Note: Descriptions are shown in the official language in which they were submitted.
WO 03/082252 PCT/EP03/02898
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80281 pct. 210
HFA suspension formulations containing an anticholinergic
The invention relates to pressurised gas preparations for metered-dose
aerosols
with suspension formulations of the crystalline monohydrate of (1
a,2(3,4(3,5(X,7(3)-7-
[(hydroxydi-2-th ienylacetyl)oxy]-9, 9-dimethyl-3-oxa-9-
azoniatricyclo[3.3.1.02.4]nonane-bromide, processes for the preparation
thereof and
the use thereof for preparing a pharmaceutical composition, particularly for
preparing
1o a pharmaceutical composition with an anticholinergic activity.
Background to the invention
The compound (1 a, 2(3,4(3, 5a, 713)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-
dimethyl-3-
oxa-9-azoniatricyclo[3.3.1.02.4]nonane-bromide, is known from European Patent
Application EP 418 716 Al and has the following chemical structure:
Mew N'
O
O H Br-
S O
OH
S
(I)
The compound has valuable pharmacological properties and is known by the name
tiotropium bromide (BA679). Tiotropium bromide is a highly effective
anticholinergic
and can therefore provide therapeutic benefit in the treatment of asthma or
COPD
(chronic obstructive pulmonary disease).
Tiotropium bromide is preferably administered by inhalation.
The aim of the present invention is to prepare HFA-metered-dose aerosols
containing tiotropium bromide as the sole active ingredient in suspended form.
Detailed description of the invention
It has been found that, depending on the choice of conditions which can be
used
when purifying the crude product obtained after industrial manufacture,
tiotropium
bromide occurs in various crystalline modifications.
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It has been found that these different modifications can be deliberately
produced by
selecting the solvents used for the crystallisation as well as by a suitable
choice of
the process conditions used in the crystallisation process. For the purposes
of
preparing the formulations according to the invention, crystalline tiotropium
bromide
monohydrate has proved particularly suitable.
Accordingly, the present invention relates to suspensions of crystalline
tiotropium
bromide monohydrate in the propellant gases HFA 227 and/or HFA 134a,
optionally
9o in admixture with one or more other propellant gases, preferably selected
from the
group consisting of propane, butane, pentane, dimethylether, CHCIF2, CH2F2,
CF3CH3, isobutane, isopentane and neopentane.
Preferred suspensions according to the invention are those which contain as
propellant gas HFA 227 on its own, a mixture of HFA 227 and HFA 134a or HFA
134a on its own. If a mixture of propellant gases HFA 227 and HFA 134a is used
in
the suspension formulations according to the invention, the weight ratios in
which
these two propellant gas components are used may be freely selected.
If in the suspension formulations according to the invention one or more other
propellant gases are used in addition to the propellant gases HFA 227 and/or
HFA
134a , selected from the group consisting of propane, butane, pentane,
dimethylether, CHCIF2, CH2F2i CF3CH3, isobutane, isopentane and neopentane,
the
proportion of this other propellant gas component is preferably less than 50
%,
preferably less than 40%, more preferably less than 30%.
The suspensions according to the invention preferably contain between 0.001
and
0.8% tiotropium. Suspensions which contain 0.08 to 0.5%, more preferably 0.2
to
0.4% tiotropium are preferred according to the invention.
3o By tiotropium is meant the free ammonium cation. The propellant gas
suspensions
according to the invention are characterised in that they contain tiotropium
in the
form of the crystalline tiotropium bromide monohydrate which is exceptionally
suitable for this application. Accordingly, the present invention preferably
relates to
suspensions which contain between 0.0012 and 1 % crystalline tiotropium
bromide
monohydrate. Of particular interest according to the invention are suspensions
which
contain 0.1 to 0.62%, more preferably 0.25 to 0.5% crystalline tiotropium
bromide
monohydrate.
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The percentages specified within the scope of the present invention are always
percent by mass. If parts by mass of tiotropium are given in percent by mass,
the
corresponding values for the crystalline tiotropium bromide monohydrate which
is
preferably used within the scope of the present invention may be obtained by
multiplying by a conversion factor of 1.2495.
