Note: Descriptions are shown in the official language in which they were submitted.
CA 02544352 2012-01-20
- 25771-1177
1
CRYSTALLINE ANHYDRATE WITH ANTICHOLINERGIC
EFFECT
The invention relates to a new crystalline anhydrate of tiotropium bromide,
processes for preparing it and its use for preparing a pharmaceutical
composition for
the treatment of respiratory complaints, particularly for the treatment of
COPD
(chronic obstructive pulmonary disease) and asthma.
Background to the invention
Tiotropium bromide is known from European Patent Application EP 418 716 Al
and has the following chemical structure:
HG +,CH
3 '1\1 3
0 Br-
HO
S S
Tiotropium bromide is a highly effective anticholinergic with a long-lasting
effect,
which may be used to treat respiratory complaints, particularly COPD (chronic
obstructive pulmonary disease) and asthma. By tiotropium is meant the free
ammonium cation.
Tiotropium bromide is preferably administered by inhalation. Suitable
inhalable
powders packed into appropriate capsules (inhalettes) may be used.
Alternatively, it
may be administered by the use of suitable inhalable aerosols. These also
include
powdered inhalable aerosols which contain, for example, HFA134a, HFA227 or
mixtures thereof as propellent gas.
The correct manufacture of the abovementioned compositions which are suitable
for use for the administration of a pharmaceutically active substance by
inhalation is
based on various parameters which are connected with the nature of the active
CA 02544352 2012-01-20
= 25771-1177
2
substance itself. In pharmaceutical compositions which are used like
tiotropium
bromide in the form of inhalable powders or inhalable aerosols, the
crystalline active
substance is used in ground (micronised) form for preparing the formulation.
Since
the pharmaceutical quality of a pharmaceutical formulation requires that the
active
substance should always have the same crystalline modification, the stability
and
properties of the crystalline active substance are subject to stringent
requirements
from this point of view as well. It is particularly desirable that the active
substance
should be prepared in the form of a uniform and clearly defined crystalline
modification. It is also particularly desirable that the active substance be
prepared in
a crystalline form which is characterised by a high degree of stability even
over long
storage periods. The lower the tendency of a crystalline modification to
absorb
moisture, for example, the greater the physical stability of its crystal
structure.
The aim of the invention is therefore to provide a new stable crystal form of
the
compound tiotropium bromide which meets the high demands mentioned above that
are made of any pharmaceutically active substance. The present invention sets
out
in particular to provide a crystalline modification of tiotropium bromide
which has only
limited hygroscopic characteristics.
Brief Description of the Drawings
Figure 1: X-ray powder diagram of anhydrous crystalline tiotropium
bromide.
Figure 2: Diagram of an inhaler for use in an invention embodiment.
Detailed description of the invention
It has been found that, depending on the choice of the conditions which may be
used
during the purification of the crude product obtained after industrial
production,
tiotropium bromide may be obtained in different crystalline modifications.
CA 02544352 2012-01-20
= 25771-1177
2a
It has been found that these different modifications can be decisively
obtained by the
choice of solvents used for the crystallisation and by the choice of the
operating
conditions selected during the crystallisation process.
It has surprisingly been found that, starting from the monohydrate of
tiotropium
bromide, which can be obtained in crystalline form by choosing specific
reaction
conditions and which was described in the prior art for the first time in WO
02/30928,
an anhydrous crystal modification of tiotropium bromide may be obtained which
meets the high requirements set out above and thereby solves the problem
underlying the present invention. Accordingly, the present invention
CA 02544352 2006-05-01
WO 2005/042527 3
PCT/EP2004/012269
,
relates to this crystalline anhydrous tiotropium bromide. Any reference made
within
the scope of the present invention to the term tiotropium bromide anhydrate is
to
be regarded as a reference to the crystalline anhydrous tiotropium bromide
according to the invention.
In another aspect the present invention relates to a method of preparing the
new
crystalline form of anhydrous tiotropium bromide which is explained by way of
example in the experimental section that follows.
