Note: Descriptions are shown in the official language in which they were submitted.
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
1
82486pct.212
Pulverulent formulation for inhalation containing tiotropium
The invention relates to powdered preparations containing tiotropium for
inhalation,
processes for preparing them as well as their use for preparing a
pharmaceutical
composition for treating respiratory complaints, particularly for treating
COPD
(chronic obstructive pulmonary disease) and asthma.
Background to the invention
Tiotropium bromide is known from European Patent Application EP 418 716 A1 and
has the following chemical structure:
H3C,N,CH3
O Br_
O
HO O
Tiotropium bromide is a highly effective anticholinergic with a long-lasting
activity
which can be used to treat respiratory complaints, particularly COPD (chronic
obstructive pulmonary disease) and asthma. The term tiotropium refers to the
free
ammonium cation.
For treating the abovementioned complaints, it is useful to administer the
active
substance by inhalation. In addition to the administration of broncholytically
active
compounds in the form of metered aerosols and inhalable solutions, the use of
inhalable powders containing active substance is of particular importance.
With active substances which have a particularly high efficacy, only small
amounts of
the active substance are needed per single dose to achieve the desired
therapeutic
effect. In such cases, the active substance has to be diluted with suitable
excipients
in order to prepare the inhalable powder. Because of the large amount of
excipient,
the properties of the inhalable powder are critically influenced by the choice
of
excipient. When choosing the excipient its particle size is particularly
important. As a
rule, the finer the excipient, the poorer its flow properties. However, good
flow
properties are a prerequisite for highly accurate metering when packing and
dividing
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
2
up the individual doses of preparation, e.g. when producing capsules
(inhalettes) for
powder inhalation or when the patient is metering the individual dose before
using a
multi-dose inhaler. Moreover, the particle size of the excipient is very
important for
the emptying characteristics of capsules when used in an inhaler. It has also
been
found that the particle size of the excipient has a considerable influence on
the
proportion of active substance in the inhalable powder which is delivered for
inhalation. The term inhalable proportion of active substance refers to the
particles of
the inhalable powder which are conveyed deep into the branches of the lungs
when
inhaled with a breath. The particle size required for this is between 1 and 10
pm,
preferably less than 6 Nm.
The aim of the invention is to prepare an inhalable powder containing
tiotropium
which, while being accurately metered (in terms of the amount of active
substance
and powder mixture packed into each capsule by the manufacturer as well as the
quantity of active substance released and delivered to the lungs from each
capsule
by the inhalation process) with only slight variations between batches,
enables the
active substance to be administered in a large inhalable proportion. A further
aim of
the present invention is to prepare an inhalable powder containing tiotropium
which
ensures good emptying characteristics of the capsules, whether it is
administered to
the patient using an inhaler, for example, as described in WO 94/28958, or in
vitro
using an impactor or impinger.
The fact that tiotropium, particularly tiotropium bromide, has a therapeutic
efficacy
even at very low doses imposes further conditions on an inhalable powder which
is
to be used with highly accurate metering. Because only a low concentration of
the
active substance is needed in the inhalable powder to achieve the therapeutic
effect,
a high degree of homogeneity of the powder mixture and only slight
fluctuations in
the dispersion characteristics from one batch of capsules to the next are
essential.
The homogeneity of the powder mixture and minor fluctuations in the dispersion
properties are crucial in ensuring that the inhalable proportion of active
substance is
released reproducibly in constant amounts and with the lowest possible
variability.
Accordingly, a further aim of the present invention is to prepare an inhalable
powder
containing tiotropium which is characterised by a high degree of homogeneity
and
uniformity of dispersion. The present invention also sets out to provide an
inhalable
powder which allows the inhalable proportion of active substance to be
administered
with the lowest possible variability.
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
3
Inhalable powders containing tiotropium which conform to the requirements
listed
above are known for example from WO 02/30389. These inhalable powders are
essentially characterised in that they contain in addition to the active
substance
tiotropium in the form of one of the pharmacologically acceptable salts formed
from
tiotropium an excipient which is obtained by mixing coarser excipient
fractions with
finer excipienty fractions. However, technically complex manufacturing and
mixing
methods are required in order to prepare these inhalable powders known from WO
02/30389. A further aim of the present invention is therefore to provide
inhalable
powders which not only solve the problems mentioned above but can also be
obtained by an easier technical method of preparation.