In some cases within the scope of the present invention the term suspension
formulation may be used instead of the term suspension. The two terms are to
be
regarded as interchangeable within the scope of the present invention.
The propellant-containing inhalation aerosols or suspension formulations
according
to the invention may also contain other ingredients such as surface-active
agents
(surfactants), adjuvants, antioxidants or flavourings.
The surface-active agents (surfactants) which may be contained in the
suspensions
according to the invention are preferably selected from among Polysorbate 20,
TM TM
Polysorbate 80, Myvacet 9-45, Myvacet 9-08, isopropylmyristate, oleic acid,
TM
propyleneglycol, polyethyleneglycol, Brij, ethyloleate, glyceryl trioleate,
glyceryl
monolaurate, glyceryl monooleate, glyceryl monosterate, glyceryl
monoricinoleate,
cetylalcohol, sterylalcohol, cetylpyridinium chloride, block polymers, natural
oil,
ethanol and isopropanol. Of the abovementioned suspension adjuvants
Polysorbate
TM TM
20, Polysorbate 80, Myvacet 9-45, Myvacet 9-08 or isopropylmyristate are
preferably
TM
used. Myvacet 9-45 or isopropylmyristate are particularly preferred.
Where the suspensions according to the invention contain surfactants, these
are
preferably present in an amount of 0.0005 - 1 %, more preferably 0.005 - 0.5
%.
The adjuvants optionally contained in the suspensions according to the
invention are
preferably selected from among alanine, albumin, ascorbic acid, aspartame,
betaine,
cysteine, phosphoric acid, nitric acid, hydrochloric acid, sulphuric acid and
citric acid.
Of these, ascorbic acid, phosphoric acid, hydrochloric acid or citric acid are
preferred, while hydrochloric acid or citric acid is more preferable.
Where the suspensions according to the invention contain adjuvants, these are
preferably present in an amount of 0.0001-1.0 %, preferably 0.0005-0.1 %, more
preferably 0.001 -0.01 %, while an amount of from 0.001-0.005 % is
particularly
preferred according to the invention.
The antioxidants optionally contained in the suspensions according to the
invention
are preferably selected from among ascorbic acid, citric acid, sodium edetate,
editic
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acid, tocopherols, butylhydroxytoluene, butylhydroxyanisol and ascorbyl
palmitate, of
which tocopherols, butylhydroxytoluene, butyihydroxyanisol and ascorbyl
palmitate
are preferred.
The flavourings which may be contained in the suspensions according to the
invention are preferably selected from among peppermint, saccharine, Dentomint
,
aspartame and ethereal oils (e.g. cinnamon, aniseed, menthol, camphor), of
which
peppermint or Dentomint is particularly preferred.
9o For administration by inhalation it is necessary to prepare the active
substance in
finely divided form. The crystalline tiotropium bromide monohydrate which may
be
obtained as detailed in the experimental section is either ground (micronised
or
obtained in finely divided form by other technical methods known in principle
in the
art (such as precipitation and spray drying). Methods of micronising active
substances are known in the art. Preferably, after micronisation, the active
substance has an average particle size of 0.5 to 10 pm, preferably 1 to 6 pm,
more
preferably 1.5 to 5 pm. Preferably, at least 50%, more preferably at least
60%, most
preferably at least 70% of the particles of active substance have a particle
size which
is within the ranges specified above. More preferably, at least 80%, most
preferably
at least 90% of the particles of active substance have a particle size within
the
ranges specified above.
Surprisingly, it has been found that it is also possible to prepare
suspensions which
contain, apart from the abovementioned propellant gases, only the active
substance
and no other additives. Accordingly, in another aspect, the present invention
relates
to suspensions which contain only the active substance and no other additives.
The suspensions according to the invention may be prepared by methods known in
the art. For this the ingredients of the formulation are mixed with the
propellant gas
or gases (optionally at low temperatures) and transferred into suitable
containers.
