Note: Descriptions are shown in the official language in which they were submitted.
WO 2004/022058 PCT/EP2003/008222
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81494pct.211
Pharmaceutical compositions for inhalation containing a new anticholinergic in
conjunction with corticosteroids and betamimetics
The present invention relates to novel pharmaceutical compositions based on a
new
anticholinergic, corticosteroids and betamimetics, 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 for
inhalation
based on a new anticholinergic, corticosteroids and betamimetics, 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 or obstructive
diseases of the
respiratory tract if a new anticholinergic is used with one or more
corticosteroids and
with one or more betamimetics. 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.
This
reduces unwanted side effects such as may occur when corticosteroids and
betamimetics are administered, for example.
The effects mentioned above may be observed both when the three 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 active substance ingredients
simultaneously in a single formulation. The pharmaceutical compositions
according to
the invention are preferably administered by inhalation according to the
invention.
Within the scope of the present invention the anticholinergics used are the
salts of
formula 1
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2
Mew+/Me X -
N
0 H
O O
Me
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-toluenesuIphonate 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 I
wherein
X - denotes bromide.
The salts of formula 1 are known from International Patent Application WO
02/32899.
Any reference to the salts of formula 1 includes a reference to any hydrates
and
solvates thereof which may be obtained.
Within the scope of the present patent application, an explicit reference to
the
pharmacologically active cation of formula
CA 02495454 2005-02-15
3
Meg+/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'.
Within the scope of the present invention, the word corticosteroids
(hereinafter 2)
denotes compounds selected from among flunisolide, beclomethasone,
triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide,
GW 215864, KSR 592, ST-126 and dexamethasone. Preferably, compound 2 is
selected from among flunisolide, beclomethasone, triamcinolone, budesonide,
fluticasone, mometasone, ciclesonide and dexamethasone. Most preferably,
compound 2 is selected from among budesonide, fluticasone, mometasone and
ciclesonide. In some cases, within the scope of the present patent
application, the
term steroids 2 may also be used on its own instead of the word
corticosteroids 2.
Any reference to steroids 2 within the scope of the present invention includes
a
reference to salts or derivatives 2' which may be formed from the steroids.
Examples
of possible salts or derivatives 2' include: sodium salts, sulphobenzoates,
phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates,
palmitates, pivalates or furoates. In some cases the compounds of formula 2
may
also occur in the form of their hydrates.
Examples of betamimetics 3 which may be used according to the invention
include
bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol,
hexoprenaline,
ibuterol, pirbuterol, procaterol, reproterol, salmeterol, sulphonterol,
terbutaline,
tolubuterol, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-
amino}ethyl]-2(3H)-benzothiazolone, 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-
benzim idazolyl)-2-methyl-2-butylamino]ethanol, 1-[3-(4-m ethoxybenzyl-amino)-
4-
hydroxyphenyl]-2-[4-(1-benzim idazolyl)-2-methyl-2-butylam ino]ethanol, 1-[2H-
5-
hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N, N-dimethylam inophenyl)-2-m
ethyl-
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4
2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-
m ethoxyphenyl)-2-methyl-2-propylamino]ethanol , 1-[2H-5-hydroxy-3-oxo-4H-1,4-
benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-
[2H-5-
hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-
3-yl]-
2-methyl-2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-
2H-
1,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5-trifluoromethyl phenyl)-2-
tert.-
butylam ino)ethanol or 1-(4-ethoxycarbonylam ino-3-cyano-5-fluorophenyl)-2-
(tert.-
butylamino)ethanol.
According to the invention the following betamimetics 3 are preferably used in
the
active substance combination: formoterol, salmeterol,
4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-
2(3H)-
benzothiazo lone,
1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1 -benzimidazolyl)-2-methyl-2-butylam
ino]ethanol,
1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzim idazolyl)-2-
methyl-2-
butylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl]-2-[3-(4-N, N-dimethylam
inophenyl)-2-
methyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-
2-
propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-
methyl-2-
propylamino]ethanol or
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-
triazol-3-yl]-2-methyl-2-butylam ino}ethanol.
Salmeterol salts or formoterol salts are preferably used as the long-acting
betamimetics 3 according to the invention. Any reference to the term
betamimetics 3
also includes a reference to the relevant enantiomers or mixtures thereof. For
example, any reference to the preferred compounds 3 according to the
invention, the
salts of salmeterol and formoterol, also includes the relevant enantiomeric
salts of R-
salmeterol, S-salmeterol, RR-formoterol, S,S-formoterol, RS-formoterol, S,R-
formoterol and the mixtures thereof, while the enantiomeric salts of R-
salmeterol and
R,R-formoterol are of particular importance. The compounds 3 may also be
present
according to the invention in the form of the hydrates or solvates thereof.
Within the scope of the present invention any reference to compounds 3 is to
be
understood as being a reference to physiologically acceptable acid addition
salts. By
physiologically acceptable acid addition salts of the betamimetics 3 are meant
according to the invention pharmaceutically acceptable salts which are
selected from
CA 02495454 2005-02-15
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, 1-hydroxy-2-naphthalenecarboxylic acid or maleic acid. If
desired,
mixtures of the abovementioned acids may be used to prepare the salts 3.
