Note: Descriptions are shown in the official language in which they were submitted.
,, Case 1/1171-foreign ' ~ BOEHRINGER INGELHEIM PHARMA KG
74511 fft.205
New pharmaceutical compositions based on tiotropium salts and salts of
salmeterol
The present invention relates to novel pharmaceutical compositions based on
tiotropium salts and salts of salmeterol, processes for preparing them and
their use
in the treatment of respiratory complaints.
Background to the invention
The compound tiotropium bromide, a salt of tiotropium, is known from European
Patent Application EP 418 716 A1 and has the following chemical structure
+ Me
Me-.N~
O _
~H Br
O
O
H
This compound may also be referred to by its chemical name (1a.,2a,4a,5oc,7a)-
7-
[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-
azoniatricyclo[3.3.1.02'4]nonane
bromide and has valuable pharmacological properties. The name tiotropium is
intended to refer to the free cation for the purposes of the present
invention.
Like other salts of tiotropium, it is a highly effective anticholinergic and
can therefore
provide therapeutic benefit in the treatment of asthma or COPD (chronic
obstructive
pulmonary disease).
Tiotropium salts are preferably administered by inhalation. Suitable inhalable
powders packed into appropriate capsules (inhalettes) and administered using
suitable powder inhalers may be used. Alternatively, they 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
propellant gas.
The tiotropium salts may also be inhaled in the form of suitable solutions.
CA 02429012 2003-04-28
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2
Detailed description of the invention
Surprisingly, it has been found that an unexpectedly beneficial therapeutic
effect,
more particularly a synergistic effect, in the treatment of inflammatory or
obstructive
respiratory complaints is observed when one or more tiotropium salts (~ are
used in
conjunction with one or more salmeterol salts (2).
As a result, it is possible to reduce substantially the undesirable side
effects which
often occur, for example, in the administration of ~i-mimetics such as
salmeterol to
humans. Examples of the central side effects of ~i-mimetics include general
malaise,
excitation, sleeplessness, anxiety, trembling fingers, sweats and headaches.
The name tiotropium is intended to refer to the free cation (~ for the
purposes of the
present invention. References to salmeterol are intended as references to the
free
base (2') for the purposes of the present invention.
The combinations of active substances according to the invention are
surprisingly
also characterised by a rapid onset of activity and also by long-lasting
effects. This
is of great importance to the wellbeing of the patient as, on the one hand,
they
experience a rapid improvement in their condition after administration of the
combination and, on the other hand, a single administration per day is
sufficient,
thanks to the long-lasting effect.
The abovementioned effects are observed both after the simultaneous
administration within a single active substance formulation and also after the
successive administration of the two active substances in separate
formulations. It is
preferred according to the invention to administer the two active substance
ingredients simultaneously in a single formulation.
In one aspect the present invention relates to a pharmaceutical composition
which
contains one or more tiotropium salts (~ and one or more salmeterol salts (2
),
optionally in the form of the solvates or hydrates thereof. The active
substances may
be contained either together in a single preparation or in two separate
preparations.
According to the invention, pharmaceutical compositions which contain the
active
substances 1 and 2 in a single preparation are preferred.
According to another aspect the present invention relates to a pharmaceutical
composition which contains, in addition to therapeutically effective amounts
of 1 and
2, a pharmaceutically acceptable excipient. In one aspect the present
invention
CA 02429012 2003-04-28
3
relates to a pharmaceutical composition which contains, in addition to
therapeutically
effective amounts of 1 and 2, no pharmaceutically acceptable excipient.
The present invention further relates to the use of 1 and 2 for preparing a
pharmaceutical composition containing therapeutically effective amounts of 1
and 2
for the treatment of inflammatory or obstructive respiratory complaints,
particularly
asthma or COPD, by simultaneous or successive administration.
The present invention is also directed to the simultaneous or successive use
of
therapeutically effective doses of the combination of the abovementioned
pharmaceutical compositions 1 and 2 for the treatment of inflammatory or
obstructive
respiratory complaints, particularly asthma or COPD.
The tiotropium salts 1 which may be used within the scope of the present
invention
include the compounds which contain, in addition to tiotropium, chloride,
bromide,
iodide, methanesulphonate, para-toluenesulphonate or methylsulphate as counter-
ion (anion). Within the scope of the present invention, of all the tiotropium
salts, the
methanesulphonate, chloride, bromide or iodide are preferred, the
methanesulphonate or bromide being of particular importance. Tiotropium
bromide is
of exceptional importance according to the invention.
By salts of salmeterol 2 are meant, according to the invention,
pharmaceutically
acceptable salts 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, xinafonic acid
or malefic acid,
with the proviso that 2 cannot denote salmeterol xinafoate if 1 denotes
tiotropium
bromide. Mixtures of the abovementioned acids may optionally also be used to
prepare the salmeterol salts.
