U.S. patent application number 12/296983 was filed with the patent office on 2009-05-07 for medicament dispensing device, medicament magazine therefor and method of removing a medicament from a medicament chamber.
This patent application is currently assigned to BOEHRINGER INGELHEIM INTERNATIONAL GMBH. Invention is credited to Johannes Geser, Andre Klopfenstein, Michael Krueger, Hubert Kunze, Antonino Lanci, Burkhard P. Metzger, Elmar Mock, Achim Moser, Michael Spallek, Herbert Wachtel.
Application Number | 20090114220 12/296983 |
Document ID | / |
Family ID | 36669868 |
Filed Date | 2009-05-07 |
United States Patent
Application |
20090114220 |
Kind Code |
A1 |
Wachtel; Herbert ; et
al. |
May 7, 2009 |
Medicament dispensing device, medicament magazine therefor and
method of removing a medicament from a medicament chamber
Abstract
The invention relates to a medicament dispensing device,
particularly a multi-dose powder inhaler, a medicament magazine
thereof, and a method of removing a medicament from the medicament
magazine as depicted in exemplary FIG. 1. The inhaler has a
mouthpiece (9) and an air channel (4) connected thereto, as well as
a medicament magazine with at least one medicament chamber
containing a powdered medicament. A drive current is produced in
the air channel, while a vacuum flow (5') can be produced by the
drive current and a constriction formed in the air channel. This
narrowest part of the air channel that produces the vacuum flow is
connected to a removal opening (2) which communicates with a
control opening (3), in order to form an emptying current through
the control opening via the removal opening. In a preferred
embodiment the at least one medicament chamber including the
control opening, the removal opening and a fill opening are housing
in the one-piece medicament magazine.
Inventors: |
Wachtel; Herbert;
(Ingelheim, DE) ; Geser; Johannes; (Ingelheim,
DE) ; Metzger; Burkhard P.; (Ingelheim, DE) ;
Spallek; Michael; (Ingelheim, DE) ; Krueger;
Michael; (Ingelheim, DE) ; Kunze; Hubert;
(Dortmund, DE) ; Moser; Achim; (Chemnitz, DE)
; Mock; Elmar; (Colombier, CH) ; Lanci;
Antonino; (Bern, CH) ; Klopfenstein; Andre;
(La Neuveville, CH) |
Correspondence
Address: |
Michael P. Morris;Boehringer Ingelheim USA Corporation
900 Ridgebury Road
Ridgefield
CT
06877-0368
US
|
Assignee: |
BOEHRINGER INGELHEIM INTERNATIONAL
GMBH
Ingelheim
DE
|
Family ID: |
36669868 |
Appl. No.: |
12/296983 |
Filed: |
April 13, 2007 |
PCT Filed: |
April 13, 2007 |
PCT NO: |
PCT/CH2007/000182 |
371 Date: |
December 30, 2008 |
Current U.S.
Class: |
128/203.15 ;
128/203.12; 128/203.21 |
Current CPC
Class: |
A61M 2202/064 20130101;
A61M 15/002 20140204; A61M 15/0038 20140204; A61M 15/0048 20140204;
A61M 2206/16 20130101; A61M 15/0043 20140204; A61M 15/0003
20140204; A61M 15/0035 20140204; A61M 15/0028 20130101; A61M
15/0045 20130101 |
Class at
Publication: |
128/203.15 ;
128/203.12; 128/203.21 |
International
Class: |
A61M 15/00 20060101
A61M015/00; A61M 16/10 20060101 A61M016/10 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 13, 2006 |
EP |
06405160.0 |
Claims
1-24. (canceled)
25. Medicament dispensing device comprising a mouthpiece (9) and an
air channel (4) connected therewith, as well as a medicament
magazine with at least one medicament chamber containing a
medicament, wherein a drive current comprising a vacuum flow can be
generated in the air channel, characterised in that a most narrow
region of the air channel that produces the vacuum flow, is
connected to a removal opening (2) provided by the medicament
magazine, this removal opening being connected to a control opening
(3), to form an emptying current through the control opening via
the removal opening.
26. Medicament dispensing device according to claim 25, wherein the
control and removal openings (3,2) are provided in the medicament
magazine.
27. Medicament dispensing device according to claim 25, wherein a
bypass opening (8) is provided in the air channel (4) for forming a
bypass flow, the bypass opening being arranged downstream of the
removal opening (2) in the direction of the mouthpiece (9).
28. Medicament dispensing device according to claim 25, having a
throttle arrangement for varying the amount of medicament removed
per unit of time.
29. Medicament dispensing device according to claim 28, wherein the
throttle arrangement comprises the control opening (3), the removal
opening (2), the inner configuration of the medicament chamber and
the configuration of the air channel connected to the removal
opening.