5
According to the invention the salts of the betamimetics 3 selected from among
the
hydrochloride, hydrobromide, sulphate, phosphate, fumarate, methanesulphonate
and xinafoate are preferred. Particularly preferably, in the case of
salmeterol, the
salts of 3 are selected from those salts which have a solubility in water of
0.1 mg/ml
or less, preferably 0.05 mg/ml or less, most preferably 0.04 mg/ml or less. In
this
context xinafoate, 4-phenylcinnamate and diflunisal are mentioned as
particularly
preferred salts of salmeterol. Particularly preferred salts 3 of salmeterol
have a
solubility in water of 0.035 mg/ml or less, such as for example 4-
phenylcinnamate or
diflunisal.
Particularly preferably, in the case of formoterol, the salts of 3 are
selected from the
hydrochloride, sulphate and fumarate, of which the hydrochloride and fumarate
are
particularly preferred. Of exceptional importance according to the invention
is
formoterol fumarate.
If, within the scope of the present invention, there is a reference to
betamimetics
which are not in the salt form, this can be taken to mean a reference to
compounds
3'. For example, the preferred betamimetics 3' according to the invention
which are
not in salt form are the free base of formoterol or salmeterol, whereas the
particularly
preferred compounds 3 according to the invention are, for example, salmeterol
xinafoate, salmeterol 4-phenylcinnamate or formoterol fumarate.
Within the scope of the present invention the betamimetics 3 are optionally
also
referred to as sympathomimetics or beta-2-receptor agonists (32-agonists). All
these
names can be regarded as equivalent within the scope of the present invention.
The pharmaceutical combinations of 1 2 and 3 according to the invention are
preferably administered by inhalation. Suitable inhalable powders packed into
suitable capsules (inhalettes) may be administered using suitable powder
inhalers.
Accordingly, in one aspect, the present invention relates to a pharmaceutical
composition which contains a combination of 1 2 and 3 .
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6
In another aspect the present invention relates to a pharmaceutical
composition
which contains one or more salts 1 , one or more compounds 2 and one or more
compounds 3, optionally in the form of their solvates or hydrates. The active
substances may be combined in a single preparation or contained in two or
three
separate formulations. Pharmaceutical compositions which contain the active
substances 1 2 and 3 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 2 and
3, 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
2 and 3.
The present invention also relates to the use of 1 2 and 3 for preparing a
pharmaceutical composition containing therapeutically effective quantities of
1 2 and
3 for treating inflammatory and/or obstructive diseases of the respiratory
tract,
particularly asthma and/or chronic obstructive pulmonary disease (COPD), by
simultaneous or successive administration. In addition the pharmaceutical
combinations according to the invention may be used to prepare a drug for
treating
cystic fibrosis or allergic alveolitis (farmer's lung), for example, by
simultaneous or
successive administration. The combinations of active substances according to
the
invention will not be used only if treatment with one of the pharmaceutically
active
ingredients is contraindicated.
The present invention also relates to the simultaneous or successive use of
therapeutically effective doses of the combination of the above pharmaceutical
compositions 1 2 and 3 for treating inflammatory or obstructive diseases of
the
respiratory tract, particularly asthma and/or chronic obstructive pulmonary
disease
(COPD), provided that treatment with steroids or betamimetics is not
contraindicated
from a therapeutic point of view, by simultaneous or successive
administration. The
invention further relates to the simultaneous or successive use of
therapeutically
effective doses of the combination of the above pharmaceutical compositions 1
2
and 3 for treating cystic fibrosis or allergic alveolitis (farmer's lung).
In the active substance combinations of 1 2 and 3 according to the invention,
ingredients 1 2 and 3 may be present in the form of their enantiomers,
mixtures of
enantiomers or in the form of racemates. For example, the pharmaceutical
CA 02495454 2005-02-15
7
compositions according to the invention contain the active substances 1 2 and
3
according to the invention in amounts such that a single administration
corresponds
to a dosage of the combination of active substances 1 2 and 3 of 1 to 10000
pg,
preferably from 10 to 2000 pg.
The proportions in which the active substances 1 2 and 3 may be used in the
active
substance combinations according to the invention are variable. Active
substances
1 2 and 3 may possibly be present in the form of their solvates or hydrates.
Depending on the choice of the compounds 1 2 and 3, 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 1:250 to 250:1, preferably from
1:150 to
150:1. In the particularly preferred pharmaceutical combinations which contain
in
addition to 1' a compound selected from among budesonide, fluticasone,
mometasone and ciclesonide as steroid 2, the weight ratios of 1' to 2 are most
preferably in a range from about 1:40 to 40:1, more preferably in the range
from 1:30
to 30:1.
For example, without restricting the scope of the invention thereto, preferred
combinations of 1 and 2 according to the invention may contain the cation 1'
and
one of the abovementioned preferred steroids 2 in the following proportions by
weight: 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 5 to 5000pg, preferably from 10 to 2000pg, more
preferably from
15 to 1000pg, even more preferably from 20 to 800pg, preferably according to
the
invention from 30 to 700pg, preferably from 40 to 600pg, preferably from 50 to
500
pg, preferably from 40 to 500 pg, more preferably from 50 to 400 pg per single
dose.
