Note: Descriptions are shown in the official language in which they were submitted.
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80361 pct.21 0
MEDICAMENTS COMPRISING STEROIDS AND A NOVEL ANTICHOLINERGIC
The present invention relates to novel pharmaceutical compositions based on
steroids with a long-lasting effect and salts of a new anticholinergic,
processes for
preparing them and their use in the treatment of respiratory complaints.
Description of the invention
The present invention relates to novel pharmaceutical compositions based on
steroids and salts of a new anticholinergic 1, processes for preparing them
and
their use in the treatment of respiratory complaints.
1s Within the scope of the present invention the anticholinergic agents used
are the
salts of formula 1
Meg+/Me X -
N
O'k:~~r H
O O
Me
wherein
X - denotes an anion with a single negative charge, preferably an anion
selected from the group consisting of chloride, bromide, iodide,
sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate,
citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-
toluenesuIphonate.
Preferably, the salts of formula 1 are used wherein
X - denotes an anion with a single negative charge selected from among
the chloride, bromide, 4-toluenesuIphonate and methanesulphonate,
preferably bromide.
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Most preferably, the salts of formula 1 are used wherein
X - denotes an anion with a single negative charge selected from among
the chloride, bromide and methanesuIphonate, preferably bromide.
Particularly preferred according to the invention is the salt of formula I
wherein
X - denotes bromide.
Anticholinergics may appropriately be used to treat a number of diseases.
Particular mention should be made, for example, of the treatment of asthma or
io COPD (chronic obstructive pulmonary disease). For treating these diseases
WO
92/16528 proposes, for example, anticholinergics which have a scopine,
tropenol
or tropine basic structure.
The problem on which WO 92/16528 is based is the preparation of
is anticholinergically active compounds which are characterised by their long-
lasting
activity. To solve this problem WO 92/16528 discloses inter a/ia benzilic acid
esters of scopine, tropenol or tropine.
For treating chronic diseases it is often desirable to prepare pharmaceutical
20 compositions with a longer-lasting effect. This will generally ensure that
the
concentration of the active substance needed to achieve the therapeutic effect
is
present in the body for a longer period of time without the need for the
pharmaceutical composition to be administered repeatedly and all too
frequently.
Moreover, if an active substance is administered at longer intervals of time,
this
25 contributes to the feeling of well-being of the patient to a considerable
degree. It is
particularly desirable to provide a pharmaceutical composition which can be
used
to therapeutically good effect by administering it once a day (single dose). A
single application per day has the advantage that the patient can become
accustomed relatively quickly to the regular taking of the medicament at a
30 particular time of the day.
If it is to be used as a medicament for administration once a day, the active
substance which is to be given must meet particular requirements. First of
all, the
desired onset of the activity after the administration of the pharmaceutical
35 composition should occur relatively quickly and ideally the activity should
remain
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as constant as possible over a fairly lengthy ensuing period. On the other
hand the
duration of activity of the pharmaceutical composition should not greatly
exceed a
period of about one day. Ideally, an active substance should have an activity
profile such that the preparation of a pharmaceutical composition which is
intended to be administered once a day and contains the active substance in
therapeutically appropriate doses can be properly controlled.
It has been found that the benzilic acid esters of scopine, tropenol or
tropine
disclosed in WO 92/16528 do not meet these more stringent requirements.
io Because of their extremely long duration of activity, significantly
exceeding the
period of about one day specified above, they cannot be used therapeutically
in a
single once-a-day dose.
Surprisingly, an unexpectedly beneficial therapeutic effect, particularly a
synergistic effect can be observed in the treatment of inflammatory and/or
obstructive diseases of the respiratory tract if the anticholinergic of
formula 1 is
used with one or more, preferably one, steroid 2. In view of this synergistic
effect
the pharmaceutical combinations according to the invention can be used in
smaller
doses than would be the case with the individual compounds used in monotherapy
in the usual way. Furthermore, this reduces unwanted side effects such as may
occur when steroids are administered, for example.
The effects mentioned above may be observed both when the two active
substances are administered simultaneously in a single active substance
formulation and when they are administered successively in separate
formulations.
According to the invention, it is preferable to administer the two active
substance
ingredients simultaneously in a single formulation. The pharmaceutical
compositions according to the invention are preferably administered by
inhalation.
Within the scope of the present invention, any reference to the compound 1' is
to
be regarded as a reference to the pharmacologically active cation of the
following
formula contained in the salts 1 :
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Me\+/Me
N
O H
O O
Me
1'.
Any reference to compounds 1 naturally also includes a reference to the cation
1'.
In the pharmaceutical combinations mentioned above the active substances) and
2 may be combined in a single preparation or contained in two separate
formulations. Pharmaceutical compositions which contain the active substances
1
and 2 in a single preparation are preferred according to the invention.
io Within the scope of the present invention, the term steroids (hereinafter
2), which
are optionally also referred to as corticosteroids, denotes compounds selected
from among flunisolide, beclomethasone, triamcinolone, budesonide,
fluticasone,
mometasone, ciclesonide, rofleponide, ST-126 and dexamethasone. Preferably,
the compound 2 is selected from among budesonide, fluticasone, mometasone,
ciclesonide and ST-126.
Any reference to steroids 2 within the scope of the present invention includes
a
reference to the salts or derivatives which may be formed from the steroids.
