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Publication numberUS20020071812 A1
Publication typeApplication
Application numberUS 10/072,400
Publication dateJun 13, 2002
Filing dateFeb 6, 2002
Priority dateJan 31, 1990
Also published asCA2075060A1, CA2075060C, DE4003270A1, DE59109161D1, EP0513099A1, EP0513099B1, US6419899, US7160538, US20040028618, US20050031548, US20070065370, US20090104127, US20110014134, WO1991011496A1
Publication number072400, 10072400, US 2002/0071812 A1, US 2002/071812 A1, US 20020071812 A1, US 20020071812A1, US 2002071812 A1, US 2002071812A1, US-A1-20020071812, US-A1-2002071812, US2002/0071812A1, US2002/071812A1, US20020071812 A1, US20020071812A1, US2002071812 A1, US2002071812A1
InventorsHans-Hermann Weil, Ottfried Daab
Original AssigneeHans-Hermann Weil, Ottfried Daab
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Contain 1,1,1,2,3,3,3-heptafluoropropane; especially with a betamimetic, an anticholinergic, a steroid, an antiallergic or a PAF-antagonist or a combination of such compounds.
US 20020071812 A1
Abstract
Pharmaceutical preparations for producing powder aerosols using as the propellant gas TG 227.
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Claims(11)
1. Propellent gases characterised in that they contain TG 227, optionally in admixture with one of more propellent gases from the group comprising TG 11, TG 12, TG 114, propane, butane, pentane and DME.
2. Propellent gases according to claim 1, characterised in that they additionally contain at least one surface-active substance.
3. Propellent gases according to claim 2, characterised in that the surface-active substance is a phospholipid, a sorbitan ester with a higher saturated or unsaturated fatty acid or a polyethoxysorbitan ester of a higher, preferably unsaturated fatty acid.
4. Propellent gases according to claim 2, characterised in that the surface-active substance is a lecithin, a polyethoxyethylenesorbitan oleate or sorbitan trioleate.
5. Pharmaceutical preparations for producing powder aerosols based on propellent gases according to claim 1, 2, 3 or 4, characterised in that they contain as active substance a betamimetic, an anticholinergic, a steroid, an antiallergic or a PAF-antagonist or a combination of such compounds.
6. Pharmaceutical preparations according to claim 5, characterised in that the betamimetic used is:
Bambuterol
Bitolterol
Carbuterol
Clenbuterol
Fenoterol
Hexoprenalin
Ibuterol
Pirbuterol
Procaterol
Reproterol
Salbutamol
Salmeterol
Sulfonterol
Terbutalin
Tulobuterol
1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol
erythro-5′-hydroxy-8′-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one
1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol
1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol
the anticholinergic used is:
Ipratropium bromide
Oxitropium bromide
Trospium chloride
Benzilic acid-N-β-fluoroethylnortropine ester methobromide
the steroid used is:
Budesonide
Beclomethasone (or the 17, 21-dipropionate thereof)
Dexamethason-21-isonicotinate
Flunisolide
The antiallergic agent is:
Disodium cromoglycate
Nedocromil
The PAF-antagonist is:
WEB 2086
WEB 2170
WEB 2347.
7. Pharmaceutical preparations according to claim 5, characterised in that the combination of the active substances comprises one of the betamimetics specified in claim 6 and one of the anticholinergics specified in claim 6.
8. Pharmaceutical preparation according to claim 5, characterised in that the combination of the active substances comprises one of the betamimetics specified in claim 6 and disodium chromoglycate.
9. Pharmaceutical preparation according to claim 5,. characterised in that the combination of the active substances contains one of the betamimetics specified in claim 6 and one of the PAF-antagonists specified in claim 6.
10. Pharmaceutical preparation according to claim 5, characterised in that the combination of the active substances comprises disodium chromoglycate and one of the PAF-antagonists specified in claim 6.
11. Process for preparing pharmaceutical preparations according to claims 5 to 10, characterised in that pharmaceutically active substances micronised by conventional methods are suspended in a liquefied propellent gas mixture according to claim 1, 2, 3 or 4, optionally with the addition of surface-active substances.
Description

[0001] The invention relates to new propellent gases which contain as a typical ingredient 1,1,1,2,3,3,3-heptafluoropropane (TG 227), the use of these propellent gases in pharmaceutical preparations suitable for producing aerosols, and these pharmaceutical preparations themselves.

