Note: Descriptions are shown in the official language in which they were submitted.
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81272pct.211
New Pharmaceutical Compositions based on new Anticholinergics and
PDE-IV inhibitors
The present invention relates to novel pharmaceutical compositions based on
new anticholinergics and PDE-IV inhibitors, processes for preparing them and
their use in the treatment of respiratory diseases.
Description of the invention
The present invention relates to novel pharmaceutical compositions based on
anticholinergics and PDE-IV inhibitors, processes for preparing them and
their use in the treatment of respiratory diseases.
Surprisingly, an unexpectedly beneficial therapeutic effect, particularly a
synergistic effect can be observed in the treatment of inflammatory and/or
obstructive diseases of the respiratory tract if one or more, preferably one,
anticholinergic of formula 1 is used with one or more, preferably one, PDE-IV
inhibitor 2. In view of this synergistic effect the pharmaceutical
combinations
according to the invention can be used in smaller doses than would be the
case with the individual compounds used in monotherapy in the usual way.
Furthermore, this reduces unwanted side effects such as may occur when
PDE-IV inhibitors are administered, for example.
The effects mentioned above may be observed both when the two active
substances are administered simultaneously in a single active substance
formulation and when they are administered successively in separate
formulations. According to the invention, it is preferable to administer the
two
active substance ingredients simultaneously in a single formulation.
Within the scope of the present invention the anticholinergics used are the
salts of formula 1
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Met+~Me -
N X
O H
O O
Me
1
wherein
X - denotes an anion with a single negative charge, preferably an
anion selected from the group consisting of chloride, bromide,
iodide, sulphate, phosphate, methanesulphonate, nitrate,
maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate,
benzoate and p-toluenesulphonate.
Preferably, the salts of formula 1 are used wherein
X - denotes an anion with a single negative charge selected from
the group consisting of chloride, bromide, 4-toluenesulphonate
and methanesulphonate, preferably bromide.
Most preferably, the salts of formula 1 are used wherein
X - denotes an anion with a single negative charge selected from
the group consisting of chloride, bromide and
methanesulphonate, preferably bromide.
Particularly preferred according to the invention is the salt of formula 1
wherein
X - denotes bromide.
The salts of formula 1 are known from International Patent Application WO
02/32899.
Within the scope of the present patent application, an explicit reference to
the
pharmacologically active cation of formula
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Met+~Me
N
O H
O O
Me
can be recognised by the use of the designation 1'. Any reference to
compounds 1 naturally includes a reference to the cation 1'.
Any reference within the scope of the present invention to the salts 1 which
may be used according to the invention includes any hydrates and solvates of
these compounds which may optionally be obtained.
Within the scope of the present invention, the word PDE-IV inhibitors
(hereinafter 2) denotes compounds selected from among enprofylline,
theophylline, roflumilast, ariflo (cilomilast), Bay-198004, CP-325,366, BY343,
D-4396 (Sch-351591), V-11294A, AWD-12-281, N-(3,5-dichloro-1-oxo-
pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide and the
tricyclic nitrogen heterocycles of general formula 2a
H 0
N . R2
R~ ~\ I N
N N ~N
N 3
R 2a
wherein
R' denotes C1-C5-alkyl, C5-Cg-cycloalkyl, phenyl, benzyl or a 5- or
6-membered, saturated or unsaturated heterocyclic ring which
may contain one or two heteroatoms selected from among
oxygen and nitrogen;
R2 denotes C1-C5-alkyl or C2-C4-alkenyl;
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R3 denotes C1-C5-alkyl which may optionally be substituted by
C1-Cq.-alkoxy, C5-C6-cycloalkyl, phenoxy or a 5- or 6-membered,
saturated or unsaturated heterocyclic ring which may contain one
or two heteroatoms selected from among oxygen and nitrogen;
C5-Cg-cycloalkyl or phenyl or benzyl optionally substituted by
C1-C4-alkoxy, optionally in the form of their racemates, their
enantiomers, in the form of the diastereomers and the mixtures
thereof, optionally in the form of their tautomers and optionally
the pharmacologically acceptable acid addition salts thereof.
Of the abovementioned compounds of formula 2a those which are preferably
used within the scope of the present invention are those compounds of
formula 2a wherein
R' denotes C1-C4-alkyl, C5-Cg-cycloalkyl, tetrahydrofuranyl,
tetrahydropyranyl, piperazinyl, morpholinyl or phenyl;
R2 denotes C1-C4-alkyl or C2-Cq-alkenyl;
R3 denotes C1-C4-alkyl which may optionally be substituted by
C1-C4-alkoxy, C5-Cg-cycloalkyl, phenoxy, (C1-C4-
alkoxy)phenyloxy, piperazine or pyrrole, C5-C6-cycloalkyl or
phenyl or benzyl optionally substituted by C1-C4-alkoxy,
optionally in the form of their racemates, their enantiomers, in the
form of the diastereomers and the mixtures thereof, optionally in
the form of their tautomers and optionally the pharmacologically
acceptable acid addition salts thereof.
Of the compounds of formula 2a those which are most preferably used within
the scope of the present invention are those compounds of formula 2a
wherein
R' denotes ethyl, propyl, butyl, cyclopentyl, tetrahydrofuranyl,
tetrahydropyranyl, N-morpholinyl or phenyl;
R2 denotes ethyl, propyl, allyl or butenyl;
R3 denotes ethyl, propyl, butyl, cyclopentyl, cyclohexylmethyl,
benzyl, phenylethyl, phenoxymethyl, methoxybenzyl or
N-pyrrolylmethyl,
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optionally in the form of their racemates, their enantiomers, in the
form of the diastereomers and the mixtures thereof, optionally in
the form of their tautomers and optionally the pharmacologically
acceptable acid addition salts thereof.
Most preferably, the compounds used as component 2 are the compounds of
formula _2a wherein
R' denotes ethyl, n-propyl, tert-butyl, cyclopentyl, 3-tetrahydrofuryl,
N-morpholinyl or phenyl;
R2 denotes ethyl or n-propyl;
R3 denotes ethyl, i-propyl, n-propyl, n-butyl, t-butyl, cyclopentyl,
cyclohexylmethyl, benzyl, phenylethyl, phenoxymethyl,
4-methoxybenzyl or N-pyrollylmethyl, optionally in the form of
their racemates, their enantiomers, in the form of the
diastereomers and the mixtures thereof, optionally in the form of
their tautomers and optionally the pharmacologically acceptable
acid addition salts thereof.
