U.S. patent application number 10/637769 was filed with the patent office on 2004-08-26 for aerosol formulation for inhalation comprising an anticholinergic.
This patent application is currently assigned to Boehringer Ingelheim Pharma GmbH & Co. KG. Invention is credited to Schmidt, Friedrich.
Application Number | 20040166065 10/637769 |
Document ID | / |
Family ID | 32872820 |
Filed Date | 2004-08-26 |
United States Patent
Application |
20040166065 |
Kind Code |
A1 |
Schmidt, Friedrich |
August 26, 2004 |
Aerosol formulation for inhalation comprising an
anticholinergic
Abstract
The present invention relates to a propellant-free, aqueous
aerosol formulation for anticholinergics of formula 1 1 wherein
X.sup.- denotes an anion.
Inventors: |
Schmidt, Friedrich;
(Ingelheim am Rhein, DE) |
Correspondence
Address: |
BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P. O. BOX 368
RIDGEFIELD
CT
06877
US
|
Assignee: |
Boehringer Ingelheim Pharma GmbH
& Co. KG
Ingelheim
DE
|
Family ID: |
32872820 |
Appl. No.: |
10/637769 |
Filed: |
August 8, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60415852 |
Oct 3, 2002 |
|
|
|
Current U.S.
Class: |
424/45 ;
514/291 |
Current CPC
Class: |
Y10S 514/826 20130101;
A61K 31/4745 20130101; A61K 9/0078 20130101; A61K 31/5375 20130101;
A61K 31/33 20130101 |
Class at
Publication: |
424/045 ;
514/291 |
International
Class: |
A61K 031/4745; A61L
009/04 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 31, 2002 |
DE |
102 40 257 |
Aug 14, 2002 |
DE |
102 37 232 |
Claims
What is claimed is:
1) An aqueous pharmaceutical formulation for inhalation comprising
at least one compound as active drug substance of formula 4wherein
X.sup.- is 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-toluenesulphonate, at least one pharmacologically
acceptable acid and water, which formulation is a liquid.
2) The aqueous pharmaceutical formulation according to claim 1
further comprising one or more pharmaceutically acceptable
excipients or complexing agents or mixtures thereof.
3) The aqueous pharmaceutical formulation according to claim 1,
containing at least one compound of formula 1 wherein X.sup.- is
selected from the group consisting of chloride, bromide,
4-toluenesulphonate and methanesulphonate.
4) The aqueous pharmaceutical formulation according to claim 1,
wherein the pharmacologically acceptable acid is selected from the
inorganic acids hydrochloric acid, hydrobromic acid, nitric acid,
sulphuric acid and phosphoric acid or from the organic acids
ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid,
succinic acid, fumaric acid, acetic acid, formic acid and propionic
acid.
5) The aqueous pharmaceutical formulation according to claim 3,
characterised by a pH of 2.5 to 6.5.
6) The aqueous pharmaceutical formulation according to claim 2,
wherein the pharmaceutical excipient is benzalkonium chloride.
7) The aqueous pharmaceutical formulation according to claim 6,
characterised in that the content of benzalkonium chloride is from
1 to 50 mg per 100 ml of solution.
8) The aqueous pharmaceutical formulation according to claim 1,
characterised in that a pharmacologically active cation of the
compound of 1 is present in the formulation in an amount of about 4
to 2000 mg per 100 ml of formulation.
9) The aqueous pharmaceutical formulation according to claim 2,
which comprises at least one complexing agent.
10) The aqueous pharmaceutical formulation according to claim 9,
characterised in that the content of the complexing agent is 5 to
20 mg per 100 ml of formulation.
11) The aqueous pharmaceutical formulation according to claim 1 in
an inhaler suitable for nebulising the formulation.
Description
[0001] The present invention relates to a propellant-free aqueous
aerosol formulation for anticholinergics of formula 1 2
[0002] wherein X.sup.- denotes an anion.
[0003] The compounds of formula 1 are known from WO 02/32899. They
have valuable pharmacological properties and can provide
therapeutic benefit as highly effective anticholinergics in the
treatment of respiratory complaints, particularly in the treatment
of inflammatory and/or obstructive diseases of the respiratory
tract, particularly for treating asthma or COPD (chronic
obstructive pulmonary disease).