[0002] Aerosols of powdered (micronised) drugs are used widely in therapy, e.g. in the treatment of obstructive diseases of the respiratory tract. If such aerosols are not produced by atomising the pharmaceutical powder or by spraying solutions, suspensions of the drugs in liquefied propellent gases are used. The latter consist primarily of mixtures of TG 11 (trichlorofluoromethane), TG 12 (dichlorodifluoromethane) and TG 114 (1,2-dichloro-1,1,2,2-tetrafluoroethane), optionally with the addition of lower alkanes such as butane or pentane, or with the addition of DME (dimethylether). Mixtures of this kind are known for example from German Patent 1178975.

[0003] Owing to their harmful effect on the earth's atmosphere (destruction of the ozone layer, Greenhouse effect) the use of chlorofluorocarbons has become a problem, with the result that the search is on for other propellent gases or propellent gas mixtures which do not have the above-mentioned harmful effects or, at least, have them to a lesser degree.

[0004] However, this search has come up against major problems, since propellent gases for therapeutic use have to satisfy numerous criteria which cannot easily be reconciled, e.g. in terms of toxicity, stability, vapour pressure, density and solubility characteristics.

[0005] As has now been found, TG 227 (1,1,1,2,3,3,3-heptafluoropropane, optionally in admixture with one of more propellent gases from the group comprising TG 11 (trichlorofluoromethane), TG 12 (dichlorodifluoro-methane), TG 114 (1,2-dichloro-1,1,2,2-tetrafluoroethane), propane, butane, pentane and DME (dimethylether) is particularly suitable for use in therapeutic preparations.

[0006] The compounds to be used in addition to TG 227 are added if the properties of the propellent gas are to be modified, e.g. if the liquefied propellents gas is to have a different density, different pressure or different solubility characteristics. Pharmaceutical preparations based on the propellent gas contain an active substance in finely divided form, usually as a suspension, and generally also contain surface-active substances, e.g. a phospholipid (such as lecithin), an ester of a polyalcohol (such as sorbitol) with higher saturated or unsaturated fatty acids (e.g. stearic, palmitic or oleic acid), such as sorbitan trioleate, or a polyethoxysorbitan ester of a higher, preferably unsaturated fatty acid. The adjuvant may be present in the mixture in dissolved or undissolved form. In some cases, the suspensions produced with the new propellent gas have a tendency to separate out. However, it has been found that the separated suspensions can easily be uniformly distributed again in the suspension medium simply by shaking.

[0007] The ratios of quantities of the individual ingredients of the propellent gas mixture may be varied within wide limits. The proportion (in percent by weight) is 10 to 100% in the case of TG 227. The mixture may also contain up to 50% propane and/or butane and/or pentane and/or DME and/or TG 11 and/or TG 12 and/or TG 114. Within the limits specified the ingredients are chosen to add up to 100%. Propellent gas mixtures which contain 30 to 100% TG 227 are preferred.

[0008] The proportion of suspended drug in the finished preparation is between 0.001 and 5%, preferably between 0.005 and 3%, more particularly between 0.01 and 2%. The surface-active substances are added in amounts of from 0.01 to 10%, preferably 0.05 to 5%, more particularly 0.1 to 3% (here, as in the case of the pharmaceutical substances, the percentage by weight of the finished preparation is given). The pharmaceutical substances used in the new preparations may be any of the substances suitable for use by inhalation or possibly for intranasal administration. They include, therefore, in particular betamimetics, anticholinergics, steroids, antiallergics, PAF-antagonists and combinations of these active substances.

