Note: Descriptions are shown in the official language in which they were submitted.
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MEDICAMENTS COMPRISING PDE IV INHIBITORS AND A NOVEL ANTICHOLINERGIC AND THEIR
USE FOR TREATING RESPIRATORY DISORDERS
The present invention relates to novel pharmaceutical compositions based on
PDE IV
inhibitors and salts of a new anticholinergic, processes for preparing them
and their use in
the treatment of respiratory complaints.
Description of the invention
The present invention relates to novel pharmaceutical compositions based on
PDE IV
1o inhibitors and salts of a new anticholinergic 1, processes for preparing
them and their use
in the treatment of respiratory complaints.
Within the scope of the present invention the anticholinergic agents used are
the 'salts of
formula 1
1
wherein
X - denotes an anion with a single negative charge, preferably an anion
selected
from the group consisting of fluoride, chloride, bromide, iodide, sulphate,
2o 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 among the
fluoride, chloride, bromide, 4-toluenesulphonate and methanesulphonate,
preferably bromide.
Most preferably, the salts of formula 1 are used wherein
Mew+~Me X _
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X ' denotes an anion with a single negative charge selected from among
the chloride, bromide and methanesulphonate, preferably bromide.
Particularly preferred according to the invention is the salt of formula 1
wherein
X - denotes bromide.
Surprisingly, an unexpectedly beneficial therapeutic effect can be observed in
the treatment
of inflammatory and/or obstructive diseases of the respiratory tract if the
anticholinergic of
formula 1 is used with one or more PDE IV inhibitors 2.
This effect may be observed both when the two active substances are
administered
simultaneously in a single active substance formulation and when they are
administered
successively in separate formulations. According to the invention, it is
preferable to
administer the two active substance ingredients simultaneously in a single
formulation.
Within the scope of the present invention, any reference to the compound 1' is
to be
regarded as a reference to the pharmacologically active cation of the
following formula
contained in the salts 1
Met+~Me
N
O \\ , H
O~ O
Me
1'.
2o Tn the pharmaceutical combinations mentioned above 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.
According to the instant invention preferred PDE IV inhibitors 2 in the
combinations
according to the invention are selected from the group consisting of
enprofylline,
theophylline, roflumilast, ariflo (cilomilast), CP-325,366, BY343, D-4396 (Sch-
351591),
AWD-12-281 (GW-842470), N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-
3-
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cyclopropylmethoxybenzamide, NCS-613, pumafentine, (-)p-[(4aR*,lObS*)-9-ethoxy-
1,2,3,4,4a,10b-hexahydro-8-methoxy-2methylbenzo [s] [ 1,6]naphthyridin-6-yl]-
N,N-
diisopropylbenzamide, (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-
methoxyphenyl]-2-pyrrolidone, 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N-2-
cyano-
S-methyl-isothioureido]benzyl)-2-pyrrolidone, cis[4-cyano-4-(3-cyclopentyloxy-
4-
methoxyphenyl)cyclohexan-1-carboxylic acid], 2-carbomethoxy-4-cyano-4-(3-
cyclopropylrnethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one, cis[4-cyano-4-(3-
cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-of], (R)-(+)-ethyl[4-
(3-
cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate, (S)-(-)-ethyl[4-
(3-
l0 cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate, CDP840, Bay-
198004, D-
4418, PD-168787, T-440, T-2585, arofylline, atizoram, V-11294A, Cl-1018, CDC-
801,
CDC-3052, D-22888, YM-58997, Z-15370, 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-
thienyl)-9H pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine, and 9-cyclopentyl-
5,6-dihydro-
7-ethyl-3-(tent-butyl)-9H-pyrazolo [3,4-c]-1,2,4-triazolo [4,3-a]pyridine,.
optionally in the form of the racemates, the enantiomers, the diastereomers
and optionally
the pharmacologically acceptable acid addition salts thereof, and the hydrates
thereof.
In a preferred embodiment according to the invention the PDE IV inhibitors 2
are selected
from the group consisting of enprofylline, roflumilast, ariflo (cilornilast),
AWD-12-281
(GW-842470), N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-
cyclopropylmethoxybenzamide, T-440, T-2585, arofylline, cis[4-cyano-4-(3-
cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic acid], 2-earbomethoxy-4-
cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one, cis[4-
cyano-
4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-of], PD-168787,
atizoram, V-11294A, Cl-1018, CDC-801, D-22888, YM-58997, Z-15370, 9-
cyclopentyl-
5,6-dihydro-7-ethyl-3-(2-thienyl)-9H pyrazolo[3,4-c]-1,2,4-triazolo[4,3-
a]pyridine, and 9-
cyclopentyl-5,6-dihydro-7-ethyl-3-(tart-butyl)-9H-pyrazolo[3,4-c]-1,2,4-
triazolo[4,3-
a]pyridine, optionally in the form of the racemates, the enantiomers, the
diastereomers and
optionally the pharmacologically acceptable acid addition salts thereof, and
the hydrates
3o thereof.
In another preferred embodiment according to the invention the PDE IV
inhibitors 2 are
selected from the group consisting of roflumilast, ariflo (cilomilast), AWD-12-
281 (GW-
842470), arofylline, Z-15370, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-
difluoromethoxyphenyl)cyclohexan-1-one, cis[4-cyano-4-(3-cyclopropylmethoxy-4-
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difluoromethoxyphenyl)cyclohexan-1-of], atizoram, 9-cyclopentyl-5,6-dihydro-7-
ethyl-3-
(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine, and 9-
cyclopentyl-5,6-
dihydro-7-ethyl-3-(tent-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-
a]pyridine, while
roflumilast, Z-15370, and AWD-12-281 are particularly preferred as compound 2
according to the invention.
