Note: Descriptions are shown in the official language in which they were submitted.
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New Pharmaceutical Compositions based on Anticholinergics
and Dopamine Agonists
The present invention relates to novel
pharmaceutical compositions based on anticholinergics and
dopamine agonists, 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
dopamine agonists, processes for preparing them and their
use in the treatment of respiratory diseases.
According to one aspect of the present invention,
there is provided a pharmaceutical composition in the form
of a propellant-free inhalable solution or suspension with a
pH of 2 to 5 comprising: (1) one or more tiotropium salts;
(2) one or more dopamine agonists, wherein the one or more
tiotropium salts and the one or more dopamine agonists are
optionally in the form of enantiomers thereof, mixtures of
the enantiomers thereof, racemates thereof, solvates thereof
or hydrates thereof; and (3) water, ethanol or a mixture of
water and ethanol.
Surprisingly, an unexpectedly beneficial
therapeutic effect, particularly a synergistic effect can be
observed in the treatment of inflammatory or obstructive
diseases of the repiratory tract if one or more, preferably
one, anticholinergic is used with one or more, preferably
one, dopamine agonist. 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.
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This reduces unwanted side effects such as may occur when
dopamine agonists 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.
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Within the scope of the present invention the term
anticholinergics 1 denotes salts which are preferably
selected from among tiotropium salts, oxitropium salts
and ipratropium salts, most preferably ipratropium salts
and tiotropium salts. In the above-mentioned salts the
cations tiotropium, oxitropium and ipratropium are the
pharmacologically active ingredients. Within the scope
of the present patent application, any reference to the
above cations is indicated by the use of the number 11.
Any reference to compounds 1 naturally also includes a
reference to the ingredients 11 (tiotropium, oxitropium
or ipratropium).
By the salts 1 which may be used within the scope of the
present invention are meant the compounds which contain,
in addition to tiotropium, oxitropium or ipratropium as
counter-ion (anion), chloride, bromide, iodide,
methanesulphonate or para-toluenesulphonate. Within the
scope of the present invention, the methanesulphonate,
chloride, bromide and iodide are preferred of all the
salts 1, the methanesulphonate and bromide being of
particular importance. Of outstanding importance
according to the invention are salts 1 selected from
among tiotropium bromide, oxitropium bromide and
ipratropium bromide. Ipratropium bromide and tiotropium
bromide are particularly preferred.
Within the scope of the present invention, the word
dopamine agonists (hereinafter 2) denotes compounds
selected from among bromocriptin, cabergolin, alpha-
dihydroergocryptin, lisuride, pergolide, pramipexol,
roxindol, ropinirol, talipexol, terguride and the 7-(2-
aminoethyl)-benzothiazolones of general formula 3
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- 3 -
H-(CH2)P-X-(CH2)q-Y-(CH2)r-Z
S
>=O
N
H
OH 3
wherein
X and Y which may be identical or different denote
-S(0)n - or -0-;
n denotes 0, 1 or 2;
p, q and r which may be identical or different denote
2 or 3;
Z denotes phenyl, which may optionally be
substituted by a group selected from among
halogen, -ORl, NOz or NR2 R3 , or
a 5- or 6-membered heterocycle containing
N, 0 or S;
R1, R2 and R3 which may be identical or different denote
hydrogen or Cl-C6-alkyl.
The abovementioned compounds of formula 3 are disclosed
in WO 93/24473.
Preferably, within the scope of the present invention,
the dopamine agonists 2 are selected from among
bromocriptin, cabergolin, alpha-dihydroergocryptin,
lisuride, pergolide, pramipexol, roxindol, ropinirol,
talipexol, terguride and the compound of formula 3'
0
I I
N ~/ ISI ~'/~~0 ~
H 0
>==0
N
H
OH 3'
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The abovementioned compound of formula 3' is also
disclosed in WO 93/24473 and is hereinafter also referred
to as viozariM
Preferably, the dopamine agonist 2 is selected from among
pramipexol, talipexol and viozan, of which pramipexol and
viozan, especially viozan, are of particular importance.
Other preferred dopamine agonists 2 in the pharmaceutical
combinations according to the invention are those which
do not overcome the blood-brain barrier and are primarily
characterised by a peripheral activity. Particularly
preferred are peripherally active dopamine agonists 2
selected from among dopamine, fenoldopam, dopexamine,
CHF 1035, tolnaperisine and RU-40021, of which dopamine,
fenoldopam, dopexamine and nolomirole (CHF 1035), especially
dopamine, fenoldopam and dopexamine are of exceptional importance.
Any reference to the abovementioned dopamine agonists 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, for example,
pharmaceutically accetable 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 maleic acid.