According to the invention, the salmeterol salts 2 selected from among
hydrochloride, hydrobromide, sulphate, phosphate and methanesulphonate are
preferred. The salts of 2 selected from hydrochloride and sulphate are
particularly
preferred, especially the sulphates. Salmeterol x %2 H2S04 is of exceptional
importance according to the invention.
In the combinations of active substances according to the invention consisting
of 1
and 2 the ingredients 1 and 2 may be in the form of their enantiomers,
mixtures of
enantiomers or in the form of the racemates.
r CA 02429012 2003-04-28
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The proportions in which the two active substances 1 and 2 may be used in the
combinations of active substances according to the invention are variable. The
active
substances 1 and 2 may optionally be in the form of the solvates or hydrates
thereof.
Depending on the choice of the salts 1 or 2 the weight ratios which may be
used for
the purposes of the present invention vary on account of the different
molecular
weights of the various salt forms. Consequently, the weight ratios specified
hereinafter are based on the tiotropium cation 1' and the free base of
salmeterol 2'.
The combinations of active substances according to the invention may contain
1' and
2' in weight ratios in the range from 1:300 to 30:1, preferably from 1:230 to
20:1,
particularly preferably from 1:150 to 10:1, more preferably from 1:50 to 5:1,
particularly preferably from 1:35 to 2:1. Of particular interest according to
the
invention are pharmaceutical compositions containing the combination of 1' and
2' in
a weight ratio in the range from 1:25 to 1:1, preferably in the range from
1:10 to 1:2,
particularly preferably in the range from 1:5 to 1:2.5.
For example, without restricting the scope of the invention, preferred
combinations of
1 and 2 according to the invention may contain tiotropium 1' and salmeterol 2'
in the
following weight ratios: 1:40; 1:20; 1:11.1; 1:10; 1:5.6; 1:5; 1:2.8; 1:2.5;
1:1.4; 1:1.25;
1.44:1, 1.8:1.
The pharmaceutical compositions according to the invention containing the
combinations of 1 and 2 are normally used so that tiotropium 1' and salmeterol
2'
are administered together in doses of 0.01 to 10000 pg, preferably 0.1 to 2000
Ng,
particularly preferably from 1 to 1000 Ng, more preferably from 5 to 500 Ng,
preferably, according to the invention, from 10 to 200 ug, preferably from 20
to
100pg, most preferably from 30 to 70 pg per single dose.
For example, combinations of 1 and 2 according to the invention contain an
amount
of tiotropium 1' and salmeterol 2' such that the total dosage per single dose
is 30Ng,
35Ng, 45ug, 55pg, 60Ng, 65ug, 90pg, 105Ng, 110ug, 110Ng, 140Ng or similar. In
these dosage ranges the active substances 1' and 2' are present in the weight
rations described hereinbefore.
For example, without restricting the scope of the invention, the combinations
of 1 and
2 according to the invention may contain an amount of tiotropium 1' and
salmeterol
2' such that 5Ng of 1' and 25Ng of 2', 5Ng of 1' and 50ug of 2', 5~rg of 1'
and 100Ng
of 2', 5Ng of 1' and 200Ng of 2', 10pg of 1' and 25Ng of 2', 10Ng of 1' and
50pg of 2',
10Ng of 1' and 100Ng of 2', 10Ng of 1' and 200pg of 2', 18pg of 1' and 25pg of
2',
18Ng of 1' and 50Ng of 2', 18Ng of 1' and 100pg of 2', 18Ng of 1' and 200Ng of
2',
CA 02429012 2003-04-28
20Ng of 1' and 25Ng of 2', 20Ng of 1' and 50pg of 2', 20pg of 1' and 100pg of
2',
20Ng of 1' and 200Ng of 2', 36Ng of 1' and 25Ng of 2', 36pg of 1' and 50trg of
2',
36pg of 1' and 100pg of 2', 36pg of 1' and 200pg of 2', 40~g of 1' and 25Ng of
2',
40Ng of 1' and 50pg of 2', 40ug of 1' and 100pg of 2' or 40Ng of 1' and 200Ng
of 2'
are administered per single dose.