In a yet another preferred embodiment according to the invention the PDE IV
inhibitors 2
are selected from the group consisting of 2-(4-fluoro-phenoxy)-N-{4-[(6-fluoro-
2-hydroxy-
benzoylamino)-methyl]-benzyl} nicotinamide, 2-(4-fluoro-phenoxy)-N-{4-[(5-
fluoro-2-
hydroxy-benzoylamino)-methyl]-benzyl} nicotinamide, 2-(4-fluoro-phenoxy)-N-{4-
[(3-
hydroxy-4-methyl-benzoylamino)methyl]benzyl} nicotinamide, 2-(4-fluoro-
phenoxy)-N-
{4-[(3hydroxy-benzoylamino)-methyl]-benzyl} nicotinamide, 2-(4-fIuoro-phenoxy)-
N-{4-
[(2-hydroxy-benzoylamino)methyl]-benzyl} nicotinamide, 2-(4-fIuoro-phenoxy)-N-
{4-[(4-
hydroxy-benzoylamino)methyl]-benzyl} nicotinamide, 2-(4-fIuoro-phenoxy)-N-{4-
[(2-
hydroxy-4-methyl-benzoylamino)methyl]-benzyl} nicotinamide, 2-(4-fIuoro-
phenoxy)-N-
{4-[(3-hydroxy-2-methyl-benzoylamino)methyl]-benzyl} nicotinamide, 2-(4-fIuoro-
phenoxy)-N-{4-[(2-hydroxy-5-methyl-benzoylamino)methyl]-benzyl} nicotinamide,
5-fluoro-2-(4-fIuoro-phenoxy)-N-{4-[(2-hydroxy-benzoylamino)methyl]-benzyl }
nicotinamide, 5-fluoro-2-(4-fIuoro-phenoxy)-N-{4-[(2-hydroxy-
acetylamino)methyl]-
2o benzyl} nicotinamide, 5-fluoro-2-(4-fIuoro-phenoxy)-N-{4-[(4-hydroxy-
benzoylamino)methyl]-benzyl} nicotinamide, 3-(3-{4-[(3-hydroxy-
benzoylamino)methyl]-
benzylcarbamoyl}-pyridin-2-yloxy)benzoic acid ethyl ester, 3-(3-{4-[(2-hydroxy-
phenacetylamino)methyl]-benzylcarbamoyl}-pyridin-2-yloxy)benzoic acid ethyl
ester,
3-(3-{ 4-[(3-hydroxy-phenacetylamino)methyl]-benzylcarbamoyl }-pyridin-2-
yloxy)benzoic
acid ethyl ester, 3-(3-{4-[(4-hydroxy-phenacetylamino)methyl]-benzylcarbamoyl}-
pyridin-
2-yloxy)benzoic acid ethyl ester, compound 2.a
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(2.a) and
compound (2.b)
(2.b),
optionally in the form of the racemates, the enantiomers, the diastereomers
and optionally
5 the pharmacologically acceptable acid addition salts thereof, and the
hydrates thereof.
Pharmaceutically acceptable~salt forms of the combinations of compounds of the
present
invention are prepared for the most part by conventional means. Where the
component
compound contains a carboxylic acid group, a suitable salt thereof may be
formed by
1o reacting the compound with an appropriate base to provide the corresponding
base addition
salt. Examples of such bases are alkali metal hydroxides including potassium
hydroxide,
sodium hydroxide, and lithium hydroxide; alkaline earth metal hydroxides such
as barium
hydroxide and calcium hydroxide; alkali metal alkoxides, e.g., potassium
ethanolate and
sodium propanolate; and various organic bases such as piperidine,
diethanolamine, and N
methylglutamine. Also included are the aluminum salts of the component
compounds of
the present invention.
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For certain component compounds acid addition salts may be formed by treating
said
compounds with pharmaceutically acceptable organic and inorganic acids, e.g.,
hydrohalides such as hydrochloride, hydrobromide, hydroiodide; other mineral
acids and
their corresponding salts such as sulfate, nitrate, phosphate, etc.; and alkyl-
and mono-
arylsulfonates such as ethanesulfonate, toluenesulfonate, and
benzenesulfonate; and other
organic acids and their corresponding salts such as acetate, tartrate,
maleate, succinate,
citrate, benzoate, salicylate, ascorbate, etc.
Accordingly, the pharmaceutically acceptable acid addition salts of the
component
compounds of the present invention include, but are not limited to: acetate,
adipate,
alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate),
bisulfate, bisulfite,
bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride,
chlorobenzoate,
citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate,
dinitrobenzoate,
dodecylsulfate, ethanesulfonate, fumarate, galacterate (from mucic acid),
galacturonate,
glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate,
hemisulfate,
heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-
hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate,
lactobionate, malate,
maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate,
monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate,
oleate,
pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,
phosphonate, phthalate.
Particularly preferred examples of pharmacologically acceptable acid addition
salts of the
compounds 2 according to the invention are the pharmaceutically acceptable
salts which
are selected from among 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
malefic acid. If
desired, mixtures of the abovementioned acids may also be used to prepare the
salts 2.
In the pharmaceutical compositions according to the invention, the compounds 2
may be
present in the form of their racemates, enantiomers or mixtures thereof. The
separation of
the enantiomers from the racemates may be carned out using methods known in
the art
(e.g. by chromatography on chiral phases, etc.).
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In one aspect the present invention relates to the abovementioned
pharmaceutical
compositions which contain, in addition to therapeutically effective
quantities of 1 and 2, a
pharmaceutically acceptable carrier. In another aspect the present invention
relates to the
abovementioned pharmaceutical compositions which do not contain any
pharmaceutically
acceptable carrier in addition to therapeutically effective quantities of 1
and 2.
The present invention also relates to the use of therapeutically effective
quantities of the
salts 1 for preparing a pharmaceutical composition containing PDE IV
inhibitors 2 for
treating inflammatory or obstructive diseases of the respiratory tract.
Preferably, the
present invention relates to the abovementioned use for preparing a
pharmaceutical
to composition for treating asthma or COPD.
Within the scope of the present invention the compounds 1 and 2 may be
administered
simultaneously or successively, while it is preferable according to the
invention to
administer compounds 1 and 2 simultaneously.
The present invention further relates to the use of therapeutically effect
amounts of salts 1
and PDEIV inhibitors 2 for treating inflammatory or obstructive respiratory
complaints,
particularly asthma or COPD.
2o The proportions in which the active substances 1 and 2 may be used in the
active substance
combinations according to the invention are variable. Active substances 1 and
2 may
possibly be present in the form of their solvates or hydrates. Depending on
the choice of
the compounds 1 and 2, the weight ratios which may be used within the scope of
the
present invention vary on the basis of the different molecular weights of the
various salt
forms.
As a rule, the pharmaceutical combinations according to the invention may
contain
compounds 1 and Z in ratios~by weight ranging from 1:100 to 100:1, preferably
from 1:80
to 80:1. In particularly preferred pharmaceutical combinations that contain as
component
2 one of the most preferred compounds ariflo, roflumilast, or AWD-12-281, the
weight
ratios of 1 to 2 are most preferably in a range in which 1' and 2 are present
in proportions
of about 1:50 to 50:1, more preferably from 1:20 to 20:1.