For example, combinations of 1 and 2 according to the invention contain a
quantity of
1' and steroid 2 such that the total dosage per single dose is about 35pg,
45pg,
50pg, 55pg, 60pg, 65pg, 70pg, 75pg, 80pg, 85pg, 90pg, 95pg, 100pg, 105pg,
110pg,
115pg, 120pg, 125pg, 130pg, 135pg,140 pg,145pg, 150pg,155pg, 160pg, 165pg,
170pg, 175pg, 180pg, 185pg, 190pg, 195pg, 200pg, 205pg, 210pg, 215pg, 220pg,
225pg, 230pg, 235pg, 240pg, 245pg, 250pg, 255pg, 260pg, 265pg, 270pg, 275pg,
280pg, 285pg, 290pg, 295pg, 300pg, 305pg, 310pg, 315pg, 320pg, 325pg, 330pg,
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8
335pg, 340pg, 345pg, 350pg, 355pg, 360pg, 365pg, 370pg, 375pg, 380pg, 385pg,
390pg, 395pg, 400pg, 405pg, 410pg, 415pg, 420pg, 425pg, 430pg, 435pg, 440pg,
445pg, 450pg, 455pg, 460pg, 465pg, 470pg, 475pg, 480pg, 485pg, 490pg, 495pg,
500pg, 505pg, 510pg, 515pg, 520pg, 525pg, 530pg, 535pg, 540pg, 545pg, 550pg,
555pg, 560pg, 565pg, 570pg, 575pg, 580pg, 585pg, 590pg, 595pg, 600pg, 605pg,
61 Opg or the like. It is clear to the skilled man that these proposed dosages
per
single dose are not to be regarded as being restricted to the numerical values
explicitly mentioned. Fluctuations of around 2.5pg , particularly
fluctuations in the
decimal range, are also covered as will be apparent to anyone skilled in the
art. In
these dosage ranges the active substances 1' and 2 may be present in the
weight
ratios described above.
For example and without restricting the scope of the invention thereto, the
combinations of 1 and 2 according to the invention may contain an amount of
cation
1' and steroid 2 such that each single dose contains 16.5pg of 1' and 25pg of
2,
16.5pg of 1' and 25pg of 2, 16.5pg of 1' and 50pg of 2, 16.5pg of 1' and 100pg
of
2, 16.5pg of V and 150pg of 2, 16.5pg of 1' and 200pg of 2, 16.5pg of 1' and
250pg of 2, 33.Opg of 1' and 25pg of 2, 33.Opg of 1' and 50pg of 2, 33.Opg of
1'
and 1 OOpg of 2, 33.Opg of 1' and 15Opg of 2, 33.Opg of 1' and 200pg of 2,
33.Opg
of 1' and 250pg of 2, 49.5 pg of 1' and 25pg of 2, 49.5pg of 1' and 50pg of 2,
49.5pg of 1' and 1 OOpg of 2, 49.5pg of 1' and 150pg of 2, 49.5pg of 1' and
200pg
of 2, 49.5pg of 1' and 250pg of 2, 82.6pg of 1' and 25pg of 2, 82.6pg of 1'
and
50pg of 2, 82.6pg of 1' and 1OOpg of 2, 82.6pg of 1' and 150pg of 2, 82.6pg of
1'
and 200pg of 2, 82.6pg of 1' and 250pg of 2, 165.1 pg of 1' and 25pg of 2,
165.1 pg of 1' and 50pg of 2, 165.1 pg of 1' and 50pg of 2, 165.1 pg of 1' and
1 OOpg of 2, 165.1 pg of 1' and 150pg of 2, 165.1 pg of 1' and 200pg of 2,
165.1 pg
of 1' and 250pg of 2, 206.4pg of 1' and 25pg of 2, 206.4pg of 1' and 50pg of
2,
206.4pg of 1' and 100pg of 2, 206.4pg of 1' and 150pg of 2, 206.4pg of 1' and
200pg of 2, 206.4pg of 1' and 250pg of 2, 412.8pg of 1' and 25pg of 2, 412.8pg
of
1' and 50pg of 2, 412.8pg of 1' and 100pg of 2, 412.8pg of 1' and 150pg of 2,
412.8pg of 1' and 200pg of 2, 412.8pg of 1' and 250pg of 2.
If the active substance combination wherein the bromide is used as the salt 1
and 2
denotes one of the preferred steroids disclosed hereinbefore is used as a
preferred
combination of 1 and 2 according to the invention, the quantities of active
substances 1' and 2 administered per single dose as specified by way of
example
correspond to the following quantities of 1 and 2 administered per single
dose:
20pg of 1 and 25pg of 2, 20pg of I and 50pg of 2, 20pg of 1 and 1 OOpg of 2,
20pg of I and 150pg of 2, 20pg of I and 200pg of 2, 20pg of 1 and 250pg of 2,
CA 02495454 2005-02-15
9
40pg of I and 25pg of 2, 40pg of 1 and 25pg of 2, 40pg of 1 and 50pg of 2,
40pg
of 1 and I OOpg of 2, 40pg of 1 and 150pg of 2, 40pg of 1 and 200pg of 2, 40pg
of
I and 250pg of 2, 60pg of I and 25pg of 2, 60pg of 1 and 50pg of 2, 60pg of 1
and 100pg of 2, 60pg of 1 and 150pg of 2, 60pg of 1 and 200pg of 2, 60pg of 1
and 250pg of 2, 100pg of 1 and 25pg of 2, 100pg of 1 and 50pg of 2, 100pg of 1
and 100pg of 2, 100pg of 1 and 150pg of 2, 100pg of 1 and 200pg of 2, 100pg of
1 and 250pg of 2, 200pg of I and 25pg of 2, 200pg of I and 50pg of 2, 200pg of
I and 100pg of 2, 200pg of 1 and 150pg of 2, 200pg of I and 200pg of 2, 200pg
of 1 and 250pg of 2, 250pg of I and 25pg of 2, 250pg of I and 50pg of 2, 250pg
of I and I OOpg of 2, 250pg of I and 150pg of 2, 250pg of 1 and 200pg of 2,
250pg of I and 250pg of 2, 500pg of 1 and 25pg of 2, 500pg of 1 and 50pg of 2,
500pg of 1 and 100pg of 2, 500pg of 1 and 150pg of 2, 500pg of I and 200pg of
2, 500pg of 1 and 250pg of 2.