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
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inhalers. Alternatively, the drug may be inhaled by the
application of suitable inhalation aerosols. These also
include inhalation aerosols which contain HFA134a, HFA227
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 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 or obstructive diseases of the
respiratory tract, particularly asthma or chronic
obstructive pulmonary diseases (COPD), and the
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complications thereof such as, for example, pulmonary
hypertension, as well as allergic and non-allergic
rhinitis, provided that treatment with dopamine agonists
is not contraindicated for therapeutic reasons, by
simultaneous or successive administration. The
pharmaceutical combinations of 1 and 2 according to the
invention may also be used to prepare a drug for treating
cystic fibrosis by simultaneous or successive
administration of 1 and 2.
The present invention further 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 or obstructive
respiratory tract diseases, particularly asthma or
chronic obstructive pulmonary diseases (COPD), and the
complications thereof such as, for example, pulmonary
hypertension, as well as allergic and non-allergic
rhinitis, provided that treatment with dopamine agonists
is not contraindicated for therapeutic reasons, by
simultaneous or successive administration. The present
invention also relates to the use of therapeutically
effective doses of the combination of the above
pharmaceutical compositions 1 and 2 for treating cystic
fibrosis by the simultaneous or successive administration
of 1 and 2.
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
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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 according to the
invention may contain compounds 1 and 2 in ratios by
weight ranging from 1:300 to 50:1, preferably from 1:250
to 40:1. In the particularly preferred pharmaceutical
combinations which contain ipratropium salt or tiotropium
salt as compound 1 and a compound selected from among
pramipexol, talipexol and viozan as the dopamine agonist
2, the weight ratios of 1 to 2 are most preferably in a
range in which ipratropium or tiotropium 11 and 2 are
present in proportions of 1:150 to 30:1, more preferably
from 1:50 to 20:1.
For example, without restricting the scope of the
invention thereto, preferred combinations of 1 and 2
according to the invention may contain ipratropium or
tiotropium 11 and dopamine agonists 2 in the following
weight ratios: 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 1000 g, better still
from 5 to 600 g per single dose. For example,
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combinations of 1 and 2 according to the invention
contain a quantity of 1' and dopamine agonist 2 such that
the total dosage per single dose is about 20 g, 25 g,
30 g, 35 g, 45 g, 50 g, 55 g, 60 g, 65 g, 70 g, 75 g,
80 g, 85 g, 90 g, 95 g, 100 g, 105 g, 110 g, 115 g,
120 g, 125 g, 130 g, 135 g, 140 g, 145 g, 150 g, 155 g,
160 g, 165 g, 170 g, 175 g, 180 g, 185 g, 190 g, 195 g,
200 g, 205 g, 210ug, 215 g, 220 g, 225 g, 230 g, 235 g,
240 g, 245 g, 250 g, 255 g, 260 g, 265 g, 270 g, 275 g,
280 g, 285 g, 290 g, 295 g, 300 g, 305 g, 310 g, 315 g,
320 g, 325 g, 330 g, 335 g, 340 g, 345 g, 350 g, 355 g,
360 g, 365 g, 370Ag, 375 g, 380 g, 385 g, 390 g, 395 g,
400 g, 405 g, 410 g, 415 g, 420 g, 425 g, 430 g, 435 g,
440 g, 445 g, 450 g, 455 g, 460 g, 465 g, 470 g, 475 g,
480 g, 485ug, 490 g, 495 g, 500 g, 505 g, 510 g, 515 g,
520 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
dopamine agonist 2 such that, for each single dose, 5 g
of 1' and 25 g of 2, 5 g of 1' and 45 g of 2, 5 g of 1'
and 50 g of 2, 5 g of 1' and 100 g of 2, 5 g of 1' and
200 g of 2, 5 g of 1' and 250 g of 2, 5 g of 1' and 270 g
of 2, 5 g of 1' and 400 g of 2, 5 g of 1' and 495 g of 2,
10 g of 1' and 25 g of 2, 10 g of 1' and 45 g of 2, 10 g
of 1' and 50 g of 2, 10 g of 1' and 100 g of 2, 10 g of
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1' and 200 g of 2, 10 g of 1' and 250 g of 2, 10 g of 1'
and 270 g of 2, 10 g of 1' and 400 g of 2, 10 g of 1' and
495 g of 2, 18 g of 1' and 25 g of 2, 18 g of 1' and 45 g
of 2, 18 g of 1' and 50 g of 2, 18 g of 1' and 100 g of
2, 18 g of 1' and 200 g of 2, 18 g of 1' and 250 g of 2,
18 g of 1' and 270 g of 2, 18 g of 1' and 400 g of 2,
18 g of 1' and 495 g of 2, 20 g of 1' and 25 g of 2, 20 g
of 1' and 45 g of 2, 20 g of 1' and 50 g of 2, 20 g of 1'
and 100 g of 2, 20 g of 1' and 200 g of 2, 20 g of 1' and
250 g of 2, 20 g of 1' and 270 g of 2, 20 g of 1' and
400 g of 2, 20 g of 1' and 495 g of 2, 36 g of 1' and
25 g of 2, 36 g of 1' and 45 g of 2, 36 g of 1' and 50 g
of 2, 36 g of 1' and 100 g of 2, 36 g of 1' and 200 g of
2, 36 g of 1' and 250 g of 2, 36 g of 1' and 270 g of 2,
36ug of 1' and 400 g of 2, 36 g of 1' and 495 g of 2,
40 g of 1' and 25 g of 2, 40 g of 1' and 45 g of 2, 40 g
of 1' and 50 g of 2, 40 g of 1' and 100 g of 2, 40 g of
1' and 200 g of 2, 40 g of 1' and 250 g of 2, 40 g of 1'
and 270 g of 2, 40 g of 1' and 400 g of 2 or 40 g of 1'
and 495 g of 2 are administered.
