300mg KBr under the monohydrated condition of 2.5 μ mol tiotropium bromides to be carried out.Following form has provided some important IR bands.
Wave number (cm
-1) the ownership oscillatory type
3570,3410 O-H stretching vibrations
3105 aryl C-H stretching vibrations
1730 C=O stretching vibrations
1260 oxide C-O stretching vibrations
1035 ester C-OC stretching vibrations
The vibration of 720 thiphene ring
The monocrystalline x ray structure analysis shows: the simple monocline structure cell that can have following size by the crystal type tiotropium bromide hydrate that said process obtains:
a＝18.0774，b＝11.9711，c＝9.9321，β＝102.691°，V＝2096.96
3。
These data are by utilizing single-frequency copper K Alpha-ray AFC7R 4-circuit diffractometer (circuitdiffractometer) (Rigaku) to obtain.The judgement of crystal structure and refinement are to refine (TeXsan program) by direct method (SHELXS86 program) and FMLQ-to obtain.
Crystal type tiotropium bromide anhydrous compound
This anhydrous form is to obtain by following process: under the condition of 80-100 ℃ of decompression, preferably under vacuum condition, the crystal type tiotropium bromide monohydrate that obtains was as mentioned above carried out carefully drying at least 30 minutes.Except under 80-100 ℃ vacuum condition, carrying out drying, also can be by at room temperature, the monohydrate of crystal type tiotropium bromide placed 24 hours on exsiccant silica gel at least and prepare anhydrous form.
The crystal structure of anhydrous tiotropium bromide determines that by high-resolution x-ray powder data (synchrotron radiation) described data are to utilize so-called " simulated annealing (simulating annealing) " process to obtain by real space mixture (real space mixture).Carrying out final Rietveld analyzes and refines structural parameters.These studies show that the crystal type tiotropium bromide that is used for suspensoid of the present invention does not have hydrate and is characterised in that elementary cell
a＝10.4336(2)，
b＝11.3297(3)，
C=17.6332 (4) and
α＝90°，
β=105.158 (2) ° and
γ=90 ° (unit cell volume=2011.89 (8)
3).
In order to prepare suspensoid of the present invention, by means commonly known in the art, can not have the hydrate micronization by the crystal type tiotropium bromide that said process obtains, and dehumidify, thereby preparation has the active substance corresponding to the described mean particle size of description of the present invention.
Formulation example
Except active substance and impelling gas, also comprise the suspensoid of other compositions:
a) 0.02％Tiotropium
*
0.20% poly-Sorbitol 20
99.78％HFA227
b) 0.02％Tiotropium
*
1.00% isopropyl myristate
98.98％HFA227
c) 0.02％Tiotropium
*
0.3％Myvacet?9-45
99.68％HFA227
d) 0.04％Tiotropium
*
1.00％Myvacet?9-08
98.96％HFA227
e) 0.04％Tiotropium
*
0.04% poly-Sorbitol 80
99.92％HFA227
f) 0.04％Tiotropium
*
0.005% oleic acid
99.955％HFA227
g) 0.02％Tiotropium
*
0.1％Myvacet?9-45
60.00％HFA227
39.88％HFA?134a
h) 0.02％Tiotropium
*
0.30% isopropyl myristate
20.00％HFA227
79.68％HFA?134a
i) 0.02％Tiotropium
*
0.01% oleic acid
60.00％HFA227
39.97％HFA?134a
*Form with the tiotropium bromide anhydrous compound is used
(conversion factor 1.2036)
The suspensoid that only contains active substance and impelling gas:
j) 0.02％Tiotropium
*
99.98％HFA227
k) 0.02％Tiotropium
*
99.98％HFA134a
l) 0.04％Tiotropium
*
99.96％HFA227
m) 0.04％Tiotropium
*
99.96％HFA134a
n) 0.02％Tiotropium
*
20.00％HFA227
79.98％HFA134a
o) 0.02％Tiotropium
*
60.00％HFA227
39.98％HFA134a
p) 0.04％Tiotropium
*
40.00％HFA227
59.96％HFA134a
q) 0.04％Tiotropium
*
80.00％HFA227
19.96％HFA134a
*Form with the tiotropium bromide anhydrous compound is used
(conversion factor 1.2036)
Claims (9)
1. the suspensoid of crystal type tiotropium bromide anhydrous compound in impelling gas HFA 227 and/or HFA 134a, this impelling gas is optional to be mixed with one or more other impelling gases, and described other impelling gases are selected from propane, butane, pentane, dimethyl ether, CHClF
2, CH
2F
2, CF
3CH
3, iso-butane, isopentane and neopentane.