[0004] The present invention relates to liquid active substance
formulations of these compounds which can be administered by
inhalation; the liquid formulations according to the invention have
to meet high quality standards. The formulations according to the
invention may be inhaled by oral or nasal route. To achieve an
optimum distribution of the active substances in the lung, it makes
sense to use a liquid formulation without propellant gases and to
administer by using suitable inhalers. A formulation of this kind
may be inhaled both by oral route and by nasal route. Those
inhalers which are capable of nebulising a small amount of a liquid
formulation in the dosage needed for therapeutic purposes within a
few seconds into an aerosol suitable for therapeutic inhalation are
particularly suitable. Within the scope of the invention, preferred
nebulisers are those in which an amount of less than 100
microlitres, preferably less than 50 microlitres, most preferably
less than 20 microlitres of active substance solution can be
nebulised preferably in one puff or two puffs, to form an aerosol
having an average particle size of less than 20 microns, preferably
less than 10 microns, so that the inhalable part of the aerosol
already corresponds to the therapeutically effective quantity.
[0005] An apparatus of this kind for the propellant-free
administration of a metered amount of a liquid pharmaceutical
composition for inhalation is described in detail in, for example
International Patent Application WO 91/14468, "Atomizing Device and
Methods" and also in WO 97/12687, cf. FIGS. 6a and 6b and the
accompanying description. In a nebuliser of this kind, a
pharmaceutical solution is converted by means of a high pressure
(up to 500 bar) into an aerosol destined for the lungs. The aerosol
is then sprayed. Within the scope of the present specification
reference is expressly made to the entire contents of the
literature mentioned above.
[0006] In inhalers of this kind, the formulations of solutions are
stored in a reservoir. It is essential that the active substance
formulations used are sufficiently stable when stored and at the
same time are such that they can be administered directly, if
possible without any further handling, in accordance with their
medical purpose. Moreover, they must not contain any ingredients
which might interact with the inhaler in such a way as to damage
the inhaler or the pharmaceutical quality of the solution or of the
aerosol produced.
[0007] To nebulise the solution, a special nozzle is used as
described, for example, in WO 94/07607 or WO 99/16530. Reference is
expressly made here to both these publications.
[0008] The aim of the invention is to provide an aqueous
formulation of the compound of formula 1 which meets the high
standards required to ensure optimum nebulisation of a solution
using the inhalers mentioned above. The active substance
[0009] formulations according to the invention must be of
sufficiently high pharmaceutical quality, i.e., they should be
pharmaceutically stable over a storage time of some years,
preferably at least one year, more preferably two years. These
propellant-free formulations of solutions must also be capable of
being nebulised by means of an inhaler under pressure, while the
composition delivered in the aerosol produced is within a specified
range.
[0010] Within the scope of the present invention, the compounds of
formula 1 are preferably used wherein the anion X.sup.- is selected
from among the chloride, bromide, iodide, sulphate, phosphate,
methanesulphonate, nitrate, maleate, acetate, citrate, fumarate,
tartrate, oxalate, succinate, benzoate and p-toluenesulphonate.
[0011] Preferably, the salts of formula 1 are used wherein X.sup.-
denotes an anion selected from the group consisting of chloride,
bromide, 4-toluenesulphonate and methanesulphonate.
[0012] Particularly preferred, within the scope of the present
invention, are the formulations which contain the compound of
formula 1 wherein X.sup.- denotes bromide.
[0013] References to the compound of formula 1 always include
within the scope of the present invention all possible amorphous
and crystalline modifications of this compound. References to the
compound of formula 1 also include within the scope of the present
invention all the possible solvates and hydrates which may be
formed from this compound.
[0014] Any reference to the compound 1' within the scope of the
present invention is to be regarded as a reference to the
pharmacologically active cation of the following formula 3
[0015] contained in the salts 1.
[0016] In the formulation according to the invention, the compound
1 is present dissolved in water. If desired, cosolvents may be
used. Preferably, according to the invention, no other solvent is
used.
[0017] According to the invention, the formulation preferably
contains only a single salt of formula 1. However, the formulation
may also contain a mixture of different salts of formula 1.
Formulations which contain active substances other than those of
formula 1 are not an object of the invention.
[0018] The concentration of the compound of formula 1 based on the
proportion of pharmacologically active cation 1' in the
pharmaceutical preparation according to the invention is about 4 to
2000 mg per 100 ml, according to the invention, preferably about 8
to 1600 mg per 100 ml. Particularly preferably, 100 ml of the
formulations according to the invention contain about 80 to about
1360 mg of 1'.
[0019] If the compound of formula 1 used is the particularly
preferred compound wherein X.sup.- denotes the bromide, the
proportion of 1 according to the invention is about 5 to 2500 mg
per 100 ml, preferably about 10 to 2000 mg per 100 ml of
pharmaceutical preparation. Most preferably, 100 ml of the
formulations according to the invention contain about 100 to 1700
mg of 1.