30. Medicament dispensing device according to one of claim 25 for
administering a medicament that contains an active substance or a
combination of active substances selected from among the group of
betamimetics, anticholinergics, steroids, antiallergics, ergot
alkaloid derivatives, triptanes, CGRP antagonists, the
phosphodiesterase-V inhibitors, phosphodiesterase-IV inhibitors,
LTD4-antagonists, EGFR-kinase inhibitors.
31. Medicament magazine (1) comprising a plurality of medicament
chambers, each having at least one opening for the removal (2) of a
medicament, characterised in that the medicament chamber has a fill
opening (13) and the removal opening (2) is connected to a control
opening (3), wherein the removal opening (2) can be attached to a
vacuum flow in order to form an emptying current through the
control opening (3) via the removal opening (2), and wherein the
removal opening, the control opening and the fill opening are
spaced from one another.
32. Medicament magazine according to claim 31, wherein the removal
opening (2) and control opening (3) are integrated and predefined
in the medicament magazine.
33. Medicament magazine (1) comprising a plurality of medicament
chambers having at least one opening for the removal (2) of a
medicament, characterised in that the medicament chamber has a fill
opening (13) and the removal opening (2) is connected to a control
opening (3), the removal opening (2) being connectable to a vacuum
flow in order to produce an emptying current through the control
opening (3) via the removal opening (2) and wherein the removal
opening (2) and control opening (3) are integrated and predefined
in the medicament magazine.
34. Medicament magazine according to claim 33, wherein the fill
opening (13), removal opening (2) and control opening (3) are
arranged at a spacing from one another.
35. Medicament magazine according to claim 31, wherein the magazine
is annular and a plurality of medicament chambers are arranged in a
ring in the magazine.
36. Medicament magazine according to claim 31, wherein the fill
opening (13) is arranged in a side of the magazine opposite the
removal and control opening (2,3).
37. Medicament magazine according to claim 31, wherein the fill
opening (13) is arranged on the same side of the magazine as the
removal and control opening (2,3).
38. Medicament magazine according to claim 31, wherein a turbulence
element (7) is arranged in the medicament chamber.
39. Medicament magazine according to claim 38, wherein the
turbulence element (7) is formed by at least a part of the wall of
the medicament chamber.
40. Medicament magazine according to claim 31, produced in one
piece by injection moulding.
41. Multi-dose powder inhaler comprising a medicament magazine
according to claim 31.
42. Multi-dose powder inhaler according to claim 41, comprising 60
medicament chambers with single doses of medicament.
43. Method of removing a medicament from a medicament chamber,
wherein a medicament is removed from the medicament chamber by the
formation of a vacuum flow, and wherein the vacuum flow produces an
emptying current through the medicament chamber, characterised in
that the vacuum flow is part of a drive current (5) and is
connected to a removal opening (2), defined by the medicament
magazine, which removal opening is connected to the medicament
chamber, wherein the emptying current is not connected with the
drive current before entering the medicament chamber.
44. Method according to claim 43, wherein the quantity of
medicament to be removed per unit of time is determined by the
strength of the emptying current, while the latter can be varied by
means of a throttle arrangement.
45. Method according to claim 43, wherein at least some of the
emptying current flows away over the medicament contained in the
medicament chamber.
46. Method according to claim 43, wherein an additional vacuum flow
in the medicament chamber is produced by means of an inner
configuration of the medicament chamber.
47. Method according to claim 43, wherein a medicament is emptied
into a preliminary chamber (105) which is attached to a vacuum flow
via a removal opening (2) for the removal of the medicament.
48. Method according to claim 43, wherein a medicament chamber is
opened before the removal of medicament, by piercing, scraping off
or peeling a sealing foil (14) that closes off the medicament
chamber.
Description
[0001] This application is the national phase entry under 35 U.S.C.
.sctn. 371 of International Application No. PCT/CH2007/000182,
filed Apr. 13, 2007, which claims priority to European Application
No. EP 06405160.0, filed Apr. 13, 2006, each of which is hereby
incorporated by reference in its entirety.
[0002] The invention relates to the field of medicament dispensing
devices with a multi-dose magazine, particularly multi-dose powder
inhalers, and relates to a medicament dispensing device according
to the preamble of the independent claim. Also claimed is a
medicament magazine for use in the medicament dispensing device,
and a method of removing a medicament, particularly a powdered
medicament.
[0003] Inhalers are known from the prior art in which a connection
is made directly to a medicament chamber by means of a vacuum flow
produced by inhaling (Venturi) and a powdered medicament contained
therein is removed. In U.S. Pat. No. 6,655,381 a powdered
medicament is placed in wells arranged in a circle in an annular
magazine. A seal that closes off the wells is removed substantially
in its entirety and a Venturi tube is arranged parallel to the
magazine with the constriction above the well. Attached to the
Venturi tube is a longer turbulence chamber which is needed as the
medicament is essentially removed from the well all in one go. With
this device it is not possible to achieve accurate dosing of a
medicament or adjustment to different dosages.