Examples of alkyl groups (including those which are part of other groups) are
branched and unbranched alkyl groups with 1 to 5 carbon atoms, such as, for
example: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. butyl,
tert.butyl, n-pentyl, isopentyl or neopentyl. The abbreviations Me, Et, n-Pr,
i-
Pr, n-Bu, i-Bu, t-Bu, etc. may optionally be used for the abovementioned
groups.
Examples of cycloalkyl groups with 5 or 6 carbon atoms include cyclopentyl
or cyclohexyl. Examples of 5- or 6-membered, saturated or unsaturated
heterocyclic rings which may contain one or two heteroatoms selected from
among oxygen and nitrogen include: furan, tetrahydrofuran,
tetrahydrofuranon, ~y-butyrolactone, a-pyran, y-pyran, dioxolan,
tetrahydropyran, dioxan, pyrrole, pyrroline, pyrrolidine, pyrazole,
pyrazoline,
imidazole, imidazoline, imidazolidine, pyridine, piperidine, pyridazine,
pyrimidine, pyrazine, piperazine, morpholine, oxazole, isoxazole, oxazine and
pyrazolidine.
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Table 1 lists the compounds of general formula 2a which are most preferably
used in conjunction with the compounds 1 within the scope of the invention.
O
H .R2
N N
R -<~
N N ~N
N 3
R 2a
Table 1:
No. R~
1 cyclopentyl n-propyl i-propyl
2 cyclopentyl n-propyl ethyl
3 t-butyl ethyl 4-methoxybenzyl
4 cyclopentyl ethyl -CH2CH2phenyl
3-tetrahydrofurylethyl benzyl
g cyclopentyl n-propyl n-propyl
7 t-butyl ethyl benzyl
g phenyl n-propyl n-propyl
g cyclopentyl ethyl benzyl
-n-propyl -n-propyl benzyl
11 cyclopentyl ethyl N-pyrrolylmethyl
12 cyclopentyl -n-propyl benzyl
13 cyclopentyl -n-propyl -t-butyl
14 cyclopentyl n-propyl n-butyl
cyclopentyl ethyl -CH2-Ophenyl
16 N-morpholinyl -n-propyl benzyl
17 cyclopentyl ethyl cyclohexylmethyl
1 g ethyl ethyl cyclohexylmethyl
1 g n-propyl n-propyl cyclopentyl
The compounds of general formula 2a may be prepared analogously to the
method described in the prior art for certain of the above-defined compounds
10 of general formula (I) (Tenor et al., Chem. Ber. Vol. 97 (1964) p. 1373-
1382),
to which reference is hereby made.
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Preferably, also, the compound 2 is selected from among enprofylline,
roflumilast, ariflo, AWD-12-281 and N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-
difluoromethoxy-3-cyclopropylmethoxybenzamide, while ariflo, roflumilast,
AWD-12-281 and the abovementioned compounds of formula 2a are
particularly preferred as compound 2 according to the invention.
Any reference to the abovementioned PDE-IV inhibitors 2 within the scope of
the present invention includes a reference to any pharmacologically
acceptable acid addition salts thereof which may exist.
By the physiologically acceptable acid addition salts which may be formed
from 2 are meant, according to the invention, pharmaceutically acceptable
salts selected from the salts of hydrochloric acid, hydrobromic acid,
sulphuric
acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid,
succinic acid, lactic acid, citric acid, tartaric acid or malefic acid.
Particularly
preferred salts of the compounds 2 according to the invention are those
selected from among the acetate, hydrochloride, hydrobromide, sulphate,
phosphate and methanesulphonate.
The pharmaceutical combinations of 1 and 2 according to the invention are
preferably administered by inhalation. Suitable inhalable powders packed
into suitable capsules (inhalettes) may be administered using suitable powder
inhalers. Alternatively, the drug may be inhaled by the application of
suitable
inhalation aerosols. These also include inhalation aerosols which contain
HFA134a (also known as TG134a), HFA227 (also known as TG227) or a
mixture thereof as propellant gas. The drug may also be inhaled using
suitable solutions of the pharmaceutical combination consisting of 1 and 2.
In one aspect, therefore, the invention relates to a pharmaceutical
composition which contains a combination of 1 and 2.
In another aspect the present invention relates to a pharmaceutical
composition which contains one or more salts 1 and one or more compounds
_2, optionally in the form of their solvates or hydrates. Again, the active
substances may be combined in a single preparation or contained in two
separate formulations. Pharmaceutical compositions which contain the active
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substances 1 and 2 in a single preparation are preferred according to the
invention.
In another aspect the present invention relates to a pharmaceutical
composition which contains, in addition to therapeutically effective
quantities
of 1 and 2, a pharmaceutically acceptable excipient. In another aspect the
present invention relates to a pharmaceutical composition which does not
contain any pharmaceutically acceptable excipient in addition to
therapeutically effective quantities of 1 and 2.
The present invention also relates to the use of 1 and 2 for preparing a
pharmaceutical composition containing therapeutically effective quantities of
1 and 2 for treating inflammatory and/or obstructive diseases of the
respiratory tract, particularly asthma or chronic obstructive pulmonary
disease
(COPD), and complications thereof such as pulmonary hypertension, as well
as allergic and non-allergic rhinitis.
The present invention also relates to the simultaneous or successive use of
therapeutically effective doses of the combination of the above
pharmaceutical compositions 1 and 2 for treating inflammatory and/or
obstructive diseases of the respiratory tract, particularly asthma or chronic
obstructive pulmonary disease (COPD), and complications thereof such as
pulmonary hypertension, as well as allergic and non-allergic rhinitis, by
simultaneous or successive administration.
In the active substance combinations of 1 and 2 according to the invention,
ingredients 1 and 2 may be present in the form of their enantiomers, mixtures
of enantiomers or in the form of racemates.
The proportions in which the two active substances 1 and 2 may be used in
the active substance combinations according to the invention are variable.