At the same time the ratio of I to 3 may bel:300 to 30:1, preferably from
1:230 to
20:1, more preferably from 1:150 to 10:1, still more preferably from 1:50 to
5:1, more
preferably from 1:35 to 2:1.
In the case of formoterol, for example, the active substance combinations
according
to the invention may contain 1' and 3' in ratios by weight which are, for
example, in
the range from about 1:10 to 300:1, preferably 1:5 to 200:1, preferably 1:3 to
150:1,
more preferably from 1:2 to 100:1.
For example and without restricting the scope of the invention thereto,
preferred
combinations of 1 and 3 according to the invention contain the
pharmacologically
active cation 1' and formoterol 3' in the following ratios by weight: 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, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1,
31:1, 32:1,
33:1,34:1,351,36:1,37:1,38:1,39:1,40:1,41:1,42:1,43:1,441,45:1,46:1,47:1,
48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1, 60:1,
61:1, 62:1,
63:1, 64:1, 65:1, 66:1, 67:1, 68:1, 69:1, 70:1, 71:1, 72:1, 73:1, 74:1, 75:1,
76:1, 77:1,
78:1, 79:1, 80:1, 81:1, 82:1, 83:1, 84:1, 85:1, 86:1, 87:1, 88:1, 89:1, 90:1,
91:1, 92:1,
93:1, 94:1, 95:1, 96:1, 97:1, 98:1, 99:1, 100:1.
The pharmaceutical compositions according to the invention containing the
combinations of 1 and 3 are normally used so that the pharmacologically active
cation 1' and formoterol 3' are present together in doses from 5 to 5000pg,
preferably
from 10 to 2000pg, more preferably from 15 to 1000pg, still more preferably
from 20
CA 02495454 2005-02-15
to 800pg, preferably according to the invention from 30 to 600pg, preferably
from 40
to 500pg.
For example, the combinations of 1 and 3 according to the invention contain an
5 amount of cation 1' and formoterol 3' such that the total dosage per single
dose is
about 10pg, 15pg, 20pg, 25pg, 30pg, 35pg, 45pg, 50pg, 55pg, 60pg, 65pg, 70pg,
75pg, 80pg, 85pg, 90pg, 95pg, 1OOpg, 105pg, 11Opg, 115pg, 120pg, 125pg, 130pg,
135pg, 140pg, 145pg, 150pg, 155pg, 160pg, 165pg, 170pg, 175pg, 180pg, 185pg,
190pg, 195pg, 200pg, 205pg, 210pg, 215pg, 220pg, 225pg, 230pg, 235pg, 240pg,
10 245pg, 250pg, 255pg, 260pg, 265pg, 270pg, 275pg, 280pg, 285pg, 290pg,
295pg,
300pg, 305pg, 310pg, 315pg, 320pg, 325pg, 330pg, 335pg, 340pg, 345pg, 350pg,
355pg, 360pg, 365pg, 370pg, 375pg, 380pg, 385pg, 390pg, 395pg, 400pg, 405pg,
410pg, 415pg, 420pg, 425pg, 430pg, 435pg, 440pg, 445pg, 450pg, 455pg, 460pg,
465pg, 470pg, 475pg, 480pg, 485pg, 490pg, 495pg, 500pg, 505pg, 510pg, 515pg,
520pg, 525pg, 530pg, 535pg, 540pg, 545pg, 550pg, 555pg, 560pg, 565pg, 570pg,
575pg, 580pg, 585pg, 590pg, 595pg, 600pg, or similar. It is clear to the
skilled man
that these proposed dosages per single dose are not to be regarded as being
restricted to the numerical values explicitly mentioned. Fluctuations of
around
2.5pg, particularly fluctuations in the decimal range, are also covered as
will be
apparent to anyone skilled in the art. In these dosage ranges the active
substances
1' and 3' are present in the weight ratios described above.