[0004] In addition, there are various inhalers in which a
medicament chamber is opened by piercing. However, openings in a
film made by piercing are not very precisely defined, which means
that on the one hand the precise amount of a medicament removed is
not known and also differences occur between successive removals.
This is undesirable particularly with medicaments the activity of
which depends to a very high degree on the dosage.
[0005] In order to achieve the best possible turbulence in a
medicament and thereby dissolve the carrier material and the active
substance itself, in EP 1 475 115 and GB 2 340 758, a medicament
chamber is essentially divided into an entry and exit chamber which
are joined together by a constricted passage. A medicament is
placed only in the entry chamber. By piercing or introducing
cannulas, an air flow is produced through the medicament chamber
from the entry chamber through the constriction into the exit
chamber and out of the medicament chamber. In EP 1 475 115, for
improved emptying of the medicament chamber, the entry and exit
caber are each provided with two openings. In both specifications,
the openings in the chambers are defined by the piercing.
[0006] In U.S. Pat. No. 5,715,810 a medicament chamber incorporated
in an annular magazine is pierced on both sides. One piercing
cannula is attached to a Venturi current, so as to produce an air
flow through the chamber. The removal takes place in one step and
cannot be metered, or can only be metered poorly. Here, too, the
chambers are defined by piercing and pins used for this.
[0007] In WO 03/045483 a medicament chamber is pierced and a
medicament contained therein is emptied out using an air flow
produced by a compressed air source.
[0008] EP 0 547 429 discloses a cylindrical medicament magazine in
which a fresh medicament chamber is brought into registry with a
removal opening inside the apparatus by a screwing movement. In the
apparatus, the air flow is subdivided: while one part empties the
medicament chamber, the other part is passed through the apparatus
and is combined with the medicament air current as an encircling
air current.
[0009] In WO 2005/002654 an air flow is injected through a
medicament chamber. Individual medicament pouches are housed in an
annular magazine. During use the pouches are pushed out of the
magazine from behind, thereby severing a sealing film and are
coupled with a removal mechanism. At the same time an air current
is guided into and through the pouch at the maximum possible speed.
To trigger aggregation of a powder and prevent medicament from
being carried forward into successive inhalations, an individual
channel is provided downstream of each pouch. With an additional
bypass channel that circumvents the pouch and also opens into a
mouthpiece, the total volume of air inhaled is increased and
inhalation facilitates or guarantees a sufficient air current being
present to transport the medicament to the user. Owing to the fact
that some of the air current is deflected through the bypass
channel, the air current through the pouch is reduced, so that the
removal process is prolonged. The removal of the medicament can
thus be spread over a somewhat longer period of time instead of all
being removed at once.
[0010] The powder inhaler from WO 2005/002654 is relatively
complicated in construction. A number of different parts are
present, some of which move and have to be coordinated with one
another. Moreover, the removal of the medicament is not triggered
by an actual Venturi principle, but rather there is an intake
current passing directly through the medicament pouches, and this
can be weakened by a bypass flow.
[0011] The aim of the invention is therefore to provide a
medicament dispensing device, a medicament magazine for use in such
a medicament dispensing device and a method of removing a
medicament form a medicament chamber in which the removal is based
on the Venturi principle and the amount taken out can be metered
accurately and reproducibly.
[0012] This aim is achieved by the medicament dispensing device,
the medicament magazine, and the method, as defined in the
claims.
[0013] The invention is based on the principle known from U.S. Pat.
No. 6,655,381, for example, of applying a Venturi-like vacuum flow
to a medicament chamber and sucking the medicament contained
therein out of the chamber by the vacuum and transporting it with
the flow towards a mouthpiece. There, the medicament travels with
the air current in the lungs of the user inhaling it.
[0014] In the device and method according to the invention, a drive
current is now produced in an air channel, which as a result of a
constriction in the air channel produces a vacuum flow in this
region. The narrowest part of the air channel causing the reduced
pressure flow is connected to a removal opening of a medicament
chamber. The removal opening is connected to a control opening, so
that an emptying current is formed through the control opening via
the removal opening and through the medicament chamber. The
emptying current is not connected to the drive current before
entering the medicament chamber, but combines with the drive
current after leaving the removal opening, so that a medicament
carried along with the emptying current is transported with the
drive current towards the mouthpiece.