Examples of possible salts or derivatives include: sodium salts,
sulphobenzoates,
phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates,
palmitates, pivalates or furoates. In some cases the compounds of formula 2
may
also occur in the form of their hydrates. Any reference to steroids 2 within
the
scope of the present invention also includes a reference to the compounds 2 in
the
form of their diastereomers, mixtures of diastereomers or in the form of the
racemates.
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In one aspect the present invention relates to the abovementioned
pharmaceutical
compositions which contain, in addition to therapeutically effective
quantities of 1
and 2, a pharmaceutically acceptable carrier. In another aspect the present
invention relates to the abovementioned pharmaceutical compositions which do
not contain any pharmaceutically acceptable carrier in addition to
therapeutically
effective quantities of 1 and 2.
The present invention also relates to the use of therapeutically effective
quantities
of the salts 1 for preparing a pharmaceutical composition also containing
steroids
2 for treating inflammatory or obstructive diseases of the respiratory tract.
io Preferably, the present invention relates to the abovementioned use for
preparing
a pharmaceutical composition for treating asthma or COPD.
Within the scope of the present invention the compounds 1 and 2 may be
administered simultaneously or successively, while it is preferable according
to the
invention to administer compounds 1 and 2 simultaneously.
The present invention further relates to the use of therapeutically effect
amounts of
salts 1 and steroids 2 for treating inflammatory or obstructive respiratory
complaints, particularly asthma or COPD.
The proportions in which the active substances 1 and 2 may be used in the
active
substance combinations according to the invention are variable. Active
substances I and 2 may possibly be present in the form of their solvates or
hydrates. Depending on the choice of the compounds 1 and 2, the weight ratios
which may be used within the scope of the present invention vary on the basis
of
the different molecular weights of the various compounds and their different
potencies. As a rule, the pharmaceutical combinations according to the
invention
may contain the cation 1' and a steroid 2 in ratios by weight ranging from
1:250 to
250:1, preferably from 1:150 to 150:1. In the particularly preferred
pharmaceutical
combinations which contain in addition to 1' a compound selected from among
the
group consisting of budesonide, fluticasone, mometasone, ciclesonide and ST-
126
as the steroid 2, the weight ratios of 1' to 2 are most preferably in a range
from
about 1:40 to 40:1, more preferably from 1:30 to 30:1.
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For example, without restricting the scope of the invention thereto, preferred
combinations of 1 and 2 according to the invention may contain the cation 1'
and
one of the abovementioned preferred steroids 2 in the following weight ratios:
1:20; 1:19; 1:18; 1:17; 1:16; 1:15; 1:14; 1:13; 1:12; 1:11; 1:10; 1:9; 1:8;
1:7; 1:6;
1:5; 1:4; 1:3; 1:2; 1:1; 2:1; 3:1; 4:1; 5:1; 6:1; 7:1; 8:1; 9:1; 10:1; 11:1;
12:1; 13:1;
14:1; 15:1; 16:1; 17:1; 18:1; 19:1; 20:1.
The pharmaceutical compositions according to the invention containing the
combinations of 1 and 2 are normally administered so that 1' and 2 are present
together in doses of 5 to 5000 g, preferably from 10 to 2000 g, more
preferably
io from 15 to 1000 g, better still from 20 to 800 g, preferably, according to
the
invention, from 30 to 700 g, preferably from 40 to 600 g, preferably from 50
to
550 g, preferably from 40 to 500 g, most preferably 50 to 400 g per single
dose.
For example, combinations of 1 and 2 according to the invention contain a
quantity
of 1' and steroid 2 such that the total dosage per single dose is about
35pg, 45pg, 50pg, 55pg, 60pg, 65pg, 70pg, 75pg, 80pg, 85pg, 90pg, 95pg,
100pg, 105pg, 110pg, 115pg, 120pg, 125pg, 130pg, 135pg,140 pg,145pg,
150pg,155pg, 160pg, 165pg, 170pg, 175pg, 180pg, 185pg, 190pg, 195pg, 200pg,
205pg, 210pg, 215pg, 220pg, 225pg, 230pg, 235pg, 240pg, 245pg, 250pg,
255pg, 260pg, 265pg, 270pg, 275pg, 280pg, 285pg, 290pg, 295pg, 300pg,
305pg, 310pg, 315pg, 320pg, 325pg, 330pg, 335pg, 340pg, 345pg, 350pg,
355pg, 360pg, 365pg, 370pg, 375pg, 380pg, 385pg, 390pg, 395pg, 400pg,
405pg, 410pg, 415pg, 420pg, 425pg, 430pg, 435pg, 440pg, 445pg, 450pg,
455pg, 460pg, 465pg, 470pg, 475pg, 480pg, 485pg, 490pg, 495pg, 500pg,
505pg, 510pg, 515pg, 520pg, 525pg, 530pg, 535pg, 540pg, 545pg, 550pg,
555pg, 560pg, 565pg, 570pg, 575pg, 580pg, 585pg, 590pg, 595pg, 600pg,
605pg, 610pg or similar. It is clear to anyone skilled in the art that the
suggested
dosages per single dose specified above are not to be regarded as being
limited to
the numerical values actually stated. Fluctuations of about 2.5 g,
particularly in
the decimal range, are also included, as will be apparent to the skilled man.