If the active substance combination in which 1 denotes
tiotropium 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: 6 g
of 1 and 25 g of 2, 6 g of 1 and 45 g of 2, 6 g of 1 and
50 g of 2, 6Ag of 1 and 100 g of 2, 6 g of 1 and 200 g of
2, 6 g of 1 and 250 g of 2, 6 g of 1 and 270 g of 2, 6 g
of 1 and 400 g of 2, 6 g of 1 and 495 g of 2, 12 g of 1
and 25 g of 2, 12 g of 1 and 45 g of 2, 12 g of 1 and
50 g of 2, 12 g of 1 and 100 g of 2, 12 g of 1 and 200 g
of 2, 12 g of 1 and 250 g of 2, 12 g of 1 and 270 g of 2,
12 g of 1 and 400 g of 2, 12 g of 1 and 495 g of 2,
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21.7jig of 1 and 25ug of 2, 21.7 g of 1 and 45 g of 2,
21.7 g of 1 and 50 g of 2, 21.7 g of 1 and 100 g of 2,
21.7 g of 1 and 200 g of 2, 21.7 g of 1 and 250 g of 2,
21.7 g of 1 and 270 g of 2, 21.7 g of 1 and 400 g of 2,
21.7 g of 1 and 495 g of 2, 24.1 g of 1 and 25 g of 2,
24.1 g of 1 and 45 g of 2, 24.1 g of 1 and 50 g of 2,
24.1 g of 1 and 100 g of 2, 24.1 g of 1 and 200 g of 2,
24.1pg of 1 and 250 g of 2, 24.1 g of 1 and 270 g of 2,
24.1 g of 1 and 400 g of 2, 24.1 g of 1 and 495 g of 2,
43.3 g of 1 and 25 g of 2, 43.3 g of 1 and 45 g of 2,
43.3 g of 1 and 50 g of 2, 43.3 g of 1 and 100 g of 2,
43.3 g of 1 and 200 g of 2, 43.3 g of 1 and 250 g of 2,
43.3 g of 1 and 270 g of 2, 43.3 g of 1 and 400 g of 2,
43.3 g of 1 and 495 g of 2, 48.1 g of 1 and 25 g of 2,
48.1 g of 1 and 45 g of 2, 48.1 g of 1 and 50 g of 2,
48.1 g of 1 and 100 g of 2, 48.1 g of 1 and 200 g of 2,
48.1 g of 1 and 250 g of 2, 48.1 g of 1 and 270 g of 2,
48.1 g of 1 and 400 g of 2, 48.1 g of 1 and 495 g of 2.