For example, without restricting the scope of the invention thereto, preferred
combinations
of 1' and PDE-IV inhibitor 2 (as for instance ariflo, roflumilast or AWD-12-
281) may
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8
contain in the following weight ratios: 1:65, 1:64, 1:63, 1:62, 1:61, 1:60,
1:59, 1:58, 1:57,
1:56, 1:55, 1:54, 1:53, 1:52, 1:51, 1:50; 1:49; 1:48; 1:47; 1:46; 1:45; 1:44;
1:43; 1:42; 1:41;
1:40; 1:39; 1:38; 1:37; 1:36; 1:35; 1:34; 1:33; 1:32; 1:31; 1:30; 1:29; 1:28;
1:27; 1:26;
1:25; 1:24; 1:23; 1:22; 1:21; 1:20; 1:19; 1:18; 1:17; 1:16; 1:15; 1:14; 1:13;
1:12; 1:11;
1:10; 1:9; 1:8; 1:7; 1:6; 1:5; 1:4; 1:3; 1:2; 1:1; 2:1; 3:1; 4:1; 5:1; 6:1;
7:1; 8:1; 9:1; 10:1;
11:1; 12:1; 13:1; 14:1; 15:1; 16:1; 17:1; 18:1; 19:1; 20:1.
The pharmaceutical compositions according to the invention containing the
combinations
of 1 and 2 are normally administered so that 1 and 2 are present together in
doses of 0.01 to
10000~g, preferably from 0.1 to 5000~,g, more preferably from 1 to 3000~,g,
better still
to from 10 to 2000 ,ug, better still from 20 to 1500~,g, yet more preferred
from 50 to 1200p,g
per single dose. For example, combinations of 1 and 2 according to the
invention contain a
quantity of 1' and PDE-IV inhibitor 2 (as for instance ariflo, roflumilast or
AWD-12-281)
such that the total dosage per single dose is about 100p.g, 105~g, 110~,g,
115~,g, 120~.g,
125~g, 130(~g, 135~.g, 140~,g, 145~,g, 150~,g, 155~,g, 160,ug, 165~,g, 170~,g;
175,ug,
180,ug, 185~,g, 190~.g, 195~,g, 200~,g, 205,ug, 210,ug, 215~,g, 220p,g,
225p,g; °230;ug,
235p,g, 240~.g, 245~,g, 250~,g, 255,ug, 260~Cg, 265~,g, 270,ug,,275~,g,
280~,g; 285~,g, .
290~,g, 295,ug, 300~g, 305~.g, 310~,g, 315,ug, 320~.g, 325~,g, 330,ug, 335~,g;
340,ug,
345~,g, 350,ug, 355,ug, 360~,g, 365,ug, 370~,g, 375,ug, 380~,g, 385,ug,
390,ug, 395,ug,
400,ug, 405~g, 410~.g, 415~,g, 420~Cg, 425,ug, 430;ug, 435~,g, 440~g, 445~,g,
450,ug,
455,ug, 460~,g, 465,ug, 470~,g, 475~,g, 480,ug, 485~.g, 490~,g, 495~,g,
500,ug, 505,ug,
510~,g, 515~,g, 520~Cg, 525,ug, 530~g, 535~g, 540p.g, 545~g, 550~g, 555~,g,
560~,g,
565~g, 570~,g, 575p,g, 580~,g, 585~,g, 590~,g, 595p,g, 600p,g, 605~,g, 610~,g,
615~.g,
620~,g, 625~,g, 630~,g, 635~.g, 640~.g, 645pg, 650~,g, 655~,g, 660p,g, 665~ug,
670~g,
675~g, 680~.g, 685~,g, 690~,g, 695~,g, 700~g, 705p,g, 710~ug, 715~,g, 720~,g,
725~,g,
730~ug, 735~.g, 740~,g, 745~,g, 750~,g, 755pg, 760~g, 765~.g, 770p,g, 775~.g,
780~g,
785~g, 790~g, 795~.g, 800~.g, 805~,g, 810~tg, 815~,g, 820~,g, 825~,g, 830~,g,
835~,g,
840~,g, 845~ug, 850~,g, 855~,g, 860~,g, 865~,g, 870~g, 875~,g, 880~,g, 885~,g,
890~g,
895~,g, 900~,g, 905p,g, 910~g, 915~g, 920~ug, 925~,g, 930~,g, 935~,g, 940~g,
945~,g,
950p,g, 955~,g, 960~ug, 965p,g, 970~g, 975~g, 980~g, 985~,g, 990~,g, 995~,g,
1000~,g,
1005p,g, 1010~,g, 1015~g, 1020~,g, 1025~,g, 1030p,g, 1035p,g, 1040~g, 1045p,g,
1050~,g,
1055~g, 1060~,g, 1065~g, 1070p,g, 1075~g, 1080~,g, 1085~,g, 1090~,g, 1095~.g,
1100~,g,
1105~,g, 1110~g, 1115~,g, 1120~,g, 1125~,g, 1130~,g, 1135~.g, 1140~g, 1145~.g,
1150~Cg,
1155~,g, 1160,ug, 1165,ug, 1170~,g, 1175~,g, 1180~,g, 1185~.g, 1190~,g,
1195~g, 1200~,g,
1205~,g, 1210,ug, 1215~,g, 1220~,g, 1225~,g, 1230,ug, 1235,ug, 1240~,g,
1245~,g, 1250,ug,
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9
1255;ug, 1260~.g, 1265~Cg, 1270~,g, 1275,ug, 1280,ug, 1285~Cg, 1290~,g,
1295,ug, 1300,ug,
1305~Cg, 1310~.g, 1315,ug, 1320~,g, 1325,~g, 1330~,g, 1335~,g, 1340~,g,
1345~,g, 1350,ug,
1355,ug, 1360,ug, 1365~,g, 1370~,g, 1375~g, 1380~,g, 1385;ug, 1390~,g,
1395,ug, 1400;ug,
1405~tg, 1410,ug, 1415,~g, 1420~,g, 1425~g, 1430~,g, 1435,ug, 1440~,g,
1445,ug, 1450~,g,
1455~,g, 1460~,g, 1465~,g, 1470~Cg, 1475,ug, 1480~Cg, 1485~,g, 1490~Cg,
1495;ug, 1500~,g,
1505~Cg, 1510,ug, 1515~,g, 1520~Cg, 1525~,g, 1530~,g, 1535~,g, 1540p,g,
1545~,g, 1550~,g,
1555~,g, 1560~.g, 1565~.g, 1570~,g, 1575~g, 1580~.g, 1585p,g, 1590~,g,
1595~.g, 1600~,g,
1605~,g, 1610~,g, 1615~g, 1620~,g, 1625~ug, 1630~,g, 1635~ug, 1640~,g,
1645~,g, 1650~,g,
1655~,g, 1660~,g, 1665~,g, 1670p,g, 1675~.g, 1680~,g, 1685~.g, 1690~,g,
1695~ug, 1700~,g,
1705~,g, 1710~,g, 1715~,g, 1720~,g, 1725~.g, 1730~g, 1735~g, 1740~,g, 1745~,g,
1750~,g,
1755~,g, 1760~,g, 1765~g, 1770~.g, 1775~,g, 1780~.g, 1785~,g, 1790~,g,
1795~ug, 1800~.g,
1805~,g, 1810~,g, 1815~.g, 1820~,g, 1825~,g, 1830~,g, 1835~,g,1840~,g,
1845~,g, 1850~,g,
1855~,g, 1860p,g, 1865~,g, 1870~g, 1875~ug, 1880~g, 1885~.g, 1890~g, 1895~,g,
1900~,g,
1905~,g, 1910~,g, 1915~g, 1920~,g, 1925~,g, 1930,ug, 1935p,g, 1940~,g,
1945~,g, 1950p,g,
1955p,g, 1960~,g, 1965~,g, 1970~,g, 1975~,g, 1980~,g, 1985~,g, 1990~g,
1995~.g, 2000~,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
2o the values given above by way of example. In these dosage ranges, the
active substances 1'
and 2 may be present in the weight ratios given above.