In
these dosage ranges, the active substances 1' and 2 may be present in the
weight
ratios given above.
For example, without restricting the scope of the invention thereto, the
combinations of 1 and 2 according to the invention may contain a quantity of
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cation 1' and steroid 2 such that, for each single dose, 16.5pg of 1' and 25pg
of
2, 16.5pg of 1' and 50pg of 2, 16.5pg of 1' and 100pg of 2, 16.5pg of 1' and
150pg of 2, 16.5pg of 1' and 200pg of 2, 16.5pg of 1' and 250pg of 2, 33.Opg
of
1' and 25pg of 2, 33.Opg of 1' and 50pg of 2, 33.Opg of 1' and I OOpg of 2,
33.Opg of 1' and 150pg of 2, 33.Opg of 1' and 200pg of 2, 33.0pg of 1' and
250pg of 2, 49.5pg of 1' and 25pg of 2, 49.5pg of 1' and 50pg of 2, 49.5pg of
1' and 100pg of 2, 49.5pg of 1' and 150pg of 2, 49.5pg of 1' and 200pg of 2,
49.5pg of 1' and 250pg of 2, 82.6pg of 1' and 25pg of 2, 82.6pg of 1' and 50pg
of 2, 82.6pg of 1' and 100pg of 2, 82.6pg of 1' and 150pg of 2, 82.6pg of 1'
io and 200pg of 2, 82.6pg of 1' and 250pg of 2, 165.1 pg of 1' and 25pg of 2,
165.1 pg of 1' and 50pg of 2, 165.1 pg of 1' and 50pg of 2, 165.1 pg of 1' and
100pg of 2, 165.1 pg of 1' and 150pg of 2, 165.1 pg of 1' and 200pg of 2,
165.1 pg of 1' and 250pg of 2, 206.4pg of 1' and 25pg of 2, 206.4pg of 1' and
50pg of 2, 206.4pg of 1' and 100pg of 2, 206.4pg of 1' and 150pg of 2, 206.4pg
of 1' and 200pg of 2, 206.4pg of 1' and 250pg of 2, 412.8pg of 1' and 25pg of
2, 412.8pg of 1' and 50pg of 2, 412.8pg of 1' and 100pg of 2, 412.8pg of 1'
and
150pg of 2, 412.8pg of 1' and 200pg of 2, 412.8pg of 1' and 250pg of 2 are
present.
If the active substance combination in which the bromide is used as the salt I
and
in which 2 denotes one of the steroids mentioned above as being preferred is
used
as the preferred combination of 1 and 2 according to the invention, the
quantities
of active substance 1' and 2 administered per single dose mentioned by way of
example correspond to the following quantities of 1 and 2 administered per
single
dose:
20pg of 1 and 25pg of 2, 20pg of 1 and 50pg of 2, 20pg of 1 and I OOpg of 2,
20pg of 1 and 150pg of 2, 20pg of 1 and 200pg of 2, 20pg of 1 and 250pg of 2,
40pg of 1 and 25pg of 2, 40pg of 1 and 25pg of 2, 40pg of 1 and 50pg of 2,
40pg of 1 and 100pg of 2, 40pg of 1 and 150pg of 2, 40pg of 1 and 200pg of 2,
40pg of 1 and 250pg of 2, 60pg of 1 and 25pg of 2, 60pg of 1 and 50pg of 2,
60pg of 1 and 100pg of 2, 60pg of 1 and 150pg of 2, 60pg of 1 and 200pg of 2,
60pg of 1 and 250pg of 2, I OOpg of 1 and 25pg of 2, 100pg of 1 and 50pg of 2,
100pg of 1 and I OOpg of 2, 100pg of 1 and 150pg of 2, 100pg of I and 200pg
of 2, 100pg of 1 and 250pg of 2, 200pg of 1 and 25pg of 2, 200pg of 1 and
50pg of 2, 200pg of I and I OOpg of 2, 200pg of 1 and 150pg of 2, 200pg of 1
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and 200pg of 2, 200pg of 1 and 250pg of 2, 250pg of I and 25pg of 2, 250pg of
1 and 50pg of 2, 250pg of 1 and 100pg of 2, 250pg of 1 and 150pg of 2, 250pg
of 1 and 200pg of 2, 250pg of 1 and 250pg of 2, 500pg of 1 and 25pg of 2,
500pg of 1 and 50pg of 2, 500pg of 1 and 100pg of 2, 500pg of 1 and 150pg of
2, 500pg of 1 and 200pg of 2, 500pg of 1 and 250pg of 2.
The active substance combinations of 1 and 2 according to the invention are
preferably administered by inhalation. For this purpose, ingredients 1 and 2
have
to be made available in forms suitable for inhalation. Inhalable preparations
io according to the invention include inhalable powders, propellant-containing
metered dose aerosols or propellant-free inhalable solutions. Inhalable
powders
according to the invention containing the combination of active substances 1
and 2
may consist of the active substances on their own or of a mixture of the
active
substances with physiologically acceptable excipients. Within the scope of the
present invention, the term carrier may optionally be used instead of the term
excipient. Within the scope of the present invention, the term propellant-free
inhalable solutions also includes concentrates or sterile inhalable solutions
ready
for use. The preparations according to the invention may contain the
combination
of active substances 1 and 2 either together in one formulation or in two
separate
formulations. These formulations which may be used within the scope of the
present invention are described in more detail in the next part of the
specification.