The anhydrous tiotropium bromide according to the invention is particularly
characterised by slightly hygroscopic characteristics, which ensure a high
degree of
stability of the crystal modification. The crystalline tiotropium bromide
anhydrate
according to the invention is highly crystalline and is therefore particularly
well
suited to the preparation of pharmaceutical formulations for administration by
inhalation.
The present invention also relates to the use of the crystalline tiotropium
bromide
anhydrate according to the invention for preparing a pharmaceutical
composition
for the treatment of respiratory complaints, particularly for the treatment of
COPD
and/or asthma.
The Examples that follow serve to illustrate the present invention still
further,
without restricting the scope of the invention to the embodiments by way of
example that follow.
CA 02544352 2006-05-01
W02005/042527 4
PCT/EP2004/012269
A. I. Starting materials
Tiotropium bromide monohydrate:
Tiotropium bromide, which was obtained for example using the method described
in European Patent Application EP 418 716, was converted into crystalline
tiotropium bromide monohydrate according to the disclosure of WO 02/30928.
This is used as the starting compound for preparing the tiotropium bromide
anhydrate according to the invention.
A. II. Examples of synthesis according to the invention
Example 1:
10.0g of tiotropium bromide monohydrate were taken up in 100 ml of water and
dissolved at boiling temperature. Then 80.0g of ammonium fluoride were added.
After 18 hours' stirring at about 20-25 C the product that crystallises out is
isolated
and dried at 70 C. The crude product obtained is dissolved in 25 ml of
methanol at
boiling temperature, filtered hot and cooled to ambient temperature (approx.
20-
C). The product that crystallises out immediately after the wall of the flask
has
been scratched (with a glass rod) is isolated and dried at 50 C .
20 Yield: 7.35 g tiotropium bromide anhydrate, white solid.
Example 2:
4.39g tiotropium bromide monohydrate were taken up in 25 ml of methanol and
dissolved at boiling temperature. The clear solution is inoculated with a few
crystals
25 of the crystalline tiotropium bromide anhydrate obtained according to
Example 1.
The product crystallises out in the warm. After slowly cooling to ambient
temperature (approx. 20-25 C) the precipitate obtained is filtered off and
dried at
50 C . Yield: 3,47 g tiotropium bromide anhydrate, white solid.
CA 02544352 2012-01-20
25771-1177
A. III. Characterisation of the tiotropium bromide anhydrate according to
the invention
The tiotropium bromide anhydrate obtained by the above method is highly
crystalline. It was investigated further by X-ray powder diffraction. The
following
5 procedure was used to record the X-ray powder diagram detailed below.
The X-ray powder diagram was recorded within the scope of the present
invention
using a BrukeTruD8 Advanced with a location-sensitive detector (Cu
radiation, X
= 1.5418 A, 30 kV, 40 rnA).
The X-ray powder diagram obtained for the tiotropium bromide anhydrate
according to the invention is shown in Figure 1.
The following Table 1 lists the characteristic peaks and standardised
intensities.
Table 1:
2 0 to] didd [Al intensity [%]
8.39 10.53 4
11.33 7.80 27
13.50 6.55 53
14.13 6.26 65
14.70 6.02 73
15.28 5.79 31
15.72 5.63 7
15.98 5.54 33
=
16.32 5.43 11
16.95 5.23 45
17.90 4.95 76
18.55 4.78 100
CA 02544352 2006-05-01
. W02005/042527 6
PCMP2004/012269
19.07 4.65 62
19.46 4.56 36
20.32 4.37 10
20.40 4.35 12
21.75 4.08 23
22.60 3.93 77
22.83 3.89 20
23.21 3.83 86
24.01 3.70 17
24.40 3.64 13
24.93 3.57 8
25.27 3.52 60
25.55 3.48 28
25.95 3.43 7
26.21 3.40 30
26.38 3.38 18
27.26 3.27 24
27.60 3.23 8
28.07 3.18 44
28.38 3.14 67
28.58 3.12 35
29.93 2.98 19
30.18 2.96 21
30.52 2.93 10
=
CA 02544352 2006-05-01
WO 2005/042527 7
PCT/EP2004/012269
30.91 2.89 17
31.82 2.81 46
32.32 2.77 13
32.94 2.72 7
33.49 2.67 13
34.80 2.58 31
In the above Table the value "2 0 r1" represents the diffraction angle in
degrees
and the value " diild [A]" represents the specified lattice plane intervals in
A.