For example, without restricting the scope of the invention thereto, the
combinations of 1
and 2 according to the invention may contain a quantity of 1' and PDE-IV
inhibitor 2 (as
for instance ariflo,~roflumilast or AWD-12-281) such that, for each single
dose, 16.5~.g of
1' and 25,ug of 2, 16.5~.g of_ 1' and 50~,g of 2, 16.5;ug of 1' and 100,ug of
2, 16.5,ug of
1' and 200,ug of 2, 16.5~,g of 1' and 300,ug of 2, 16.5~,g of 1' and 400~,g of
2, 16.5~Cg of
1' and 500~,g of 2, 16.5~.g of 1' and 600~,g of 2, 16.5~,g of 1' and 700~g of
2, 16.5,ug of
1' and 800~,g of 2, 16.5~g of 1' and 900,ug of 2, 16.5~,g of 1' and 1000,ug of
2, 16.5~,g
of 1' and 1250~,g of 2, 16.5~Cg of 1' and 1500~,g of 2, 16.5~.g of 1' and
1750~,g of 2,
16.5,ug of 1' and 2000~,g of 2, 33.O,ug of 1' and 25~.g of 2, 33.O~,g of 1'
and 50~.g of 2,
33.O~.g of 1' and 100,ug of 2, 33.O,ug of 1' and 200,ug of 2, 33.O~Cg of 1'
and 300~Cg of
2, 33.O,ug of 1' and 400~g of 2, 33.O~,g of 1' and 500~,g of 2, 33.O,ug of 1'
and 600~g of
2, 33.O~,g of 1' and 700~,g of 2, 33.O~.g of 1' and 800~,g of 2, 33.O~Cg of 1'
and 900~.g of
2, 33.O~.g of 1' and 1000~g of 2, 33.O,ug of 1' and 1250,ug of 2, 33.O,ug of
1' and
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1500~,g of 2, 33.O~,g of 1' and 1750~,g of 2, 33.O~g of 1' and 2000~,g of 2,
49.5,ug of 1'
and 25~.g of Z, 49.5,ug of 1' and 50,ug of 2, 49.5,ug of 1' and 100;ug of 2,
49.5,ug of 1'
and 200~,g of 2, 49.5~,g of 1' and 300~g of 2, 49.5,ug of 1' and 400~,g of 2,
49.5~,g of
1' and 500,ug of 2, 49.5~.g of 1' and 600~,g of 2, 49.5,ug of 1' and 700,ug of
2, 49.5~.g of
5 1' and 800;ug of 2, 49.5~,g of 1' arid 900,ug of 2, 49.5~,g of 1' and
1000~,g of 2, 49.5,ug
of 1' and 1250~g of 2, 49.5~,g of 1' and 1500;ug of 2, 49.5,ug of 1' and
1750,ug of 2,
49.5~,g of 1' and 2000,ug of 2, 82.5~,g of 1' and 25,ug of 2, 82.5~.g of 1'
and 50,ug of 2,
82.5~,g of 1' and 100p,g of 2, 82.5~g of 1' and 200~Cg of 2, 82.5~,g of 1' and
300,ug of
2, 82.5~,g of 1' and 400~,g of 2, 82.5~,g of 1' and 500,ug of 2, 82.5~,g of 1'
and 600,ug of
l0 2, 82.5,ug of 1' and 700,ug of 2, 82.5~g of 1' and 800~g of 2, 82.5~Cg of
1' and 900~,g of
2, 82.5~.g of 1' and 1000~,g of 2, 82.5,ug of 1' and 1250~,g of 2, 82.5~,g of
1' and
1500,ug of 2, 82.5,ug of 1' and 1750~,g of 2, 82.5,ug of 1' and 2000~,g of 2,
165.O,ug of
1' and 25~.g of 2, 165.O~,g of 1' and 50~Cg of 2, 165.O~.g of 1' and 100~Cg of
2, 165.O~,g
of 1' and 200~g of 2, 165.O,ug of 1' and 300~,g of 2, 165.O~,g of 1' and
400~.g of 2,
165.O~,g of 1' and 500~,g of 2, 165.O~g of 1' and 600~,g of 2, 165.O,ug of 1'
and 700,ug
of 2, 165.O~,g of 1' and 800,ug of 2, 165.O,ug of 1' and 900,ug of 2, 165.O~,g
of 1' and
1000~,g of 2, 165.O~,g of 1' and 1250~,g of 2, 165.O~,g of 1', and 1500,ug of
2, 165.O~,g
of 1' and 1750,ug of 2, 165.O~,g of 1' and 2000,ug of 2, 206.2,ug of 1' and
25~,g of 2,
206.2~g of 1' and 50~Cg of 2, 206.2~,g of 1' and 100~,g of 2, 206.2,ug of 1'
and 200,ug of
2, 206.2,ug of 1' and 300~,g of 2, 206.2~Cg of 1' and 400~g of Z, 206.2,ug of
1' and
500~,g of 2 or 206.2,ug of 1' and 600~,g of 2, 206.2~,g of 1' and 700~,g of 2,
206.2~.g of
1' and 800~,g of 2, 206.2,ug of 1' and 900~,g of 2, 206.2,ug of 1' and 1000;ug
of 2,
206.2~,g of 1' and 1250,ug of 2, 206.2~,g of 1' and 1500,ug of 2, 206.2,ug of
1' and
1750,ug of 2, 206.2~,g of 1' and 2000~,g of 2, 412.5~,g of 1' and 25~,g of 2,
412.5~,g of
1' and 50,ug of 2, 412.5,ug of 1' and 100,ug of 2, 412.5~tg of 1' and 200~,g
of 2, 412.5~,g
of 1' and 300~,g of 2, 412.5,ug of 1' and 400~,g of 2, 412.5~.g of 1' and
500~Cg of 2 or
412.5~,g of 1' and 600,ug of 2, 412.5~Cg of 1' and 700,ug of 2, 412.5,ug of 1'
and 800,ug
of 2, 412.5,ug of 1' and 900;ug of 2, 412.5~,g of 1' and 1000,ug of 2, 412.5~g
of 1' and
1250~,g of 2, 412.5~,g of 1' and 1500;ug of 2 , 412.5,ug of 1' and 1750~,g of
2, 412.5,ug
of 1' and 2000~,g of Z are administered.