If the active substance combination in which 1 denotes tiotropium bromide and
2
denotes salmeterol x'/ZH2S04 is used as the preferred combination of 1 and 2
according to the invention, the quantities of active substances 1' and 2'
administered
per single dose as specified above by way of example correspond to the
following
quantities of 1 and 2 administered per single dose: hug of 1 and 27.9pg of 2,
6pg of
1 and 55.9Ng of 2, 6pg of 1 and 111.8trg of 2, 6pg of 1 and 223.6Ng of 2, 12pg
of 1
and 27.9pg of 2, 12Ng of 1 and 55.9Ng of 2, 12Ng of 1 and 111.8pg of 2, 12pg
of 1
and 223.6Ng of 2, 21.7Ng of 1 and 27.9Ng of 2, 21.7pg of 1 and 55.9pg of 2,
21.7Ng
of 1 and 111.8Ng of 2, 21.7Ng of 1 and 223.6pg of 2, 24.1 pg of 1 and 27.9pg
of 2,
24.1 Ng of 1 and 55.9Ng of 2, 24.1 Ng of 1 and 111.8Ng of 2, 24.1 pg of 1 and
223.6Ng
of 2, 43.3pg of 1 and 27.9Ng of 2, 43.3pg of 1 and 55.9Ng of 2, 43.3pg of 1
and
111.BNg of 2, 43.3pg of 1 and 223.6Ng of 2, 48.1 Ng of 1 and 27.9Ng of 2, 48.1
pg of 1
and 55.9pg of 2, 48.1 pg of 1 and 111.8pg of 2 or 48.1 Ng of 1 and 223.6Ng of
2.
If, in the combination of 1 and 2 preferred according to the invention,
wherein 2
denotes salmeterol x'hH2S04 tiotropium bromide monohydrate is used as 1, for
example, the quantities of active substances 1' and 2' administered per single
dose
as specified above by way of example correspond to the following quantities of
1 and
2 administered per single dose: 6.2ug of 1 and 27.9~rg of 2, 6.2pg of 1 and
55.9Ng
of 2, 6.2pg of 1 and 111.8pg of 2, 6.2pg of 1 and 223.6pg of 2, 12.5pg of 1
and
27.9pg of 2, 12.5Ng of 1 and 55.9pg of 2, 12.5pg of 1 and 111.BNg of 2, 12.5ug
of 1
and 223.6~rg of 2, 22.5Ng of 1 and 27.9pg of 2, 22.5pg of 1 and 55.9pg of 2,
22.5Ng
of 1 and 111.8Ng of 2, 22.5pg of 1 and 223.6Ng of 2, 25Ng of 1 and 27.9Ng of
2,
25Ng of 1 and 55.9Ng of 2, 25pg of 1 and 111.BNg of 2, 25Ng of 1 and 223.6ug
of 2,
45Ng of 1 and 27.9Ng of 2, 45Ng of 1 and 55.9Ng of 2, 45pg of 1 and 111.8Ng of
2,
45Ng of 1 and 223.6pg of 2, 50Ng of 1 and 27.9pg of 2, 50pg of 1 and 55.9Ng of
2,
50Ng of 1 and 111.8Ng of 2 or 50pg of 1 and 223.6pg of 2.
The combinations of active substances 1 and 2 according to the invention are
preferably administered by inhalation. For this purpose, the ingredients 1 and
2 have
to be incorporated in inhalable preparations.
CA 02429012 2003-04-28
6
Suitable inhalable preparations include inhalable powders, metering aerosols
containing propellant gases or inhalable solutions free from propellant gases.
Inhalable powders according to the invention containing the active substance
combination of 1 and 2 may consist solely of the abovementioned active
substances
or of a mixture of the abovementioned active substances with physiologically
acceptable adjuvants. Within the scope of the present invention the term
propellant-
free solutions for inhalation also includes concentrates or sterile, ready-to-
use
solutions for inhalation. The preparations according to the invention may
contain the
active substance combination of 1 and 2 either together in one preparation or
in two
separate preparations. These preparations which may be used within the scope
of
the present invention are described in detail in the following section of the
specification.
A) Inhalable powders containing the active substance combinations of 1 and 2
according to the invention
The powders for inhalation according to the invention may contain _1 and 2
either on
their own or in admixture with suitable physiologically harmless adjuvants
If the active substances 1 and 2 are present in admixture with physiologically
harmless adjuvants, the following physiologically harmless adjuvants may be
used
to prepare these inhalable powders according to the invention: monosaccharides
(e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose,
maltose), oligo-
and polysaccharides (e.g. dextranes), polyalcohols (e.g. sorbitol, mannitol,
xylitol),
salts (e.g. sodium chloride, calcium carbonate) or mixtures of these adjuvants
with
one another. Mono- or disaccharides are preferably used, the use of lactose or
glucose, particularly but not exclusively in the form of their hydrates, being
preferred.
The particularly preferred adjuvant according to the invention is lactose,
most
preferably lactose monohydrate.
Within the scope of the powders for inhalation according to the invention the
adjuvants have a maximum mean particle size of up to 250um, preferably between
and 150pm, particularly preferably between 15 and 80Nm. If desired it may be
useful to add finer adjuvant fractions having a mean particle size of 1 to 9Nm
to the
abovementioned adjuvants. These latter finer adjuvants are also selected from
the
abovementioned group of adjuvants which may be used. Finally, in order to
prepare
the powders for inhalation according to the invention, micronised active
substance _1
and 2, preferably having an average particle size of 0.5 to 10pm, particularly
CA 02429012 2003-04-28
7
preferably from 1 to 6pm, is added to the adjuvant mixture. Processes for
preparing
the powders for inhalation according to the invention by grinding and
micronising and
finally mixing the ingredients together are known from the prior art. The
powders for
inhalation 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 and 2.