A) Inhalable powder containing the combinations of active substances 1 and
2 according to the invention:
The inhalable powders according to the invention may contain 1 and 2 either on
their own or in admixture with suitable physiologically acceptable excipients.
If the active substances 1 and 2 are present in admixture with physiologically
acceptable excipients, the following physiologically acceptable excipients may
be
used to prepare these inhalable powders according to the invention:
monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose,
saccharose, maltose, trehalose), oligo- and polysaccharides (e.g. dextran),
polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride,
calcium
carbonate) or mixtures of these excipients with one another. Preferably, mono-
or
disaccharides are used, while the use of lactose or glucose is preferred,
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9
particularly, but not exclusively, in the form of their hydrates. For the
purposes of
the invention, lactose is the particularly preferred excipient, while lactose
monohydrate is most particularly preferred.
Within the scope of the inhalable powders according to the invention the
excipients
have a maximum average particle size of up to 250pm, preferably between 10 and
150pm, most preferably between 15 and 80pm. It may sometimes seem
appropriate to add finer excipient fractions with an average particle size of
1 to
9pm to the excipient mentioned above. These finer excipients are also selected
from the group of possible excipients listed hereinbefore. Finally, in order
to
io prepare the inhalable powders according to the invention, micronised active
substance 1 and 2, preferably with an average particle size of 0.5 to 10 m,
more
preferably from 1 to 5 m, is added to the excipient mixture. Processes for
producing the inhalable powders according to the invention by grinding and
micronising and by finally mixing the ingredients together are known from the
prior
art. The inhalable powders according to the invention may be prepared and
administered either in the form of a single powder mixture which contains both
1
and 2 or in the form of separate inhalable powders which contain only 1 or 2.
The inhalable powders according to the invention may be administered using
inhalers known from the prior art. Inhalable powders according to the
invention
which contain one or more physiologically acceptable excipients in addition to
1
and 2 may be administered, for example, by means of inhalers which deliver a
single dose from a supply using a measuring chamber as described in
US 4570630A, or by other means as described in DE 36 25 685 A. Preferably, the
inhalable powders according to the invention which contain physiologically
acceptable excipients in addition to I and 2 are packed into capsules (to
produce
so-called inhalettes) which are used in inhalers as described, for example, in
WO 94/28958.
A particularly preferred inhaler for using the pharmaceutical combination
according
to the invention in inhalettes is shown in Figure 1.
TM
3o This inhaler (Handyhaler) for inhaling powdered pharmaceutical compositions
from
capsules is characterised by a housing I containing two windows 2, a deck 3 in
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25771-954
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 8 provided with two sharpened pins 7 and movable counter to a
spring 8, an actuating member 9, and a mouthpiece 12 which is connected to the
housing 1, the deck 3
5 and a cover 11 via a spindle 10 to enable it to be flipped open or shut, as
well as
airholes 13 for adjusting the flow resistance.
If the inhalable powders according to the invention are packed into capsules
(inhalers) for the preferred use described above, the quantities packed into
each
capsule should be 1 to 30mg, preferably 3 to 20mg, more particularly 5 to 10mg
of
1o inhalable powder per capsule. These capsules contain, according to the
invention,
either together or separately, the doses of I or 1' and 2 mentioned
hereinbefore
for each single dose.
B) Propellant gas-driven inhalation aerosols containing the combinations of
active substances 1 and 2:
Inhalation aerosols containing propellant gas according to the invention may
contain substances 1 and 2 dissolved in the propellant gas or in dispersed
form. 1
and 2 may be present in separate formulations or in a single preparation, in
which
1 and 2 are either both dissolved, both dispersed or only one component is
dissolved and the other is dispersed. The propellant gases which may be used
to
prepare the inhalation aerosols according to the invention are known from the
prior
art. Suitable propellant gases are selected from among hydrocarbons such as
n-propane, n-butane or isobutane and halohydrocarbons such as fluorinated
derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
The propellant gases mentioned above may be used on their own or in mixtures
thereof. Particularly preferred propellant gases are halogenated alkane
derivatives selected from, TG12, TG134a (1,1,1,2-tetrafluoroethane) and TG227
(1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof, of which the
propellant
gases TG134a, TG227 and mixtures thereof are preferred.
The propellant-driven inhalation aerosols according to the invention may also
contain other ingredients such as co-solvents, stabilisers, surfactants,
antioxidants, lubricants, preservatives and pH adjusters. All these
ingredients are
known in the art.
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The inhalation aerosols containing propellant gas according to the invention
may
contain up to 5 wt.-% of active substance 1 and/or 2. Aerosols according to
the
invention contain, for example, 0.002 to 5 wt.-%, 0.01 to 3 wt.-%, 0.015 to 2
wt.-%,
0.1 to 2 wt.-%, 0.5 to 2 wt.-% or 0.5 to 1 wt.-% of active substance 1 and/or
2.
If the active substances 1 and/or 2 are present in dispersed form, the
particles of
active substance preferably have an average particle size of up to 10 m,
preferably from 0.1 to 6 m, more preferably from 1 to 5 m.