[0015] The removal and control openings are preferably integrated
directly in a medicament magazine. If the openings or the
medicament magazine as a whole are produced by injection moulding
from plastics, for example, these openings are very precisely
defined, in a way which is not possible when an opening is produced
by piercing, for example. By integrating the removal and control
openings in the medicament magazine, these two openings are
pre-defined and are fixed both before and after opening a
medicament chamber.
[0016] The control and removal openings form a major part of a
throttle arrangement by which it is possible to control the
emptying current and hence to vary the quantity of medicament
removed per unit of time. Other elements of the throttle
arrangement with different effects may be the inner configuration
of the medicament chamber itself, and the construction of the air
channel connected to the removal opening, particularly its
diameter.
[0017] As a result, the removal can be deliberately controlled, is
precisely defined and above all reproducible. A throttle effect and
hence an emptying current can be deliberately selected on the basis
of the accurately defined but variable elements such as the control
opening, removal opening, inner configuration of the medicament
chamber and can also easily be changed to other dosages, quantities
and types of medicaments.
[0018] The inhaler may also have at least one bypass opening to
assist the inhalation process, e.g. for children or people with
weakened lungs. This bypass opening serves to form a bypass flow
which also leads to the mouthpiece and is preferably arranged
downstream of a removal opening in the direction of the mouthpiece.
However, it does not have any direct influence on a defined
correlation between the vacuum flow, the removal opening and
control opening.
[0019] A medicament chamber is preferably constructed so that at
least some of the emptying current flows away over the medicament
contained in the medicament chamber. By a suitable inner
configuration of the medicament chamber it is also possible to
influence the disaggregation and dispersion of a medicament. For
example, additional turbulence can be introduced into an emptying
current by means of a turbulence element, which is preferably
formed by at least one part of the wall of the medicament chamber
itself. This can increase the throttling effect or, if necessary,
reduce it.
[0020] In the medicament chamber an additional vacuum flow can be
produced, for example by means of a special configuration of a
chamber wall or by means of a turbulence element. This is
preferably arranged in a direct line between the control and
removal openings, such that a medicament located on the floor of
the medicament chamber is detached by this additional vacuum flow
in the chamber. This can be achieved by, for example, the
medicament chamber itself forming a kind of Venturi tube in all or
part of the region between the control and removal openings.
[0021] A medicament magazine typically has a fill opening in
addition to a control and removal opening. This fill opening is
preferably formed independently of the other two openings in the
magazine. This has the advantage that the fill opening can be very
large, to assist with the filling operation. The fill opening is
closed off, preferably sealed with a foil, after the introduction
of a powder. If the medicament magazine is constructed as an
annular magazine with a plurality of medicament chambers arranged
in a circle therein, the control and removal openings of each
chamber are spaced from one another, preferably on one side of the
magazine, while the fill opening is arranged on the opposite side
of the magazine. Thus, the opening of the control and removal
openings is also independent of the removal of a sealing foil.
Preferably a medicament magazine has a plurality of medicament
chambers and single doses contained therein. The number is
preferably in the range from 1 to 100 or up to 200 single doses,
preferably in the range from 1-60, for example between 7-180 or
14-150, e.g. 30-120, 45-100, 30, 90, 60, 120. For inhalers the
maximum number of single doses is preferably 60, for reasons of
convenience and therapy.
[0022] An inhaler with a medicament magazine of this kind is very
versatile in use. Besides the various possibilities of coordination
and deliberate and very precise dosing possibilities, particularly
their reproducibility, there is also the option of using the
inhaler with a wide range of amounts and types of medicament. It is
relatively simple to use a different medicament magazine, e.g. with
a medicament chamber with a different, e.g. greater or smaller,
capacity. If a removal opening is accurately defined by the
medicament magazine itself, an adjacent (vacuum) opening in the
Venturi suction tube may also be made larger without affecting the
removal opening and hence the emptying current. As a result an
inhaler can also be used with different medicament magazines, e.g.
those with differently designed removal openings. Owing to the fact
that only one removal opening has to be coupled at the inhaler end,
the remainder of the construction of the inhaler and also the
medicament chamber, in relation to a removal mechanism, is
substantially independent of the medicament magazine and vice
versa. In particular, a medicament chamber may be very elongated,
may have an angle, etc., and a control opening may be arranged
accordingly at different locations in the magazine. This is
possible as the control opening is not directly connected to the
arrangement of the Venturi tube, and in particular, the drive
current produced in the Venturi tube and the emptying current
formed by the coupling of the vacuum flow to the magazine have a
different origin.
