U.S. patent application number 12/891076 was filed with the patent office on 2011-01-20 for suspension aerosol formulations of pharmaceutical products.
This patent application is currently assigned to Boehringer Ingelheim KG. Invention is credited to Ottfried Daab, Hans-Hermann WEIL.
Application Number | 20110014134 12/891076 |
Document ID | / |
Family ID | 6399399 |
Filed Date | 2011-01-20 |
United States Patent
Application |
20110014134 |
Kind Code |
A1 |
WEIL; Hans-Hermann ; et
al. |
January 20, 2011 |
SUSPENSION AEROSOL FORMULATIONS OF PHARMACEUTICAL PRODUCTS
Abstract
Pharmaceutical preparations for producing powder aerosols using
propellant gases which use TG 227, and possibly also TG 11, TG 12,
TGH 114, propane, butane, pentane or DME.
Inventors: |
WEIL; Hans-Hermann;
(Gau-Bickelheim, DE) ; Daab; Ottfried; (Ingelheim,
DE) |
Correspondence
Address: |
MICHAEL P. MORRIS;BOEHRINGER INGELHEIM USA CORPORATION
900 RIDGEBURY ROAD, P. O. BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Assignee: |
Boehringer Ingelheim KG
Ingelheim
DE
|
Family ID: |
6399399 |
Appl. No.: |
12/891076 |
Filed: |
September 27, 2010 |
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Application
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12179785 |
Jul 25, 2008 |
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12891076 |
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11553508 |
Oct 27, 2006 |
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12179785 |
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10934611 |
Sep 3, 2004 |
7160538 |
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11553508 |
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10638987 |
Aug 12, 2003 |
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10934611 |
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10072400 |
Feb 6, 2002 |
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10638987 |
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09525431 |
Mar 14, 2000 |
6419899 |
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10072400 |
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08990252 |
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09525431 |
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08597230 |
Feb 6, 1996 |
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08990252 |
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08282402 |
Jul 28, 1994 |
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08597230 |
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07910353 |
Oct 1, 1992 |
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08282402 |
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Current U.S.
Class: |
424/45 ;
252/372 |
Current CPC
Class: |
A61K 9/008 20130101;
A61K 9/124 20130101; C09K 3/30 20130101 |
Class at
Publication: |
424/45 ;
252/372 |
International
Class: |
A61K 9/12 20060101
A61K009/12; C09K 3/00 20060101 C09K003/00 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 3, 1990 |
DE |
P4003270.1 |
Jan 31, 1991 |
EP |
PCT/EP91/00178 |
Claims
1. Propellent gases characterised in that they contain TG 227, in
admixture with one or 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 prospholipid, 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 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 selected from the group consisting
of 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-butylamin-
o]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,
and
1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)-
ethanol; the anticholinergic used is selected from the group
consisting of Ipratropium bromide, Oxitropium bromide, Trospium
chloride, Benzilic acid-N-.beta.-fluoroethylnortropine ester, and
methobromide; The steroid used is selected from the group
consisting Budesonide, Beclomethasone or the 17, 21-dipropionate
thereof, Dexamethason-21-isonicotinate, and Flunisolide; the
antiallergic agent is selected from the group consisting of
Disodium cromoglycate and Nedocromil; and the PAF-antagonist is
selected from the group consisting of
4-(2-Chlorophenyl)-9-methyl-2-[3-(4-morpholinyl)-3-propanon-1-yl]-6H-thie-
no [3.2-f][1.2.4]triazolo [4.3-a][1.4]diazepine,
3-(Morpholin-4-yl-carbonyl)-5-(2-chlorphenyl)-10-methyl-7H-cyclopental[4.-
5]thieno-[3.2-f][1.2.4]triazolo[4.3-a][1.4]diazepine, and
3-(Di-n-propylamincarbonyl)-5-(2-chlorphenyl)-10-methyl-7H-cyclopental[4.-
5]thieno-[3.2-f][1.2.4]triazolo[4.3-a][1.4]diazepine.
7. Process for preparing pharmaceutical preparations according to
claim 5, characterised in that pharmaceutically active substances
micronised by conventional methods are suspended in a liquefied
propellent gas mixture optionally with the addition of
surface-active substances.