The propellant gas-containing suspensions according to the invention mentioned
above may be administered using inhalers known in the art (pMDls = pressurised
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. In addition, the present invention relates to inhalers which are
characterised in that they contain the propellant gas-containing suspensions
described above according to the invention. The present invention also relates
to
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containers (e.g. cartridges) which are fitted with a suitable valve and can be
used in
a suitable inhaler and which contain one of the above-mentioned propellant gas-
containing suspensions according to the invention. Suitable containers (e.g.
cartridges) and methods of filling these cartridges with the propellant gas-
containing
5 suspensions according to the invention are known from the prior art.
In view of the pharmaceutical activity of tiotropium the present invention
further
relates to the use of the suspensions according to the invention for preparing
a drug
for administration by inhalation or by nasal route, preferably for preparing a
drug for
the treatment by inhalation or by nasal route of diseases in which
anticholinergics
1o may provide a therapeutic benefit.
Most preferably, the invention further relates to the use of the suspensions
according
to the invention for preparing a pharmaceutical composition for the treatment
by
inhalation of respiratory complaints, preferably asthma or COPD.
The Examples that follow serve to illustrate the present invention more fully
by way
of example, without restricting it to their content.
Starting materials
Crystalline tiotropium bromide monohydrate:
The tiotropium obtained according to EP 418 716 Al may be used to prepare the
crystalline tiotropium bromide monohydrate. This is then reacted as described
below.
15.0 kg of tiotropium bromide are added to 25.7 kg of water in a suitable
reaction
vessel. The mixture is heated to 80-90 C and stirred at constant temperature
until a
clear solution is formed. Activated charcoal (0.8 kg), moistened with water,
is
suspended in 4.4 kg of water, this mixture is added to the solution containing
tiotropium bromide and rinsed with 4.3 kg of water. The mixture thus obtained
is
stirred for at least 15 min. at 80-90 C and then filtered through a heated
filter into an
apparatus which has been preheated to an outer temperature of 70 C. The filter
is
rinsed with 8.6 kg of water. The contents of the apparatus are cooled to a
temperature of 20-25 C at a rate of 3-5 C every 20 minutes. Using cold water
the
apparatus is cooled further to 10-15 C and crystallisation is completed by
stirring for
at least another hour. The crystals are isolated using a suction filter drier,
the crystal
slurry isolated is washed with 9 L of cold water (10-15 C) and cold acetone
(10-
15 C). The crystals obtained are dried at 25 C for 2 hours in a nitrogen
current.
Yield: 13.4 kg of tiotropium bromide monohydrate (86 % of theory).
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The tiotropium bromide monohydrate obtainable using the method described above
was investigated by DSC (Differential Scanning Calorimetry). The DSC diagram
shows two characteristic signals. The first, relatively broad, endothermic
signal
between 50-120 C can be attributed to the dehydration of the tiotropium
bromide
monohydrate into the anhydrous form. The second, relatively sharp, endothermic
peak at 230- 5 C can be put down to the melting of the substance. This data
was
obtained using a Mettler DSC 821 and evaluated using the Mettler STAR software
package. The data was recorded at a heating rate of 10 K/min.
1o The crystalline tiotropium bromide monohydrate was characterised by IR
TM
spectroscopy. The data was obtained using a Nicolet FTIR spectrometer and
TM
evaluated with the Nicolet OMNIC software package, version 3.1. The
measurement
was carried out with 2.5 pmol of tiotropium bromide monohydrate in 300 mg of
KBr.
The following Table shows some of the essential bands of the IR spectrum.
Wave number (cm-1) Attribution Type of oscillation
.3570, 3410 O-H elongated
oscillation
3105 Aryl C-H elongated
oscillation
1730 C=O elongated
oscillation
1260 Epoxide C-0 elongated
oscillation
1035 Ester C-OC elongated
oscillation
720 Thiophene cyclic oscillation
The monocrystal X-ray structural analysis carried out showed that the
crystalline
tiotropium bromide monohydrate obtainable by the above process has a simple
monoclinic cell with the following dimensions:
a = 18.0774 A, b = 11.9711 A, c = 9.9321 A, R = 102.691 , V = 2096.96 A3.