The inhalable powders according to the invention can be administered using
inhalers
known from the prior art.
Inhalable powders according to the invention which contain a physiologically
harmless adjuvant in addition to 1 and 2 may for example be administered using
inhalers which meter a single dose from a reservoir by means of a measuring
chamber, as described in US 4570630A, or by other devices as described in DE
36
25 685 A. Preferably, the inhalable powders according to the invention which
contain
physiologically harmless adjuvant in addition to 1 and 2 are packed into
capsules (to
form so-called inhalettes), which are used in inhalers such as those
described, for
example, in WO 94/28958.
If the inhalable powders according to the invention are to be packed into
capsules
(inhalettes) as in the preferred application mentioned above, fillings of 1 to
30mg,
preferably from 3 to 20mg, preferably 5 to 10 mg of inhalable powder per
capsule
are suggested. According to the invention, these contain the dosages specified
above for 1' and 2' either together or separately per single dose.
B) Inhalable aerosols containing propellant, comprising the active substance
combinations of 1 and 2 according to the invention:
Inhalable aerosols containing propellant according to the invention may
contain 1
and 2 dissolved in the propellent gas or in dispersed form. 1 and 2 may be
present
in separate preparations or in a combined preparation, with 1 and 2 either
both
dissolved, both dispersed or only one component dissolved while the other is
present in dispersed form.
The propellent gases which can be used to prepare the inhalable aerosols
according
to the invention are known from the prior art. Suitable propellent gases are
selected
from among hydrocarbons such as n-propane, n-butane or isobutane and
halohydrocarbons such as chlorinated and/or fluorinated derivatives of
methane,
ethane, propane, butane, cyclopropane or cyclobutane. The abovementioned
propellent gases may be used on their own or in mixtures thereof. Particularly
preferred propellent gases are halogenated alkane derivatives selected from
among
TG11, TG12, TG134a and TG227. Of the abovementioned halogenated
CA 02429012 2003-04-28
s
hydrocarbons, TG134a (1,1,1,2-tetrafluoroethane) and TG227 (1,1,1,2,3,3,3-
heptafluoropropane) and mixtures thereof are preferred according to the
invention.
The propellant-gas-containing inhalable aerosols according to the invention
may also
contain other ingredients such as cosolvents, stabilisers, surface-active
agents
(surfactants), antioxidants, lubricants and means for adjusting the pH. All
these
ingredients are known in the art.
The propellant-gas-containing inhalable aerosols according to the invention
may
contain up to 5 % by weight of active substance 1 and/or 2. Aerosols according
to
the invention contain, for example, 0.002 to 5 % by weight , 0.01 to 3 % by
weight ,
0.015 to 2 % by weight , 0.1 to 2 % by weight , 0.5 to 2 % by weight or 0.5 to
1 % by
weight of active substance 1 andlor 2.
If the active substances 1 andlor 2 are present in dispersed form the
particles of
active substance preferably have a mean particle size of up to 10 Nm,
preferably
from 0.1 to 5 pm, particularly preferably from 1 to 5 Nm.
The abovementioned propellant-gas-containing inhalable aerosols according to
the
invention can be administered by means of inhalers known in the art (MDIs =
metered dose inhalers). Accordingly, a further aspect of the present invention
relates
to pharmaceutical compositions in the form of propellant-gas-containing
aerosols as
described above combined with one or more inhalers suitable for administering
these
aerosols. Furthermore, the present invention relates to inhalers,
characterised in that
they contain the propellant-gas-containing aerosols according to the invention
as
described above.
The present invention also relates to cartridges which are fitted with a
suitable valve
and can be used in a suitable inhaler and which contain one of the
abovementioned
propellant-gas-containing inhalable aerosols according to the invention.
Suitable
cartridges and methods of filling these cartridges with the propellant-gas-
containing
inhalable aerosols according to the invention are known from the prior art.
C) Propellant-free inhalable solutions containing the active substance
combinations of 1 and 2 according to the invention:
It is particularly preferable for the active substance combination according
to the
invention to be administered in the form of propellant-free solutions for
inhalation.
Suitable solvents for this include aqueous or alcoholic, preferably ethanolic
solutions.