[0009] The following are given as specific examples:

[0010] Examples of Betamimetics

[0011] Bambuterol

[0012] Bitolterol

[0013] Carbuterol

[0014] Clenbuterol

[0015] Fenoterol

[0016] Hexoprenalin

[0017] Ibuterol

[0018] Pirbuterol

[0019] Procaterol

[0020] Reproterol

[0021] Salbutamol

[0022] Salmeterol

[0023] Sulfonterol

[0024] Terbutalin

[0025] Tulobuterol

[0026] 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol

[0027] erythro-5′-hydroxy-8′-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one

[0028] 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol

[0029] 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol.

[0030] Examples of Anticholinergics

[0031] Ipratropium bromide

[0032] Oxitropium bromide

[0033] Trospium chloride

[0034] Benzilic acid-N-β-fluoroethylnortropine ester

[0035] methobromide

[0036] Examples of Steroids

[0037] Budesonide

[0038] Beclomethasone (or the 17,21-dipropionate thereof)

[0039] Dexamethason-21-isonicotinate

[0040] Flunisolide

[0041] Examples of Antiallergics

[0042] Disodium cromoglycate

[0043] Nedocromil

[0044] Examples of PAF-antagonists

[0045] WEB 2086

[0046] WEB 2170

[0047] WEB 2347

[0048] The active substances may also be combined, e.g. betamimetics plus anticholinergics or betamimetics plus antiallergics.

[0049] Examples of Preparations According to the Invention (Amounts Given in Percent by Weight)

[0050] 1) 0.10% Oxitropium bromide

[0051] 0.01% Soya lecithin

[0052] 4.0% Pentane

[0053] 95.89% TG 227

[0054] 2) 0.3% Fenoterol

[0055] 0.1% Soya lecithin

[0056] 10.0% Pentane

[0057] 70.0% TG 227

[0058] 19.6% TG 134a

[0059] 3) 0.1% Ipratropium bromide

[0060] 0.1% Soya lecithin

[0061] 20.0% Pentane

[0062] 20.0% Butane

[0063] 49.8% TG 11

[0064] 4) 0.3% Fenoterol

[0065] 0.1% Soya lecithin

[0066] 30.0% TG 11

[0067] 69.6 TG 227

[0068] 5) 1.5% Disodium cromoglicate

[0069] 0.1% Tween 20

[0070] 98.4% TG 227

[0071] 1.4% Butane

[0072] 6) 0.3% Salbutamol

[0073] 0.2% Span 85

[0074] 20.0% Pentane

[0075] 60.0% TG 227

[0076] 19.5% TG 12

[0077] 7) 0.15% Fenoterol

[0078] 0.06% Ipratropium-bromide

[0079] 0.10% Soya lecithin

[0080] 40.00% TG 11

[0081] 19.69% Propane

[0082] 40.00% TG 227

[0083] 8) 0.1% Ipratropium-bromide

[0084] 0.1% Soya lecithin

[0085] 15.3% Propane

[0086] 30.5% TG 11

[0087] 54.0% TG 227

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US6743413May 31, 1995Jun 1, 20043M CompanySuspension aerosol formulations
US6919069Apr 30, 2003Jul 19, 2005Glaxo Group LimitedAerosol formulation containing particulate formoterol, propellant and polar cosolvent
US6932962Dec 19, 1995Aug 23, 2005Astrazeneca Abfor use in pressurized metered dose inhalers (pMDI's); surfactants such as decyl glucoside or dodecyl maltoside
US7101534May 31, 1995Sep 5, 20063M Innovative Properties CompanySuspension aerosol formulations
US7105152May 31, 1995Sep 12, 20063M Innovative Properties CompanySuspension aerosol formulations
Classifications
U.S. Classification424/45
International ClassificationC07C19/08, A61K31/573, A61K9/12, C09K3/30, A61K47/14, A61K47/06, A61K9/00, A61K9/72
Cooperative ClassificationA61K9/124, C09K3/30, A61K9/008
European ClassificationA61K9/12D, A61K9/00M20B6, C09K3/30