The characteristics of emptying from the powder reservoir (the container from
which
the inhalable powder containing the active substance is released for
inhalation) play
an important part, not exclusively, but especially in the administration of
inhalable
powders using capsules containing powder. If only a small amount of the powder
formulation is released from the powder reservoir as a result of minimal or
poor
emptying characteristics, significant amounts of the inhalable powder
containing the
active substance are left in the powder reservoir (e.g. the capsule) and are
unavailable to the patient for therapeutic use. The result of this is that the
dosage of
active substance in the powder mixture has to be increased so that the
quantity of
active substance delivered is sufficient to produce the desired therapeutic
effect.
Against this background the present invention further sets out to provide an
inhalable
powder which is also characterised by very good emptying characteristics.
Detailed description of the invention
It was found that, surprisingly, the objectives outlined above can be achieved
by
means of the powdered preparations for inhalation (inhalable powders)
according to
the invention described hereinafter.
Accordingly, the present invention relates to inhalable powders containing
0.001 to
3% of tiotropium mixed with a physiologically acceptable excipient,
characterised in
that the excipient has an average particle size of 10 - 50 pm, a 10 % fine
content of
0.5 to 6 pm and a specific surface area of 0.1 to 2 m2/g .
By the average particle size is meant here the 50% value of the volume
distribution
measured using a laser diffractometer by the dry dispersion method.
Analogously,
the 10% fine content in this instance refers to the 10% value of the volume
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
4
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).
By specific surface area is meant, for the purposes of the invention, the mass-
specific powder surface area, calculated from the NZ absorption isotherm which
is
observed at the boiling point of liquid nitrogen (method of Brunauer, Emmett
and
Teller).
Inhalable powders which contain 0.01 to 2% of tiotropium are preferred
according to
the invention. Particularly preferred inhalable powders contain tiotropium in
an
amount of about 0.03 to 1 %, preferably 0.05 to 0.6 %, more preferably 0.06 to
0.3%.
Of particular importance according to the invention are, finally, inhalable
powders
which contain about 0.08 to 0.22 % tiotropium.
By tiotropium is meant the free ammonium cation. Where the term active
substance
is used within the scope of the present invention, this should be interpreted
as being
a reference to tiotropium combined with a corresponding counter-ion. The
counter-
ion (anion) may preferably be chloride, bromide, iodide, methanesulphonate or
para-
toluenesulphonate. Of these anions, the bromide is preferred.
Accordingly, the present invention preferably relates to inhalable powders
which
contain between 0.0012 and 3.6 %, preferably 0.012 to 2.4 % tiotropium
bromide. Of
particular interest according to the invention are inhalable powders which
contain
about 0.036 to 1.2 %, preferably 0.06 to 0.72 %, more preferably 0.072 to 0.36
tiotropium bromide. Of particular interest according to the invention are
inhalable
powders which contain about 0.096 to 0.264 % tiotropium bromide.
The tiotropium bromide which is preferably contained in the inhalable powders
according to the invention may include solvent molecules during
crystallisation.
Preferably, the hydrates of tiotropium bromide are used to prepare the
tiotropium-
containing inhalable powder according to the invention. Most preferably, the
crystalline tiotropium bromide monohydrate known from WO 02/30928 is used.
This
crystalline tiotropium bromide monohydrate is characterised by an endothermic
maximum at 230 ~ 5°C at a heating rate of 10K/min, when thermally
analysed by
DSC. It is also characterised in that in the IR spectrum it has bands inter
alia at
wavelengths 3570, 3410, 3105, 1730, 1260, 1035 and 720 cm-'. Finally, this
crystalline tiotropium bromide monohydrate has a simple monoclinic cell with
the
following dimensions: a = 18.0774 ~, b = 11.9711 ~, c = 9.9321 ~, a = 102.691
°, V =
2096.96 ~3 as determined by monocrystalline X-ray structural analysis.