If the active substance combination in which 1 is
tiotropium bromide monohydrate is used as the preferred
combination of 1 and 2 according to the invention, the
quantities of 11 and 2 administered per single dose
specified by way of example hereinbefore correspond to
the following quantities of 1 and 2 administered per
single dose: 6,2 g of 1 and 25 g of 2, 6,2 g of 1 and
45 g of 2, 6,2 g of 1 and 50 g of 2, 6,2 g of 1 and 100 g
of 2, 6,2 g of 1 and 200 g of 2, 6,2 g of 1 and 250 g of
2, 6,2 g of 1 and 270 g of 2, 6,2 g of 1 and 400 g of 2,
6,2 g of 1 and 495 g of 2, 12,5 g of 1 and 25 g of 2,
12,5 g of 1 and 45 g of 2, 12,5 g of 1 and 50 g of 2,
12,5 g of 1 and l00 g of 2, 12,5 g of 1 and 200 g of 2,
12,5 g of 1 and 250 g of 2, 12,5 g of 1 and 270 g of 2,
12,5 g of 1 and 400 g of 2, 12,5 g of 1 and 495 g of 2,
22,5 g of 1 and 25 g of 2, 22,5 g of 1 and 45 g of 2,
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22,5 g of 1 and 50 g of 2, 22,5 g of 1 and l00 g of 2,
22,5 g of 1 and 200 g of 2, 22,5 g of 1 and 250 g of 2,
22,5 g of 1 and 270 g of 2, 22,5 g of 1 and 400 g of 2,
22,5 g of 1 and 495 g of 2, 25 g of 1 and 25 g of 2, 25 g
of 1 and 45 g of 2, 25 g of 1 and 50 g of 2, 25 g of 1
and 100 g of 2, 25 g of 1 and 200 g of 2, 25 g of 1 and
250 g of 2, 25 g of 1 and 270 g of 2, 25 g of 1 and 400Ag
of 2, 25 g of 1 and 495 g of 2, 45 g of 1 and 25 g of 2,
45 g of 1 and 45 g of 2, 45 g of 1 and 50 g of 2, 45 g of
1 and l00 g of 2, 45 g of 1 and 200 g of 2, 45 g of 1 and
250 g of 2, 45 g of 1 and 270 g of 2, 45 g of 1 and 400 g
of 2, 45 g of 1 and 495 g of 2, 50 g of 1 and 25 g of 2,
50 g of 1 and 45 g of 2, 50 g of 1 and 50 g of 2, 50 g of
1 and 100 g of 2, 50 g of 1 and 200 g of 2, 50 g of 1 and
250 g of 2, 50 g of 1 and 270 g of 2, 50gg of 1 and 400 g
of 2, 50 g of 1 and 495 g 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 metering 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
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within the scope of the present invention are described
in more detail in the next part of the specification.
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), oligo-
and polysaccharides (e.g. dextrane), 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 250 m, preferably between 10 and
150 m, most preferably between 15 and 80 m. It may
sometimes seem appropriate to add finer excipient
fractions with an average particle size of 1 to 9 m to
the excipient 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
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active substance 1 and 2, preferably with an average
particle size of 0.5 to 10 m, more preferably from 1 to
6gm, 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 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. The inhalable powders according to the
invention which contain 1 and 2 optionally in conjunction
with a physiologically acceptable excipient may be
administered, for example, using the inhaler known by the
name Turbuhaler or using inhalers as disclosed for
example in EP 237507 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.
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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 portions 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 8 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.
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 11 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 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 preferably fluorinated
derivatives of methane, ethane, propane, butane,
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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
(1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-
heptafluoropropane) and mixtures thereof.
The propellant-driven inhalation aerosols according to
the invention may also contain other ingredients such as
co-solvents, stabilisers, surfactants, 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 and/or 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
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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 cartridges with the inhalable aerosols
containing propellant gas according to the invention are
known from the prior art.
C) Propellant-free inhalable solutions or suspensions
containing the combinations of active substances 1 and 2
according to the inventions
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
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, tartartic acid, maleic 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
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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 editate,
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 editate is less than
100mg/100ml, preferably less than 50mg/l00 ml, more
preferably less than 20mg/100 ml. Generally, inhalable
solutions in which the content of sodium editate is from
0 to l0mg/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.
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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 and/or 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 and 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/100ml, more preferably
between 5 and 20mg/100m1.
Preferred formulations contain, in addition to the
solvent water and the combination of active substances 1
and 2, only benzalkonium chloride and sodium editate. In
another preferred embodiment, no sodium editate is
present.
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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 50 L,
more preferably between 10 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
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mechanism, a spring housing, a spring and a storage
container, characterised by
- 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 rotatably 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 valve body.
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The nozzle in the nozzle body is preferably
microstructured, i.e. produced by microtechnology.
Microstructured valve 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 valve 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 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
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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 surfaces of the locking member move into the path
of the power takeoff flange and prevent the spring from
relaxing. The locking member is actuated by means of a
button. The actuating button is connected or coupled to
the locking member. In 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 annual plane.
Details of the construction of the locking mechanism are
given in WO 97/20590.
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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 part 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 97/12683 and WO 97/20590, to which
reference is hereby made.
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The components of the atomiser (nebuliser) are made of a
material which is suitable for its purpose. The housing
of the atomiser and - if its operation permits, other
parts as well are preferably made of plastics, e.g. by
injection moulding. For medicinal purposes,
physiologically safe materials are used.