If the active substance combination in which 1 denotes the bromide is used as
the preferred
combination of 1 and 2 according to the invention, the quantities of active
substance 1' and
2 administered per single dose mentioned before by way of example correspond
to the
following quantities of 1 and 2 administered per single dose: 20~,g of 1 and
25~,g of 2,
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11
20,ug of 1 and 50~,g of 2, 20~Cg of 1 and 100~,g of 2, 20,ug of 1 and 200~,g
of 2, 20~g of 1
and 300~,g of 2, 20~,g of 1 and 400,ug of 2, 20,ug of 1 and 500~,g of 2, 20~.g
of 1 and 600~,g
of 2, 20,ug of 1 and 700~,g of 2, 20~g of 1 and 800~,g of 2, 20,ug of 1 and
900~,g of 2, 20~,g
of 1 and 1000~Cg of 2, 20~,g of 1 and 1250~,g of 2, 20~,g of 1 and 1500~,g of
2, 20,ug of 1
and 1750,ug of 2, 20~g of 1 and 2000~,g of 2, 40~.g of 1 and 25~,g of 2, 40~,g
of 1 and 50~,g
of 2, 40;ug of 1 and 100~.g of 2, 40~.g of 1 and 200~,g of 2, 40,ug of 1 and
300,ug of 2, 40~,g
of 1 and 400,ug of 2, 40~,g of 1 and 500~,g of 2, 40~,g of 1 and 600,ug of 2,
40~,g of 1 and
700~g of 2, 40~,g of 1 and 800~Cg of 2, 40~.g of 1 and 900,ug of 2, 40~,g of 1
and 1000~,g of
2, 40~,g of 1 and 1250~,g of 2, 40~,g of 1 and 1500~,g of 2, 40,ug of 1 and
1750~,g of 2,
l0 40~,g of 1 and 2000~,g of 2, 60~,g of 1 and 25~,g of 2, 60,ug of 1 and
50~,g of 2, 60~,g of 1
and 100~,g of 2, 60~,g of 1 and 200,ug of 2, 60,ug of 1 and 300~,g of 2, 60~g
of l and 400~,g
of 2, 60~.g of 1 and 500~,g of 2, 60,ug of 1 and 600~Zg of 2, 60,ug of 1 and
700~,g of 2, 60~,g
of 1 and 800~,g of 2, 60,ug of 1 and 900,ug of 2, 60~,g of 1 and 1000~,g of 2,
60,ug of 1 and
1250,ug of 2, 60,ug of 1 and 1500~g of 2, 60,ug of 1 and 1750~,g of 2; 60,ug
of 1 and
2000~.g of 2, 100~,g of 1 and 25,ug of 2, 100~,g of 1 and 50~,g of 2, 100,ug
of 1 and 100,ug
of 2, 100~,g of 1 and 200,ug of 2, 100,ug of 1 and 30'O~Cg of 2, 100,~g of 1
and 400~Cg of 2,
100~Cg of 1 and 500~.g of 2, 100,ug of 1 and 600,ug of 2, 100~,g of 1 and
700~,g of 2, 100,ug
of 1 and 800~,g of 2, 100,ug of 1 and 900,ug of 2, 100~,g of 1 and 1000,ug of
2, 100~,g of 1
and 1250,ug of 2, 100,ug of 1 and 1500,ug of 2, 100,ug of 1 and 1750~,g of 2,
100,ug of 1
2o and 2000,ug of 2, 200~,g of 1 and 25~,g of 2, 200,ug of 1 and 50~.g of 2,
200,ug of 1 and
100~,g of 2, 200~.g of 1 and 200,ug of 2, 200~,g of 1 and 300;ug of 2, ZOO,ug
of 1 and 400,ug
of 2, 200~,g of 1 and 500~,g of 2, 200~,g of 1 and 600,ug of 2, 200~,g of 1
and 700~,g of 2,
200~,g of 1 and 800,ug of 2, 200,ug of 1 and 900~,g of 2, 200~,g of 1 and
1000~g of 2,
200~,g of 1 and 1250,~g of 2, 200~,g of 1 and 1500,ug of 2, 200~,g of 1 and
1750,ug of 2,
200~,g of 1 and 2000,ug of 2, 250~,g of 1 and 25~Cg of 2, 250,ug of 1 and
50~,g of 2, 250~,g
of 1 and 100,ug of 2, 250~g of 1 and 200~Cg of 2, 250~g of 1 and 300~,g of 2,
250,ug of 1
and 400~,g of 2, 250,ug of 1 and 500~,g of 2, 250~,g of 1 and 600,ug of 2,
250~,g of 1 and
700,ug of 2, 250,ug of 1 and 800~,g of 2, 250~g of 1 and 900~,g of 2, 250~,g
of 1 and
1000~.g of 2, 250~,g of 1 and 1250,ug of 2, 250~.g of 1 and 1500,ug of 2,
250~,g of 1 and
1750,ug of 2, 250~,g of 1 and 2000,ug of 2, 500,ug of 1 and 25~,g of 2, 500,ug
of 1 and 50,ug
of 2, 500~,g of 1 and 100,ug of 2, 500,ug of 1 and 200~,g of 2, 500,ug of 1
and 300~.g of 2,
500,ug of 1 and 400,ug of 2, 500,ug of 1 and 500,ug of 2, 500~,g of 1 and
600~,g of 2, 500~,g
of 1 and 700~g of 2, 500,ug of 1 and 800~,g of 2, 500,ug of 1 and 900~,g of 2
or 500~.g of 1
and 1000~,g of 2, 500~,g of 1 and 1250,ug of 2, 500~,g of 1 and 1500~,g of 2,
500~,g of 1
and 1750~,g of 2 or 500,ug of 1 and 2000~g of 2.
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12
The aforementioned examples of possible doses applicable for the combinations
according
to the invention are to be understood as referring to doses per single
application. However,
these examples are not be understood as excluding the possibility of
administering the
combinations according to the invention multiple times. Depending on the
medical need
patients may receive also multiple inhalative applications. As an example
patients may
receive the combinations according to the invention for instance two or three
times (e.g.
two or three puffs with a powder inhaler, an MDI etc) in the morning of each
treatment
day. As the aforementioned dose examples are only to be understood as dose
examples per
single application (i.e. per puff) multiple application of the combinations
according to the
invention leads to multiple doses of the aforementioned examples. The
application of the
combositions according to the invention can be for instance once a day, or
depending on
the duration of action of the anticholinergic agent twice a day, or once every
2 or 3 days.