These data were obtained using an AFC7R 4-circuit diffractometer (Rigaku)
using
monochromatic copper Ka radiation. The structural resolution and refinement of
the
crystal structure were obtained by direct methods (SHELXS86 Program) and FMLQ-
refinement (TeXsan Program).
To prepare the suspensions according to the invention the crystalline
tiotropium
bromide monohydrate obtainable by the above process is micronised by methods
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known per se in the art, to prepare the active substance in the form of the
average
particle size which corresponds to the specifications according to the
invention.
A method of determining the average particle size of the active substance will
now
be described.
Determining the particle size of micronised tiotropium bromide monohydrate:
Measuring equipment and settings:
The equipment is operated according to the manufacturer's instructions.
Measuring equipment: HELOS Laser diffraction spectrometer, SympaTec
Dispersing unit: RODOS dry disperser with suction funnel,
SympaTec
Sample quantity: 50 mg - 400 mg
Product feed: Vibri Vibrating channel, Messrs. Sympatec
Frequency of vibrating channel: 40 rising to 100 %
Duration of sample feed: 15 to 25 sec. (in the case of 200 mg)
Focal length: 100 mm (measuring range: 0.9 - 175 pm)
Measuring time: about 15 s (in the case of 200 mg)
Cycle time: 20 ms
Start/stop at: 1 % on channel 28
Dispersing gas: compressed air
Pressure: 3 bar
Vacuum: maximum
Evaluation method: HRLD
Sample preparation /product feed:
About 200 mg of the test substance are weighed onto a piece of card.
Using another piece of card all the larger lumps are broken up. The powder is
then
sprinkled finely over the front half of the vibrating channel (starting about
1 cm from
the front edge). After the start of the measurement the frequency of the
vibrating
channel is varied from about 40 % up to 100 % (towards the end of the
measurement). The sample should be fed in as continuously as possible.
However,
the quantity of product should not be too great, so as to ensure adequate
dispersal.
The time taken to feed in the entire 200 mg sample is about 15 to 25 sec., for
example.
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Examples of formulations
Suspensions containing other ingredients in addition to active substance and
propellant gas:
a) 0.02 % Tiotropium*
0.20 % Polysorbate 20
99.78 % HFA 227
b) 0.02 % Tiotropium*
1.00 % Isopropylmyristate
98.98 % HFA 227
c) 0.02% Tiotropium
0.3 % Myvacet 9=45
99.68 % HFA 227
d) 0.04 % Tiotropiti m*
1.00 % Myvacet 9-08
98.96% HFA 227
e) 0.04 % Tiotropium*
0.04 % Polysorbate 80
99.92% HFA 227
f) 0.04 % Tiotropium*
0.005 % Oleic acid
99.955% HFA 227
g) 0.02% Tiotropium*
0.1 % Myvacet 9-45
60.00% HFA 227
39.88% HFA 134a
h) 0.02% Tiotropium*
0.30 % lsopropylmyri state
20.00% HFA 227
79.68% HFA 134a
i) 0.02 % Tiotropium*
0.01 % Oleic acid
60.00 % HFA 227
39.97% HFA 134a
*used in the form of the tiotropium bromide monohydrate
(conversion factor 1.2495)
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Suspensions containing only active substance and propellant gas:
j) 0.02 % Tiotropium*
99.98% HFA 227
k) 0.02 % Tiotropium*
99.98% HFA 134a
I) 0.04% Tiotropium*
99.96% HFA 227
m) 0.04 % Tiotropium*
99.96% HFA134a
n) 0.02% Tiotropium*
20.00% HFA 227
79.98% HFA 134a
0) 0.02% Tiotropium*
60.00% HFA 227
39.98% HFA 134a
p) 0.04 % Tiotropium*
40.00% HFA 227
59.96% HFA134a
q) 0.04 % Tiotropium*
80.00% HFA 227
19.96% HFA 134a
* used in the form of the tiotropium bromide monohydrate
(conversion factor 1.2495)
