Note: Descriptions are shown in the official language in which they were submitted.
CA 02343123 2001-03-08 ''uhvr~1Vn
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70689fft.201
Foreign application Boehringer ingelheim Pharma KG
Active substance concentrate with Formoterol, suitable for
storage
The present invention relates to a propellant-free, active
substance concentrate suitable for storage containing
formoterol, for use in inhalers for inhalation or nasal
therapy.
Formoterol is an anilide of formula I derived from
adrenaline and is used as a(32-stimulator in inhalation
therapy of respiratory diseases, particularly for the
treatment of bronchial asthma. In patients with
reversible obstructive respiratory diseases, formoterol
has a bronchodilatory effect. Only 1-3 minutes after
inhalation the effect sets in and the bronchodilatory
effect is still significantly present after 12 hours.
Formoterol inhibits the release of leukotrienes and other
messenger substances involved with inflammation, such as
histamines. In addition, formoterol may bring about a
hyperglycaemic activity.
Formula I
OH
~ NHCHO
HC-C-H-C-H ~ ~ OMe
OH H2 CH3 2
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In the past it has been found that liquid aerosol
formulations of formoterol are not suitable for use in
inhalers intended for ambulatory inhalation treatment since
formoterol cannot be stored in a sufficiently stable manner
in solution to guarantee the pharmaceutical quality of the
formulation over lengthy periods of time. For this reason,
formoterol has previously only been used in powder form for
inhalation therapy.
According to one aspect of the present invention,
there is provided a propellant-free, liquid, storage-stable
pharmaceutical concentrate comprising formoterol, a
pharmacologically acceptable salt thereof or a
pharmaceutically acceptable addition product thereof and a
pharmacologically acceptable solvent or suspension agent,
wherein the concentration of formoterol is between 75 mg/ml
and 500 mg/ml.
The present invention relates to a liquid active
substance concentrate containing formoterol in the form of
its free base or in the form of one of the pharmacologically
acceptable salts or addition products (adducts) thereof as
active substance. The preferred salt is formoterol fumarate
whilst the preferred addition product is a hydrate of
formoterol. In the wider context of this specification, the
term formoterol refers both to the free base according to
formula I and also to salts and other addition products of
formoterol unless otherwise specified or clearly stated in
the context.
The active substance concentrate according to the
invention may be converted, by diluting with a
pharmacologically acceptable liquid which optionally
contains pharmaceutical adjuvants and additives, into a
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pharmaceutical preparation (aerosol formulation) which is
converted by means of a nebuliser into an inhalable aerosol.
The invention therefore also relates to the use of
an active substance concentrate of this kind in inhalation
therapy.
The active substance concentrate according to the
invention refers to solutions or suspensions in which
formoterol is dissolved or suspended in highly
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concentrated form in a pharmacologically"suitable fluid
and which are characterised in that the active substance,
formoterol, can be stored therein for a period from
several months possibly up to several years without any
deterioration in the pharmaceutical quality.
The term "active substance concentrate" denotes a solution
or suspension of an active substance in which the active
substance Formoterol is present in highly concentrated
form in a pharmacologically acceptable liquid as a
solution or suspension. Suspensions are preferred as they
have proved particularly stable on storage.
The term "highly concentrated" means a concentration of
the active substance which is usually too high to enable
the corresponding solution or suspension to be used
therapeutically for inhalation without being diluted.
According to the invention the formoterol concentration in
the active substance concentrate is between 10 mg/ml and
500 mg/ml. Preferably, the minimum concentration is at
least 75 mg/ml. Preferred concentrations are between 100
mg/ml and 400 mg/ml, particularly between 250 mg/ml and
350 mg/ml. The concentration data relate to mg of free
base formoterol per ml of active substance concentrate.
In the case of formoterol salts or the addition compounds
thereof, the concentration data should be converted
according to the free base.
The term "pharmacologically suitable fluid" for the
purposes of the present invention means a solvent or
suspension agent which is not a liquefied propellant gas.
Polar fluids are preferred, particularly protic fluids.
Examples of polar solvents or suspension agents are e.g.
dimethylsulphoxide or compounds which contain hydroxyl
groups or other polar groups, e.g. water or alcohols -
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particularly ethanol, isopropylalcohol, glycols,
especially propyleneglycol, polyethyleneglycol,
polypropyleneglycol, glycolether, glycerol,
polyoxyethylene alcohols and polyoxyethylene fatty acid
esters etc.
Examples of protic liquids, which are the most preferred
solvents or suspension agents in the context of the
invention, are water, aqueous saline solutions with one or
more pharmacologically acceptable salt(s), ethanol or a
mixture thereof.