Moreover it is emphazised that the aforementioned dose examples are to be
understood as
examples of metered doses only. In other terms, the aforementioned dose
examples are not
to be understood as the effective doses of the combinations according to the
invention that
do in fact reach the lung. It is clear for the person of ordinary skill in the
art that the
delivered dose to the lung is generally lower than the metered dose of the
administered
active ingredients.
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 according
to the
invention include rnhalable powders, propellant-containing metered dose
aerosols or
propellant-free inhalable solutions. Inhalable powders according to the
invention
containing the combination of active substances 1 and 2 may consist of the
active
substances on their own or of a mixture of the active substances with
physiologically
acceptable excipients. Within the scope of the present invention, the term
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 and 2 either together in one formulation or
in two
separate formulations. These formulations which may be used within the scope
of the
present invention are described in more detail in the next part of the
specification.
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WO 2005/013967 PCT/EP2004/008003
13
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: rnonosaccharides (e.g.
glucose or
arabinose), disaccharides (e.g. lactose, saccharose, maltose, trehalose),
oligo- and
polysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol,
xylitol),
cyclodextrines (e.g. oc-cyclodextrine, (3-cyclodextrine, x-cyclodextrine,
methyl-(3-
cyclodextrine, hydroxypropyl-(3-cyclodextrine), 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, trehalose or glucose is
preferred,
particularly, but not exclusively, in the form of their hydrates.
Within the scope of the inhalable powders according to the invention the
excipients have a
maximum average particle size of up to 250,um, preferably between 10 and
150,um, most
preferably between 15 and 80,um. 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 active substance 1 and 2, preferably with an average particle size
of 0.5 to
10~,m, more preferably from 1 to 6~um, is added to the excipient mixture.
Processes for
producing the inha~lable 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 one
or more physiologically acceptable excipients 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
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14
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.
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, as well as airholes 13 for adjusting the flow
resistance.
If the inhalable powders according to the invention are packed into capsules
(inhalers) for
the preferred use described above, the quantities packed into each capsule
should be 1 to
30mg per capsule. These capsules contain, according to the invention, either
together or
separately, the doses of 1 or 1' and 2 mentioned hereinbefore for each single
dose.
B) Propellant gas-driven inhalation aerosols containing the combinations of
active
substances 1 and 2:
Inhalation aerosols containing propellant gas according to the invention may
contain
substances 1 and 2 dissolved in the propellant gas or in dispersed form. 1 and
2 may be
present in separate formulations or in a single preparation, in which 1 and 2
are either both
dissolved, both dispersed or only one component is dissolved and the other is
dispersed.
3o 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
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
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WO 2005/013967 PCT/EP2004/008003
TG11, TG12, TG134a (1,1,1,2-tetrafluoroethane) and TG227 (1,1,1,2,3,3,3-
heptafluoropropane) and mixtures thereof, of which the propellant gases
TG134a, TG227
and mixtures thereof are preferred.
5 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
l0 up to 5 wt.-% of active substance 1 and/or 2. Aerosols according to the
invention contain,
for example, 0.002 to 5 wt.-%, 0.01 to 3 wt.-%, 0.015 to 2 wt.-%, 0.1 to 2 wt.-
%, 0.5 to
2 wt.-% or 0.5 to 1 wt.-% of active substance 1 and/or 2.
If the active substances 1 andlor 2 are present in dispersed form, the
particles of active
15 substance preferably have an average particle size of up to 10~,m,
preferably from 0.1 to
6~.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 (1VIDIs = 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 fitted with a suitable valve which 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 invention:
Propellant-free inhalable solutions and suspensions according to the invention
contain, for
example, aqueous or alcoholic, preferably ethanolic solvents, optionally
ethanolic solvents
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16
mixed with aqueous solvents. If aqueous/ethanolic solvent mixtures are used
the relative
proportion of ethanol compared with water is not limited but preferably the
maximum is up
to 70 percent by volume, more particularly up to 60 percent by volume of
ethanol. The
remainder of the volume is made up of water. The solutions or suspensions
containing 1
and 2, separately or together, are adjusted to a pH of 2 to 7, preferably 2 to
5, using
suitable acids. The pH may be adjusted using acids selected from inorganic or
organic
acids. Examples of particularly suitable inorganic acids include hydrochloric
acid,
hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples
of
particularly suitable organic acids include ascorbic acid, citric acid, malic
acid, tartaric
to acid, malefic acid, succinic acid, fumaric acid, acetic acid, formic acid
and/or propionic acid
etc. Preferred inorganic acids are hydrochloric and sulphuric acids. It is
also possible to
use the acids which have already formed an acid addition salt with one of the
active
substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid
are preferred.
If desired, mixtures of the above acids may be used, particularly in the case
of acids which
have other properties in addition to their acidifying qualities, e.g. as
flavourings,
antioxidants or complexing agents, such as citric acid or ascorbic acid, for
example.
According to the invention, it is particularly preferred to use hydrochloric
acid to adjust the
pH.
2o 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/100m1,
preferably less than 50mg/100 ml, more preferably less than 20mg/100 rnl.
Generally,
inhalable solutions in which the content of sodium editate is from 0 to
lOmgll00ml are
preferred.
Co-solvents and/or other excipients rnay 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
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17
active substance formulation. Preferably, these substances have no
pharmacological effect
or, in connection with the desired therapy, no appreciable or at least no
undesirable
pharmacological effect. The excipients and additives include, for example,
surfactants
such as Soya lecithin, oleic acid, sorbitan esters, such as polysorbates,
polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants
andlor
preservatives which guarantee or prolong the shelf life of the finished
pharmaceutical
formulation, flavourings, vitamins and/or other additives known in the art.
The additives
also include pharmacologically acceptable salts such as sodium chloride as
isotonic agents.
The preferred excipients include antioxidants such as ascorbic acid, for
example, provided
to 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/100m1, more preferably
between 5 and
20mg/100m1.
2o 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.
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 20 and 30E.~L of active substance solution can be nebulised
in
3o 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
CA 02533786 2006-O1-26
WO 2005/013967 PCT/EP2004/008003
18
Application WO 91/14468 and also in WO 97/12687 (cf. in particular Figures 6a
and 6b).
The nebulisers (devices) described therein are known by the name Respimat~.
This nebuliser (Respimat~) can advantageously be used to produce the inhalable
aerosols
according to the invention containing the combination of active substances 1
and 2.
Because of its cylindrical shape and handy size of less than 9 to 15 cm long
and 2 to 4 cm
wide, this device can be carried at all times by the patient. The nebuliser
sprays a defined
volume of pharmaceutical formulation using high pressures through small
nozzles so as to
produce inhalable aerosols.