[0023] In the inhaler according to the invention essentially any
kind of opening mechanism is possible: a medicament chamber can be
opened before the removal of the medicament by piercing, scraping
or peeling off a sealing foil that closes off the medicament
chamber. A medicament chamber is designed accordingly, preferably
such that the removal and control opening, which may also be
referred to as control openings, are not affected by the opening
mechanism. In particular, they are not affected by openings in the
sealing foil itself or by an opening mechanism of the apparatus
which produces such openings. This may be achieved for example by
removing a sealing foil entirely from the control openings before
the medicament is taken out, or by making an opening in a sealing
foil so big that its effect on the control openings is
negligible.
[0024] In one embodiment of the magazine, a medicament is emptied
into a preliminary chamber, the preliminary chamber having a
corresponding control and removal opening which is connected to a
vacuum flow for removing the medicament. For this purpose, a
medicament may be sealed in its own medicament chamber with a
sealing foil which is preferably opening by an opening means that
may be installed in the chamber itself. In this embodiment this
fill opening is arranged substantially on the same side as the
control openings. The preliminary chamber may be an integral part
of the medicament chamber or the medicament magazine, or it may be
an integral part formed on an air channel. The advantage of the
first variant is that a new unused chamber is available each time
medicament is taken.
[0025] In a preferred embodiment of the inhaler, two medicament
chambers are joined together through a common mouthpiece. In this
way, the number of single doses of medicament can be doubled. For
this, the individual medicament chambers of the two magazines are
preferably arranged offset from one another. However, it is also
possible, when removing the medicament, to open one chamber of each
magazine and take one medicament from each. This is particularly
advantageous if two medicaments have to be taken which cannot be
stored together, or if every second time a double quantity of a
medicament or medicament mixture has to be taken. For producing a
medicament magazine and optionally also certain parts of a device,
pharmaceutically permitted materials are preferably used. The films
used may be multi-layer films, for example, which are suitable as
films for peeling or piercing or for scraping off. Multi-layer
films usually have a layer of PE, PP or PVC and an aluminium layer.
Dependingon the particular requirement, a film is made more stable
or tear-resistant, and this is pref done by incorporating a PET
layer. In preferred material combinations, an outer layer of a film
comprises the same material as an injected-moulded magazine, for
example. In this way it is possible to seal or weld the different
elements of a medicament magazine with the same materials. It is
also possible to use sealing lacquer, e.g. heat-sealing lacquer. As
a result, there are more possible material combinations for the
individual elements. A sealing lacquer is applied, for example, to
a film and/or to a magazine that is to be closed off. It is also
possible for a foil to have a layer of sealing lacquer directly.
The strength of the seal is preferably also optimally tailored to
the use, so that, for example, a peelable film adheres directly but
removably to an elements which is to be sealed.
[0026] The compounds specified below may be used in the apparatus
according to the invention on their own or in combination. In the
compounds specified below, W is a pharmacologically active
substance and (for example) is selected from among the
betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors,
LTD4-antagonists, EGFR-inhibitors, dopamine agonists,
H1-antihistamines, PAF-antagonists and PI3-kinase inhibitors.
Moreover, double or triple combinations of W may be combined and
used in the apparatus accin. Combinations of W might be, for
example: [0027] W denotes a betamimetic, combined with an
anticholinergic, corticosteroid, PDE4-inhibitor, EGFR-inhibitor or
LTD4-antagonist, [0028] W denotes an anticholinergic, combined with
a betamimetic, corticosteroid, PDE4-inhibitor, EGFR-inhibitor or
LTD4-antagonist, [0029] W denotes a corticosteroid, combined with a
PDE4-inhibitor, EGFR-inhibitor or LTD4-antagonist [0030] W denotes
a PDE4-inhibitor, combined with an EGFR-inhibitor or
LTD4-antagonist [0031] W denotes an EGFR-inhibitor, combined with
an LTD4-antagonist.