For example and without restricting the scope of the invention thereto, the
combinations of 1 and 3 according to the invention contain an amount of cation
1'
and formoterol 3' such that they contain, per single dose, for example 8.3pg
of 1'
and 2.5pg of 3', 8.3pg of 1' and 4.9pg of 3', 8.3pg of 1' and 9.8pg of 3',
8.3pg of
1' and 14.7pg of 3', 8.3pg of 1' and 19.6pg of 3', 8.3pg of 1' and 24.4pg of
3',
16.5pg of 1' and 2.5pg of 3', 16.5pg of 1' and 4.9pg of 3', 16.5pg of 1' and
9.8pg
of 3', 16.5pg of 1' and 14.7pg of 3', 16.5pg of 1' and 19.6pg of 3', 16.5pg of
1'
and 24.4pg of 3', 33.0pg of 1' and 2.5pg of 3', 33.Opg of 1' and 4.9pg of 3',
33.0pg
of 1' and 9.8pg of 3', 33.Opg of 1' and 14.7pg of 3', 33.Opg of 1' and 19.6pg
of 3',
33.Opg of 1' and 24.4pg of 3', 49.5pg of 1' and 2.5pg of 3', 49.5pg of 1' and
4.9pg
of 3, 49.5pg of 1' and 9.8pg of 3', 49.5pg of 1' and 14.7pg of 3', 49.5pg of
1' and
19.6pg of 3', 49.5pg of 1' and 24.4pg of 3', 82.6pg of 1' and 2.5pg of 3',
82.6pg of
1' and 4.9pg of 3', 82.6pg of 1' and 9.8pg of 3', 82.6pg of 1' and 14.7pg of
3',
82.6pg of 1' and 19.6pg of 3', 82.6pg of 1' and 24.4pg of 3', 165.1 pg of 1'
and
2.5pg of 3', 165.1 pg of 1' and 4.9pg of 3', 165.1 pg of 1' and 9.8pg of 3',
165.1 pg
of 1' and 14.7pg of 3', 165.1 pg of 1' and 19.6pg of 3', 165.1 pg of 1' and
24.4pg of
3', 206.4pg of 1' and 2.5pg of 3', 206.4pg of 1' and 4.9pg of 3', 206.4pg of
1' and
CA 02495454 2005-02-15
11
9.8pg of 3', 206.4pg of 1' and 14.7pg of 3', 206.4pg of 1' and 19.6pg of 3',
206.4pg of 1' and 24.4pg of 3', 412.8pg of 1' and 2.5pg of 3', 412.8pg of 1'
and
4.9pg of 3', 412.8pg of 1' and 9.8pg of 3', 412.8pg of 1' and 14.7pg of 3',
412.8pg
of 1' and 19.6pg of 3', 412.8pg of 1' and 24.4pg of 3'.
If the active substance combination wherein the salt 1 is the bromide and 3
denotes
formoterol fumarate is used as a preferred combination of 1 and 3 according to
the
invention, the quantities of active substances 1' and 3 administered per
single dose
as specified by way of example correspond to the following quantities of 1 and
3
administered per single dose: 1 Opg of 1 and 2.9pg of 3, 1Opg of I and 5.7pg
of 3,
1 Opg of 1 and 11.5pg of 3, 1 Opg of 1 and 17.2pg of 3, 10pg of 1 and 22.9pg
of 3,
10pg of I and 28.5pg of 3, 20pg of 1 and 2.9pg of 3, 20pg of 1 and 5.7pg of 3,
20pg of 1 and 11.5pg of 3, 20pg of 1 and 17.2pg of 3, 20pg of 1 and 22.9pg of
3,
20pg of 1 and 28.5pg of 3, 40pg of 1 and 2.9pg of 3, 40pg of 1 and 5.7pg of 3,
40pg of 1 and 11.5pg of 3, 40pg of 1 and 17.2pg of 3, 40pg of 1 and 22.9pg of
3,
40pg of I and 28.5pg of 3, 60pg of 1 and 2.9pg of 3, 60pg of 1 and 5.7pg of 3,
60pg of 1 and 11.5pg of 3, 60pg of 1 and 17.2pg of 3, 60pg of 1 and 22.9pg of
3,
60pg of 1 and 28.5pg of 3, 100pg of 1 and 2.9pg of 3, 100pg of 1 and 5.7pg of
3,
100pg of 1 and 11.5pg of 3, 100pg of 1 and 17.2pg of 3, 100pg of 1 and 22.9pg
of
3, 100pg of I and 28.5pg of 3, 200pg of 1 and 2.9pg of 3, 200pg of 1 and 5.7pg
of
3, 200pg of 1 and 11.5pg of 3, 200pg of 1 and 17.2pg of 3, 200pg of 1 and
22.9pg
of 3, 200pg of 1 and 28.5pg of 3, 250pg of 1 and 2.9pg of 3, 250pg of I and
5.7pg of 3, 250pg of 1 and 11.5pg of 3, 250pg of 1 and 17.2pg of 3, 250pg of 1
and 22.9pg of 3, 250pg of I and 28.5pg of 3, 500pg of 1 and 2.9pg of 3, 500pg
of
1 and 5.7pg of 3, 500pg of 1 and 11.5pg of 3, 500pg of 1 and 17.2pg of 3,
500pg
of 1 and 22.9pg of 3, 500pg of 1 and 28.5pg of 3.