The present invention therefore relates to crystalline tiotropium bromide
anhydrate
which is characterised in that in the X-ray powder diagram it has the
characteristic
values d= 6.02 A; 4.95 A; 4.78 A; ; 3.93 A and 3.83 A, inter alia.
B. Formulations containing the tiotropium bromide anhydrate according to
the invention
The crystalline tiotropium bromide anhydrate according to the invention is
highly
crystalline and is therefore particularly well suited to the preparation of,
for
example, pharmaceutical formulations for administration by inhalation such as
inhalable powders or for example propellant-containing aerosol formulations,
particularly inhalable powders and propellant-containing aerosol suspensions.
B.1. Inhalable powders
The present invention also relates to inhalable powder containing 0.001 to 3 %
tiotropium in the form of the crystalline tiotropium bromide anhydrate
according to
the invention combined with a physiologically acceptable excipient. By
tiotropium
is meant the ammonium cation.
Inhalable powders which contain 0.01 to 2 `)/0 tiotropium are preferred
according to
the invention. Particularly preferred inhalable powders contain tiotropium in
an
amount from about 0.03 to 1 %, preferably 0.05 to 0.6 %, particularly
preferably
0.06 to 0.3 %. Of particular importance according to the invention, finally,
are
inhalable powders which contain about 0.08 to 0.22 A tiotropium.
=
CA 02544352 2006-05-01
WO 2005/042527 8
PCT/EP2004/012269
The amounts of tiotropium specified above are based on the amount of
tiotropium
cation contained.
The excipients that are used for the purposes of the present invention are
prepared
by suitable grinding and/or screening using current methods known in the art.
The
excipients used according to the invention may also be mixtures of excipients
which
are obtained by mixing excipient fractions of different mean particle sizes.
Examples of physiologically acceptable excipients which may be used to prepare
the
inhalable powders for use in the inhalettes according to the invention include
monosaccharides (e.g. glucose, fructose or arabinose), disaccharides (e.g.
lactose,
saccharose, maltose, trehalose), oligo- and polysaccharides (e.g. dextrans,
dextrins,
maltodextrin, starch, cellulose), polyalcohols (e.g. sorbitol, mannitol,
xylitol),
cyclodextrins (e.g. a-cyclodextrin,13-cyclodextrin, x-cyclodextrin, methyl-13-
cyclodextrin, hydroxypropyl-f3-cyclodextrin), amino acids (e.g. arginine
hydrochloride) or salts (e.g. sodium chloride, calcium carbonate), or mixtures
thereof. Preferably, mono- or disaccharides are used, while the use of lactose
or
glucose is preferred, particularly, but not exclusively, in the form of their
hydrates.
For the purposes of the invention, lactose is the particularly preferred
excipient,
while lactose monohydrate is most particularly preferred.
Within the scope of the inhalable powders according to the invention the
excipients
have a maximum average particle size of up to 250 m, preferably between 10 and
150pm, most preferably between 15 and 8011m. It may sometimes seem appropriate
to add finer excipient fractions with an average particle size of 1 to 9i1m to
the
excipients mentioned above. These finer excipients are also selected from the
group
of possible excipients listed hereinbefore. The average particle size may be
determined using methods known in the art (cf. for example WO 02/30389,
paragraphs A and C). Finally, in order to prepare the inhalable powders
according
to the invention, micronised crystalline tiotropium bromide anhydrate, which
is
preferably characterised by an average particle size of 0.5 to 10p,m,
particularly
preferably from 1 to 51.tm, is added to the excipient mixture (cf. for example
WO
02/30389, paragraph B). Processes for grinding and micronising active
substances
are known from the prior art.
CA 02544352 2006-05-01
WO 2005/042527 9
PCT/EP2004/012269
If no specifically prepared excipient mixture is used as the excipient, it is
particularly
preferable to use excipients which have a mean particle size of 10 - 50 gm and
a 10
% fine content of 0.5 to 6 gm.