[0032] The compounds used as betamimetics are preferably compounds
selected from among albuterol, arformoterol, bambuterol,
bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol,
formoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline,
levosalbutamol, mabuterol, meluadrine, metaproterenol,
orciprenaline, pirbuterol, procaterol, reproterol, rimiterol,
ritodrine, salmefamol, salmeterol, soterenol, sulphonterol,
terbutaline, tiaramide, tolubuterol, zinterol, CHF-1035, HOKU-81,
KUL-1248 and [0033]
3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyl-
oxy}-butyl)-benzyl-sulphonamide [0034]
5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-
e-2-one [0035]
4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethy-
l]-2(3H)-benzothiazolone [0036]
1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamin-
o]ethanol [0037]
1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-m-
ethyl-2-butylamino]ethanol [0038]
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminoph-
enyl)-2-methyl-2-propylamino]ethanol [0039]
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-me-
thyl-2-propylamino]ethanol [0040]
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-
-methyl-2-propylamino]ethanol [0041]
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1-
,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol [0042]
5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-on
[0043]
1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)et-
hanol [0044]
6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-e-
thyl}-4H-benzo[1,4]oxazin-3-one [0045]
6-hydroxy-8-{1-hydroxy-2-[2-(ethyl
4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3--
one [0046] 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic
acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one
[0047]
8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-
-6-hydroxy-4H-benzo[1,4]oxazin-3-one [0048]
6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-e-
thyl}-4H-benzo[1,4]oxazin-3-one [0049]
6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1.1
dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one [0050]
8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydr-
oxy-4H-benzo[1,4]oxazin-3-one [0051]
8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hyd-
roxy-4H-benzo[1,4]oxazin-3-one [0052]
4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-y-
l)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid [0053]
8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-
-hydroxy-4H-benzo[1,4]oxazin-3-one [0054]
1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)etha-
nol [0055]
2-hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)--
phenyl]-ethylamino}-ethyl)-benzaldehyde [0056]
N-[2-hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-
-ethylamino}-ethyl)-phenyl]-formamide [0057]
8-hydroxy-5-(1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-eth-
ylamino}-ethyl)-1H-quinolin-2-one [0058]
8-hydroxy-5-[1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1H-quinolin-
-2-one [0059]
5-[2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-
-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one [0060]
[3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexy-
loxy}-butyl)-5-methyl-phenyl]-urea [0061]
4-(2-{6-[2-(2,6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)--
2-hydroxymethyl-phenol [0062]
[3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexy-
loxy}-butyl)-benzylsulphonamide [0063]
3-(3-{7-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hepty-
loxy}-propyl)-benzylsulphonamide [0064]
4-(2-{6-[4-(3-cyclopentanesulphonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy-
-ethyl)-2-hydroxymethyl-phenol [0065]
N-adamantan-2-yl-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)--
ethylamino]-propyl}-phenyl)-acetamide, optionally in the form of
the racemates, enantiomers, diastereomers thereof and optionally in
the form of the pharmacologically acceptable acid addition salts,
solvates or hydrates thereof. According to the invention the acid
addition salts of the betamimetics are preferably selected from
among the hydrochloride, hydrobromide, hydriodide, hydrosulphate,
hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,
hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate,
hydroxalate, hydrosuccinate, hydrobenzoate and
hydro-p-toluenesulphonate.
[0066] The anticholinergics used are preferably compounds selected
from among the tiotropium salts, preferably the bromide salt,
oxitropium salts, preferably the bromide salt, flutropium salts,
preferably the bromide salt, ipratropium salts, preferably the
bromide salt, glycopyrronium salts, preferably the bromide salt,
trospium salts, preferably the chloride salt, tolterodine. In the
above-mentioned salts the cations are the pharmacologically active
constituents. As anions the above-mentioned salts may preferably
contain the chloride, bromide, iodide, sulphate, phosphate,
methanesulphonate, nitrate, maleate, acetate, citrate, fumarate,
tartrate, oxalate, succinate, benzoate or p-toluenesulphonate,
while chloride, bromide, iodide, sulphate, methanesulphonate or
p-toluenesulphonate are preferred as counter-ions. Of all the salts
the chlorides, bromides, iodides and methanesulphonates are
particularly preferred.
[0067] Other preferred anticholinergics are selected from among the
salts of formula AC-1
##STR00001##
wherein X.sup.- denotes an anion with a single negative charge,
preferably an anion selected from among the fluoride, chloride,
bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate,
maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate,
benzoate and p-toluenesulphonate, preferably an anion with a single
negative charge, particularly preferably an anion selected from
among the fluoride, chloride, bromide, methanesulphonate and
p-toluenesulphonate, particularly preferably bromide, optionally in
the form of the racemates, enantiomers or hydrates thereof. Of
particular importance are those pharmaceutical combinations which
contain the enantiomers of formula AC-1-ene
##STR00002##
wherein X.sup.- may have the above-mentioned meanings. Other
preferred anticholinergics are selected from the salts of formula
AC-2
##STR00003##
wherein R denotes either methyl or ethyl and wherein X.sup.- may
have the above-mentioned meanings. In an alternative embodiment the
compound of formula AC-2 may also be present in the form of the
free base AC-2-base.