If the active substance combination wherein 3 denotes formoterol fumarate
dihydrate
and the salt 1 is the bromide is used as a preferred combination of 1 and 3
according to the invention, the quantities of active substances 1' and 3'
administered
per single dose as specified by way of example correspond to the following
quantities
of 1 and 3 administered per single dose: 1Opg of 1 and 3pg of 3, 10pg of 1 and
6pg
of 3, 10pg of 1 and 12pg of 3, 10pg of 1 and 18pg of 3, 10pg of 1 and 24pg of
3,
1 Opg of 1 and 30pg of 3, 20pg of 1 and 3pg of 3, 20pg of 1 and 6pg of 3, 20pg
of
1 and 12pg of 3, 20pg of 1 and 18pg of 3, 20pg of I and 24pg of 3, 20pg of 1
and
30pg of 3, 40pg of 1 and 3pg of 3, 40pg of 1 and 6pg of 3, 40pg of 1 and 12pg
of
3, 40pg of 1 and 18pg of 3, 40pg of 1 and 24pg of 3, 40pg of 1 and 30pg of 3,
60pg of 1 and 3pg of 3, 60pg of 1 and 6pg of 3, 60pg of 1 and 12pg of 3, 60pg
of
1 and 18pg of 3, 60pg of I and 24pg of 3, 60pg of 1 and 30pg of 3, 1 00pg of 1
CA 02495454 2005-02-15
12
and 3pg of 3, 100pg of 1 and 6pg of 3, 100pg of I and 12pg of 3, 100pg of I
and
18pg of 3, 100pg of 1 and 24pg of 3, 100pg of 1 and 30pg of 3, 200pg of 1 and
3pg of 3, 200pg of 1 and 6pg of 3, 200pg of 1 and 12pg of 3, 200pg of 1 and
18pg of 3, 200pg of 1 and 24pg of 3, 200pg of 1 and 30pg of 3, 250pg of 1 and
3pg of 3, 250pg of I and 6pg of 3, 250pg of 1 and 12pg of 3, 250pg of 1 and
18pg of 3, 250pg of 1 and 24pg of 3, 250pg of 1 and 30pg of 3, 500pg of 1 and
3pg of 3, 500pg of 1 and 6pg of 3, 500pg of I and 12pg of 3, 500pg of 1 and
18pg of 3, 500pg of I and 24pg of 3, 500pg of I and 30pg of 3.
In the case of salmeterol, for example, the active substance combinations
according
to the invention may contain 1' and 3' in ratios by weight which are in the
range from
about 1:30 to 400:1, preferably 1:25 to 200:1, preferably 1:20 to 100:1, more
preferably from 1:15 to 50:1, for example.
For example, and without restricting the scope of the invention thereto, the
preferred
combinations of 1 and 3 according to the invention may contain the cation 1'
and
salmeterol 3' in the following ratios by weight: 1 : 1 5 , 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, 21:1, 22:1, 23:1, 24:1,
25:1, 26:1,
27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1.
The pharmaceutical compositions according to the invention containing the
combinations of I and 3 are normally used so that the cation 1' and salmeterol
3' are
present together in doses from 5 to 5000pg, preferably from 10 to 2000pg, more
preferably from 15 to 1000pg, still more preferably from 20 to 800pg,
preferably
according to the invention from 30 to 750pg, preferably from 40 to 700pg.
For example, the combinations of 1 and 3 according to the invention contain an
amount of 1' and salmeterol 3' such that the total dosage per single dose is
about
15pg, 20pg, 25pg, 30pg, 35pg, 45pg, 50pg, 55pg, 60pg, 65pg, 70pg, 75pg, 80pg,
85pg, 90pg, 95pg, 100pg, 105pg, 110pg, 115pg, 120pg, 125pg, 130pg, 135pg,
140pg, 145pg, 150pg, 155pg, 16Opg, 165pg, 170pg, 175pg, 180pg, 185pg, 190pg,
195pg, 200pg, 205pg, 210pg, 215pg, 220pg, 225pg, 230pg, 235pg, 240pg, 245pg,
250pg, 255pg, 260pg, 265pg, 270pg, 275pg, 280pg, 285pg, 290pg, 295pg, 300pg,
305pg, 310pg, 315pg, 320pg, 325pg, 330pg, 335pg, 340pg, 345pg, 350pg, 355pg,
360pg, 365pg, 370pg, 375pg, 380pg, 385pg, 390pg, 395pg, 400pg, 405pg, 410pg,
415pg, 420pg, 425pg, 430pg, 435pg, 440pg, 445pg, 450pg, 455pg, 460pg, 465pg,
470pg, 475pg, 480pg, 485pg, 490pg, 495pg, 500pg, 505pg, 510pg, 515pg, 520pg,
525pg, 530pg, 535pg, 540pg, 545pg, 550pg, 555pg, 560pg, 565pg, 570pg, 575pg,
CA 02495454 2005-02-15
13
580pg, 585pg, 590pg, 595pg, 600pg, 605pg, 610pg, 615pg, 620pg, 625pg, 630pg,
635pg, 640pg, 645pg, 650pg, 655pg, 660pg, 665pg, 670pg, 675pg, 680pg, 685pg,
690pg, 695pg, 700pg or the like. It is clear to the skilled man that these
proposed
dosages per single dose are not to be regarded as being restricted to the
numerical
values explicitly mentioned. Fluctuations of around 2.5pg, particularly
fluctuations in
the decimal range, are also covered as will be apparent to anyone skilled in
the art. In
these dosage ranges the active substances 1' and 3' are present in the weight
ratios
described above.