By average particle size is meant here the 50 % value of the volume
distribution
measured with a laser diffractometer using the dry dispersion method . The
average
particle size may be determined using methods known in the art (cf. for
example
WO 02/30389, paragraphs A and C). Analogously, the 10% fine content in this
instance refers to the 10% value of the volume distribution measured using a
laser
diffractometer. In other words, for the purposes of the present invention, the
10%
fine content denotes the particle size below which 10% of the quantity of
particles is
found (based on the volume distribution).
The percentages given within the scope of the present invention are always
percent
by weight, unless specifically stated to the contrary.
In particularly preferred inhalable powders the excipient is characterised by
a mean
particle size of 12 to 35 gm, particularly preferably from 13 to 30 gm.
Also particularly preferred are those inhalable powders wherein the 10 % fine
content is about 1 to 4 gm, preferably about 1.5 to 3 gm.
The inhalable powders according to the invention are characterised, in
accordance
with the problem on which the invention is based, by a high degree of
homogeneity
in the sense of the accuracy of single doses. This is in the region of < 8 A
,
preferably < 6 A , most preferably < 4 %.
After the starting materials have been weighed out the inhalable powders are
prepared from the excipient and the active substance using methods known in
the
art. Reference may be made to the disclosure of WO 02/30390, for example. The
inhalable powders according to the invention may accordingly be obtained by
the
method described below, for example. In the preparation methods described
hereinafter the components are used in the proportions by weight described in
the
above-mentioned compositions of the inhalable powders.
CA 02544352 2006-05-01
WO 2005/042527 10
PCT/EP2004/012269
First, the excipient and the active substance are placed in a suitable mixing
container. The active substance used has an average particle size of 0.5 to 10
gm,
preferably 1 to 6 gm, most preferably 2 to 5 gm. The excipient and the active
substance are preferably added using a sieve or a granulating sieve with a
mesh size
of 0.1 to 2 mm, preferably 0.3 to 1 mm, most preferably 0.3 to 0.6 mm.
Preferably,
the excipient is put in first and then the active substance is added to the
mixing
container. During this mixing process the two components are preferably added
in
batches. It is particularly preferred to sieve in the two components in
alternate
layers. The mixing of the excipient with the active substance may take place
while
the two components are still being added. Preferably, however, mixing is only
done
once the two components have been sieved in layer by layer.
The present invention also relates to the use of the inhalable powders
according to
the invention for preparing a pharmaceutical composition for the treatment of
respiratory complaints, particularly for the treatment of COPD and/or asthma.
The inhalable powders according to the invention may for example be
administered
using inhalers which meter a single dose from a reservoir by means of a
measuring
chamber (e.g. according to US 4570630A) or by other means (e.g. according to
DE
36 25 685 A). Preferably, however, the inhalable powders according to the
invention are packed into capsules (to make so-called inhalettes), which are
used in
inhalers such as those described in WO 94/28958, for example.
Most preferably, the capsules containing the inhalable powder according to the
invention are administered using an inhaler as shown in Figure 2. This inhaler
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 airholes 13 for
adjusting the
flow resistance.
CA 02544352 2006-05-01
WO 2005/042527 11
PCT/EP2004/012269
The present invention further relates to the use of the inhalable powders
containing
the crystalline tiotropium bromide anhydrate according to the invention for
preparing a pharmaceutical composition for treating respiratory complaints,
particularly for the treatment of COPD and/or asthma, characterised in that
the
inhaler described above and shown in Figure 2 is used.
For administering the inhalable powders containing the crystalline tiotropium
bromide anhydrate according to the invention using powder-filled capsules it
is
particularly preferred to use capsules the material of which is selected from
among
the synthetic plastics, most preferably selected from among polyethylene,
polycarbonate, polyester, polypropylene and polyethylene terephthalate.