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
Accordingly the present invention relates to powders for inhalation which
contain
between 0.0013 and 3.75 %, preferably 0.0125 to 2.5 % of tiotropium bromide
monohydrate. Of particular interest according to the invention are inhalable
powders
which contain about 0.0375 to 1.25 %, preferably 0.0625 to 0.75 %, more
preferably
0.075 to 0.375 % of tiotropium bromide monohydrate. Finally, of particular
importance according to the invention are inhalable powders which contain
about 0.1
to 0.275 % tiotropium bromide monohydrate.
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
an
average particle size of 12 to 35 Nm, more preferably 13 to 30 Nm. Also
particularly
preferred are those inhalable powders wherein the 10% fine content is about 1
to 4
pm, preferably about 1.5 to 3 Nm.
Also preferred according to the invention are those inhalable powders wherein
the
excipient has a specific surface area of between 0.2 and 1.5 mz/g, preferably
between 0.3 and 1.0 m2/g.
The excipients which are used for the purposes of the present invention are
prepared by suitable milling and/or screening using conventional methods known
in
the art. In particular, the excipients used according to the invention are not
mixtures
of excipients obtained by mixing together excipient fractions with different
average
particle sizes.
Examples of physiologically acceptable excipients which may be used to prepare
the
inhalable powders used for the inhalettes according to the invention include,
for
example, monosaccharides (e.g. glucose or arabinose), disaccharides (e.g.
lactose,
saccharose, maltose, trehalose), oligo- and polysaccharides (e.g. dextrane),
polyalcohols (e.g. sorbitol, mannitol, xylitol), or salts (e.g. sodium
chloride, calcium
carbonate). 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.
Preferably, excipients of high crystallinity are used for the powder
formulations
according to the invention. This crystallinity can be assessed by means of the
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
6
enthalpy released as the excipient is dissolved (solution enthalpy). In the
case of the
excipient lactose monohydrate, which is most preferably used acording to the
invention, it is preferable to use lactose which is characterised by a
solution enthalpy
of > 45 J/g, preferably > 50 J/g, particularly preferably > 52 J/g.
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 % ,
preferably < 6 % , most preferably < 4 %.
After the starting materials have been weighed in 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.
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
Nm,
preferably 1 to 6 pm, most preferably 2 to 5 pm. 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.
If after being chemically prepared the active substance used in the process
described above is not already obtainable in a crystalline form with the
particle sizes
mentioned earlier, it can be ground up into the particle sizes which conform
to the
above-mentioned parameters (so-called micronising).
If the active substance used is the crystalline tiotropium bromide monohydrate
disclosed by WO 02/30928 which is particularly preferred according to the
invention
the following procedure has proved particularly suitable for micronising this
crystalline active substance modification. The process may be carried out
using
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
7
conventional mills. Preferably, the micronisation is carried out with the
exclusion of
moisture, more preferably, using a corresponding inert gas such as nitrogen,
for
example. It has proved particularly preferable to use air jet mills in which
the material
is comminuted by the impact of the particles on one another and on the walls
of the
grinding container. According to the invention, nitrogen is preferably used as
the
grinding gas. The material for grinding is conveyed by the grinding gas under
specific pressures (grinding pressure). Within the scope of the present
invention, the
grinding pressure is usually set to a value between about 2 and 8 bar,
preferably
between about 3 and 7 bar, most preferably between about 3.5 and 6.5 bar. The
material for grinding is fed into the air jet mill by means of the feed gas
under specific
pressures (feed pressure). Within the scope of the present invention a feed
pressure of between about 2 and 8 bar, preferably between about 3 and 7 bar
and
most preferably between about 3.5 and 6 bar has proved satisfactory. The feed
gas
used is also preferably an inert gas, most preferably nitrogen again. The
material to
be ground (crystalline tiotropium bromide monohydrate) may be fed in at a rate
of
about 5 - 35 g/min, preferably at about 10-30 g/min.
For example, without restricting the subject of the invention thereto, the
following
apparatus has proved suitable as a possible embodiment of an air jet mill: a 2-
inch
Microniser with grinding ring, 0.8 mm bore, made by Messrs Sturtevant Inc.,
348
Circuit Street, Hanover, MA 02239, USA. Using the apparatus, the grinding
process
is preferably carried out with the following grinding parameters: grinding
pressure:
about 4.5 - 6.5 bar; feed pressure: about 4.5 - 6.5 bar; supply of grinding
material:
about 17 - 21 g/min.