For example and without restricting the scope of the invention thereto, the
combinations of 1 and 3 according to the invention contain an amount of cation
1'
and salmeterol 3' such that they contain, per single dose, for example 8.3pg
of 1'
and 12.5pg of 3', 8.3pg of 1' and 25pg of 3', 8.3pg of 1' and 50pg of 3',
8.3pg of
1' and 75pg of 3', 8.3pg of 1' and 100pg of 3', 8.3pg of 1' and 200pg of 3,
16.5pg
of 1' and 12.5pg of 3', 16.5pg of 1' and 25pg of 3', 16.5pg of 1' and 50pg of
3',
16.5pg of 1' and 75pg of 3', 16.5pg of 1' and 1 OOpg of 3', 16.5pg of 1' and
200pg
of 3', 33.Opg of 1' and 12.5pg of 3', 33.Opg of 1' and 25pg of 3', 33.Opg of
1' and
50pg of 3', 33.Opg of 1' and 75pg of 3', 33.Opg of 1' and 1O0pg of 3', 33.Opg
of 1'
and 200pg of 3', 49.5pg of 1' and 12.5pg of 3', 49.5pg of 1' and 25pg of 3',
49.5pg
of 1' and 50pg of 3', 49.5pg of 1' and 75pg of 3, 49.5pg of 1' and I OOpg of
3',
49.5pg of 1' and 200pg of 3', 82.6pg of 1' and 12.5pg of 3', 82.6pg of 1' and
25pg
of 3', 82.6pg of 1' and 50pg of 3', 82.6pg of 1' and 75pg of 3', 82.6pg of 1'
and
1 OOpg of 3', 82.6pg of 1' and 200pg of 3', 165.1 pg of 1' and 12.5pg of 3,
165.1 pg
of 1' and 25pg of 3', 165.1 pg of 1' and 50pg of 3', 165.1 pg of 1' and 75pg
of 3',
165.1 pg of 1' and 1 OOpg of 3', 165.1 pg of 1' and 200pg of 3', 206.4pg of 1'
and
12.5pg of 3', 206.4pg of 1' and 25pg of 3', 206.4pg of 1' and 50pg of 3,
206.4pg
of 1' and 75pg of 3', 206.4pg of 1' and I OOpg of 3', 206.4pg of 1' and 200pg
of 3',
412.8pg of 1' and 12.5pg of 3, 412.8pg of 1' and 25pg of 3', 412.8pg of 1' and
50pg of 3', 412.8pg of 1' and 75pg of 3', 412.8pg of 1' and 100pg of 3',
412.8pg of
1' and 200pg of 3'.
If the active substance combination wherein the bromide is used as the salt 1
and 3
denotes salmeterol xinafoate is used as a preferred combination of 1 and 3
according to the invention, the quantities of active substances 1' and 3'
administered
per single dose as specified by way of example correspond to the following
quantities
of I and 3 administered per single dose: 10pg of 1 and 18.2pg of 3, 10pg of 1
and
36.3pg of 3, 10pg of 1 and 72.6pg of 3, 10pg of I and 108.9pg of 3, 10pg of I
and 145.2pg of 3, 1 Opg of I and 290,4pg of 3, 20pg of I and 18.2pg of 3, 20pg
of
1 and 36.3pg of 3, 20pg of 1 and 72.6pg of 3, 20pg of 1 and 108.9pg of 3, 20pg
of
CA 02495454 2005-02-15
14
1 and 145.2pg of 3, 20pg of 1 and 290.4pg of 3, 40pg of 1 and 18.2pg of 3,
40pg
of 1 and 36.3pg of 3, 40pg of 1 and 72.6pg of 3, 40pg of 1 and 108.9pg of 3,
40pg of 1 and 145.2pg of 3, 40pg of 1 and 290.4pg of 3, 60pg of 1 and 18.2pg
of
3, 60pg of 1 and 36.3pg of 3, 60pg of 1 and 72.6pg of 3, 60pg of 1 and 108.9pg
of
3, 60pg of 1 and 145.2pg of 3, 60pg of 1 and 290.4pg of 3, 100pg of 1 and
18.2pg
of 3, 100pg of 1 and 36.3pg of 3, 100pg of 1 and 72.6pg of 3, 100pg of 1 and
108.9pg of 3, 100pg of 1 and 145.2pg of 3, 100pg of 1 and 290.4pg of 3, 200pg
of
1 and 18.2pg of 3, 200pg of 1 and 36.3pg of 3, 200pg of 1 and 72.6pg of 3,
200pg
of 1 and 108.9pg of 3, 200pg of 1 and 145.2pg of 3, 200pg of 1 and 290.4pg of
3,
250pg of 1 and 18.2pg of 3, 250pg of 1 and 36.3pg of 3, 250pg of 1 and 72.6pg
of
3, 250pg of 1 and 108.9pg of 3, 250pg of 1 and 145.2pg of 3, 250pg of 1 and
290.4pg of 3, 500pg of 1 and 18.2pg of 3, 500pg of 1 and 36.3pg of 3, 500pg of
1
and 72.6pg of 3, 500pg of 1 and 108.9pg of 3, 500pg of 1 and 145.2pg of 3,
500pg of 1 and 290.4pg of 3.
The quantities of active substance in the pharmaceutical combinations
according to
the invention can be calculated analogously if instead of salmeterol xinafoate
the
compounds 3 salmeterol-4-phenylcinnamic acid salt (4-phenylcinnamate) and
salmeterol-5-(2,4-difluorophenyl)salicylic acid salt (5-(2,4-
difluorophenyl)salicylate;
diflunisal) are used, which are equally preferred according to the invention.
The active substance combinations of 1 , 2 and 3 according to the invention
are
preferably administered by inhalation. For this purpose, ingredients 1 , 2 and
3 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 , 2 and 3 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 carrier may
optionally
be used instead of the term excipient. 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 , 2 and 3 either together in one
formulation or in
two or three 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.
CA 02495454 2005-02-15
A) Inhalable powder containing the combinations of active substances 1 , 2 and
3 according to the invention:
The inhalable powders according to the invention may contain 1 , 2 and 3
either on
their own or in admixture with suitable physiologically acceptable excipients.