Figures 2a/b attached to this patent application, which
are identical to Figures 6a/b of WO 97/12687, show the
nebuliser (Respimat ) which can advantageously be used
for inhaling the aqueous aerosol preparations according
to the invention.
Figure 2a shows a longitudinal section through the
atomiser with the spring biased while Figure 2b 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
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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).
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
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described above, e.g. jet stream inhalers or other
stationary nebulisers.
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.
According to the invention, inhalable solutions which
contain the active substances 1 and 2 in a single
preparation are preferred. The term "single preparation"
also includes preparations which contain the two
ingredients 1 and 2 in two-chamber cartridges, as
disclosed for example in WO 00/23037. Reference is hereby
made to this publication in its entirety.
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
isotonic saline solutions. Sterile formulations ready
for use may be administered using energy-operated fixed
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or portable nebulisers which 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.
Starting materials
Tio_roziLm bromide:
The tiotropium bromide used in the following formulations
examples may be obtained as described in European Patent
Application 418 716 Al.
In order to prepare the inhalable powders according to
the invention, crystalline tiotropium bromide monohydrate
may also be used. This crystalline tiotropium bromide
monohydrate may be obtained by the method described
below.
15.0 kg of tiotropium bromide are placed in 25.7 kg of
water in a suitable reaction vessel. The mixture is
heated to 80-90 C and stirred at constant temperature
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until a clear solution is formed. Activated charcoal
(0.8 kg) moistened with water is suspended in 4.4 kg of
water, this mixture is added to the solution containing
the tiotropium bromide and the resulting mixture is
rinsed with 4.3 kg of water. The mixture thus obtained
is stirred for at least 15 minutes at 80-90 C and then
filtered through a heated filter into an apparatus
preheated to an external temperature of 70 C. The filter
is rinsed with 8.6 kg of water. The contents of the
apparatus are cooled at 3-5 C for every 20 minutes to a
temperature of 20-25 C. The apparatus is cooled further
to 10-15 C using cold water and crystallisation is
completed by stirring for at least another hour. The
crystals are isolated using a suction filter dryer, the
crystal slurry isolated is washed with 9 litres of cold
water (10-15 C) and cold acetone (10-15 C). The crystals
obtained are dried at 25 C in a nitrogen current over a
period of 2 hours.
Yield: 13.4 kg of tiotropium bromide monohydrate (86% of
theory).
The crystalline tiotropium bromide monohydrate thus
obtained is micronised by known methods in order to
prepare the active substance in the form of the average
particle size corresponding to the specifications
according to the invention.
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Examples of Formulations
A1 Tnralable nowders:
1)
Ingredients g per capsule
Tiotropium bromi.de 21.7
ViozanTM 270
Lactose 4708.3
Total 5000
2)
Ingredients g per capsule
Tiitropiiliil bro~~ide 21.7
ViozanTM 45
Lactose 4933.3
Total 5000
3)
Ingredients g per capsule
Tiotropium bromide x HZ0 22.5
ViozanTM 495
Lactose 4482.5
Total 5000
4)
Ingredients g per capsule
Tiotronium bromide 21.7
ViozanTM 400
Lactose 4578.3
Total 5000
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- 30 -
5)
Ingredients g per capsule
Ipratropium bromide 40
ViozanTM 270
Lactose 4690
Total 5000
6)
Ingredients g per capsule
Ipratropium bromide 20
ViozanTM 45
Lactose 4935
Total 5000
7)
Ingredients pg per capsule
Tiotropium bromide 21.7
Pramipexol 400
Lactose 4578.3
Total 5000
8)
Ingredients pg per capsule
Tiotropium bromide 21.7
Talipexol 400
Lactose 4578.3
Total 5000
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Bl pronPllanfi ~_4as-rontaining4 aerosols for ~ h la ion:
1) Suspension aerosol:
Ingredients wt.-%
Tiotropium bromide 0.015
ViozanTM 0.3
Soya lecithin 0.2
TG 134a: TG227 = 2:3 ad 100
2) Suspension aerosol:
Ingredients wt.-o
Ipratropium bromiue 0.015
ViozanTM 0.3
soya lecithin 0.2
TG 227 ad 100
3) Suspension aerosol:
Ingredients wt.-%
Tiotropium bromide 0.029
ViozanT"' 0.45
absolute ethanol 0.5
Isopropyl myristate 0.1
TG 227 ad 100
4) Suspension aerosol:
Ingredients wt.-%
Ipratropium bromide 0.029
ViozanTM 0.3
absolute ethanol 0.5
Isopropyl myristate 0.1
TG 227 ad 100