The ground material thus obtained is then further processed under the
following
specific conditions. The micronisate is exposed to a water vapour at a
relative
humidity of at least 40% at a temperature of 15-40°C, preferably 20-
35°C, most
preferably 25-30°C . Preferably, the humidity is set to a value of 50 -
95% r. h.,
preferably 60 - 90% r.h., most preferably 70 - 80% r.h. By relative humidity
(r.h.) is
meant the quotient of the partial steam pressure and the steam pressure of the
water
at the temperature in question. Preferably, the micronisate obtained from the
grinding process described above is subjected to the chamber conditions
mentioned
above for a period of at least 6 hours. Preferably, however, the micronisate
is
subjected to the chamber conditions mentioned above for about 12 to 48 hours,
preferably about 18 to 36 hours, more preferably about 20 to 28 hours.
The micronisate of tiotropium bromide obtainable by the above method has a
characteristic particle size of between 1.0 Nm and 3.5 Nm, preferably between
1.1 pm
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
8
and 3.3 Nm, most preferably between 1.2 Nm and 3.Opm and Q~5.8~ of more than
60%,
preferably more than 70 %, most preferably more than 80%. The characteristic
value
Q~5.8~ indicates the quantity of particles below 5.8 Nm , based on the volume
distribution of the particles. The particle sizes were determined within the
scope of
the present invention by laser diffraction (Fraunhofer diffraction). More
detailed
information on this subject can be found in the experimental descriptions of
the
invention.
Also characteristic of the tiotropium micronisate according to the invention
which was
prepared by the above process are Specific Surface Area values in the range
between 2 m2/g and 5 m2/g, more particularly between 2.5 m2/g and 4.5 mz/g and
most outstandingly between 3.0 m2/g and 4.0 m2/g.
A particularly preferred aspect of the present invention relates to the
inhalable
powders according to the invention which are characterised by a content of the
tiotropium bromide monohydrate micronisate described hereinbefore.
The present invention further relates to the use of the inhalable powders
according
to the invention for preparing a pharmaceutical composition for the treatment
of
respiratory diseases, particularly for treating 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 1. 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.
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
9
The present invention further relates to the use of the inhalable powders
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 1 is used.
For administering the inhalable powders 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 powders 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 1.
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.
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
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.
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.
Starting materials
I) 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. In
addition, this lactose has the above-mentioned preferred solution enthalpy
values for
lactose according to the invention.
II) Micronisation of crystalline tiotropium bromide monohydrate:
The tiotropium bromide monohydrate obtainable according to WO 02/30928 is
micronised with an air jet mill of the 2-inch microniser type with grinding
ring, 0.8 mm
bore, made by Messrs Sturtevant Inc., 348 Circuit Street, Hanover, MA 02239,
USA.
Using nitrogen as the grinding gas the following grinding parameters are set,
for
example:
grinding pressure: 5.5 bar; feed pressure: 5.5 bar; supply (of crystalline
monohydrate) or flow speed: 19 g/min.
The ground material obtained is then spread out on sheet metal racks in a
layer
thickness of about 1 cm and subjected to the following climatic conditions for
24 -
24.5 hours: temperature: 25 - 30 °C; relative humidity: 70-80%.
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
11
Measuring methods:
Determining the particle size of micronised tiotropium 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: 200 mg t 150 mg
Product feed: Vibri Vibrating channel, Messrs. Sympatec
Frequency of vibratingnnel: rising to 100
cha
Duration of sample 15 to 25 sec. (in the case of 200 mg)
feed:
Focal length: 100 mm (measuring range: 0.9 - 175 Nm)
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 so that the sample is fed in as continuously as possible.
However,
the quantity of product should not be too great either, so as to ensure
adequate
dispersal.
II) Determining the particle size of the lactose:
Measuring equipment and settings:
The equipment is operated according to the manufacturer's instructions.
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
12
Measuring equipment: HELOS Laser-diffraction spectrometer, (SympaTec)
Dispersing unit: RODOS dry disperser with suction funnel,
(SympaTec)
Sample quantity: 200 mg 100 mg
Product feed: Vibri Vibrating channel, Messrs.