[0020] The pH of the formulation according to the invention is
preferably between 2.5 and 6.5 and more preferably between 3.0 and
5.0, more preferably between about 3.5 and 4.5.
[0021] The pH is adjusted by the addition of pharmacologically
acceptable acids. Pharmacologically acceptable inorganic acids or
organic acids may be used for this purpose. Examples of preferred
inorganic acids are selected from the group consisting of
hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid
and phosphoric acid. Examples of particularly suitable organic
acids are selected from the group consisting of ascorbic acid,
citric acid, malic acid, tartaric acid, maleic acid, succinic acid,
fumaric acid, acetic acid, formic acid and propionic acid.
Preferred inorganic acids are hydrochloric acid and sulphuric acid,
of which hydrochloric acid is particularly preferred according to
the invention. 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 other properties in addition to their acidifying
properties, e.g. those which act as flavourings or antioxidants,
such as for example citric acid or ascorbic acid.
[0022] If desired, pharmacologically acceptable bases may be used
to titrate the pH precisely. Suitable bases include for example
alkali metal hydroxides and alkali metal carbonates. The preferred
alkali metal ion is sodium. If bases of this kind are used, care
must be taken to ensure that the resulting salts, which are then
contained in the finished pharmaceutical formulation, are
pharmacologically compatible with the abovementioned acid.
[0023] The formulations according to the invention may contain
complexing agents as other ingredients. By complexing agents are
meant within the scope of the present invention molecules which are
capable of entering into complex bonds. Preferably, these compounds
should have the effect of complexing cations, most preferably metal
cations. The formulations according to the invention preferably
contain editic acid (EDTA) or one of the known salts thereof, e.g.
sodium EDTA or disodium EDTA dihydrate (sodium edetate), as
complexing agent. Preferably, sodium edetate is used, optionally in
the form of its hydrates, more preferably in the form of its
dihydrate. If complexing agents are used within the formulations
according to the invention, their content is preferably in the
range from 5 to 20 mg per 100 ml, more preferably in the range from
7 to 15 mg per 100 ml of the formulation according to the
invention. Preferably, the formulations according to the invention
contain a complexing agent in an amount of about 9 to 12 mg per 100
ml, more preferably about 10 mg per 100 ml of the formulation
according to the invention.
[0024] The remarks made concerning sodium edetate also apply
analogously to other possible additives which are comparable to
EDTA or the salts thereof, which have complexing properties and can
be used instead of them, such as for example nitrilotriacetic acid
and the salts thereof.
[0025] Other pharmacologically acceptable excipients may also be
added to the formulation according to the invention. By adjuvants
and additives are meant, in this context, any pharmacologically
acceptable and therapeutically useful substance which is not an
active substance, but can be formulated together with the active
substance in the pharmacologically suitable solvent, in order to
improve the qualities of the active substance formulation.
Preferably, these substances have no pharmacological effects or no
appreciable or at least no undesirable pharmacological effects in
the context of the desired therapy. The adjuvants and additives
include, for example, stabilisers, antioxidants and/or
preservatives which prolong the shelf life of the finished
pharmaceutical formulation, as well as flavourings, vitamins and/or
other additives known in the art. The additives also include
pharmacologically acceptable salts such as sodium chloride, for
example.
[0026] 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 or provitamins occurring in the human body.
[0027] Preservatives can be added to protect the formulation from
contamination with pathogenic bacteria. Suitable preservatives are
those known from the prior art, particularly benzalkonium chloride
or benzoic acid or benzoates such as sodium benzoate in the
concentration known from the prior art. Preferably, benzalkonium
chloride is added to the formulation according to the invention.
The amount of benzalkonium chloride is between 1 mg and 50 mg per
100 ml of formulation, preferably about 7 to 15 mg per 100 ml, more
preferably about 9 to 12 mg per 100 ml of the formulation according
to the invention.
[0028] Preferred formulations contain only benzalkonium chloride,
sodium edetate and the acid needed to adjust the pH, preferably
hydrochloric acid, in addition to the solvent water and the
compounds of formula 1.
[0029] The pharmaceutical formulations according to the invention
containing compounds of formula 1 are preferably used in an inhaler
of the kind described hereinbefore in order to produce the
propellant-free aerosols according to the invention. At this point,
we should once again expressly mention the patent documents
described hereinbefore, to which reference is hereby made.