The preferred atomiser essentially consists of an upper housing part, a pump
housing, a
nozzle, a locking mechanism, a spring housing, a spring and a storage
container,
characterised by
- 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
3o 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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19
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.
In the case of a plurality of nozzle openings, preferably two, the directions
of spraying of
the nozzles in the nozzle body may extend parallel to one another or may be
inclined
relative to one another in the direction of the nozzle opening. In a nozzle
body with at
least two nozzle openings at the outlet end the directions of spraying may be
at an angle of
20 to 160° to one another, preferably 60 to 150°, most
preferably 80 to 100°. The nozzle
openings are preferably arranged at a spacing of 10 to 200 microns, more
preferably at a
spacing of 10 to 100 microns, most preferably 30 to 70 microns. Spacings of 50
microns
are most preferred. The directions of spraying will therefore meet in the
vicinity of the
nozzle openings.
The liquid pharmaceutical preparation strikes the nozzle body with an entry
pressure of up
to 600 bar, preferably 200 to 300 bar, and is atomised into an inhalable
aerosol through the
nozzle openings. The preferred particle or droplet sizes of the aerosol are up
to 20
microns, preferably 3 to 10 microns.
The locking mechanism contains a spring, preferably a cylindrical helical
compression
spring, as a store fox the mechanical energy. The spring acts on the power
takeoff flange
as an actuating member the movement bf 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
3o 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.
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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
1o mechanism are given in WO 97/20590.
The lower housing part is pushed axially over the spring housing and covers
the mounting,
the drive of the spindle and the storage container for the fluid.
When the atomiser is actuated the upper housing part is rotated relative to
the lower
15 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
20 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
3o 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
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21
preferably made of plastics, e.g. by injection moulding. For medicinal
purposes,
physiologically safe materials are used.
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 6a of WO 97/12687 shows a longitudinal section through the atomiser
with the
spring biased while Figure 6b of WO 97/12687 shows a longitudinal section
through the
atomiser with the spring relaxed.
The upper housing part (51) contains the pump housing (52) on the end of which
is
mounted the holder (53) for the atomiser nozzle. In the holder is the nozzle
body (54) and
a filter (55). The hollow plunger (57) fixed in the power takeoff flange (56)
of the locking
mechanism projects partially into the cylinder of the pump housing. At its end
the hollow
plunger carries the valve body ~(58). The hollow plunger is sealed off by
means of the seal
(59). Inside the upper housing part is the stop (60) on which the power
takeoff flange
abuts when the spring is relaxed: On the power takeoff flange is the stop (61)
on which the
power takeoff flange abuts when the spring is biased. After the biasing of the
spring the
locking member (62) moves between the stop (61) and a support (63) in the
upper housing
part. The actuating button (64) is connected to the locking member. The upper
housing
part ends in the mouthpiece (65) and is sealed off by means of the protective
cover (66)
2o 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
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22
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 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
2o 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 00123037. 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
RespimatQ.
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
3o administered using energy-operated free-standing 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
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23
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.
First, the preparation of compounds 1 which are not known in the art will be
described.
1) Preuaration of the compounds of formula 1 (in form of the bromide saltO
1.1.: 9-methyl-fluorene-9-carboxylic acid:
a) methyl 9-methyl-fluorene-9-carboxylate:
From 7.6 g (0.33 mol) of sodium and 300 ml of ethanol a sodium ethoxide
solution is
prepared, to which 69.6 g (0.33 mol) of 9-fluorenecarboxylic acid are added
batchwise.
After the addition has ended the mixture is stirred for 2.5 hours at ambient
temperature.
Then it is evaporated to dryness, the residue is suspended in 600 ml of
dimethylformamide
and 93.96 g (0.662 mol) of methyl iodide are added dropwise. The mixture is
stirred for 3
hours at constant temperature. The cloudy solution is stirred into 500 ml of
water and 300
ml of diethyl ether with cooling and extracted, the organic phase is washed
with water and
10% sodium carbonate solution, dried and evaporated to dryness. The residue is
purified
by column chromatography, eluant: cyclohexane / ethyl acetate 96:4.
Yield: 12.61 g of white crystals (= 16% of theoretical); melting point:
108°-109°C.
b) 9-methyl-fluorene-9-carboxylic acid:
12.6 g (0.053 mol) of methyl 9-methyl-fluorene-9-carboxylate and 53 ml of 2
molar,
aqueous sodium hydroxide solution are stirred in 120 ml of 1,4-dioxane for 24
hours at
ambient temperature. The dioxane is distilled off, made up to a total volume
of 300 ml with
water and extracted with diethyl ether. The aqueous phase is acidified with 3
molar,
aqueous HCl, crystallised and filtered.
Yield: 11.25 g of white crystals (= 95% of theoretical); melting point:
168°-169°C.
1.2: tropenol 9-methyl-fluorene-9-carbox,1
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24
6.73 g (0.03 mol) of 9-methyl-fluorene-9-carboxylic acid are suspended in 60
ml
dichloromethane, combined with 5.0 g of oxalyl chloride and 1 drop of
dimethylformamide, then stirred for one hour at ambient temperature and
finally the
solvent is distilled off. The acid chloride remaining is used in the next step
without any
further purification. 4.18 g (0.03 mol) of tropenol and 4.27 g (0.033 mol) of
diisopropylethylamine are suspended in 100 ml of dichloroethane, the acid
chloride is
added dropwise to 30 ml of dichloroethane at 35-40°C and then stirred
for 24 hours at 40°
C. The suspension is diluted with dichloromethane and extracted with dilute
hydrochloric
acid. The organic phase is then washed with water, dried over MgSO~. and the
product is
l0 converted into its hydrochloride with a solution of HCl in diethyl ether.
The solvent is
then removed. To purify it the precipitated hydrochloride is taken up in water
and extracted
with diethyl ether. The aqueous phase is made basic with 10% aq. sodium
carbonate
solution and extracted with dichloromethane. The organic phase is dried over
MgS04 and
the solvent is distilled off.
Yield: 4.40 g of yellow oil (= 42% of theoretical);
1.3: scopine 9-methyl-fluorene-9-carbox ly ate:
2.5 g (0.007 mol) of tropenol 9-methyl-fluorene-9-carboxylate are suspended in
about 25
ml of dimethylformamide and combined with 0.13 g (0.001 mol) of vanadium-(V)-
oxide.
At 60°C a solution of 1.43 g (0.015 mol) of H202-urea in about 5.5 ml
of water is added
dropwise and stirred for 6 hours at 60°C. After cooling to 20°C
the precipitate formed is
suction filtered, the filtrate is adjusted to pH 2 with 4 N hydrochloric acid
and combined
with Na2S2O5 dissolved in water. The resulting solution is evaporated to
dryness, the
residue is extracted with dichloromethane/water. The acidic aqueous phase is
made basic
with Na2CO3, extracted with dichloromethane and the organic phase is dried
over Na2S04
and concentrated. Then about 0.4 ml of acetylchloride is added at ambient
temperature and
the mixture is stirred for 1 hour. After extraction with 1 N hydrochloric acid
the aqueous
phase is made basic, extracted with dichloromethane, the organic phase is
washed with
water and dried over Na2S04. Then the solvent is removed by distillation. The
crude
3o product is purified by recrystallisation from diethyl ether.