In the case of aqueous ethanol mixtures, the ratio by
volume of ethanol to water or to the aqueous saline
solution is between 5:95 and 99:1, preferably between
40:60 and 96:4, most preferably between 75:25 and 96:4. A
particularly preferred ratio is between 40:60 and 60:40.
For a saline solution as the solvent or suspension agent
or as a component thereof, particularly suitable salts are
those which display no or only negligibly little
pharmacological activity after administration. Saline
solutions are preferably used for suspension concentrates.
The addition of the salt significantly reduces the
dissolving power of water for the active substance or
substances, so as to achieve a stabilising effect on the
suspended particles. If desired, saturated saline
solutions may be used. The quantity of salt depends on
the precise composition of the solvent or suspension agent
and its ability to dissolve the active substance.
Formoterol should be present in dissolved form in an
amount of less than 0.5% by weight, preferably less than
0.1% by weight, in aqueous formoterol suspensions in the
sense of the active substance concentrate according to the
invention, these amounts being based on the total amount
(weight) of formoterol. However, if the amount of
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dissolved material is above the specified levels, it can
be reduced to below these levels by the addition of salt.
As a rule, the solubility can be halved by the addition of
salt, and in some cases reduced to one fifth or even less.
Preferred are saline solutions with a salt content of up
to 50% by weight, especially up to 20% by weight.
Both inorganic and organic salts may be used as the salts.
Inorganic salts such as sodium chloride, alkali metal or
ammonium halogen salts are preferred. Sodium chloride is
particularly preferred. Suitable organic salts are, for
example, the sodium, potassium or ammonium salts of the
following acids: ascorbic acid, citric acid, malic acid,
tartaric acid, maleic acid, succinic acid, fumaric acid,
acetic acid, formic acid and/or propionic acid.
Cosolvents may be added to the solvent or suspension
agent. Co-solvents are suitable for increasing the
solubility of additives and optionally the formoterol.
Preferred cosolvents are those which contain hydroxyl
groups or other polar groups, for example alcohols -
especially isopropyl alcohol, glycols - especially
propylene glycol, polyethylene glycol, polypropylene
glycol, glycol ether, glycerol, polyoxyethylene alcohols
and polyoxyethylene fatty acid esters, provided that these
are not already used as the solvent or suspension agent.
Other excipients and additives may also be added to the
active substance concentrate according to the invention.
The term excipients and additives iri this context denotes
any pharmacologically suitable and therapeutically useful
substance which is not an active substance but can be
formulated together with the formoterol in the
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pharmacologically suitable solvent or suspension agent in
order to improve the qualitative properties of the active
substance concentrate or the pharmaceutical preparation
which is to be obtained by dilution ready for inhalation.
Preferably, these substances have no pharmacological
activity or, in the context of the desired therapy, no
appreciable or at least no undesirable pharmacological
activity. The excipients and additives include, for
example, surfactants for stabilising suspensions, other
stabilisers, complexing agents, antioxidants and/or
preservatives which prolong the duration of use of the
finished pharmaceutical formulation, flavourings,
vitamins, antioxidants and/or other additives known in the
prior art.
As surfactants the active substance concentrate may
contain, for example, soya lecithin, oleic acid, sorbitan
esters such as sorbitan trioleate or other surfactants
known from the prior art in the usual concentrations.
It has been found that addition of an organic or inorganic
acid, preferably in combination with a complexing agent,
leads to improvement in the stability (shelf life) of some
solutions or suspensions containing formoterol,
particularly if they contain ethanol as solvent.
Examples of inorganic acids which are preferred in this
respect are: hydrochloric acid, nitric acid, sulphuric
acid and/or phosphoric acid. Examples of especially
suitable organic acids are: ascorbic acid, citric acid,
malic acid, tartaric acid, maleic acid, succinic acid,
fumaric acid, acetic acid, formic acid and/or propionic
acid, etc. The preferred acids are hydrochloric acid
and/or fumaric acid.
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The concentration of acid is selected so that the active
substance concentrate has a pH of between 2.0 and 7.0,
preferably between 4.0 and 6.0 and most preferably between
4.5 and 5.5.
Examples of complexing agents which may be used include
EDTA (ethylenediaminetetraacetic acid, or a salt thereof,
such as the disodium salt), citric acid, nitrilotriacetic
acid and the salts thereof. EDTA is preferred.
Preservatives can be used to protect the concentrate from
contamination with pathogenic germs. Those preservatives
which are known in the prior art are suitable, especially
benzalkonium chloride or benzoic acid, or benzoates such
as sodium benzoate.