##STR00004##
[0068] Other specified compounds are: [0069] tropenol
2,2-diphenylpropionate methobromide, [0070] scopine
2,2-diphenylpropionate methobromide, [0071] scopine
2-fluoro-2,2-diphenylacetate methobromide, [0072] tropenol
2-fluoro-2,2-diphenylacetate methobromide; [0073] tropenol
3,3',4,4'-tetrafluorobenzilate methobromide, [0074] scopine
3,3',4,4'-tetrafluorobenzilate methobromide, [0075] tropenol
4,4'-difluorobenzilate methobromide, [0076] scopine
4,4'-difluorobenzilate methobromide, [0077] tropenol
3,3'-difluorobenzilate methobromide, [0078] scopine
3,3'-difluorobenzilate methobromide; [0079] tropenol
9-hydroxy-fluorene-9-carboxylate methobromide; [0080] tropenol
9-fluoro-fluorene-9-carboxylate methobromide; [0081] scopine
9-hydroxy-fluorene-9-carboxylate methobromide; [0082] scopine
9-fluoro-fluorene-9-carboxylate methobromide; [0083] tropenol
9-methyl-fluorene-9-carboxylate methobromide; [0084] scopine
9-methyl-fluorene-9-carboxylate methobromide; [0085]
cyclopropyltropine benzilate methobromide; [0086]
cyclopropyltropine 2,2-diphenylpropionate methobromide; [0087]
cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide;
[0088] cyclopropyltropine 9-methyl-fluorene-9-carboxylate
methobromide; [0089] cyclopropyltropine
9-methyl-xanthene-9-carboxylate methobromide; [0090]
cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide;
[0091] cyclopropyltropine methyl 4,4'-difluorobenzilate
methobromide. [0092] tropenol 9-hydroxy-xanthene-9-carboxylate
methobromide; [0093] scopine 9-hydroxy-xanthene-9-carboxylate
methobromide; [0094] tropenol
9-methyl-xanthene-9-carboxylate-methobromide; [0095] scopine
9-methyl-xanthene-9-carboxylate-methobromide; [0096] tropenol
9-ethyl-xanthene-9-carboxylate methobromide; [0097] tropenol
9-difluoromethyl-xanthene-9-carboxylate methobromide; [0098]
scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide,
[0099] The above-mentioned compounds may also be used as salts
within the scope of the present invention, wherein instead of the
methobromide the salts metho-X are used, wherein X may have the
meanings given hereinbefore for X.sup.-.
[0100] As corticosteroids it is preferable to use compounds
selected from among beclomethasone, betamethasone, budesonide,
butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol,
flunisolide, fluticasone, loteprednol, mometasone, prednisolone,
prednisone, rofleponide, triamcinolone, RPR-106541, NS-126, ST-26
and [0101] (S)-fluoromethyl
6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-andro-
sta-1,4-diene-17-carbothionate [0102] (S)-(2-oxo-tetrahydro-furan-3
S-yl)6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-
-diene-17-carbothionate, [0103] cyanomethyl
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alp-
ha.-(2,2,3,3-tetramethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17.beta-
.-carboxylate optionally in the form of the racemates, enantiomers
or diastereomers thereof and optionally in the form of the salts
and derivatives thereof, the solvates and/or hydrates thereof. Any
reference to steroids includes a reference to any salts or
derivatives, hydrates or solvates thereof which may exist. Examples
of possible salts and derivatives of the steroids may be: alkali
metal salts, such as for example sodium or potassium salts,
sulphobenzoates, phosphates, isonicotinates, acetates,
dichloroacetates, propionates, dihydrogen phosphates, palmitates,
pivalates or furoates.
[0104] PDE4-inhibitors which may be used are preferably compounds
selected from among enprofyllin, theophyllin, roflumilast, ariflo
(cilomilast), tofimilast, pumafentrin, lirimilast, arofyllin,
atizoram, D-4418, Bay-198004, BY343, CP-325,366, D-4396
(Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418,
PD-168787, T-440, T-2585, V-11294A, CI-1018, CDC-801, CDC-3052,
D-22888, YM-58997, Z-15370 and [0105]
N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropy-
lmethoxybenzamide [0106] (-)p-[(4aR*,
10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]n-
aphthyridin-6-yl]-N,N-diisopropylbenzamide [0107]
(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrol-
idone [0108]
3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N.sup.2-cyano-5-methyl-isothi-
oureido]benzyl)-2-pyrrolidone [0109] cis
[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic
acid] [0110]
2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)c-
yclohexan-1-one [0111] cis
[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]
[0112]
(R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yli-
dene]acetate [0113]
(S)-(-)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]ac-
etate [0114]
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4--
triazolo[4,3-a]pyridine [0115]
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-
-triazolo[4,3-a]pyridine optionally in the form of the racemates,
enantiomers or diastereomers thereof and optionally in the form of
the pharmacologically acceptable acid addition salts thereof, the
solvates and/or hydrates thereof. According to the invention the
acid addition salts of the PDE4 inhibitors are preferably selected
from among the hydrochloride, hydrobromide, hydriodide,
hydrosulphate, hydrophosphate, hydromethanesulphonate,
hydronitrate, hydromaleate, hydroacetate, hydrocitrate,
hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate,
hydrobenzoate and hydro-p-toluenesulphonate.