Sympatec
Frequency of vibratingchannel: 100 % rising
Focal length: 200 mm (measuring range: 1.8 - 350
Nm)
Measuring time: about 10 s (in the case of 200 mg)
Cycle time: 10 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
transferred into the vibrating channel. A gap of 1.2 to 1.4 mm is set between
the
vibrating channel and funnel. After the start of the measurement the frequency
of the
vibrating channel is increased as continuously as possible to 100 % towards
the end
of the measurement.
III) Determining the specific surface area of tiotropium bromide
monohydrate, micronised ~1-point BET method:
Method:
The specific surface is determined by exposing the powder sample to a
nitrogen/helium atmosphere at different pressures. Cooling the sample causes
the
nitrogen molecules to be condensed on the surface of the particles. The
quantity of
condensed nitrogen is determined by means of the change in the thermal heat
conductivity of the nitrogen/helium mixture and the surface of the sample is
calculated by means of the surtace nitrogen requirement. Using this value and
the
weight of the sample, the specific surface is calculated.
Equipment and materials:
Measuring equipment: Monosorb, Messrs Quantachrome
Heater: Monotektor, Messrs Quantachrome
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
13
Measuring and drying gas: nitrogen (5.0) / helium (4.6) 70/30, Messer
Griesheim
Adsorbate: 30% nitrogen in helium
Coolant: liquid nitrogen
Measuring cell: with capillary tube, Messrs. W. Pabisch GmbH&Co.KG
Calibration peak; 1000 NI, Messrs. Precision Sampling Corp.
Analytical scale: R 160 P, Messrs. Satorius
Calculating the specific surface:
The measured values are indicated by the equipment in [m2] and are usually
converted into [cmz/g] on weighing (dry mass):
Aspez = specific surface [cm2lg]
Aspez = MW * 10000 MW = Measured value [m2]
m'r mtr = dry mass [g]
10000 = conversion factor [cm2/m2]
IV)_Determining the specific surtace area of the lactose (multi-point BET
method):
Method:
The specific surface is determined by exposing the powder sample to a nitrogen
atmosphere at different pressures. Cooling the sample causes the nitrogen
molecules to be condensed on the surface of the particles. The quantity of
condensed nitrogen is determined by means of the drop in pressure in the
system
and the specific surface of the sample is calculated by means of the surface
nitrogen
requirement and the weight of the sample.
The equipment is operated according to the manufacturer's instructions.
Measuring equipment and settings:
Measuring equipment Tri Star Multi Point BET, Messrs Micromeritics
Heater: VacPrep 061, Messrs. Micromeritics
Heating: about 12h / 40°C
Sample tube: '/z inch; use filler rod
Analysis Condition: 10 point BET surface 0,1 to 0,20 plp0
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
14
Absolute P. tolerance:5.0 mmHg
rel. P. tolerance:5.0 l
Evacuation rate:50.0 mmHg/sec.
Unrestricted 10.0 mmHg
evac f.:
Evac. time: 0.1 hours
Free Space: Lower Dewar, time: 0,5 h
Equilibration 20 sec
interv.:
Min. equl. delay:600 sec
Adsorptive: Nitrogen
V) Determining the heat of solution (enthalpy of solution) E~:
The solution enthalpy is determined using a solution calorimeter 2225
Precision
Solution Calorimeter made by Messrs. Thermometric.
The heat of solution is calculated by means of the change in temperature
occurring
(as a result of the dissolving process) and the system-related change in
temperature
calculated from the base line.
Before and after the ampoule is broken, electrical calibration is carried out
with an
integrated heating resistor of a precisely known power. A known heat output is
delivered to the system over a set period and the jump in temperature is
determined.