Suitable antioxidants are the known pharmacologically
acceptable antioxidants, especially vitamins or
provitamins, as present in the human body, e.g. ascorbic
acid or vitamin E.
If the formoterol is present in the active substance
concentrate according to the invention as a suspension,
the particles are preferably formulated in a particle size
of up to 20 m, preferably up to 10 m and especially
preferably up to 5 m.
Suspensions are most preferred as the active substance
concentrate.
The active substance concentrate according to the
invention has the advantage that formoterol can be
formulated in such a way as to remain stable over a fairly
long period of time. It is not necessary for the
concentrate to correspond to the composition of the
finished pharmaceutical preparation, apart from the
concentration of the active substance. For example, the
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pH of the concentrate may differ substantially from the pH
of the pharmaceutical preparation which is to be
administered, if this ensures more stable storage of
formoterol.
The active substance concentrate according to the
invention is not usually suitable as such for direct
medicinal use, particularly for inhalation. As already
explained, use of the active substance concentrate
comprises converting it into a pharmaceutical preparation
(aerosol formulation). The term "pharmaceutical
preparation" denotes a formulation of a pharmaceutical
substance suitable for inhalation wherein a pharmaceutical
substance or mixture of substances can be administered in
the required and/or recommended concentration.
The pharmaceutical preparation is preferably such that it
can be administered by inhalation using a suitable
nebuliser.
A preferred method of converting the active substance
concentrate into a pharmaceutical preparation suitable for
administration is by diluting the active substance
concentrate according to the invention with a
pharmacologically suitable solvent or suspension agent.
In order to obtain the formulation for administration, the
formoterol active substance concentrate is diluted to 0.9
mg/ml to 1.5 mg/ml, for example, with the diluent.
Preferred solvents or suspension agents for the dilution
are propellant-free liquids, preferably polar, more
particularly protic liquids. It should be pointed out
here that the individual components or ingredients of the
diluent are defined as specified in connection with the
active substance concentrate, in so far as these
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components or ingredients were described there or unless
otherwise stated.
Particularly preferred diluents are water, aqueous saline
solutions with one or more pharmacologically acceptable
salts, ethanol or a mixture thereof. In the case of
aqueous ethanol mixtures, the ratio by volume of ethanol
to water or to the aqueous saline solution is between 5:95
and 99:1, preferably between 40:60 and 96:4, most
preferably between 75:25 and 96:4. A particularly
preferred ratio is between 40:60 and 60:40.
It is neither obvious nor necessary for the diluent to be
identical to the solvent or suspension agent of the active
substance concentrate. If desired, the latter may also
contain only one or a few constituents of the diluent.
It should be expressly pointed out here that the
cosolvents and/or excipients or additives and/or active
substances mentioned above in connection with the active
substance concentrate according to the invention may also
or only be dissolved or suspended iri the diluent.
Preferred embodiments of the diluent contain preservatives
and/or complexing agents.
Optionally, the diluent may contain a buffer substance,
e.g. trisodium phosphate, disodium hydrogen phosphate,
sodium dihydrogen phosphate, Na-EDTA, EDTA, mixtures
thereof and other substances known from the prior art.
Preferred substances are sodium dihydrogen phosphate,
disodium hydrogen phosphate, trisodium hydrogen phosphate,
potassium dihydrogen phosphate, potassium hydrogen
phosphate, tripotassium hydrogen phosphate, and mixtures
thereof. Buffer substances are particularly beneficial
when the active substance concentrate suitable for storage
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according to the invention has a pH which differs
significantly from that which is desired for the
application, e.g. when this increases the stability of the
active substance during storage. In this case the buffer
substance is present in the diluent in a concentration
such that, after mixing the active substance concentrate
with the diluent, an aerosol formulation suitable for
administration is obtained with the desired pH, preferably
between 2.0 and 7.0, particularly between 4.0 and 6.0,
most preferably between 4.5 and 5.5.
In a preferred embodiment, the pharmaceutical preparation
contains a complexing agent which is preferably selected
from a complexing agent mentioned in connection with the
active substance concentrate. The quantity of complexing
agent is up to 100 mg/100 ml, preferably up to 50
mg/100ml. The preferred complexing agent is EDTA.
The pharmaceutical preparation which is to be administered
together with the active substance concentrate determines
the precise composition of the diluent.
Neither the active substance concentrate suitable for
storage according to the invention nor the pharmaceutical
preparation for administration obtained by dilution
contains a propellant.