Active substances 1 and 2 may possibly be present in the form of their
solvates or hydrates. Depending on the choice of the compounds 1 and 2,
the weight ratios which may be used within the scope of the present invention
vary on the basis of the different molecular weights of the various compounds
and their different potencies. As a rule, the pharmaceutical combinations
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according to the invention may contain compounds 1 and 2 in ratios by
weight ranging from 1:100 to 100:1, preferably from 1:80 to 80:1. In
particularly preferred pharmaceutical combinations, the weight ratios of 1 to
2
are most preferably in a range in which 1' and 2 are present in proportions of
1:50 to 50:1, more preferably from 1:20 to 20:1.
For example, without restricting the scope of the invention thereto, preferred
combinations of 1' and PDE-IV inhibitor 2 may contain [error in the German
text] in the following weight ratios:
1:65, 1:64, 1:63, 1:62, 1:61, 1:60, 1:59, 1:58, 1:57, 1:56, 1:55, 1:54, 1:53,
1:52, 1:51, 1:50; 1:49; 1:48; 1:47; 1:46; 1:45; 1:44; 1:43; 1:42; 1:41; 1:40;
1: 39; 1:38; 1:37; 1:36; 1:35; 1:34; 1:33; 1:32; 1:31; 1:30; 1:29; 1:28; 1:27;
1:26; 1:25; 1:24; 1:23; 1:22; 1:21; 1:20; 1:19; 1:18; 1:17; 1:16; 1:15; 1:14;
1:13;1:12;1:11;1:10;1:9;1:8;1:7;1:6;1:5;1:4;1:3;1:2;1:1;2:1;3:1;4:1;
5:1; 6:1; 7:1; 8:1; 9:1; 10:1; 11:1; 12:1; 13:1; 14:1; 15:1; 16:1; 17:1; 18:1;
19:1; 20:1.
The pharmaceutical compositions according to the invention containing the
combinations of 1 and 2 are normally administered so that 1 and 2 are
present together in doses of 0.01 to 10000~g, preferably from 0.1 to 2000~,g,
more preferably from 1 to 1500~.g, better still from 50 to 1200~g per single
dose. For example, combinations of 1 and 2 according to the invention
contain a quantity of tiotropium 1' and PDE-IV inhibitor 2 such that the total
dosage per single dose is about 100~,g, 105~g, 110~g, 115~,g, 120~,g, 125~g,
130~,g, 135~g, 140pg, 145Ng, 150Ng, 155Ng, 160pg, 165pg, 170Ng, 175pg,
180Ng, 185Ng, 190Ng, 195Ng, 200pg, 205Ng, 210pg, 215pg, 220pg, 225Ng,
230pg, 235pg, 240Ng, 245Ng, 250pg, 255Ng, 260Ng, 265pg, 270Ng, 275Ng,
280pg, 285pg, 290Ng, 295Ng, 300pg, 305pg, 310Ng, 315Ng, 320Ng, 325Ng,
330pg, 335Ng, 340Ng, 345pg, 350Ng, 355Ng, 360pg, 365pg, 370pg, 375Ng,
380pg, 385Ng, 390pg, 395pg, 400pg, 405Ng, 410pg, 415pg, 420Ng, 425pg,
430pg, 435pg, 440Ng, 445Ng, 450Ng, 455pg, 460Ng, 465Ng, 470Ng, 475pg,
480Ng, 485Ng, 490pg, 495Ng, 500pg, 505Ng, 510Ng, 515pg, 520pg, 525~g,
530~,g, 535~g, 540~g, 545g,g, 550~g, 555~,g, 560g,g, 565~g, 570g.g, 575g,g,
580~.g, 585~g, 590~,g, 595~g, 600~,g, 605~g, 610~g, 615~,g, 620~,g, 625~.g,
630~.g, 635gg, 640~g, 645~g, 650~,g, 655g,g, 660~g, 665g,g, 670~g, 675~,g,
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680~g, 685p,g, 690~,g, 695~,g, 700~,g, 705p,g, 710p,g, 715~g, 720p,g, 725~g,
730~g, 735~,g, 740~g, 745~g, 750~g, 755p,g, 760p,g, 765~g, 770p,g, 775~,g,
780p,g, 785~g, 790p,g, 795p,g, 800p,g, 805~,g, 810~,g, 815~,g, 820pg, 825pg,
830~,g, 835~g, 840~g, 845~.g, 850~g, 855~g, 860~g, 865~g, 870~g, 875~.g,
880~g, 885~,g, 890p,g, 895~g, 900~,g, 905~,g, 910p,g, 915~,g, 920~,g, 925wg,
930~g, 935~g, 940~g, 945~g, 950~g, 955~,g, 960~,g, 965~,g, 970~g, 975~g,
980~g, 985~,g, 990~,g, 995~g, 1000~g, 1005p,g, 1010~,g, 1015~,g, 1020~,g,
1025~,g, 1030~,g, 1035~,g, 1040~g, 1045~,g, 1050p,g, 1055~,g, 1060~,g,
1065~g, 1070~,g, 1075~g, 1080~.g, 1085~.g, 1090~g, 1095~g, 1100~g or
similar. The suggested dosages per single dose specified above are not to
be regarded as being limited to the numerical values actually stated, but are
intended as dosages which are disclosed by way of example. Of course,
dosages which may fluctuate about the abovementioned numerical values
within a range of about +/- 2.5 ~,g are also included in the values given
above
by way of example. In these dosage ranges, the active substances 1' and 2
may be present in the weight ratios given above.