[0030] As described at the beginning, a further developed
embodiment of the preferred inhaler is disclosed in WO 97/12687
(cf. in particular FIGS. 6a and 6b and the associated passages of
description). This nebuliser (known under the trademark
Respimat.RTM.) can advantageously be used to produce the inhalable
aerosols according to the invention containing a tiotropium salt as
active substance. Because of its cylindrical shape and handy size
of less than 9 to 15 cm long and 2 to 4 cm wide, the device can be
carried anywhere by the patient. The nebuliser sprays a defined
volume of the pharmaceutical formulation out through small nozzles
at high pressures, so as to produce inhalable aerosols.
[0031] 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
[0032] a pump housing fixed in the upper housing part and carrying
at one end a nozzle body with the nozzle or nozzle arrangement,
[0033] a hollow piston with valve body,
[0034] a power take-off flange in which the hollow body is fixed
and which is located in the upper housing part,
[0035] a locking clamping mechanism located in the upper housing
part,
[0036] a spring housing with the spring located therein, which is
rotatably mounted on the upper housing part by means of a rotary
bearing,
[0037] a lower housing part which is fitted onto the spring housing
in the axial direction.
[0038] The hollow piston with valve body corresponds to a device
disclosed in WO 97/12687. It projects partially into the cylinder
of the pump housing and is disposed to be axially movable in the
cylinder. Reference is made particularly to FIGS. 1-4--especially
FIG. 3--and the associated passages of description in the
abovementioned International Patent Application. At the moment of
release of the spring, the hollow piston with valve body exerts, at
its high pressure end, 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,
which is a measured amount of active substance solution. Volumes of
10 to 50 microlitres are preferred, volumes of 10 to 20 microlitres
are more preferable, whilst a volume of 10 to 15 microlitres per
actuation is particularly preferred.
[0039] The valve body is preferably mounted at the end of the
hollow piston which faces the nozzle body.
[0040] The nozzle in the nozzle body is preferably microstructured,
i.e., produced by micro-engineering. Microstructured nozzle bodies
are disclosed for example in WO-99/16530; reference is hereby made
to the contents of this specification, especially FIG. 1 and the
associated description.
[0041] The nozzle body consists for example of two sheets of glass
and/or silicon securely fixed 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 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 and
the length being 7 to 9 microns.
[0042] If there is a plurality of nozzle openings, preferably two,
the directions of spraying of the nozzles in the nozzle body may
run parallel to each other or may be inclined relative to one
another in the direction of the nozzle opening. In the case of a
nozzle body having at least two nozzle openings at the outlet end,
the directions of spraying may be inclined relative to one another
at an angle of 20 degrees to 160 degrees, preferably at an angle of
60 to 150 degrees, most preferably 80 to 1000. The nozzle openings
are preferably arranged at a spacing of 10 to 200 microns, more
preferably at a spacing of 10 to 100 microns, still more preferably
30 to 70 microns. A spacing of 50 microns is most preferred.
[0043] The directions of spraying therefore meet in the region of
the nozzle openings.
[0044] As already mentioned, the liquid pharmaceutical preparation
hits the nozzle body at an entry pressure of up to 600 bar,
preferably 200 to 300 bar and is atomised through the nozzle
openings into an inhalable aerosol. The preferred particle sizes of
the aerosol are up to 20 microns, preferably 3 to 10 microns.
[0045] The locking clamping mechanism contains a spring, preferably
a cylindrical helical compression spring, as a store for the
mechanical energy. The spring acts on the power take-off flange as
a 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 stop and a lower stop. The
spring is preferably tensioned via a stepping-up gear, e.g., a
helical sliding gear, by an external torque which is generated when
the upper housing part is turned 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 multi-speed spline
gear.
[0046] The locking member with the engaging locking surfaces is
arranged in an annular configuration around the power take-off
flange. It consists, for example, of a ring of plastics or metal
which is inherently radially elastically deformable. The ring is
arranged in a plane perpendicular to the axis of the atomiser.
After locking of the spring, the locking surfaces of the locking
member slide into the path of the power take-off flange and prevent
the spring from being released. The locking member is actuated by
means of a button. The actuating button is connected or coupled to
the locking member. In order to actuate the locking clamping
mechanism, the actuating button is moved parallel to the annular
plane, preferably into the atomiser, and the deformable ring is
thereby deformed in the annular plane. Details of the construction
of the locking clamping mechanism are described in WO 97/20590.
[0047] The lower housing part is pushed axially over the spring
housing and covers the bearing, the drive for the spindle and the
storage container for the fluid.