Preferably, the mixing takes place at ambient temperature
and under normal pressure. One advantage of the active
substance concentrate according to the invention is that
it can be converted by dilution into a therapeutically
effective formulation and/or one which is suitable for use
in a nebuliser within a very short time, e.g. within a few
minutes or possibly a few seconds. The mixing can also be
done by patients, who generally have no pharmaceutical
knowledge.
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For use in inhalation therapy, the activd substance
concentrate according to the invention is preferably
diluted by means of a suitable nebuliser before the first
application and the pharmaceutical preparation obtained is
then atomised by the nebuliser.
Suitable nebulisers in this context are those which can
nebulise liquid formulations containing no propellant.
Preferred nebulisers are, for example, inhalers or high
pressure atomisers as disclosed in W091/14468 "Atomizing
Device and Methods" or W097/12687, particularly those
described by Figures 6a and 6b, to which reference is
hereby made in its entirety. In nebulisers of this kind,
pharmaceutical preparations intended for administration in
the form of solutions are generally preferred to
suspensions.
Preferably, the active substance concentrate according to
the invention and the diluent are stored separately in a
container which is suitable for inhalers and which is so
designed that the two components are automatically mixed
together as the container is inserted in the nebuliser or
immediately before the first use, so to speak in situ.
Containers which are preferred for this purpose are
disclosed for example in WO 96/06011 in W097/39831 and
particularly Figures 1, 2, 2a or 3b therein or in the
German Patent Publication No. DE 19847968 and particularly
the cartridges illustrated in
Figures 1 to 11 therein, especially Figure 3, to which
reference is hereby made in their entirety. These
containers are particularly suitable for use in a high
pressure atomiser of the type described above.
Two or more separate chambers might be formed in such a
container, the active substance concentrate according to
the invention being stored in at least one of the chambers
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while the diluent is stored in another chamber. The
container is designed so that the two components stored
separately can be mixed together simply by inserting the
container in the inhaler designed for this purpose. The
quantity of the two components is such that after the two
components have been mixed together an aerosol formulation
is obtained in which the active substance or substances is
or are concentrated to such an extent that the recommended
therapeutic dose can be administered by a single spray or
just a few sprays of the appropriate nebuliser. Within the
scope of the present description, a method of this kind or
a similar method for producing the aerosol formulation
which is to be administered might be designated an "in
situ" method or a "quasi in situ" method if the user is
not required to take any measures going beyond or
preceding the normal measures for operating an inhaler and
using the aerosol formulation by means of the inhaler.
For the purpose of storage in the abovementioned
cartridge, in preferred embodiments, the quantity of the
active substance concentrate suitable for storage
according to the invention is chosen so as to correspond
to a volume of from 0.001 up to about 0.05 ml, preferably
from 0.001 to 0.02 ml.
In addition to those described, other containers may also
be used to store the formulation according to the
invention.
Of course, the dilution may also be carried out
differently with a pharmacologically acceptable diluent,
e.g. by mixing the diluent with the active substance
concentrate in an open vessel or by some other method.
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Examples
Example 1
mg of formoterol (particle size: 5 m) are formulated as
5 a suspension with 0.015 ml of water for storage. A pH of
5.0 is obtained by the addition of fumaric acid.
Preparation of the pharmaceutical preparation for
administration by inhalation:
For administration by inhalation, the suspension is
diluted with 4.5 ml of a 1:1 solution of water/ethanol
(v/v), the diluted solution containing 0.45 mg of
benzalkonium chloride and 2.25 mg of Na-EDTA and being
adjusted to a pH of 5.0 using HC1.
The concentration of the active substance concentrate is
about 300 times higher than the concentration of the
solution to be administered.
Example 2
5 mg of formoterol (particle size: 5 m) are formulated as
a suspension for storage with 0.015 ml of a 20% by weight
aqueous NaCl solution. The pH is adjusted to 5.0 by the
addition of fumaric acid.
Preparation of the pharmaceutical preparation for
administration by inhalation:
For inhalation, the suspension is diluted with 4.5 ml of a
1:1 solution of water/ethanol (v/v), the dilute solution
containing 0.45 mg of benzalkonium chloride and 2.25 mg of
Na-EDTA and being adjusted with HC1 to a pH of 5Ø
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The concentration of the active substance concentrate is
around 300 times greater than the concentration of the
solution to be administered.
Example 3
In an aqueous solution with a pH of 5.0, formoterol breaks
down to 10% at 40 C within only 3 months. In a comparable
suspension, no breakdown of any kind can be observed even
after 6 months' storage at 40 C.