Particularly
preferred synthetic plastic materials are polyethylene, polycarbonate or
polyethylene
terephthalate. If polyethylene is used as one of the capsule materials which
is
particularly preferred according to the invention, it is preferable to use
polyethylene
with a density of between 900 and 1000 kg/m3, preferably 940 - 980 kg/m3, more
preferably about 960 - 970 kg/m3 (high density polyethylene). The synthetic
plastics according to the invention may be processed in various ways using
manufacturing methods known in the art. Injection moulding of the plastics is
preferred according to the invention. Injection moulding without the use of
mould
release agents is particularly preferred. This method of production is well
defined
and is characterised by being particularly reproducible.
In another aspect the present invention relates to the abovementioned capsules
which contain the abovementioned inhalable powder according to the invention.
These capsules may contain about 1 to 20 mg, preferably about 3 to 15 mg, most
preferably about 4 to 12 mg of inhalable powder. Preferred formulations
according
to the invention contain 4 to 6 mg of inhalable powder. Of equivalent
importance
according to the invention are capsules for inhalation which contain the
formulations according to the invention in an amount of from 8 to 12 mg.
The present invention also relates to an inhalation kit consisting of one or
more of
the above capsules characterised by a content of inhalable powder according to
the
invention in conjunction with the inhaler according to Figure 2.
CA 02544352 2006-05-01
WO 2005/042527 12
PCT/EP2004/012269
=
The present invention also relates to the use of the abovementioned capsules
characterised by a content of inhalable powder according to the invention, for
preparing a pharmaceutical composition for treating respiratory complaints,
especially for treating COPD and/or asthma.
Filled capsules which contain the inhalable powders according to the invention
are
produced by methods known in the art, by filling the empty capsules with the
inhalable powders according to the invention.
B.1.1. Examples of inhalable powders according to the invention
The following Examples serve to illustrate the present invention in more
detail
without restricting the scope of the invention to the exemplifying embodiments
that
follow.
B.1.1.1. Starting materials
Active substance
The crystalline tiotropium bromide anhydrate according to the invention is
used to
produce the inhalable powders according to the invention. The micronisation of
this
active substance is carried out analogously to methods known in the art (cf
for
example WO 03/078429 Al). Where reference is made within the scope of the
present invention to the mean particle size of the crystalline tiotropium
bromide
anhydrate according to the invention, this is determined using methods of
measurement known in the art (cf for example WO 03/078429 Al, para. D.2).
Excipient:
In the Examples that follow lactose-monohydrate is used as excipient. It may
be
obtained for example from Borculo Domo Ingredients, Borculo/NL under the
product name Lactochem Extra Fine Powder. The specifications according to the
invention for the particle size and specific surface area are met by this
grade of
lactose. For example, in the Examples that follow, batches of lactose were
used
having the following specifications:
=
CA 02544352 2006-05-01
W02005/042527 13
PCT/EP2004/012269
B.1.1.2. Preparation of the powder formulations according to the invention:
I) Apparatus
The following machines and equipment, for example, may be used to prepare the
inhalable powders:
Mixing container or powder mixer: Turbulamischer 2 L, Type 2C; made by Willy
A. Bachofen AG, CH-4500 Basel
Hand-held screen: 0.135 mm mesh size
The empty inhalation capsules may be filled with inhalable powders containing
tiotropium by hand or mechanically. The following equipment may be used.
Capsule filling machine:
MG2, Type G100, manufacturer: MG2 S.r.1, 1-40065 Pian di Macina di Pianoro
(BO), Italy
Formulation Example 1:
Powder mixture :
To prepare the powder mixture, 299.39 g of excipient and 0.61 g of micronised
crystalline tiotropium bromide anhydrate are used.
About 40-45 g of excipient are placed in a suitable mixing container through a
hand-held screen with a mesh size of 0.315 mm. Then crystalline tiotropium
bromide anhydrate in batches of about 90-110 mg and excipient in batches of
about
40-45 g are screened in in alternate layers. The excipient and active
substance are
added in 7 and 6 layers, respectively.
Having been screened in, the ingredients are then mixed (mixing speed 900
rpm).
The final mixture is passed twice more through a hand-held screen and then
mixed
again at 900 rpm.