Method and equipment parameters:
Solution calorimeter: 2225 Precision Solution Calorimeter,
Messrs Thermometric
Reaction cell: 100 ml
Thermistor resistance:
30.0 kSZ (at
25 C)
Speed of stirrer:500 U/min
Thermostat: Thermostat of 2277 Thermal Activity Monitor
TAM, Messrs
Thermometric
Temperature: 25 C 0.0001 C (over 24h)
Measuring ampoules:Crushing ampoules 1 ml, Messrs Thermometric
Seal: Silicon stopper and beeswax, Messrs. Thermometric
Weight: 40 to 50 mg
Solvent: Chemically pure water
Volume of solvent:100 ml
Bath temperature:25C
Temperature resolution: High
Starting temperature:-40mK ( 10mK) temperature-offset
Intertace: 2280-002 TAM accessory interface 50 Hz,
Messrs Thermometric
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
Software: SoICaI V 1.1 for WINDOWS
Evaluation: Automatic evaluation with Menu point CALCULATION/
ANALYSE EXPERIMENT. (Dynamics of base line ; calibration
after breakage of ampoule).
Electrical calibration:
The electrical calibration takes place during the measurement, once before and
once
after the breakage of the ampoule. The calibration after the breakage of the
ampoule is used for the evaluation.
Amount of heat: 2.5 J
Heating power: 500 mW
Heating time: 10 s
Duration of base 5 min (before and after
lines: heating)
Preparation of the powder formulations according to the invention:
I) Ap~~aratus
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 6100, manufacturer: MG2 S.r.l, I-40065 Pian di Macina di Pianoro
(BO),
Italy
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
16
Example 1:
Powder mixture
To prepare the powder mixture, 299.39 g of excipient and 0.61 g of micronised
tiotropium bromide-monohydrate are used. In the resulting 300 g of inhalable
powder
the content of active substance is 0.2 % (based on tiotropium).
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 tiotropium bromide-monohydrate
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.
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:
Example 2:
tiotropium bromide monohydrate: 0.0113 mg
lactose monohydrate*~: 5.4887 mg
polyethylene capsules: 100.0 ma
Total: 105.5 mg
*~ the excipient is characterised by the following parameters:
average particle size: 17.9 Nm;
% fine content: 2.3 Nm;
specific surface: 0.61 mz/g;
Example 3:
tiotropium bromide monohydrate: 0.0113 mg
lactose monohydrate*~: 5.4887 mg
polyethylene capsules: 100.0 mq
Total: 105.5 mg
*~ the excipient is characterised by the following parameters:
average particle size: 18.5 Nm;
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
17
% fine content: 2.2 Nm;
specific surface: 0.83 m2/g;
Example 4:
tiotropium bromide monohydrate: 0.0113 mg
lactose monohydrate*~: 5.4887 mg
polyethylene capsules: 100.0 mg
Total: 105.5 mg
*~ the excipient is characterised by the following parameters:
average particle size: 21.6 pm;
10 % fine content: 2.5 Nm;
specific surface: 0.59 mz/g;
Example 5:
tiotropium bromide monohydrate:0.0113 mg
lactose monohydrate*': 5.4887 mg
polyethylene capsules: 100.0 mg
Total: 105.5 mg
*~ the excipient is characterised
by the following parameters:
average particle size: 16.0 pm;
10 % fine content: 2.0 Nm;
specific surface: 0.79 mz/g;
Example 6:
tiotropium bromide monohydrate:0.0225 mg
lactose monohydrate*': 5.4775 mg
polyethylene capsules: 100.0 mg
Total: 105.5 mg
*' the excipient is characterised
by the following parameters:
average particle size: 17.9 Nm;
10 % fine content: 2.3 Nm;
specific surface: 0.61 m2lg;
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
18
Example 7:
tiotropium bromide monohydrate:0.0225 mg
lactose monohydrate*~: 5.4775 mg
polyethylene capsules: 100.0 mg
Total: 105.5 mg
*' the excipient is characterised
by the following parameters:
average particle size: 18.5 pm;
% fine content: 2.2 pm;
specific surface: 0.83 m2/g;
Example 8:
tiotropium bromide monohydrate:0.0225 mg