The propellant-driven inhalation aerosols according to the invention mentioned
above may be administered using inhalers known in the art (MDIs = metered dose
1o inhalers). Accordingly, in another aspect, the present invention relates to
pharmaceutical compositions in the form of propellant-driven aerosols as
hereinbefore described combined with one or more inhalers suitable for
administering these aerosols. In addition, the present invention relates to
inhalers
which are characterised in that they contain the propellant gas-containing
aerosols
1s described above according to the invention. 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 above-mentioned propellant gas-containing
inhalation aerosols according to the invention. Suitable cartridges and
methods of
filling these cartridges with the inhalable aerosols containing propellant gas
20 according to the invention are known from the prior art.
C) Propellant-free inhalable solutions or suspensions containing the
combinations of active substances 1 and 2 according to the invention:
Propellant-free inhalable solutions and suspensions according to the invention
contain, for example, aqueous or alcoholic, preferably ethanolic solvents,
25 optionally ethanolic solvents mixed with aqueous solvents. If
aqueous/ethanolic
solvent mixtures are used the relative proportion of ethanol compared with
water
is not limited but the maximum is up to 70 percent by volume, more
particularly up
to 60 percent by volume and most preferably up to 30 percent by volume. The
remainder of the volume is made up of water. The solutions or suspensions
30 containing 1 and 2, separately or together, are adjusted to a pH of 2 to 7,
preferably 2 to 5, using suitable acids. The pH may be adjusted using acids
selected from inorganic or organic acids. Examples of suitable inorganic acids
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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, maleic acid, succinic acid,
fumaric acid,
acetic acid, formic acid and/or propionic acid etc. Preferred inorganic acids
are
hydrochloric and sulphuric acids. It is also possible to use the acids which
have
already formed an acid addition salt with one of the active substances. Of the
organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If
desired,
mixtures of the above acids may be used, particularly in the case of acids
which
have other properties in addition to their acidifying qualities, e.g. as
flavourings,
1o 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, the addition of editic acid (EDTA) or one of the
known
salts thereof, sodium editate, as stabiliser or complexing agent is
unnecessary in
the present formulation. Other embodiments may contain this compound or these
compounds. In a preferred embodiment the content based on sodium editate is
less than 100mg/100ml, preferably less than 50mg/100 ml, more preferably less
than 20mg/100 ml. Generally, inhalable solutions in which the content of
sodium
editate is from 0 to 10mg/100ml are preferred.
Co-solvents and/or other excipients 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
isopropyl
alcohol, glycols - particularly propyleneglycol, polyethyleneglycol,
polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and
polyoxyethylene fatty acid esters. The terms excipients and additives in this
context denote any pharmacologically acceptable substance which is not an
active
substance but which can be formulated with the active substance or substances
in
the physiologically suitable solvent in order to improve the qualitative
properties of
the active substance formulation. Preferably, these substances have no
pharmacological effect or, in connection with the desired therapy, no
appreciable
or at least no undesirable pharmacological effect. The excipients and
additives
include, for example, surfactants such as soya lecithin, oleic acid, sorbitan
esters,
such as polysorbates, polyvinylpyrrolidone, other stabilisers, complexing
agents,
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antioxidants and/or preservatives which guarantee or prolong the shelf life of
the
finished pharmaceutical formulation, flavourings, vitamins and/or other
additives
known in the art. The additives also include pharmacologically acceptable
salts
such as sodium chloride as isotonic agents.
The preferred excipients include antioxidants such as ascorbic acid, for
example,
provided that it has not already been used to adjust the pH, vitamin A,
vitamin E,
tocopherols and similar vitamins and provitamins occurring in the human body.
Preservatives may be used to protect the formulation from contamination with
pathogens. Suitable preservatives are those which are known in the art,
1o particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic
acid or
benzoates such as sodium benzoate in the concentration known from the prior
art.
The preservatives mentioned above are preferably present in concentrations of
up
to 50mg/100ml, more preferably between 5 and 20mg/100ml.
Preferred formulations contain, in addition to the solvent water and the
combination of active substances 1 and 2, only benzalkonium chloride and
sodium
editate. In another preferred embodiment, no sodium editate is present.
The propellant-free inhalable solutions according to the invention are
administered
in particular using inhalers of the kind which are capable of nebulising a
small
amount of a liquid formulation in the therapeutic dose within a few seconds to
produce an aerosol suitable for therapeutic inhalation. Within the scope of
the
present invention, preferred inhalers are those in which a quantity of less
than
100 L, preferably less than 50 L, more preferably between 20 and 30 L of
active
substance solution can be nebulised in preferably one spray action to form an
aerosol with an average particle size of less than 20 m, preferably less than
10 m, in such a way that the inhalable part of the aerosol corresponds to the
therapeutically effective quantity.
An apparatus of this kind for propellant-free delivery of a metered quantity
of a
liquid pharmaceutical composition for inhalation is described for example in
International Patent Application WO 91/14468 and also in WO 97/12687 (cf. in
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particular Figures 6a and 6b). The nebulisers (devices) described therein are
known by the name Respimat .
This nebuliser (Respimat ) can advantageously be used to produce the inhalable
aerosols according to the invention containing the combination of active
substances 1 and 2. Because of its cylindrical shape and handy size of less
than
9 to 15 cm long and 2 to 4 cm wide, this device can be carried at all times by
the
patient. The nebuliser sprays a defined volume of pharmaceutical formulation
using high pressures through small nozzles so as to produce inhalable
aerosols.