CA 02544352 2006-05-01
W02005/042527 14
PCT/EP2004/012269
Using the method described in Example 1 it is possible to obtain inhalable
powders
which when packed into suitable plastic capsules may be used to produce the
following capsules for inhalation, for example:
Formulation Example 2:
tiotropium bromide anhydrate:0.0113 mg
lactose monohydrate: 5.4887 mg
capsule: 100.0 mg
Total: 105.5 mg
Formulation Example 3:
tiotropium bromide anhydrate:0.0225 mg
lactose monohydrate: 5.4775 mg
polyethylene capsules: 100.0 mg
Total: 105.5 mg
Formulation Example 4:
tiotropium bromide anhydrate:0.0056 mg
lactose monohydrate: 5.4944 mg
polyethylene capsules: 100.0 mg
Total: 105.5 mg
Formulation Example 5:
tiotropium bromide anhydrate:0.0113 mg
lactose monohydrate:* 5.4887 mg
capsule: 100.0 mg
Total: 105.5 mg
*) the lactose contains 5% specifically added fine content of micronised
lactose
monohydrate with a mean particle size of about 41,tm.
CA 02544352 2006-05-01
, W020051042527 15
PCT/EP2004/012269
Formulation Example 6:
tiotropium bromide anhydrate:0.0225 mg
lactose monohydrate:* 5.4775 mg
polyethylene capsules: 100.0 mg
Total: 105.5 mg
*) the lactose contains 5% specifically added fine content of micronised
lactose
monohydrate with a mean particle size of about 41.un.
Formulation Example 7:
tiotropium bromide anhydrate :0.0056 mg
lactose monohydrate:* 5.4944 mg
polyethylene capsules: 100.0 mg
Total: 105.5 mg
*) the lactose contains 5% specifically added fine content of micronised
lactose
monohydrate with a mean particle size of about 41..tm.
B.2. Propellant-containing aerosol suspensions containing crystalline
tiotropium bromide anhydrate
The crystalline tiotropium bromide anhydrate according to the invention may
optionally also be administered in the form of propellant-containing inhalable
aerosols. Aerosol suspensions are particularly suitable for this.
The present invention therefore also relates to suspensions of the crystalline
tiotropium bromide anhydrate according to the invention in the propellent
gases
HFA 227 and/or HFA 134a, optionally combined with one or more other
propellent gases, preferably selected from the group consisting of propane,
butane,
pentane, dimethylether, CHC1F2, CH2F2, CF3CH3, isobutane, isopentane and
neopentane.
According to the invention those suspensions which contain as propellent gas
only
HFA 227, a mixture of HFA 227 and HFA 134a or only HFA 134a are preferred.
CA 02544352 2012-01-20
25771-1177
16
If a mixture of the propellent gases HFA 227 and HFA 134a is used in the
suspension formulations according to the invention, the weight ratios in which
these
two propellent gas components are used are freely variable.
If one or more other propellent gases, selected from the group consisting of
propane, butane, pentane, dimethylether, CHC1F2, CH2F2, CF3CH3,isobutane,
isopentane and neopentane are used in addition to the propellent gases HFA 227
and/or HFA 134a in the suspension formulations according to the invention, the
amount of this additional propellent gas component is preferably less than 50
%,
preferably less than 40%, particularly preferably less than 30%.
The suspensions according to the invention preferably contain an amount of
tiotropium bromide anhydrate such that the amount of tiotropium cation is
between
0.001 and 0.8%, preferably between 0.08 and 0.5%, and particularly preferably
between 0.2 and 0.4% according to the invention.
Unless stated to the contrary, the percentages given within the scope of the
present
invention are always percent by weight.
In some cases, the term suspension formulation is used within the scope of the
present invention instead of the term suspension. The two terms are to be
regarded
as equivalent within the scope of the present invention.
The propellant-containing inhalable aerosols or suspension formulations
according
to the invention may also contain other constituents such .as surface-active
agents
(surfactants), adjuvants, antioxidants or flavourings.