For example, without restricting the scope of the invention thereto, the
combinations of _1 and _2 according to the invention may contain a quantity of
_1' and PDE-IV inhibitor 2 such that, for each single dose, 16.5Ng of 1' and
25Ng of _2, 16.5Ng of _1' and 50Ng of 2, 16.5Ng of 1' and 100Ng of 2, 16.5pg
of _1' and 200Ng _ -of _2, 16.5pg of 1' and 300Ng of 2, 16.5Ng of 1' and 400Ng
of _2, 16.5pg of _1' and 500Ng of 2, 16.5Ng of 1' and 600Ng of 2, 16.5Ng of
_1' and 700Ng of _2, 16.5Ng of 1' and 800Ng of 2, 16.5Ng of 1' and 900Ng of
_2, 16.5Ng of _1' and 1000Ng of 2, 33.1 Ng of 1' and 25Ng of 2, 33.1 pg of 1'
and 50pg of _2, 33.1 pg of 1' and 1 OOpg of 2, 33.1 Ng of 1' and 200Ng of 2,
33.1 Ng - - -of _1' and 300Ng of 2, 33.1 pg of 1' and 400Ng of 2, 33.1 Ng of
1' and
500Ng -of _2, 33.1 ~g of _1' and 600Ng of 2, 33.1 pg of 1' and 700pg of 2,
33.1 Ng of _1' and 800Ng of _2, 33.1 Ng of 1' and 900pg of 2, 33.1 pg of 1'
and
1000pg of _2, 49.5Ng of _1' and 25Ng of 2, 49.5pg of 1' and 50pg of 2,
49.5pg of _1' and 100Ng of _2, 49.5pg of 1' and 200Ng of 2, 49.5Ng of 1' and
300Ng of 2, 49.5Ng of _1' and 400pg of _2, 49.5pg of 1' and 500Ng of 2,
49.5Ng of _1' and 600pg of _2, 49.5Ng of 1' and 700pg of 2, 49.5Ng of 1' and
800pg of _2, 49.5Ng of _1' and 900Ng of 2, 49.5Ng of 1' and 1000pg of 2,
82.6Ng of _1' and 25Ng of 2, 82.6pg of 1' and 50Ng of 2, 82.6pg of 1' and
100Ng -of 2, 82.6pg of 1' and 200pg of 2, 82.6Ng of 1' and 300Ng of 2,
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82.6Ng of 1' and 400Ng of 2, 82.6Ng of 1' and 500pg of 2, 82.6Ng of 1' and
600pg of 2, 82.6pg of 1' and 700Ng of 2, 82.6Ng of 1' and 800Ng of 2,
82.6pg of 1' and 900pg of 2, 82.6Ng of 1' and 1 OOOpg of 2, 165.1 Ng of 1'
and 25Ng of 2, 165.1 pg of 1' and 50pg of 2, 165.1 pg of 1' and 1 OOpg of 2,
165.1 Ng of 1' and 200Ng of 2, 165.1 Ng of 1' and 300pg of 2, 165.1 pg of 1'
and 400pg of 2, 165.1 Ng of 1' and 500pg of 2, 165.1 pg of 1' and 600pg of
_2, 165.1 pg _of 1' and 700Ng of 2, 165.1 Ng of 1' and 800Ng of 2, 165.1 ~g of
_1' and 900Ng of 2, 165.1 Ng of 1' and 1000Ng of 2, 206.4Ng of 1' and 25Ng
of _2, 206.4pg of 1' and 50Ng of 2, 206.4Ng of 1' and 100pg of 2, 206.4Ng
of _1' and 200Ng -of 2, 206.4Ng of 1' and 300pg of 2, 206.4~g of 1' and
400pg - -of _2, 206.4Ng of 1' and 500pg of 2 or 206.4pg of 1' and 600pg of 2,
206.4Ng -of _1' and 700Ng of 2, 206.4Ng of 1' and 800Ng of 2, 206.4Ng of 1'
and 900Ng of _2, 206.4pg of 1' and 1000pg of 2, 412.8pg of 1' and 25pg of
_2, 412.8pg of _1' and 50Ng of 2, 412.8pg of 1' and 100pg of 2, 412.8pg of
_1' and 200Ng of _2, 412.8Ng of 1' and 300Ng of 2, 412.8Ng of 1' and 400Ng
of _2, 412.8pg of _1' and 500Ng of 2 or 412.8Ng of 1' and 600pg of 2,
412.8pg of _1' and 700pg of 2, 412.8Ng of 1' and 800Ng of 2, 412.8Ng of 1'
and 900Ng _of 2, 412.8Ng of 1' and 1000pg of 2 are administered.
If the active substance combination in which 1 denotes the bromide is used
as the preferred combination of 1 and 2 according to the invention, the
quantities of active substance _1' and 2 administered per single dose
mentioned by way of example correspond to the following quantities of 1 and
_2 administered per single dose: 20Ng of 1 and 25pg of 2, 20pg of 1 and 50Ng
of _2, 20Ng - -of _1 and 100Ng of _2, 20Ng of 1 and 200Ng of 2, 20Ng of 1 and
300Ng - - -of _2, 20Ng of _1 and 400Ng of _2, 20Ng of 1 and 500Ng of 2, 20Ng
of 1
and 600pg - -of _2, 20Ng of _1 and 700Ng of 2, 20Ng of 1 and 800pg of 2, 20pg
of
_1 and 900pg - -of _2, 20pg of _1 and 1000Ng of 2, 40pg of 1 and 25pg of 2,
40Ng
of _1 and 50pg - -of _2, 40Ng of _1 and 100pg of 2, 40pg of 1 and 200pg of 2,
40Ng
of _1 and 300Ng - -of _2, 40Ng of _1 and 400pg of 2, 40pg of 1 and 500Ng of 2,
40Ng - -of _1 and 600pg of _2, 40Ng of _1 and 700Ng of 2, 40pg of 1 and 800pg
of
_2, 40pg - -of _1 and 900Ng of 2, 40Ng of _1 and 1000Ng of 2, 60Ng of 1 and
25pg
of _2, 60Ng - -of _1 and 50pg of _2, 60pg of 1 and 100pg of 2, 60pg of 1 and
200Ng
of _2, 60pg - -of _1 and 300Ng of _2, 60pg of 1 and 400Ng of 2, 60Ng of 1 and
500Ng - -of _2, 60pg of _1 and 600pg of 2, 60pg of 1 and 700pg of 2, 60Ng of 1
and 800pg _ _ -of 2, 60Ng of 1 and 900Ng of 2, 60Ng of 1 and 1000pg of 2,
100Ng
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of 1 and 25Ng of 2, 100Ng of 1 and 50Ng of 2, 100pg of 1 and 100pg of 2,
100Ng of 1 and 200pg of 2, 100Ng of 1 and 300pg of 2, 100pg of 1 and 400pg
of 2, 100Ng of 1 and 500pg of 2, 100pg of 1 and 600Ng of 2, 100Ng of 1 and
700pg of 2, 100Ng of 1 and 800pg of 2, 100Ng of 1 and 900pg of 2, 100Ng of
_1 and 1000pg _of 2, 200Ng of 1 and 25pg of 2, 200pg of 1 and 50Ng of 2,
200Ng of 1 and 100pg of 2, 200pg of 1 and 200pg of 2, 200pg of 1 and 300pg
of _2, 200pg _of 1 and 400pg of 2, 200pg of 1 and 500pg of 2, 200pg of 1 and
600Ng of 2, 200Ng of 1 and 700pg of 2, 200Ng of 1 and 800Ng of 2, 200pg of
_1 and 900Ng _of 2, 200pg of 1 and 1000pg of 2, 250pg of 1 and 25pg of 2,
250pg _of _1 and 50pg of 2, 250pg of 1 and 100pg of 2, 250pg of 1 and 200pg
of _2, 250pg _of _1 and 300Ng of 2, 250pg of 1 and 400pg of 2, 250Ng of 1 and
500Ng _of _2, 250Ng of 1 and 600Ng of 2, 250pg of 1 and 700Ng of 2, 250pg of
_1 and 800pg _ _of _2, 250pg of 1 and 900Ng of 2, 250Ng of 1 and 1000Ng of 2,
500pg -of _1 and 25pg of 2, 500Ng of 1 and 50pg of 2, 500pg of 1 and 100Ng of
_2, 500pg _ -of _1 and 200pg of _2, 500Ng of 1 and 300Ng of 2, 500Ng of 1 and