The solvent may be water on its own or a mixture of water and ethanol. The
relative
CA 02429012 2003-04-28
9
proportion of ethanol to water is not restricted, but the maximum limit is
preferably up
to 70 percent by volume, particularly up to 60 percent by volume and most
preferably
up to 30 percent by volume. The remaining percent by volume are made up with
water. The preferred solvent is water without the addition of ethanol. The
solutions
containing 1 and 2 , separately or together, are adjusted to a pH of 2 to 7,
preferably
2 to 5, particularly preferably 2.5 to 3.5, with suitable acids. Most
preferably,
inhalable solutions according to the invention which contain 1 and 2 together
have a
pH of about 2.9. This pH may be achieved using acids selected from among
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 acid, malefic acid, succinic acid, fumaric acid,
acetic acid,
formic acid and/or propionic acid and others. Preferred inorganic acids are
hydrochloric acid and sulphuric acid. It is also possible to use the acids
which are
forming an acid addition salt with the active substance or, in the case of
combined
preparations, with one of the active substances. Of the organic acids,
ascorbic acid,
fumaric acid and citric acid are preferred. If desired, mixtures of the
abovementioned
acids may also be used, particularly in the case of acids which have
properties other
than their acidifying properties, e.g. as flavourings, antioxidants or
complexing
agents, such as citric acid or ascorbic acid, for example. According to the
invention,
it is particularly preferred to use hydrochloric acid to adjust the pH.
According to the invention, there is no need to add editic acid (EDTA) or one
of the
known salts thereof, sodium edetate, to the present formulation as a
stabiliser or
complexing agent.
Other embodiments contains these compound(s).
In a preferred embodiment of this kind, the content based on sodium edetate is
less
than 100 mg I 100 ml, preferably less than 50 mg/100 ml, most preferably less
than
20 mg/100 ml.
Inhalable solutions in which the content of sodium edetate is 0 to 10mgI100m1
are
generally preferred.
Co-solvents and/or other adjuvants may be added to the propellant-free
inhalable
solutions according to the invention.
Preferred co-solvents are those which contain hydroxyl groups or other polar
groups,
e.g. alcohols - particularly isopropylalcohol, glycols - particularly
propyleneglycol,
polyethyleneglycol, polypropyleneglycol, glycolether, glycerol,
polyoxyethylene
alcohols and polyoxyethylene fatty acid esters.
CA 02429012 2003-04-28
By excipients and additives is meant, in this context, any pharmacologically
acceptable substance which is not an active substance, but can be formulated
together with the active substances) in the pharmacologically suitable
solvent, in
order to improve the qualitative properties of the active substance
formulation.
Preferably, these substances do not have any appreciable pharmacological
effects
or at least have no undesirable effects in the context of the intended
therapy. The
excipients and additives include e.g. surfactants such as e.g. soya lecithin,
oleic acid,
sorbitan esters such as polysorbates, polyvinylpyrrolidone, other stabilisers,
complexing agents, antioxidants and/or preservatives which guarantee or extend
the
shelf life of the finished pharmaceutical formulation, flavourings, vitamins
and/or
other additives known in the art. The additives also include pharmacologically
harmless salts such as sodium chloride, for example, as isotonic agents.
The preferred adjuvants include antioxidants, such as ascorbic acid, for
example,
unless it has already been used to adjust the pH, vitamin A, vitamin E,
tocopherols
and similar vitamins or provitamins occurring in the human body.
Preservatives can be used to protect the formulation from contamination with
pathogens. Suitable preservatives are those known from the prior art,
particularly
cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates
such
as sodium benzoate in the concentration known from the prior art. The
abovementioned preservatives are preferably present in concentrations of up to
50mg/100m1, particularly between 5 and 20 mg/100m1.
Preferred formulations contain only benzalkonium chloride and sodium edetate
in
addition to the solvent water and the active substance combination of _1 and
2.
In another preferred embodiment, sodium edetate is omitted.
The propellant-free inhalable solutions according to the invention may be
administered particularly using inhalers which are able to nebulise a small
amount of
a liquid formulation in the therapeutically necessary dose within a few
seconds to
form an aerosol suitable for therapeutic inhalation. Within the scope of the
present
invention, nebulisers are preferred in which a quantity of less than 100 NL,
preferably
less than 50 NL, particularly preferably between 20 and 30 pL of active
substance
solution can be nebulised, preferably in one operation, to produce an aerosol
having
an average particle size of less than 20 pm, preferably less than 10 Nm, in
such a
way that the inhalable part of the aerosol corresponds to the therapeutically
effective
amount.
CA 02429012 2003-04-28
11
A device of this kind for the propellant-free administration of a metered
amount of a
liquid pharmaceutical composition for inhalation is described in detail, for
example, in
International Patent Application WO 91114468 and also in WO 97112687
(particularly
Figures 6a and 6b). The nebulisers (devices) described therein are also known
by
the name Respimat~.