2. suspensoid as claimed in claim 1 is characterized in that suspensoid comprises the tiotropium of 0.001-0.8%.
3. suspensoid as claimed in claim 1 or 2 is characterized in that comprising the surface-active reagent of tool (surfactant), adjuvant, antioxidant or flavoring agent as other compositions.
4. suspensoid as claimed in claim 3 is characterized in that containing one or more and is selected from polysorbate20, polysorbate80, Myvacet 9-45, Myvacet 9-08, isopropyl myristate, oleic acid, propylene glycol, Polyethylene Glycol, Brij, ethyl oleate, glycerol trioleate, glyceryl monolaurate, glyceryl monooleate, glyceryl monostearate, single castor oil acid glyceride, spermol, sterol, cetylpyridinium chloride, block copolymer, natural oil, the chemical compound of ethanol and isopropyl alcohol is as the surface-active reagent of tool (surfactant).
5. suspensoid as claimed in claim 3 is characterized in that containing one or more chemical compounds that are selected from alanine, albumin, ascorbic acid, aspartyl-phenylalanine methyl ester, betanin, cysteine, phosphoric acid, nitric acid, hydrochloric acid, sulphuric acid or citric acid as adjuvant.
6. suspensoid as claimed in claim 3 is characterized in that containing one or more chemical compounds that are selected from ascorbic acid, citric acid, edetate sodium, edetic acid, vitamin E, butylated hydroxytoluene, butylated hydroxyanisole (BHA) and ascorbic palmitate as antioxidant.
7. suspensoid as claimed in claim 1 or 2 is characterized in that only containing active substance and one or more impelling gases.
8. as claim 1-7 suspensoid purposes in pharmaceutical compositions as described in each, preferably treat purposes in the pharmaceutical composition of those diseases that can the alkali medicine with anti-gallbladder treat by suction or nasal passage in preparation.
9. purposes as claimed in claim 8 is characterized in that described disease is a respiratory disorder, is 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 |
| DE10214264.5 | 2002-03-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1642525A true CN1642525A (en) | 2005-07-20 |
Family
ID=28050990
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA038072475A Pending CN1642525A (en) | 2002-03-28 | 2003-03-20 | HFA suspension formulations 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) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102753152A (en) * | 2009-05-29 | 2012-10-24 | 珍珠治疗公司 | Compositions, methods & systems for respiratory delivery of two or more active agents |
| CN115252552A (en) * | 2016-09-19 | 2022-11-01 | 墨西哥氟石股份公司 | Pharmaceutical composition |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2007013691A (en) * | 2005-05-02 | 2008-01-21 | Boehringer Ingelheim Int | Crystalline forms of tiotropium bromide. |
| PT1881980E (en) * | 2005-05-02 | 2012-12-06 | Boehringer Ingelheim Int | Novel crystalline forms of tiotropium bromide |
| 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 |
| WO2014144894A1 (en) | 2013-03-15 | 2014-09-18 | Pearl Therapeutics, Inc. | Methods and systems for conditioning of particulate crystalline materials |
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 |
| EP1102579B1 (en) * | 1998-08-04 | 2003-03-19 | Jago Research Ag | Medicinal aerosol formulations |