Description
[0001] The invention relates to new propellent gases which contain
as a typical ingredient 1,1,1,3,3,3,3-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 atomizing
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 TG114 (1,
2-dichloro-1,1,2,2-tetrafluoroehane), optionally with the addition
of lower alkanes such as butane or pentane, or with the addition of
DME (dimethylether). Mixtures of this kind are knows 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 (dichlorodifluoromethane), 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 propellent 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
phospholipids (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
a 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 mixtures 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 RG and/or TG 11 and/or TG 12
and/or 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 to 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, steroids,
antiallergics, PAF-antagonists and combinations of these active
substances.
[0009] The following are given as specific examples:
EXAMPLES OF BETAMIMETICS
[0010] Bambuterol
[0011] Bitolterol
[0012] Carbuterol
[0013] Clenbuterol
[0014] Fenoterol
[0015] Hexoprenalin
[0016] Ibuterol
[0017] Pirbuterol
[0018] Procaterol
[0019] Reproterol
[0020] Salbutamol
[0021] Salmeterol
[0022] Sulfonterol
[0023] Terbutalin
[0024] Tulobuterol
[0025]
1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-but-
ylamino]ethanol
[0026]
erythro-5'-hydroxy-8'-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benz-
oxazin-3-(4H)-one
[0027]
1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-ter.-butylamino)
ethanol
[0028] 1-(4-ethoxyc
arbonylamino-3-cyano-5-fluorophenyl-2-(tert.-butylamino)ethanol.
Examples of Anticholinergics:
[0029] Ipratropium bromide
[0030] Oxitropium bromide
[0031] Trospium chloride
[0032] Benzilic acid-N-.beta.-fluoroethylnortropine ester
[0033] methobromide
Examples of Steroids:
[0034] Budesonide
[0035] Beclomethasone (or the 17, 21-dipropionate thereof)
[0036] Dexamethason-21-isonicotinate
[0037] Flunisolide
Examples of Anti-Allergies:
[0038] Disodium cromoglycate
[0039] Nedocromil
Examples of PAF-Antagonists:
[0040]
4-(2-Chlorophenyl)-9-methyl-2-[3-(4-morpholinyl)-3-propanon-1-yl]-6-
H-thieno [3.2-f][1.2.4]triazolo [4.3-a] [1.4]diazepine.
[0041]
3-(Morpholin-4-yl-carbonyl)-5-(2-chlorphenyl)-10-methyl-7H-cyclopen-
tal[4.5]thieno-[3.2-f][1.2.4]triazolo [4.3-a][1.4]diazepine
[0042]
3-(Di-n-propylamincarbonyl)-5-(2-chlorphenyl)-10-methyl-7H-cyc
lopental [4.5]thieno-[3.2-f][1.2.4]triazolo
[4.3-a][1.4]diazepine
[0043] The active substances may also be combined, e.g.,
betamimetics plus anticholinergics or betamimetics plus
anti-allergies.
[0044] Examples of preparations according to the invention (amounts
given in percent by weight):
TABLE-US-00001 1) 0.10% Oxitropium bromide 2) 0.3% Fenoterol 0.01%
Soya lecithin 0.1% Soyalecithin 4.0% Pentane 10.0% Pentane 95.89%
TG 227 70.0% TG 227 19.6% TG 134a 3) 0.1% Ipratropium bromide 4)
0.3% Fenoterol 0.1% Soya lecithin 0.1% Soya lecithin 20.0% Pentane
30.0% TG 11 20.0% Butane 69.6% TG 227 49.8% TG 11 5) 1.5% Disodium
cromoglicate 6) 0.3% Salbutamol 0.1% Tween 20 0.2% Span 85 98.4% TG
227 20.0% Pentane 1.4% Butane 60.0% TG 227 19.5% TG 12 7) 0.15%
Fenoterol 8) 0.1% Ipratropium bromide 0.06% Ipratropium bromide
0.1% Soya lecithin 0.10% Soya lecithin 15.3% Propane 40.00% TG 11
30.5% TG 11 19.69% Propane 54.0% TG 227 40.00% TG 227
* * * * *