400Ng -of _2, 500Ng of 1 and 500pg of 2, 500Ng of 1 and 600Ng of 2, 500pg of
1 and 700Ng _ -of 2, 500Ng of 1 and 800Ng of 2, 500pg of 1 and 900Ng of 2 or
500pg of 1 and 1000pg of 2.
The active substance combinations of 1 and 2 according to the invention are
preferably administered by inhalation. For this purpose, ingredients 1 and 2
have to be made available in forms suitable for inhalation. Inhalable
preparations include inhalable powders, propellant-containing metered-dose
aerosols or propellant-free inhalable solutions. Inhalable powders according
to the invention containing the combination of active substances 1 and 2 may
consist of the active substances on their own or of a mixture of the active
substances with physiologically acceptable excipients. Within the scope of
the present invention, the term propellant-free inhalable solutions also
includes concentrates or sterile inhalable solutions ready for use. The
preparations according to the invention may contain the combination of active
substances _1 and _2 either together in one formulation or in two separate
formulations. These formulations which may be used within the scope of the
present invention are described in more detail in the next part of the
specification.
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A) Inhalable powder containing the combinations of active substances 1
and 2 according to the invention:
The inhalable powders according to the invention may contain 1 and 2 either
on their own or in admixture with suitable physiologically acceptable
excipients.
If the active substances 1 and 2 are present in admixture with physiologically
acceptable excipients, the following physiologically acceptable excipients
may be used to prepare these inhalable powders according to the invention:
monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose,
saccharose, maltose, trehalose), oligo- and polysaccharides (e.g. dextran),
polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride,
calcium carbonate) or mixtures of these excipients with one another.
Preferably, mono- or disaccharides are used, while the use of lactose or
glucose is preferred, particularly, but not exclusively, in the form of their
hydrates. For the purposes of the invention, lactose is the particularly
preferred excipient, while lactose monohydrate is most particularly preferred.
Within the scope of the inhalable powders according to the invention the
excipients have a maximum average particle size of up to 250Nm, preferably
between 10 and 150Nm, most preferably between 15 and 80Nm. It may
sometimes seem appropriate to add finer excipient fractions with an average
particle size of 1 to 9pm to the excipients mentioned above. These finer
excipients are also selected from the group of possible excipients listed
hereinbefore. Finally, in order to prepare the inhalable powders according to
the invention, micronised active substance 1 and 2, preferably with an
average particle size of 0.5 to 10pm, more preferably from 1 to 5p,m, is added
to the excipient mixture. Processes for producing the inhalable powders
according to the invention by grinding and micronising and by finally mixing
the ingredients together are known from the prior art. The inhalable powders
according to the invention may be prepared and administered either in the
form of a single powder mixture which contains both 1 and 2 or in the form of
separate inhalable _powders which contain only 1 or 2.
The inhalable powders according to the invention may be administered using
inhalers known from the prior art. Inhalable powders according to the
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invention which contain a physiologically acceptable excipient in addition to
1
and 2 may be administered, for example, by means of inhalers which deliver
a single dose from a supply using a measuring chamber as described in
US 4570630A, or by other means as described in DE 36 25 685 A.
Preferably, the inhalable powders according to the invention which contain
physiologically acceptable excipient in addition to 1 and 2 are packed into
capsules (to produce so-called inhalettes) which are used in inhalers as
described, for example, in WO 94/28958.
A particularly preferred inhaler for using the pharmaceutical combination
according to the invention in inhalettes is shown in Figure 1.
This inhaler (Handyhaler) for inhaling powdered pharmaceutical compositions
from capsules is characterised by a housing 1 containing two windows 2, a
deck 3 in which there are air inlet ports and which is provided with a screen
5
secured via a screen housing 4, an inhalation chamber 6 connected to the
deck 3 on which there is a push button 9 provided with two sharpened pins 7
and movable counter to a spring 8, and a mouthpiece 12 which is connected
to the housing 1, the deck 3 and a cover 11 via a spindle 10 to enable it to
be
flipped open or shut, and air through-flow holes 13 for adjusting the flow
resistance.
If the inhalable powders according to the invention are packed into capsules
(inhalers) for the preferred use described above, the quantities packed into
each capsule should be 1 to 30mg, preferably 3 to 20mg, more particularly 5
to 10mg of inhalable powder per capsule. These capsules contain, according
to the invention, either together or separately, the doses of 1' and 2
mentioned hereinbefore for each single dose.