| GB0009605D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Medicaments |
| GB0009583D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Respiratory formulations |
| 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 |
| 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 |
| DE10111058A1 (en) * | 2001-03-08 | 2002-09-12 | Boehringer Ingelheim Pharma | New drug compositions based on anticholinergics and NK¶1¶ receptor antagonists |
| DE50115277D1 (en) * | 2000-10-31 | 2010-02-04 | Boehringer Ingelheim Pharma | DRUG COMPOSITIONS FROM TIOTROPIUM SALTS AND |
-
2002
- 2002-03-28 DE DE10214264A patent/DE10214264A1/en not_active Withdrawn
-
2003
- 2003-03-20 MX MXPA04009338A patent/MXPA04009338A/en active IP Right Grant
- 2003-03-20 EA EA200401159A patent/EA008610B1/en unknown
- 2003-03-20 BR BR0308709-3A patent/BR0308709A/en active Pending
- 2003-03-20 IL IL16369603A patent/IL163696A0/en unknown
- 2003-03-20 WO PCT/EP2003/002899 patent/WO2003082244A2/en active Application Filing
- 2003-03-20 KR KR1020047015174A patent/KR101005717B1/en active IP Right Grant
- 2003-03-20 PL PL03371295A patent/PL371295A1/en not_active Application Discontinuation
- 2003-03-20 UA UA20041008758A patent/UA79776C2/en unknown
- 2003-03-20 RS YU86004A patent/RS52481B/en unknown
- 2003-03-20 AU AU2003221509A patent/AU2003221509B2/en not_active Expired
- 2003-03-20 ME MEP-2008-473A patent/ME00246B/en unknown
- 2003-03-20 CN CNA038072475A patent/CN1642525A/en active Pending
- 2003-03-20 NZ NZ536030A patent/NZ536030A/en not_active IP Right Cessation
- 2003-03-20 JP JP2003579782A patent/JP5147158B2/en not_active Expired - Lifetime
- 2003-03-20 CA CA2479638A patent/CA2479638C/en not_active Expired - Fee Related
- 2003-03-20 EP EP03717219A patent/EP1492498A2/en not_active Withdrawn
-
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
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102753152A (en) * | 2009-05-29 | 2012-10-24 | 珍珠治疗公司 | Compositions, methods & systems for respiratory delivery of two or more active agents |
| CN102753152B (en) * | 2009-05-29 | 2015-09-23 | 珍珠治疗公司 | The breathing of activating agent is sent |
| CN115252552A (en) * | 2016-09-19 | 2022-11-01 | 墨西哥氟石股份公司 | Pharmaceutical composition |
Also Published As
| Publication number | Publication date |
|---|---|
| JP5147158B2 (en) | 2013-02-20 |
| CA2479638C (en) | 2011-01-04 |
| MXPA04009338A (en) | 2005-01-25 |
| IL163696A0 (en) | 2005-12-18 |
| EP1492498A2 (en) | 2005-01-05 |
| AU2003221509A1 (en) | 2003-10-13 |
| NZ536030A (en) | 2006-07-28 |
| NO20044004L (en) | 2004-10-05 |
| WO2003082244A2 (en) | 2003-10-09 |
| EA200401159A1 (en) | 2005-04-28 |
| CA2479638A1 (en) | 2003-10-09 |
| PL371295A1 (en) | 2005-06-13 |
| WO2003082244A3 (en) | 2004-02-05 |
| AU2003221509B2 (en) | 2008-01-24 |
| JP2005527550A (en) | 2005-09-15 |
| MEP47308A (en) | 2011-02-10 |
| ECSP045322A (en) | 2005-01-28 |
| ME00246B (en) | 2011-05-10 |
| YU86004A (en) | 2006-08-17 |
| HRP20040890A2 (en) | 2005-06-30 |
| ZA200405637B (en) | 2005-07-27 |
| DE10214264A1 (en) | 2003-10-16 |
| UA79776C2 (en) | 2007-07-25 |
| RS52481B (en) | 2013-02-28 |
| BR0308709A (en) | 2005-01-04 |
| KR20040098022A (en) | 2004-11-18 |
| EA008610B1 (en) | 2007-06-29 |
| KR101005717B1 (en) | 2011-01-05 |
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