This nebuliser (Respimat~) can advantageously be used to produce inhalable
aerosols according to the invention containing the active substance
combination of _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 anywhere by the patient. The
nebuliser
sprays a defined volume of the pharmaceutical formulation under high pressure
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 clamp, a spring housing, a spring and a storage
container, characterised by
- a pump housing which is fixed in the upper housing part and carries, at one
end, a nozzle member with the nozzle or nozzle arrangement,
- a hollow piston with valve member,
- a power take-off flange in which the hollow piston is secured, and which is
located in the upper housing part,
- a locking clamp which is located in the upper housing part,
- a spring housing with the spring located 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 piston with valve member corresponds to a device disclosed in WO
97/12687. It projects partially into the cylinder of the pump housing and is
mounted
to be axially movable in the cylinder. Reference is made particularly to
Figures 1-4 -
particularly Figure 3 - and the associated parts of the description. At the
moment of
actuation of the spring, the hollow piston with valve member exerts a pressure
at its
high pressure end 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 quantity of active substance
solution. Volumes of 10 to 50 microlitres are preferred, volumes of 10 to 20
microlitres are particularly preferred, while a volume of 15 microlitres per
spray is
most particularly preferred.
CA 02429012 2003-04-28
12
The valve member is preferably mounted at the end of the hollow piston facing
the
nozzle member.
The nozzle in the nozzle member is preferably microstructured, i.e. produced
by
microtechnology. Microstructured nozzle members are disclosed, for example, in
WO-94/07607; reference is hereby made to this specification, particularly
Figure 1
and the description thereof.
The nozzle member consists e.g. of two sheets of glass andlor 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 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 and the length 7 to 9
microns.
In the event of a plurality of nozzle openings, two being preferred, the
directions of
the jets from the nozzles in the nozzle member run parallel or slope relative
to one
another in the direction of the nozzle opening. In the case of a nozzle member
with
at least two nozzle openings at the inlet end the directions of the jets may
be inclined
relative to one another at an angle of 20 degrees to 160 degrees, preferably
60 to
150 degrees, 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.
A spacing of 50 microns is most preferred.
The directions of the jets accordingly meet in the vicinity of the nozzle
openings.
The liquid pharmaceutical preparation meets the nozzle member at an entry
pressure of up to 600 bar, preferably 200 to 300 bar, and is atomised by means
of
the nozzle openings to form an inhalable aerosol. The preferred particle or
droplet
sizes of the aerosol are up to 20 microns, preferably 3 to 10 microns.
The locking clamp contains a spring, preferably a cylindrical helical
compression
spring, as a store for mechanical energy. The spring acts on the power take-
off
flange as spring member, the movement of which is determined by the position
of a
locking member. The travel of the power take-off flange is precisely limited
by an
upper and lower stop. The spring is preferably tensioned by a force-
transmitting
gear, e.g. a helical thrust gear, by means of an external torque which is
produced by
rotating the upper housing part relative to the spring housing in the lower
housing
part. In this case, the upper housing part and the power take-off flange
contain a
single or multiple spline gear.
CA 02429012 2003-04-28
13
The locking member with engaging locking surfaces is annually disposed about
the
power take-off flange. It consists, for example, of an inherently radially
elastically
deformable ring made of plastics or metal. The ring is disposed in a plane at
right
angles to the atomiser axis. After the tensioning of the spring, the locking
surfaces
of the locking member move into the path of the power take-off flange and
prevent
the spring from being released. The locking member is actuated by a button.
The
actuating button is connected or coupled to the locking member. In order to
actuate
the locking clamp, the actuating button is pushed parallel to the ring plane,
preferably
into the atomiser; at the same time the deformable ring is deformed in the
ring plane.
Details of the construction of the locking clamp are described 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
housing part, the latter carrying the spring housing with it. The spring is
compressed
and tensioned 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 tensioned,
the
power take-off component is pushed a certain distance in the upper housing
part, the
hollow piston is pulled back within the cylinder in the pump housing, as a
result of
which some of the fluid is sucked out of the storage container into the high
pressure
chamber in front of the nozzle.
A plurality of exchangeable storage containers containing the fluid to be
atomised
can be pushed into the atomiser as required and then used. The storage
container
contains the aqueous aerosol preparation according to the invention.
The atomising process is initiated by gently pressing the actuating button.
The
locking mechanism then opens the way for the power take-off component. The
tensioned spring pushes the piston into the cylinder of the pump housing. The
fluid
leaves the nozzle of the atomiser in atomised form.
Other details of construction are disclosed in PCT applications WO 97/12683
and
WO 97/20590, to which reference is hereby made.
CA 02429012 2003-04-28
14
The components of the atomiser (nebuliser) are made from a material suitable
for
their purpose. The housing of the atomiser and - if operation permits - other
components too are preferably made of plastics, e.g. by injection moulding.
For
medical purposes, physiologically harmless materials are used.
Figures 1 a/b, which are identical to Figure 6 alb of WO 97/12687, illustrate
the
nebuliser (Respimat~) with which the aqueous aerosol preparations according to
the
invention can advantageously be inhaled.
Figure 1 a shows a longitudinal section through the atomiser with the spring
under
tension, Figure 2 b shows a longitudinal section through the atomiser with the
spring
released.