The preferred atomiser essentially consists of an upper housing part, a pump
1o housing, a nozzle, a locking mechanism, a spring housing, a spring and a
storage
container, characterised by
- a pump housing which is secured in the upper housing part and which
comprises at one end a nozzle body with the nozzle or nozzle arrangement,
- a hollow plunger with valve body,
1s - a power takeoff flange in which the hollow plunger is secured and which
is
located in the upper housing part,
- a locking mechanism situated in the upper housing part,
- a spring housing with the spring contained therein, which is rotatably
mounted on the upper housing part by means of a rotary bearing,
20 - a lower housing part which is fitted onto the spring housing in the axial
direction.
The hollow plunger with valve body corresponds to a device disclosed in
WO 97/12687. It projects partially into the cylinder of the pump housing and
is
axially movable within the cylinder. Reference is made in particular to
Figures 1 to
25 4, especially Figure 3, and the relevant parts of the description. The
hollow
plunger with valve body exerts a pressure of 5 to 60 Mpa (about 50 to 600
bar),
preferably 10 to 60 Mpa (about 100 to 600 bar) on the fluid, the measured
amount
of active substance solution, at its high pressure end at the moment when the
spring is actuated. Volumes of 10 to 50 microlitres are preferred, while
volumes of
30 10 to 20 microlitres are particularly preferred and a volume of 15
microlitres per
spray is most particularly preferred.
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The valve body is preferably mounted at the end of the hollow plunger facing
the
valve body.
The nozzle in the nozzle body is preferably microstructured, i.e. produced by
microtechnology. Microstructured nozzle bodies are disclosed for example in
WO-94/07607; reference is hereby made to the contents of this specification,
particularly Figure 1 therein and the associated description.
The nozzle body consists for example of two sheets of glass and/or silicon
firmly
joined together, at least one of which has one or more microstructured
channels
1o which connect the nozzle inlet end to the nozzle outlet end. At the nozzle
outlet
end there is at least one round or non-round opening 2 to 10 microns deep and
5
to 15 microns wide, the depth preferably being 4.5 to 6.5 microns while the
length
is preferably 7 to 9 microns.
In the case of a plurality of nozzle openings, preferably two, the directions
of
spraying of the nozzles in the nozzle body may extend parallel to one another
or
may be inclined relative to one another in the direction of the nozzle
opening. In a
nozzle body with at least two nozzle openings at the outlet end the directions
of
spraying may be at an angle of 20 to 160 to one another, preferably 60 to 150
,
most preferably 80 to 100 . The nozzle openings are preferably arranged at a
spacing of 10 to 200 microns, more preferably at a spacing of 10 to 100
microns,
most preferably 30 to 70 microns. Spacings of 50 microns are most preferred.
The directions of spraying will therefore meet in the vicinity of the nozzle
openings.
The liquid pharmaceutical preparation strikes the nozzle body with an entry
pressure of up to 600 bar, preferably 200 to 300 bar, and is atomised into an
inhalable aerosol through the nozzle openings. The preferred particle or
droplet
sizes of the aerosol are up to 20 microns, preferably 3 to 10 microns.
The locking mechanism contains a spring, preferably a cylindrical helical
compression spring, as a store for the mechanical energy. The spring acts on
the
power takeoff flange as an actuating member the movement of which is
determined by the position of a locking member. The travel of the power
takeoff
flange is precisely limited by an upper and lower stop. The spring is
preferably
biased, via a power step-up gear, e.g. a helical thrust gear, by an external
torque
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WO 03/086399 16 PCT/EP03/03668
which is produced when the upper housing part is rotated counter to the spring
housing in the lower housing part. In this case, the upper housing part and
the
power takeoff flange have a single or multiple V-shaped gear.
The locking member with engaging locking surfaces is arranged in a ring around
the power takeoff flange. It consists, for example, of a ring of plastic or
metal
which is inherently radially elastically deformable. The ring is arranged in a
plane
at right angles to the atomiser axis. After the biasing of the spring, the
locking
surfaces of the locking member move into the path of the power takeoff flange
and
prevent the spring from relaxing. The locking member is actuated by means of a
to button. The actuating button is connected or coupled to the locking member.
In
order to actuate the locking mechanism, the actuating button is moved parallel
to
the annular plane, preferably into the atomiser; this causes the deformable
ring to
deform in the annual plane. Details of the construction of the locking
mechanism
are given in WO 97/20590.
The lower housing part is pushed axially over the spring housing and covers
the
mounting, the drive of the spindle and the storage container for the fluid.
When the atomiser is actuated the upper housing part is rotated relative to
the
lower housing part, the lower housing part taking the spring housing with it.
The
spring is thereby compressed and biased by means of the helical thrust gear
and
the locking mechanism engages automatically. The angle of rotation is
preferably
a whole-number fraction of 360 degrees, e.g. 180 degrees. At the same time as
the spring is biased, the power takeoff part in the upper housing part is
moved
along by a given distance, the hollow plunger is withdrawn inside the cylinder
in
the pump housing, as a result of which some of the fluid is sucked out of the
storage container and into the high pressure chamber in front of the nozzle.
If desired, a number of exchangeable storage containers which contain the
fluid to
be atomised may be pushed into the atomiser one after another and used in
succession. The storage container contains the aqueous aerosol preparation
according to the invention.