[0048] When the atomiser is operated, the upper part of the housing
is rotated relative to the lower part, the lower part taking the
spring housing with it. The spring meanwhile is compressed and
biased by means of the helical sliding gear, and the clamping
mechanism engages automatically. The angle of rotation is
preferably a whole-number fraction of 360 degrees, e.g., 180
degrees. At the same time that the spring is tensioned, the power
take-off component in the upper housing part is moved along by a
given amount, the hollow piston is pulled back inside the cylinder
in the pump housing, as a result of which some of the fluid from
the storage container is sucked into the high pressure chamber in
front of the nozzle.
[0049] If desired, a plurality of replaceable storage containers
containing the fluid to be atomised can be inserted in the atomiser
one after another and then used. The storage container contains the
aqueous aerosol preparation according to the invention.
[0050] The atomising process is initiated by gently pressing the
actuating button. The clamping mechanism then opens the way for the
power take-off component. The biased spring pushes the piston into
the cylinder in the pump housing. The fluid emerges from the nozzle
of the atomiser in the form of a spray.
[0051] Further details of the construction are disclosed in PCT
applications WO 97/12683 and WO 97/20590, to which reference is
hereby made.
[0052] The components of the atomiser (nebuliser) are made of a
material suitable for their function. The housing of the atomiser
and--if the function allows--other parts as well are preferably
made of plastics, e.g., by injection moulding. For medical
applications, physiologically acceptable materials are used.
[0053] FIGS. 6a/b of WO 97/12687 show the Respimat.RTM. nebuliser
with which the aqueous aerosol preparations according to the
invention can advantageously be inhaled.
[0054] FIG. 6a shows a longitudinal section through the atomiser
with the spring under tension, FIG. 6b shows a longitudinal section
through the atomiser with the spring released.
[0055] Referencing those drawings, 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 piston (57) fixed in the
power take-off flange (56) of the locking clamping mechanism
projects partly into the cylinder of the pump housing. At its end
the hollow piston carries the valve body (58). The hollow piston is
sealed off by the gasket (59). Inside the upper housing part is the
stop (60) on which the power take-off flange rests when the spring
is relaxed. Located on the power take-off flange is the stop (61)
on which the power take-off flange rests when the spring is under
tension. After the tensioning of the spring, the locking member
(62) slides 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
closed off by the removable protective cap (66).
[0056] 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 bearings. The lower housing part (70)
is pushed over the spring housing. Inside the spring housing is the
replaceable storage container (71) for the fluid (72) which is to
be atomised. The storage container is closed off by the stopper
(73), through which the hollow piston projects into the storage
container and dips its end into the fluid (supply of active
substance solution).
[0057] The spindle (74) for the mechanical counter is mounted on
the outside of the spring housing. The drive pinion (75) is located
at the end of the spindle facing the upper housing part. On the
spindle is the slider (76).
[0058] The nebuliser described above is suitable for nebulising the
aerosol preparations according to the invention to form an aerosol
suitable for inhalation.
[0059] If the formulation according to the invention is nebulised
using the method described above (that is, by use of the
Respimat.RTM. device), the mass expelled, in at least 97%,
preferably at least 98% of all the actuations of the inhaler
(puffs) should correspond to a defined quantity with a range of
tolerance of not more than 25%, preferably 20%, of this quantity.
Preferably, between 5 and 30 mg, and more preferably between 5 and
20 mg, of formulation are delivered as a defined mass per puff.
[0060] However, the formulation according to the invention can also
be nebulised using inhalers other than those described above, for
example, using jet-stream inhalers.
[0061] The present invention also relates to an inhalation kit
consisting of one of the pharmaceutical preparations according to
the invention described above, and an inhaler suitable for
nebulising this pharmaceutical preparation. The present invention
preferably relates to an inhalation kit consisting of one of the
pharmaceutical preparations according to the invention described
above and the Respimatat.RTM. inhaler described above.
[0062] The examples of formulations given below serve as
illustrations without restricting the subject matter of the present
invention to the compositions shown by way of example.
I. EXAMPLES OF FORMULATIONS
[0063] 100 ml of pharmaceutical preparation contain, in purified
water or water for injections, with a density of 1.00 g/cm.sup.3,
at a temperature of 15.degree. C. to 31.degree. C.:
1 Disodium Benzalkonium edetate 1 (1'-Bromide) chloride dihydrate
Citric acid Example (mg) (mg) (mg) (mg) 1 2000 10 10 3 2 1000 9 9 3
3 1500 12 12 5 4 500 10 12 2 5 150 7 12 3 6 250 15 7 2 7 750 12 15
4 8 150 -- 12 3 9 250 -- 7 4 10 750 -- 15 3 11 100 5 10 3
* * * * *