lactose monohydrate*~: 5.4775 mg
polyethylene capsules: 100.0 mg
Total: 105.5 mg
*' the excipient is characterised
by the following parameters:
average particle size: 21.6 pm;
10 % fine content: 2.5 pm;
specific surface: 0.59 mz/g;
Example 9:
tiotropium bromide monohydrate:0.0225 mg
lactose monohydrate*': 5.4775 mg
polyethylene capsules: 100.0 mg
Total: 105.5 mg
*~ the excipient is characterised
by the following parameters:
average particle size: 16.0 pm;
10 % fine content: 2.0 pm;
specific surface: 0.79 m2/g;
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
19
Example 10:
tiotropium bromide monohydrate:0.0056 mg
lactose monohydrate*~: 5.4944 mg
polyethylene capsules: 100.0 mg
Total: 105.5 mg
*~ the excipient is characterised
by the following parameters:
average particle size: 17.9 pm;
% fine content: 2.3 Nm;
specific surface: 0.61 m2/g;
Example 11:
tiotropium bromide monohydrate:0.0056 mg
lactose monohydrate*': 5.4944 mg
polyethylene capsules: 100.0 mg
Total: 105.5 mg
*' the excipient is characterised
by the following parameters:
average particle size: 18.5 Nm;
10 % fine content: 2.2 Nm;
specific surface: 0.83 m2/g;
Example 12:
tiotropium bromide monohydrate:0.0056 mg
lactose monohydrate*~: 5.4944 mg
polyethylene capsules: 100.0 m4
Total: 105.5 mg
*~ the excipient is characterised
by the following parameters:
average particle size: 21.6 Nm;
10 % fine content: 2.5 pm;
specific surface: 0.59 mz/g;
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
Example 13:
tiotropium bromide monohydrate:0.0056 mg
lactose monohydrate*': 5.4944 mg
~olyethylene capsules: 100.0 mg
Total: 105.5 mg
*~ the excipient is characterised
by the following parameters:
average particle size: 16.0 Nm;
10 % fine content: 2.0 Nm;
specific surface: 0.79 m2/g;
Example 14:
tiotropium bromide monohydrate:0.0056 mg
lactose monohydrate*': 9.9944 mg
polyethylene capsules: 100.0 mg
Total: 110.0 mg
*' the excipient is characterised
by the following parameters:
average particle size: 17.9 Nm;
10 % fine content: 2.3 pm;
specific surface: 0.61 m2/g;
Example 15:
tiotropium bromide monohydrate:0.0113 mg
lactose monohydrate*~: 9.9887 mg
polyethylene capsules: 100.0 mg
Total: 110.0 mg
*' the excipient is characterised
by the following parameters:
average particle size: 18.5 Nm;
10 % fine content: 2.2 Nm;
specific surface: 0.83 m2lg;
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
21
Example 16:
tiotropium bromide monohydrate:
0.0225 mg
lactose monohydrate*~: 9.9775 mg
polyethylene capsules: 100.0 mg
Total: 110.0 mg
*~ the excipient is by the following parameters:
characterised
average particle size: 21.6 Nm;
% fine content: 2.5 Nm;
specific surface: 0.59 m2/g;
Example 17:
tiotropium bromide monohydrate: 0.0125 mg
lactose monohydrate*~: 9.9875 mg
polyethylene capsules: 100.0 mg
Total: 110.0 mg
*~ the excipient is characterised by the following parameters:
average particle size: 17.9 Nm;
10 % fine content: 2.3 pm;
specific surface: 0.61 m2/g;
Example 18:
tiotropium bromide monohydrate: 0.0125 mg
lactose monohydrate*': 9.9875 mg
polyethylene capsules: 100.0 mg
Total: 110.0 mg
*~ the excipient is characterised by the following parameters:
average particle size: 18.5 pm;
10 % fine content: 2.2 Nm;
specific surtace: 0.83 mzlg;
WO 2004/047796 CA 02507579 2005-05-26 PCT/EP2003/012911
22
Example 19:
tiotropium bromide monohydrate: 0.0125 mg
lactose monohydrate*': 9.9875 mg
polyethylene capsules: 100.0 mg
Total: 110.0 mg
*~ the excipient is characterised by the following parameters:
average particle size: 21.6 Nm;
% fine content: 2.5 Nm;
specific surface: 0.59 m2/g;
Example 20:
tiotropium bromide monohydrate:0.0125 mg
lactose monohydrate*': 9.9875 mg
polyethylene capsules: 100.0 mg
Total: 110.0 mg
*~ the excipient is characterised
by the following parameters:
average particle size: 16.0 Nm;
10 % fine content: 2.0 pm;
specific surface: 0.79 m2/g;