B) Propellant gas-driven inhalation aerosols containing the
combinations of active substances 1 and 2:
Inhalation aerosols containing propellant gas according to the invention may
contain substances _1 and 2 dissolved in the propellant gas or in dispersed
form. _1 and 2 may be present in separate formulations or in a single
preparation, in which 1 and 2 are either both dissolved, both dispersed or
only one component is dissolved and the other is dispersed. The propellant
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gases which may be used to prepare the inhalation aerosols according to the
invention are known from the prior art. Suitable propellant gases are selected
from among hydrocarbons such as n-propane, n-butane or isobutane and
halohydrocarbons such as fluorinated derivatives of methane, ethane,
propane, butane, cyclopropane or cyclobutane. The propellant gases
mentioned above may be used on their own or in mixtures thereof.
Particularly preferred propellant gases are halogenated alkane derivatives
selected from TG134a, TG227 and mixtures thereof.
The propellant-driven inhalation aerosols according to the invention may also
contain other ingredients such as co-solvents, stabilisers, surtactants,
antioxidants, lubricants and pH adjusters. All these ingredients are known in
the art.
The inhalation aerosols containing propellant gas according to the invention
may contain up to 5 wt.-% of active substance 1 and/or 2. Aerosols
according to the invention contain, for example, 0.002 to 5 wt.-%, 0.01 to
3 wt.-%, 0.015 to 2 wt.-%, 0.1 to 2 wt.-%, 0.5 to 2 wt.-% or 0.5 to 1 wt.% of
active substance 1 and/or 2.
If the active substances 1 andlor 2 are present in dispersed form, the
particles of active substance preferably have an average particle size of up
to
10~m, preferably from 0.1 to 5~m, more preferably from 1 to 5~m.
The propellant-driven inhalation aerosols according to the invention
mentioned above may be administered using inhalers known in the art (MDIs
= metered dose inhalers). Accordingly, in another aspect, the present
invention relates to pharmaceutical compositions in the form of propellant-
driven aerosols as hereinbefore described combined with one or more
inhalers suitable for administering these aerosols. In addition, the present
invention relates to inhalers which are characterised in that they contain the
propellant gas-containing aerosols described above according to the
invention. The present invention also relates to cartridges which are fitted
with a suitable valve and can be used in a suitable inhaler and which contain
one of the above-mentioned propellant gas-containing inhalation aerosols
according to the invention. Suitable cartridges and methods of filling these
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cartridges with the inhalable aerosols containing propellant gas according to
the invention are known from the prior art. w
C) Propellant-free inhalable solutions or suspensions containing the
combinations of active substances 1 and 2 according to the invention:
It is particularly preferred to use the active substance combination according
to the invention in the form of propellant-free inhalable solutions and
suspensions. The solvent used may be an aqueous or alcoholic, preferably
an ethanolic solution. The solvent may be water on its own or a mixture of
water and ethanol. The relative proportion of ethanol compared with water is
not limited but the maximum is up to 70 percent by volume, more particularly
up to 60 percent by volume and most preferably up to 30 percent by volume.
The remainder of the volume is made up of water. The solutions or
suspensions containing 1 and 2, separately or together, are adjusted to a pH
of 2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjusted
using acids selected from inorganic or organic acids. Examples of
particularly suitable inorganic acids include hydrochloric acid, hydrobromic
acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples of
particularly suitable organic acids include ascorbic acid, citric acid, malic
acid,
tartaric acid, malefic acid, succinic acid, fumaric acid, acetic acid, formic
acid
and/or propionic acid etc. Preferred inorganic acids are hydrochloric and
sulphuric acids. It is also possible to use the acids which have already
formed an acid addition salt with one of the active substances. Of the organic
acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired,
mixtures of the above acids may be used, particularly in the case of acids
which have other properties in addition to their acidifying qualities, e.g. as
flavourings, antioxidants or complexing agents, such as citric acid or
ascorbic
acid, for example. According to the invention, it is particularly preferred to
use hydrochloric acid to adjust the pH.
According to the invention, the addition of editic acid (EDTA) or one of the
known salts thereof, sodium edetate, as stabiliser or complexing agent is
unnecessary in the present formulation. Other embodiments may contain this
compound or these compounds. In a preferred embodiment the content
based on sodium edetate is less than 100mg1100m1, preferably less than
50mg/100 ml, more preferably less than 20mg/100 ml. Generally, inhalable
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solutions in which the content of sodium edetate is from 0 to 10mg/100m1 are
preferred.
Co-solvents and/or other excipients may be added to the propellant-free
inhalable solutions according to the invention. Preferred co-solvents are
those which contain hydroxyl groups or other polar groups, e.g. alcohols -
particularly isopropyl alcohol, glycols - particularly propyleneglycol,
polyethyleneglycol, polypropyleneglycol, glycolether, glycerol,
polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms
excipients and additives in this context denote any pharmacologically
acceptable substance which is not an active substance but which can be
formulated with the active substance or substances in the pharmacologically
suitable solvent in order to improve the qualitative properties of the active
substance formulation. Preferably, these substances have no
pharmacological effect or, in connection with the desired therapy, no
appreciable or at least no undesirable pharmacological effect. The excipients
and additives include, for example, surfactants such as soya lecithin, oleic
acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other
stabilisers, complexing agents, antioxidants andlor preservatives which
guarantee or prolong the shelf life of the finished pharmaceutical
formulation,
flavourings, vitamins and/or other additives known in the art. The additives
also include pharmacologically acceptable salts such as sodium chloride as
isotonic agents.
The preferred excipients include antioxidants such as ascorbic acid, for
example, provided that it has not already been used to adjust the pH, vitamin
A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the
human body.
Preservatives may be used to protect the formulation from contamination with
pathogens. Suitable preservatives are those which are known in the art,
particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid
or benzoates such as sodium benzoate in the concentration known from the
prior art. The preservatives mentioned above are preferably present in
concentrations of up to 50mg/100m1, more preferably between 5 and
20mg/1 OOm I.
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Preferred formulations contain, in addition to the solvent water and the
combination of active substances 1 and 2, only benzalkonium chloride and
sodium edetate. In another preferred embodiment, no sodium edetate is
present.