Yield: 1.8 g of white crystals (= 71 % of theoretical).
1.4. scopine 9-methyl-fluorene-9-carboxylate methobromide
1.8 g (0.005 mol) of scopine 9-methyl-fluorene-9-carboxylate are taken up in
30 ml
acetonitrile and reacted with 2.848 g (0.015 mol) of 50% methyl bromide
solution in
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WO 2005/013967 PCT/EP2004/008003
acetonitrile. The reaction mixture is left to stand fox 3 days at ambient
temperature, during
which time the product crystallises. The crystals precipitated are separated
off and
recrystallised from diethyl ether to purify them.
Yield: 1.6 g of white crystals (= 70 °Io of theoretical); melting
point: 214°C.
5 Elemental analysis:
calculated: C (62.13) H (5.93) N (4.26)
found: C (62.23) H (6.05) N (4.32).
2) Examples of Formulations
to The following examples of formulations, which may be obtained analogously
to methods
known in the art, serve to illustrate the present invention more fully without
restricting it to
the contents of these examples.
Inhalable powders:
1)
2)
3)
In redients ~ er ca sule
1'-bromide 80
AWD-12-281 200
Lactose 12220
Total 12500
In redients ~, er ca sule
~ 1'-bromide ~ 30
AWI~-12-281 100
Lactose 12370
Total 12500
In redients ~g per capsule
1'-bromide 80
ariflo 100
Lactose 12320 '
Total 12500
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26
4)
5)
6)
7)
l0 8)
In redients er ca sule
1'-bromide 100
ariflo 200
Lactose 24700
Total . 25000
In redients ,ug per capsule
1'-bromide g0
roflumilast 100
Lactose 12320
Total 12500
In redients er ca sule -
1'-bromide 100
roflumilast 200
Lactose 24700
Total ~ 25000
-In redients ~u er capsule
1'-bromide g0
Z-15370 100
Lactose 12320
Total 12500
In redients er ca sine
1'-bromide 100
Z-15370 200
Lactose 24700
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27
9)
10)
11)
12)
Total 25000
In redients ~ er ca rule
1'-bromide 250
AWD-12-281 2000
Lactose 12750
Total 15000
In redients her capsule
1'-bromide 80
compound 2.a 100
Lactose 12320
Total 12500
In redients ~u er ca sule
1'-bromide 100
com ound 2.b 200
Lactose 24700
Total 25000
In redients er ca sule
1'-bromide 250
compound-2.a 2000
Lactose 12750
Total 15000
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28
13)
In redients er ca sule
1'-bromide g0
100
Lactose 12320
Total 12500
*~
2
=
each
of
the
following
compounds:
2-(4-fluoro-phenoxy)-N-{4-[(2hydroxy-3-methyl-benzoyl amino)-methyl]-benzyl}
-nicotinamide, 3-(3-{4-[(3-Hydroxy-benzoylamino)-methyl]-benzyl carbamoyl}
pyridin-2-yloxy)- benzoic acid ethyl ester, 2-(4-fluoro-phenoxy)-N-{4-[(6-
fluoro-2-
hydroxy-benzoylamino)-methyl]-benzyl} nicotinamide, 2-(4-fluoro-phenoxy)-N-{4-
[(5-fluoro-2-hydroxy-benzoylamino)-methyl]-benzyl } nicotinamide, 2-(4-fluoro-
phenoxy)-N-{4-[(3-hydroxy-4-methyl-benzoylamino)methyl]benzyl} nicotinamide,
2-(4-fluoro-phenoxy)-N-{ 4-[(3hydroxy-benzoylamino)-methyl]-benzyl }
l0 nicotinamide, 2-(4-fIuoro-phenoxy)-N-{4-[(2-hydroxy-benzoylamino)methyl]-
benzyl} nicotinamide, 2-(4-fluoro-phenoxy)-N-{4-[(4-hydroxy-
benzoylamino)methyl]-benzyl} nicotinamide, 2-(4-fIuoro-phenoxy)-N-{4-[(2-
hydroxy-4-methyl-benzoylamino)methyl]-benzyl} nicotinamide, 2-(4-fIuoro-
phenoxy)-N-{4-[(3-hydroxy-2-methyl-benzoylamino)methyl]-benzyl} nicotinamide,
2-(4-fIuoro-phenoxy)-N-{4-[(2-hydroxy-5-methyl-benzoylamino)methyl]-benzyl}
nicotinamide, 5-fluoro-2-(4-fIuoro-phenoxy)-N-{4-[(2-hydroxy-
benzoylamino)methyl]-benzyl} nicotinamide, 5-fluoro-2-(4-fluoro-phenoxy)-N-{4-
[(2-hydroxy-acetylamino)methyl]-benzyl } nicotinamide, 5-fluoro-2-(4-fIuoro-
phenoxy)-N-{4-[(4-hydroxy-benzoylamino)methyl]-benzyl} nicotinamide, 3-(3-{4-
[(3-hydroxy-benzoylamino)methyl]-benzylcarbamoyl}-pyridin-2-yloxy)benzoic acid
ethyl ester, 3-(3-{4-[(2-hydroxy-phenacetylamino)methyl]-benzylcarbamoyl}-
pyridin-2-yloxy)benzoic acid ethyl ester, 3-(3-{4-[(3-hydroxy-
phenacetylamino)methyl]-benzylcarliamoyl}-pyridin-2-yloxy)benzoic acid ethyl
ester, and 3-(3-{4-[(4-hydroxy-phenacetylamino)methyl]-benzylcarbamoyl}-
pyridin-
2-yloxy)benzoic acid ethyl ester, compound 2.a
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29
(2.a) and
compound (2.b)
(2.b)
optionally in the form of the racemates, the enantiomers, the diastereomers
arid
optionally the pharmacologically acceptable acid addition salts thereof, and
the hydrates
thereof.
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B Propellant-containing inhalable aerosols:
1) Suspension aerosol:
In redients % b wei ht
1'-bromide 0.010
AWD-12-2~ 1 0.060
So a lecithin 0.2
TG 134a : TG 227 = 2:3 ~ ad 100
2) Suspension aerosol:
In redients % b wei ht
1'-bromide 0.010
ariflo 0.035
TG 134a ad 100
3) Suspension aerosol:
to
In redients 7o b wei ht
1'-bromide 0.010
Z-15370 0.035
TG 134a ad 100