The surface-active agents (surfactants) optionally present in the suspensions
according to the invention are preferably selected from the group consisting
of
Polysorbate 20, Polysorbate 80, Myvacer9-45, Myvacer9-08, isopropyl myristate,
oleic acid, propyleneglycol, polyethyleneglycol, Brij, ethyl oleate, glyceryl
trioleate,
glyceryl monoliurate, glyceryl monooleate, glyceryl monostearate, glyceryl
monoricinoleate, cetylalcohol, sterylalcohol, cetylpyridinium chloride, block
polymers, natural oil, ethanol and isopropanol. Of the above-mentioned
suspension
adjuvants Polysorbate 20, Polysorbate 80, Myvacet 9-45, Myvacer9-08 or
isopropyl
myristate are preferably used. Myvacer9-45 or isopropyl myristate are most
preferably used.
CA 02544352 2006-05-01
WO 2005/042527 17
PCT/EP2004/012269
If the suspensions according to the invention contain surfactants these are
preferably used in an amount of 0.0005 - 1 %, particularly preferably 0.005 -
0.5 A.
The adjuvants optionally contained in the suspensions according to the
invention
are preferably selected from the group consisting of alanine, albumin,
ascorbic acid,
aspartame, betaine, cysteine, phosphoric acid, nitric acid, hydrochloric acid,
sulphuric acid and citric acid. Ascorbic acid, phosphoric acid, hydrochloric
acid or
citric acid are preferably used, while hydrochloric acid or citric acid is
most
preferably used.
If adjuvants are present in the suspensions according to the invention, these
are
preferably used in an amount of 0.0001-1.0%, preferably 0.0005-0.1 A,
particularly preferably 0.001-0.01 %, while an amount of 0.001-0.005 A is
particularly important according to the invention.
The antioxidants optionally contained in the suspensions according to the
invention
are preferably selected from the group consisting of ascorbic acid, citric
acid,
sodium edetate, editic acid, tocopherols, butylhydroxytoluene,
butylhydroxyanisol
and ascorbylpalmitate, while tocopherols, butylhydroxytoluene,
butylhydroxyanisol
or ascorbylpalmitate are preferably used.
The flavourings optionally contained in the suspensions according to the
invention
are preferably selected from the group consisting of peppermint, saccharine,
Dentomint, aspartame and ethereal oils (for example cinnamon, aniseed,
menthol,
camphor), of which peppermint or Dentomint are particularly preferred.
With a view to administration by inhalation it is essential to provide the
active
substances in finely divided form. For this purpose, the crystalline
tiotropium
bromide anhydrate according to the invention is obtained in finely divided
form
using methods known in the prior art. Methods of micronising active substances
are
known in the art. Preferably after micronising the active substance has a mean
particle size of 0.5 to 10 m, preferably 1 to 6 m, particularly preferably 1.5
to 5 m.
Preferably at least 50%, preferably at least 60%, particularly preferably at
least 70%
of the particles of active substance have a particle size which is within the
size ranges
CA 02544352 2006-05-01
W020051042527 18
PCT/EP2004/012269
mentioned above. Particularly preferably at least 80%, most preferably at
least 90%
of the particles of active substance have a particle size which is within the
size ranges
mentioned above.
In another aspect the present invention relates to suspensions which contain
only
one of the two active substances according to the invention without any other
additives.
The suspensions according to the invention may be prepared using methods known
in the art. For this, the constituents of the formulation are mixed with the
propellent gas or gases (optionally at low temperatures) and filled into
suitable
containers.
The above-mentioned propellant-containing suspensions according to the
invention may be administered using inhalers known in the art (pMDIs =
pressurized metered dose inhalers). Accordingly, in another aspect, the
present
invention relates to pharmaceutical compositions in the form of suspensions as
hereinbefore described combined with one or more inhalers suitable for
administering these suspensions. Moreover the present invention relates to
inhalers,
characterised in that they contain the propellant-containing suspensions
according
to the invention described hereinbefore.
The present invention also relates to containers (cartridges) which when
fitted with
a suitable valve can be used in a suitable inhaler and which contain one of
the
above-mentioned propellant-containing suspensions according to the invention.