The propellant-free inhalable solutions according to the invention are
administered in particular using inhalers of the kind which are capable of
nebulising a small amount of a liquid formulation in the therapeutic dose
within a few seconds to produce an aerosol suitable for therapeutic
inhalation. Within the scope of the present invention, preferred inhalers are
those in which a quantity of less than 100~L, preferably less than 50pL, more
preferably between 20 and 30~L of active substance solution can be
nebulised in preferably one spray action to form an aerosol with an average
particle size of less than 20~m, preferably less than 10~,m, in such a way
that
the inhalable part of the aerosol corresponds to the therapeutically effective
quantity.
An apparatus of this kind for propellant-free delivery of a metered quantity
of
a liquid pharmaceutical composition for inhalation is described for example in
International Patent Application WO 91 /14468 and also in WO 97/12687 (cf.
in particular Figures 6a and 6b). The nebulisers (devices) described therein
are known by the name Respimat~.
This nebuliser (Respimat~) can advantageously be used to produce the
inhalable aerosols according to the invention containing the combination of
active substances 1 and 2. Because of its cylindrical shape and handy size
of less than 9 to 15 cm long and 2 to 4 cm wide, this device can be carried at
all times by the patient. The nebuliser sprays a defined volume of
pharmaceutical formulation using high pressures through small nozzles so as
to produce inhalable aerosols.
The preferred atomiser essentially consists of an upper housing part, a pump
housing, a nozzle, a locking mechanism, a spring housing, a spring and a
storage container, characterised by
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- a pump housing which is secured in the upper housing part and which
comprises at one end a nozzle body with the nozzle or nozzle
arrangement,
- a hollow plunger with valve body,
- a power takeoff flange in which the hollow plunger is secured and
which is located in the upper housing part,
- a locking mechanism situated in the upper housing part,
- a spring housing with the spring contained therein, which is rotatabiy
mounted on the upper housing part by means of a rotary bearing,
- a lower housing part which is fitted onto the spring housing in the axial
direction.
The hollow plunger with valve body corresponds to a device disclosed in
WO 97/12687. It projects partially into the cylinder of the pump housing and
is axially movable within the cylinder. Reference is made in particular to
Figures 1 to 4, especially Figure 3, and the relevant parts of the
description.
The hollow plunger with valve body exerts a pressure of 5 to 60 Mpa (about
50 to 600 bar), preferably 10 to 60 Mpa (about 100 to 600 bar) on the fluid,
the measured amount of active substance solution, at its high pressure end at
the moment when the spring is actuated. Volumes of 10 to 50 microlitres are
preferred, while volumes of 10 to 20 microlitres are particularly preferred
and
a volume of 15 microlitres per spray is most particularly preferred.
The valve body is preferably mounted at the end of the hollow plunger facing
the nozzle body.
The nozzle in the nozzle body is preferably microstructured, i.e. produced by
microtechnology. Microstructured nozzle bodies are disclosed for example in
WO-94/07607; reference is hereby made to the contents of this specification,
particularly Figure 1 therein and the associated description.
The nozzle body consists for example of two sheets of glass and/or silicon
firmly joined together, at least one of which has one or more microstructured
channels which connect the nozzle inlet end to the nozzle outlet end. At the
nozzle outlet end there is at least one round or non-round opening 2 to 10
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microns deep and 5 to 15 microns wide, the depth preferably being 4.5 to 6.5
microns while the length is preferably 7 to 9 microns.
In the case of a plurality of nozzle openings, preferably two, the directions
of
spraying of the nozzles in the nozzle body may extend parallel to one another
or may be inclined relative to one another in the direction of the nozzle
opening. In a nozzle body with at least two nozzle openings at the outlet end
the directions of spraying may be at an angle of 20 to 160° to one
another,
preferably 60 to 150°, most preferably 80 to 100°. The nozzle
openings are
preferably arranged at a spacing of 10 to 200 microns, more preferably at a
spacing of 10 to 100 microns, most preferably 30 to 70 microns. Spacings of
50 microns are most preferred. The directions of spraying will therefore meet
in the vicinity of the nozzle openings.
The liquid pharmaceutical preparation strikes the nozzle body with an entry
pressure of up to 600 bar, preferably 200 to 300 bar, and is atomised into an
inhalable aerosol through the nozzle openings. The preferred particle or
droplet sizes of the aerosol are up to 20 microns, preferably 3 to 10 microns.
The locking mechanism contains a spring, preferably a cylindrical helical
compression spring, as a store for the mechanical energy. The spring acts
on the power takeoff flange as an actuating member the movement of which
is determined by the position of a locking member. The travel of the power
takeoff flange is precisely limited by an upper and lower stop. The spring is
preferably biased, via a power step-up gear, e.g. a helical thrust gear, by an
external torque which is produced when the upper housing part is rotated
counter to the spring housing in the lower housing part. In this case, the
upper housing part and the power takeoff flange have a single or multiple
V-shaped gear.
The locking member with engaging locking surfaces is arranged in a ring
around the power takeoff flange. It consists, for example, of a ring of
plastic
or metal which is inherently radially elastically deformable. The ring is
arranged in a plane at right angles to the atomiser axis. After the biasing of
the spring, the locking surtaces of the locking member move into the path of
the power takeoff flange and prevent the spring from relaxing. The locking
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member is actuated by means of a button. The actuating button is connected
or coupled to the locking member. !n order to actuate the locking
mechanism, the actuating button is moved parallel to the annular plane,
preferably into the atomiser; this causes the deformable ring to deform in the
annular plane. Details of the construction of the locking mechanism are given
in WO 97/20590.
The lower housing part is pushed axially over the spring housing and covers
the mounting, the drive of the spindle and the storage container for the
fluid.
When the atomiser is actuated the upper housing part is rotated relative to
the lower housing part, the lower housing part taking the spring housing with
it. The spring is thereby compressed and biased by means of the helical
thrust gear and the locking mechanism engages automatically. The angle of
rotation is preferably a whole-number fraction of 360 degrees, e.g. 180
degrees. At the same time as the spring is biased, the power takeoff member
in the upper housing part is moved along by a given distance, the hollow
plunger is withdrawn inside the cylinder in the pump housing, as a result of
which some of the fluid is sucked out of the storage container and into the
high pressure chamber in front of the nozzle.