The upper housing part (51 ) contains the pump housing (52), at whose end is
mounted the holder (53) for the atomiser nozzle. In the holder is the nozzle
member
(54) and a filter (55). The hollow piston (57) secured in the power take-off
flange (56)
of the locking clamp projects partially into the cylinder of the pump housing.
At its
end the hollow piston carries the valve member (58). The hollow piston is
sealed off
by means of the gasket (59). Inside the upper housing part is the stop (60) on
which
the power take-off flange abuts when the spring is released. On the power take-
off
flange is the stop (61 ) on which the power take-off flange abuts when the
spring is
tensioned. After the spring has been tensioned, 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 cap (66) which
can be
fitted thereon.
The spring housing (67) with compression spring (68) is rotatably mounted on
the
upper housing part by means of the snap-fit lugs (69) and rotary bearing. The
lower
housing part (70) is pushed over the spring housing. Inside the spring housing
is the
replaceable storage container (71 ) for the fluid which is to be atomised
(72). The
storage container is sealed off by means of the stopper (73) through which the
hollow piston projects into the storage container and dips its end in the
fluid (store of
active substance solution).
The spindle (74) for the mechanical counter is mounted in the casing surface
of the
spring housing. The drive pinion (75) is located on the end of the spindle
which
faces the upper housing part. The slider (76) is located on the spindle.
CA 02429012 2003-04-28
The nebuliser described above is suitable for nebulising the aerosol
preparations
according to the invention to form an aerosol suitable for inhalation.
If the formulation according to the invention is nebulised by the technology
described
above (Respimat~), the mass delivered should correspond to a defined amount
with
a tolerance range of not more than 25%, preferably 20% of this amount, in at
least
97%, preferably at least 98% of all actuations (sprays) of the inhaler.
Preferably,
between 5 and 30 mg, particularly preferably between 5 and 20 mg of
formulation,
are delivered per spray as a defined mass.
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.
Accordingly, in another aspect, the present invention relates to
pharmaceutical
compositions in the form of propellant-free inhalable solutions as described
above in
conjunction with a device suitable for administering these solutions,
preferably in
conjunction with the Respimat~. The present invention is preferably directed
to
propellant-free inhalable solutions characterised by the active substance
combination of _1 and 2 according to the invention in conjunction with the
device
known by the name Respimat~. Moreover, the present invention relates to the
inhalation devices mentioned above, preferably the Respimat~, characterised in
that
they contain the propellant-free inhalable solutions according to the
invention
described hereinbefore.
The propellant-free solutions for inhalation according to the invention may
also be
presented as concentrates or sterile ready-to-use solutions for inhalation, in
addition
to the abovementioned solutions intended for administration using the
Respimat.
Ready-to-use solutions for inhalation may be produced from the concentrates,
for
example by the addition of isotonic saline solutions. Sterile ready-to-use
solutions for
inhalation can be administered using energy-operated free-standing or portable
nebulisers which produce inhalable aerosols by 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 as described
above,
which take the form of concentrates or sterile ready-to-use solutions, in
conjunction
with a device suitable for administering these solutions, characterised in
that this
CA 02429012 2003-04-28
16
device is an energy-operated free-standing or portable nebuliser which
produces
inhalable aerosols by ultrasound or compressed air by the venturi principle or
other
principles.
The following Examples serve to illustrate the present invention in more
detail,
although without restricting the scope of the invention to the following
embodiments
provided by way of example.
~
, CA 02429012 2003-04-28
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Starting materials
Tiotropium bromide:
The tiotropium bromide used in the following examples of formulations may be
obtained as described in European Patent Application EP 418 716 A1.
The inhalable powders according to the invention may also be prepared using
crystalline tiotropium bromide monohydrate. This crystalline tiotropium
bromide
monohydrate may be obtained by the following method.
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 tiotropium bromide-
containing solution 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 at 3-
5°C per 20
minutes to a temperature of 20-25°C. The apparatus is further cooled to
10-15°C
using cold water and crystallisation is completed by stirring for at least one
hour. The
crystals are isolated using a suction drier, the isolated crystal slurry is
washed with 9
litres 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)
The crystalline tiotropium bromide rnonohydrate thus obtained is micronised by
known methods in order to prepare the active substance in the form of the
average
particle size which corresponds to the specifications according to the
invention.
Salmeterol x'/ZH2S04_
Where reference is made to salmeterol x %Z H2S04 in the following embodiments,
this was obtained as follows:
A suspension of 2.5 g (4.15 mmol) of salmeterol xinafoate is dissolved in 6 ml
of
ethanol. A solution of 0.14 ml of 98% sulphuric acid is slowly added to the
suspension with stirring. It is heated to 35-40 °C until fully
dissolved. Then the
solution is diluted with 10 ml of diethylether and inoculated with salmeterol
sulphate.
The salmeterol sulphate is suction filtered after 1.5 hours and washed with 20
ml of
cold ethanol, acetone and diethylether.
1.5 g (78%) of salmeterol '/2-sulphate are obtained.