Suitable containers (cartridges) and processes for filling these cartridges
with the
propellant-containing suspensions according to the invention are known in the
art.
In view of the pharmaceutical activity of tiotropium the present invention
also
relates to the use of the suspensions according to the invention for preparing
a
pharmaceutical composition for inhalation or nasal administration, preferably
for
preparing a pharmaceutical composition for inhalative or nasal treatment of
diseases
in which anticholinergics may develop a therapeutic benefit.
CA 02544352 2006-05-01
W020051042527 19
PCT/EP2004/012269
Particularly preferably the present invention also relates to the use of the
suspensions according to the invention for preparing a pharmaceutical
composition
for the inhalative treatment of respiratory complaints, preferably asthma or
COPD.
The Examples that follow serve to illustrate the present invention in more
detail, by
way of example, without restricting it to their contents.
B.2.1 Examples of aerosol suspension formulations
Suspensions containing other ingredients in addition to active substance and
propellent gas:
Formulation Example 8:
constituents concentration ro w/w]
tiotropium bromide anhydrate 0.04
oleic acid 0.005
HFA-227 99.955
Formulation Example 9:
constituents concentration ro w/w]
tiotropium bromide anhydrate 0.02
oleic acid 0.01
HFA-227 60.00
HFA-134a 39.97
Formulation Example 10:
constituents concentration [% w/w]
tiotropium bromide anhydrate 0.02
isopropylmyristate 1.00
HFA-227 98.98
CA 02544352 2006-05-01
WO 2005/042527 20
PCT/EP2004/012269
Formulation Example 11:
constituents concentration [% w/w]
tiotropium bromide anhydrate 0.02
Myvacet 9-45 0.3
HFA-227 99.68
Formulation Example 12:
constituents concentration ro w/w]
tiotropium bromide anhydrate 0.02
Myvacet 9-45 0.1
HFA-227 60.00
HFA-134a 39.88
Formulation Example 13:
constituents concentration [(1/0 w/w]
tiotropium bromide anhydrate 0.04
Polysorbate 80 0.04
HFA-227 99.92
Formulation Example 14:
constituents concentration [3/0 w/w]
tiotropium bromide anhydrate 0.01
Polysorbate 20 0.20
HFA-227 99.78
CA 02544352 2006-05-01
WO 2005/042527 21
PCT/EP2004/012269
Formulation Example 15:
constituents concentration [% w/w]
tiotropium bromide anhydrate 0.04
Myvacet 9-08 01.00
HFA-227 98.96
Formulation Example 16:
constituents concentration [% w/w]
tiotropium bromide anhydrate 0.02
isopropylmyristate 0.30
HFA-227 20.00
HFA-134a 79.68
Suspensions containing only active substance and propellent gas:
Formulation Example 17:
constituents concentration [0k w/w1
tiotropium bromide anhydrate 0.02
HFA-227 60.00
HFA-134a 39.98
Formulation Example 18:
constituents concentration [13/o w/w]
tiotropium bromide anhydrate 0.02
HFA-227 99.98
CA 02544352 2006-05-01
WO 2005/042527 22
PCT/EP2004/012269
Formulation Example 19:
constituents concentration [% w/w1
tiotropium bromide anhydrate 0.02
HFA-134a 99.98
Formulation Example 20:
_
constituents concentration [`)/0 w/w]
tiotropium bromide anhydrate 0.02
HFA-227 99.98
Formulation Example 21:
constituents concentration [ /0 w/w]
tiotropium bromide anhydrate 0.02
HFA-134a 99.98
Formulation Example 22:
constituents concentration [0/o w/w]
tiotropium bromide anhydrate 0.02
HFA-227 20.00
HFA-134a 79.98
Formulation Example 23:
constituents concentration r/o w/w]
tiotropium bromide anhydrate 0.04
HFA-227 40.00
HFA-134a 59.96
CA 02544352 2006-05-01
WO 2005/042527 23
PCT/EP2004/012269
Formulation Example 24:
constituents concentration ro w/w]
tiotropium bromide anhydrate 0.04
HFA-227 80.00
HFA-134a 19.96