If desired, a number of exchangeable storage containers which contain the
fluid to be atomised may be pushed into the atomiser one after another and
used in succession. The storage container contains the aqueous aerosol
preparation according to the invention.
The atomising process is initiated by pressing gently on the actuating button.
As a result, the locking mechanism opens up the path for the power takeoff
member. The biased spring pushes the plunger into the cylinder of the pump
housing. The fluid leaves the nozzle of the atomiser in atomised form.
Further details of construction are disclosed in PCT Applications
WO 97112683 and WO 97/20590, to which reference is hereby made.
The components of the atomiser (nebuiiser) are made of a material which is
suitable for its purpose. The housing of the atomiser and, if its operation
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permits, other parts as well, are preferably made of plastics, e.g. by
injection
moulding. For medicinal purposes, physiologically safe materials are used:
Figures 6alb of WO 97/12687 show the nebuliser (Respimat~) which can
advantageously be used for inhaling the aqueous aerosol preparations
according to the invention.
Figure 6a of WO 97/12687 to which explicit reference is hereby made shows
a longitudinal section through the atomiser with the spring biased. Figure 6b
of WO 97/12687 to which explicit reference is hereby made shows a
longitudinal section through the atomiser with the spring relaxed. The upper
housing part (51 ) contains the pump housing (52) on the end of which is
mounted the holder (53) for the atomiser nozzle. In the holder is the nozzle
body (54) and a filter (55). The hollow plunger (57) fixed in the power
takeoff
flange (56) of the locking mechanism projects partially into the cylinder of
the
pump housing. At its end the hollow plunger carries the valve body (58). The
hollow plunger is sealed off by means of the seal (59). Inside the upper
housing part is the stop (60) on which the power takeoff flange abuts when
the spring is relaxed. On the power takeoff flange is the stop (61 ) on which
the power takeoff flange abuts when the spring is biased. After the biasing of
the spring the locking member (62) moves between the stop (61 ) and a
support (63) in the upper housing part. The actuating button (64) is
connected to the locking member. The upper housing part ends in the
mouthpiece (65) and is sealed off by means of the protective cover (66)
which can be placed thereon.
The spring housing (67) with compression spring (68) is rotatably mounted on
the upper housing part by means of the snap-in lugs (69) and rotary bearing.
The lower housing part (70) is pushed over the spring housing. Inside the
spring housing is the exchangeable storage container (71 ) for the fluid (72)
which is to be atomised. The storage container is sealed off by the stopper
(73) through which the hollow plunger projects into the storage container and
is immersed at its end in the fluid (supply of active substance solution).
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The spindle (74) for the mechanical counter is mounted in the covering of the
spring housing. At the end of the spindle facing the upper housing part is the
drive pinion (75). The slider (76) sits on the spindle.
The nebuliser described above is suitable for nebulising the aerosol
preparations according to the invention to produce an aerosol suitable for
inhalation.
If the formulation according to the invention is nebulised using the method
described above (Respimat~) the quantity delivered should correspond to a
defined quantity with a tolerance of not more than 25%, preferably 20% of
this amount in at least 97%, preferably at least 98% of all operations of the
inhaler (spray actuations). Preferably, between 5 and 30 mg of formulation,
most preferably between 5 and 20 mg of formulation are delivered as a
defined mass on each actuation.
However, the formulation according to the invention may also be nebulised by
means of inhalers other than those described above, e.g. jet stream inhalers.
Accordingly, in a further aspect, the invention relates to pharmaceutical
formulations in the form of propellant-free inhalable solutions or suspensions
as described above combined with a device suitable for administering these
formulations, preferably in conjunction with the Respimat~. Preferably, the
invention relates to propellant-free inhalable solutions or suspensions
characterised by the combination of active substances 1 and 2 according to
the invention in conjunction with the device known by the name Respimat~.
in addition, the present invention relates to the above-mentioned devices for
inhalation, preferably the Respimat~, characterised in that they contain the
propellant-free inhalable solutions or suspensions according to the invention
as described hereinbefore.
The propellant-free inhalable solutions or suspensions according to the
invention may take the form of concentrates or sterile inhalable solutions or
suspensions ready for use, as well as the above-mentioned solutions and
suspensions designed for use in a Respimat~. Formulations ready for use
may be produced from the concentrates, for example, by the addition of
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isotonic saline solutions. Sterile formulations ready for use may be
administered using energy-operated fixed or portable nebulisers which w
produce inhalable aerosols by means of ultrasound or compressed air by the
Venturi principle or other principles.
Accordingly, in another aspect, the present invention relates to
pharmaceutical compositions in the form of propellant-free inhalable solutions
or suspensions as described hereinbefore which take the form of
concentrates or sterile formulations ready for use, combined with a device
suitable for administering these solutions, characterised in that the device
is
an energy-operated free-standing or portable nebuliser which produces
inhalable aerosols by means of ultrasound or compressed air by the Venturi
principle or other methods.
The Examples which follow serve to illustrate the present invention in more
detail without restricting the scope of the invention to the following
embodiments by way of example.
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Examples of Formulations
A~ Inhalable powders:
1)
Ingredients ~.g per capsule
1'- bromide 200
AWD-12-281 200
Lactose 4778.3
Total ~ 25000
2)
3)
Ingredients ~g per capsule
1'- bromide 100
compound of formula 2a 125
Lactose 12350
Total 12500
Ingredients ~.g per capsule
1'- bromide 200
ariflo 250
Lactose 12250
Total 12500
4)
Ingredients ~.g per capsule
1'- bromide 200
roflumilast 200
Lactose 24600
Total ~ 25000
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5)
6)
Ingredients Ng per capsule
1'- bromide 100
roflum ilast 250
Lactose 12150
Total 125000
Ingredients Ng ~4r capsule
1'- bromide 200
roflumilast 50
Lactose 12250
Total 12500
B~ Propellant gas-containing aerosols for inhalation:
1 ) Suspension aerosol:
Ingredients wt.%
1'- bromide 0.020
AWD-12-281 0.060
Soya lecithin 0.2
TG 134a: TG227 = 2:3 ~ ad 100
2) Suspension aerosol:
Ingredients wt.%
1'- bromide 0.039
ariflo 0.033
TG 134a ~ ad 100