CA 02429012 2003-04-28
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Examples of formulations
A) Powders for inhalation:
1)
Ingredients Ng per capsule
tiotropium bromide 10.8
salmeterol x'/2 H SO 27.9
lactose 4961.3
Tota I 5000
2)
Ingredients pg per capsule
tiotropium bromide 21.7
salmeterol x'h H SO 55.9
lactose 4922.4
Total 5000
3)
Ingredients Ng per capsule
tiotropium bromide x 22.5
H O
salmeterol x %2 H SO 55.9
lactose 4921.6
Total 5000
B) Inhalable aerosols containing propellants:
1 ) Suspension aerosol:
Ingredients % by weight
tiotropium bromide 0.015
salmeterol X '/2 H SO 0.066
soya lecithin 0.2
TG 11 : TG12 = 2:3 ad 100
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2) Suspension aerosol:
Ingredients % by weight
tiotropium bromide 0.029
salmeterol x %2 H SO 0.033
absolute ethanol 0.5
isopropyl m ristate 0.1
TG 227 ad 100
3) Solution aerosol:
Ingredients % by weight
tiotropium bromide 0.042
salmeterol X ~~2 H SO 0.047
absolute ethanol 30
purified water 1.5
anhydrous citric acid 0.002
TG 134a ad 100
C) Propellant-free inhalable solutions:
1 ) Solution for use in the Respimat~:
Ingredients mg1100mL
tiotropium bromide 148.5
salmeterol x %2 H SO 276.7
benzalkonium chloride 10
sodium edetate 10
hydrochloric acid (aq) ad pH 2.9
water ad 100 mL
Use of the solution in the Respimat leads to a dosage of 10 pg per dose of 1
and 25 pg/dose of 2.
CA 02429012 2003-04-28
2) Solution for use in the Respimat~:
_ Ingredients mg1100mL
tiotropium bromide 148.5
salmeterol X 1/2 H SO 276.7
benzalkonium chloride 10
hydrochloric acid (aq) ad pH 2.9
water ad 100mL
Use of the solution in the Respimat leads to a dosage of 10 Ng per dose of 1
and 25 pg/dose of 2.
3) Solution for use in the Respimat~:
Ingredients mg1100mL
tiotropium bromide 297.1
salmeterol X 1/2 H SO 276.7
benzalkoniurn chloride 10
sodium edetate 10
hydrochloric acid (aq) ad pH 2.9
water ad 100 mL
Use of the solution in the Respimat leads to a dosage of 20 pg per dose of 1
and 25 Ng/dose of 2.
4) Solution for use in the Respimat~:
Ingredients mg1100mL
tiotropium bromide 297.1
salmeterol x '/Z H SO 276.7
benzalkonium chloride 10
hydrochloric acid (aq) ad pH 2.9
water ad 100mL
Use of the solution in the Respimat leads to a dosage of 20 Ng per dose of 1
and 25
ug/dose of 2.
'. CA 02429012 2003-04-28
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5) Solution for use in the Respimat~:
Ingredients mgI100mL
.~ tiotropium bromide 148.5
salmeterol x'/2 H SO 1106.3
benzalkonium chloride 8
sodium edetate 50
hydrochloric acid (aq) ad pH 2.5
water ad 100mL
Use of the solution in the Respimat leads to a dosage of 10 pg per dose of 1
and 100 pg/dose of 2.
6) Solution for use in the Respimat~:
Ingredients mg/100mL
tiotropium bromide 1.5
salmeterol x'/2 H SO 276.7
benzalkonium chloride 8
sodium edetate 10
hydrochloric acid (aq) ad pH 2.5
water ad 100mL
Use of the solution in the Respimat leads to a dosage of 0.1 pg per dose of 1
and 25 pg/dose of 2.
7) Solution for use in the Respimat~:
Ingredients mg1100mL
_ 14.9
tiotropium bromide
salmeterol x'h H SO 1106.32
benzalkonium chloride 10
sodium edetate 50
hydrochloric acid (aq) ad pH 3.5
water ad 100mL
~ , . CA 02429012 2003-04-28
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Use of the solution in the Respimat leads to a dosage of 1 pg per dose of 1
and 100 Ng/dose of 2.
8) Solution for use in the Respimat~:
Ingredients mgI100mL
tiotropium bromide 1486.1
salmeterol X ~~2 H SO 1106.32
benzalkonium chloride 10
sodium edetate 10
hydrochloric acid (aq) ad pH 3.5
water ad 100mL
Use of the solution in the Respimat leads to a dosage of 100 pg per dose of 1
and 100 Ngldose of 2.
9) Concentrated solution:
Ingredients mg1100mL
tiotropium bromide 1486.1
salmeterol X ~~2 H SO 11063.2
benzalkonium chloride 20
sodium edetate 100
hydrochloric acid (aq) ad pH 3.5
water ad 100mL