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WO 03/086399 17 PCT/EP03/03668
The atomising process is initiated by pressing gently on the actuating button.
As a
result, the locking mechanism opens up the path for the power takeoff member.
The biased spring pushes the plunger into the cylinder of the pump housing.
The
fluid leaves the nozzle of the atomiser in atomised form.
Further details of construction are disclosed in PCT Applications WO 97/12683
and WO 97/20590, to which reference is hereby made.
The components of the atomiser (nebuliser) are made of a material which is
suitable for its purpose. The housing of the atomiser and - if its operation
permits,
other parts as well are preferably made of plastics, e.g. by injection
moulding. For
1o medicinal purposes, physiologically safe materials are used.
Figures 2a/b attached to this patent application, which are identical to
Figures 6a/b
of WO 97/12687, show the nebuliser (Respimat ) which can advantageously be
used for inhaling the aqueous aerosol preparations according to the invention.
Figure 2a shows a longitudinal section through the atomiser with the spring
biased
while Figure 2b shows a longitudinal section through the atomiser with the
spring
relaxed.
The upper housing part (51) contains the pump housing (52) on the end of which
is mounted the holder (53) for the atomiser nozzle. In the holder is the
nozzle
body (54) and a filter (55). The hollow plunger (57) fixed in the power
takeoff
flange (56) of the locking mechanism projects partially into the cylinder of
the
pump housing. At its end the hollow plunger carries the valve body (58). The
hollow plunger is sealed off by means of the seal (59). Inside the upper
housing
part is the stop (60) on which the power takeoff flange abuts when the spring
is
relaxed. On the power takeoff flange is the stop (61) on which the power
takeoff
flange abuts when the spring is biased. After the biasing of the spring the
locking
member (62) moves between the stop (61) and a support (63) in the upper
housing part. The actuating button (64) is connected to the locking member.
The
upper housing part ends in the mouthpiece (65) and is sealed off by means of
the
protective cover (66) which can be placed thereon.
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The spring housing (67) with compression spring (68) is rotatably mounted on
the
upper housing part by means of the snap-in lugs (69) and rotary bearing. The
lower housing part (70) is pushed over the spring housing. Inside the spring
housing is the exchangeable storage container (71) for the fluid (72) which is
to be
atomised. The storage container is sealed off by the stopper (73) through
which
the hollow plunger projects into the storage container and is immersed at its
end in
the fluid (supply of active substance solution).
The spindle (74) for the mechanical counter is mounted in the covering of the
spring housing. At the end of the spindle facing the upper housing part is the
drive
1o pinion (75). The slider (76) sits on the spindle.
The nebuliser described above is suitable for nebulising the aerosol
preparations
according to the invention to produce an aerosol suitable for inhalation.
If the formulation according to the invention is nebulised using the method
described above (Respimat ) the quantity delivered should correspond to a
1s defined quantity with a tolerance of not more than 25%, preferably 20% of
this
amount in at least 97%, preferably at least 98% of all operations of the
inhaler
(spray actuations). Preferably, between 5 and 30 mg of formulation, most
preferably between 5 and 20 mg of formulation are delivered as a defined mass
on
each actuation.
20 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 a further aspect, the invention relates to pharmaceutical
formulations in the form of propellant-free inhalable solutions or suspensions
as
described above combined with a device suitable for administering these
25 formulations, preferably in conjunction with the Respimat . Preferably, the
invention relates to propellant-free inhalable solutions or suspensions
characterised by the combination of active substances 1 and 2 according to the
invention in conjunction with the device known by the name Respimat . In
addition, the present invention relates to the above-mentioned devices for
30 inhalation, preferably the Respimat , characterised in that they contain
the
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propellant-free inhalable solutions or suspensions according to the invention
as
described hereinbefore.
The propellant-free inhalable solutions or suspensions according to the
invention
may take the form of concentrates or sterile inhalable solutions or
suspensions
ready for use, as well as the above-mentioned solutions and suspensions
designed for use in a Respimat . Formulations ready for use may be produced
from the concentrates, for example, by the addition of isotonic saline
solutions.
Sterile formulations ready for use may be administered using energy-operated
free-standing or portable nebulisers which produce inhalable aerosols by means
of
to ultrasound or compressed air by the Venturi principle or other principles.
Accordingly, in another aspect, the present invention relates to
pharmaceutical
compositions in the form of propellant-free inhalable solutions or suspensions
as
described hereinbefore which take the form of concentrates or sterile
formulations
ready for use, combined with a device suitable for administering these
solutions,
characterised in that the device is an energy-operated free-standing or
portable
nebuliser which produces inhalable aerosols by means of ultrasound or
compressed air by the Venturi principle or other methods.
The Examples which follow serve to illustrate the present invention in more
detail
without restricting the scope of the invention to the following embodiments by
way
of example.
First, the preparation of compounds I used within the scope of the present
invention which are not known in the art will be described.
Preparation of the compounds of formula 1:
1.a.: 2,2-Diphenylpropionic acid chloride:
52.08g (0.33 mol) of oxalyl chloride are slowly added dropwise at 20 C to a
suspension of 25.0 g (0.11 mol) of 2,2-diphenylpropionic acid, 100 ml of
dichloromethane and 4 drops of dimethylformamide. The mixture is stirred for 1
h
3o at 20 C and 0.5 h at 50 C. The solvent is distilled off and the residue
remaining is
used in the next step without any further purification.