5 If the active substances 1 , 2 and 3 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. dextran), polyalcohols
(e.g.
10 sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium
carbonate) or mixtures
of these excipients. 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.
15 Within the scope of the inhalable powders according to the invention the
excipients
have a maximum average particle size of up to 250pm, preferably between 10 and
150pm, most preferably between 15 and 80pm. 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 , 2 and 3,
preferably with an average particle size of 0.5 to 10 m, more preferably from
1 to
5 m, is added to the excipient mixture. Processes for producing the inhalable
powders according to the invention by grinding and micronising and lastly
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 and 3 or in the form of separate
inhalable powders which contain only 1 , 2 or 3.
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 , 2 and 3 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 excipients in addition to 1 , 2 and 3
are
CA 02495454 2010-09-22
25771-1000
16
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.
rM
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 holes 13
for
adjusting the flow resistance.
If the inhalable powders according to the invention are to be 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 , 2 and 3 mentioned hereinbefore
for
each single dose.
B) Propellant gas-driven inhalation aerosols containing the combinations of
active substances 1 , 2 and 3 according to the invention:
Inhalation aerosols containing propellant gas according to the invention may
contain
substances 1 , 2 and 3 dissolved in the propellant gas or in dispersed form. 1
, 2 and
3 may be present in separate formulations or in a single preparation, in which
1 , 2
and 3 are either each dissolved, dispersed or only one or two of the
components is or
are dissolved and the other or others is or are dispersed. The propellant
gases which
maybe 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.
CA 02495454 2005-02-15
17
The propellant-driven inhalation aerosols according to the invention may also
contain
other ingredients such as co-solvents, stabilisers, surfactants, antioxidants,
lubricants, preservatives 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 , 2 and/or 3. 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 , 2
and/or 3.
If the active substances 1 , 2 and/or 3 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 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 , 2 and 3 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 , 2 and 3, 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
CA 02495454 2005-02-15
18
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, 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
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 100 mg/100ml, preferably less than 50mg/100ml, more preferably less than
20mg/100ml. Generally, inhalable solutions in which the content of sodium
edetate is
from 0 to 10mg/100ml 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 physiologically 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 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
physiologically
acceptable salts such as sodium chloride as isotonic agents.
CA 02495454 2005-02-15
19
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/100ml.
Preferred formulations contain, in addition to the solvent water and the
combination
of active substances 1 , 2 and 3, 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 required therapeutic dose within a few seconds
to
produce an aerosol suitable for therapeutic inhalation. Within the scope of
the
present invention, preferred nebulisers are those in which a quantity of less
than
100 L, preferably less than 50 1, 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 , 2 and 3. 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.
CA 02495454 2005-02-15
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
- a pump housing which is secured in the upper housing part and which
5 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,
10 - 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.
15 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
20 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 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.
CA 02495454 2005-02-15
21
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 1000. The nozzle openings are preferably arranged at a
spacing of
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
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
annular
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
atom ised may be pushed into the atom iser 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.
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.
CA 02495454 2005-02-15
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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).
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.
CA 02495454 2005-02-15
24
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 2 and 3 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 isotonic saline solutions.
Sterile
formulations ready for use may be administered using energy-operated fixed 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.
CA 02495454 2005-02-15
Examples of Formulations
A) Inhalable powders:
1)
Ingredients pg per capsule
1'-bromide 100
budesonide 200
salmeterol xinafoate 55.9
lactose 4721.6
Total 5000
5
2)
Ingredients pg per capsule
1'-bromide 75
fluticasone propionate 125
salmeterol-4-phenylcinnamate 50
lactose 4802.5
Total 5000
3)
Ingredients pg per capsule
1'-bromide 75
mometasone furoate 250
formoterol fumarate dihydrate 12
lactose 4715.5
Total 5000
4)
Ingredients pg per capsule
1'-bromide 100
fluticasone propionate 250
formoterol fumarate dihydrate 12
lactose 4715.5
Total 5000
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5)
Ingredients pg per capsule
1'-bromide 200
formoterol fumarate dihydrate 12
fluticasone propionate 250
lactose 24538
Total 25000
6)
Ingredients pg per capsule
1'-bromide 75
fluticasone propionate 125
salmeterol-diflunisal 50
lactose 4802.5
Total 5000
B) Inhalable aerosols containing propellant gas:
1) Suspension aerosol:
Ingredients Wt-%
1'-bromide 0.035
budesonide 0.4
formoterol fumarate dihydrate 0.066
soya lecithin 0.2
TG 134a : TG227 = 2:3 ad 100
2) Suspension aerosol:
Ingredients Wt-%
1'-bromide 0.039
fluticasone propionate 0.3
salmeterol xinafoate 0.033
isopropyl myristate 0.1
TG 227 ad 100
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3) Suspension aerosol:
Ingredients Wt-%
1'-bromide 0.039
mometasone furoate 0.6
salmeterol x diflunisal 0.066
isopropyl myristate 0.1
TG 227 ad 100
4) Suspension aerosol:
Ingredients Wt-%
1'-bromide 0.035
fluticasone propionate 0.3
salmeterol 4-phenylcinnamate 0.066
soya lecithin 0.2
TG 11 : TG12 = 2:3 ad 100
5) Suspension aerosol:
Ingredients Wt-%
1'-bromide 0.039
salmeterol xinafoate 0.033
budesonide 0.4
absolute ethanol 0.5
isopropyl myristate 0.1
TG 227 ad 100