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1.b.: scopine 2,2-diphenylpropionate:
The residue obtained from step 1.a. is dissolved in 100 ml of dichioromethane
and
at 40 C a solution of 51.45 g (0.33 mol) of scopine in 200 ml of
dichioromethane is
added dropwise thereto. The resulting suspension is stirred for 24 h at 40 C,
then
the precipitate formed is suction filtered and the filtrate is extracted first
with water,
then with aqueous hydrochloric acid. The combined aqueous phases are made
alkaline with aqueous sodium carbonate solution, extracted with
dichloromethane,
the organic phase is dried over Na2SO4, evaporated to dryness and the
to hydrochloride is precipitated from the residue. The product is purified by
recrystallisation from acetonitrile.
Yield: 20.85 g (= 47 % of theory)
DC: Rf value: 0.24 (eluant: sec. butanol/formic acid/water 75:15:10);
m.p.: 203-204 C.
1.c: scopine 2,2-diphenylpropionate methobromide :
11.98 g (0.033 mol) of the compound of step 1.b, 210 ml of acetonitrile, 70 ml
of
dichloromethane and 20.16 g (0.1 mol) of 46.92 % bromomethane in acetonitrile
are combined at 20 C and left to stand for 3 days. The solution is evaporated
to
dryness and the residue is recrystallised from isopropanol.
Yield: 11,34 g (= 75 % of theory); m.p.: 208-209 C.
C24H28NO3xBr (458.4);
Elemental analysis: calculated: C (62.89) H (6.16) N (3.06)
found: C (62.85) H (6.12) N (3.07).
The salts I wherein X" denotes an anion with a single negative charge other
than
bromide may be obtained in a manner similar to step 1.3.
The following examples of formulations, which may be obtained analogously to
methods known in the art, serve to illustrate the present invention more fully
without restricting it to the contents of these examples.
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Examples of Formulations
A) Inhalable powders:
1)
Ingredients pg per capsule
1'-bromide 100
budesonide 200
lactose 4700
Total 5000
2)
Ingredients pg per capsule
1'-bromide 100
Fluticasone-propionate 125
lactose 4775
Total 5000
3)
Ingredients pg per capsule
1'-bromide 100
Mometasone-furoate X H2O 250
lactose 4650
Total 5000
4)
Ingredients pg per capsule
1'-bromide 100
Ciclesonide 250
lactose 4650
Total 5000
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5)
Ingredients pg per capsule
1'-bromide 50
budesonide 125
lactose 4825
Total 5000
6)
Ingredients pg per capsule
1'-bromide 50
Fluticasone-propionate 200
lactose 4750
Total 5000
7)
Ingredients pg per capsule
1'-bromide 75
Mometasone-furoate X H2O 250
lactose 4675
Total 5000
8)
Ingredients pg per capsule
1'-bromide 75
Ciclesonide 250
lactose 4675
Total 5000
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9)
Ingredients lag per capsule
1'-bromide 100
ST-126 250
lactose 4650
Total 5000
10)
Ingredients lag per capsule
1'-bromide 50
ST-126 125
lactose 4825
Total 5000
B) Propellant-containing aerosols for inhalation:
1) Suspension aerosol:
Ingredients % by weight
1'-bromide 0.020
budesonide 0.4
soya lecithin 0.2
TG 134a : TG227 = 2:3 ad 100
2) Suspension aerosol:
Ingredients % by weight
1'-bromide 0.020
Fluticasone-propionate 0.3
Isopropyl myristate 0.1
TG 227 ad 100
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3) Suspension aerosol:
Ingredients % by weight
1'-bromide 0.020
Mometasone-furoate X H2O 0.6
Isopropyl myristate 0.1
TG 227 ad 100
4) Suspension aerosol:
Ingredients % by weight
1'-bromide 0.020
Ciclesonide 0.4
Isopropyl myristate 0.1
TG 134a : TG227 = 2:3 ad 100
5) Solution aerosol:
Ingredients % by weight
1'-bromide 0.039
budesonide 0.4
absolute ethanol 0.5
Isopropyl myristate 0.1
TG 134a: TG227 = 2:3 ad 100
6) Solution aerosol:
Ingredients % by weight
1'-bromide 0.039
Fluticasone-propionate 0.3
absolute ethanol 0.5
Isopropyl myristate 0.1
TG 134a : TG227 = 2:3 ad 100
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7) Solution aerosol:
Ingredients % by weight
1'-bromide 0.039
Mometasone-furoate X H2O 0.6
absolute ethanol 0.5
Isopropyl myristate 0.1
TG 134a : TG227 = 2:3 ad 100
8) Solution aerosol:
Ingredients % by weight
1'-bromide 0.039
Ciclesonide 0.4
absolute ethanol 0.5
Isopropyl myristate 0.1
TG 134a : TG227 = 2:3 ad 100
9) Solution aerosol:
Ingredients % by weight
1'-bromide 0.039
ST-126 0.6
absolute ethanol 0.5
Isopropyl myristate 0.1
TG 134a : TG227 = 2:3 ad 100
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10) Solution aerosol:
Ingredients % by weight
1'-bromide 0.039
ST-126 0.4
absolute ethanol 0.5
Isopropyl myristate 0.1
TG 134a : TG227 = 2:3 ad 100
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