[0116] The LTD4-antagonists used are preferably compounds selected
from among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523),
MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321 and
[0117]
1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy--
2-propyl)phenyl)thio)methylcyclopropane-acetic acid, [0118]
1-(((1(R)-3
(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-
-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic
acid [0119]
[2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]-
acetic acid optionally in the form of the racemates, enantiomers or
diastereomers thereof and optionally in the form of the
pharmacologically acceptable acid addition salts, solvates and/or
hydrates thereof. According to the invention these acid addition
salts are preferably selected from among the hydrochloride,
hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,
ydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,
hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,
hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate. By
salts or derivatives which the LTD4-antagonists may optionally be
capable of forming are meant, for example: alkali metal salts, such
as for example sodium or potassium salts, alkaline earth metal
salts, sulphobenzoates, phosphates, isonicotinates, acetates,
propionates, dihydrogen phosphates, palmitates, pivalates or
furoates.
[0120] EGFR-inhibitors which may be used are preferably compounds
selected from among cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and
[0121]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]-amino}-7-cyclopropylmethoxy-quinazoline [0122]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-
-1-yl]amino}-7-cyclopropylmethoxy-quinazoline [0123]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclopropylmethoxy-quinazoline [0124]
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]--
amino}-7-cyclopentyloxy-quinazoline [0125]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-
-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline
[0126]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-
-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoli-
ne [0127]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-
-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinaz-
oline [0128]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4--
yl)-ethoxy]-7-methoxy-quinazoline [0129]
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-am-
ino]-1-oxo-2-buten-1-yl} amino)-7-cyclopropylmethoxy-quinazoline
[0130]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclopentyloxy-quinazoline [0131]
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-o-
xo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline [0132]
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-
-oxo-2-buten-1-yl} amino)-7-cyclopropylmethoxy-quinazoline [0133]
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]--
1-oxo-2-buten-1-yl} amino)-7-cyclopropylmethoxy-quinazoline [0134]
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-am-
ino]-1-oxo-2-buten-1-yl} amino)-7-cyclopropylmethoxy-quinazoline
[0135]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline [0136]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline [0137]
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-am-
ino]-1-oxo-2-buten-1-yl} amino)-7-cyclopentyloxy-quinazoline [0138]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-
-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline [0139]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline
[0140]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline
[0141]
4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline
[0142]
4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(v-
inyl-carbonyl)amino]-quinazoline [0143]
4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrim-
idine [0144]
3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-ox-
o-2-buten-1-yl]amino}-7-ethoxy-quinoline [0145]
4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulpho-
nyl-ethyl)amino]methyl}-furan-2-yl)quinazoline [0146]
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-
-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline [0147]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]-amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline [0148]
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino-
]-1-oxo-2-buten-1-yl}
amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline [0149]
4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4--
yl)-1-oxo-2-buten-1-yl]amino}-quinazoline [0150]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4--
yl)-ethoxy]-7-methoxy-quinazoline [0151]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4--
yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline
[0152]
4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4--
yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline
[0153]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperi-
din-1-yl]-ethoxy}-7-methoxy-quinazoline [0154]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperid-
in-4-yloxy]-7-methoxy-quinazoline [0155]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)--
7-methoxy-quinazoline [0156]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cycl-
ohexan-1-yloxy)-7-methoxy-quinazoline [0157]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-
-quinazoline [0158]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-meth-
oxy-quinazoline [0159]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline [0160]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperi-
din-4-yloxy}-7-methoxy-quinazoline [0161]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quina-
zoline [0162]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin--
4-yloxy]-7-methoxy-quinazoline [0163]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy--
quinazoline [0164]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hyd-
roxy-quinazoline [0165]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-meth-
oxy-ethoxy)-quinazoline [0166]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonyla-
mino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline [0167]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonyla-
mino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline [0168]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonyl-
amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline [0169]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acet-
ylamino-ethoxy)-quinazoline [0170]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-meth-
anesulphonylamino-ethoxy)-quinazoline [0171]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline [0172]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4--
yloxy)-7-methoxy-quinazoline [0173]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)ca-
rbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline
[0174]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl-
]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline [0175]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphony-
l]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline [0176]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethansulphonylamino-cycloh-
exan-1-yloxy)-7-methoxy-quinazoline [0177]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-ylo-
xy)-7-ethoxy-quinazoline [0178]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-ylo-
xy)-7-(2-methoxy-ethoxy)-quinazoline [0179]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-y-
loxy]-7-(2-methoxy-ethoxy)-quinazoline [0180]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-ylo-
xy)-7-methoxy-quinazoline [0181]
4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-ylo-
xy]-7-methoxy-quinazoline [0182]
4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazo-
line [0183]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl-
]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline [0184]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl-
)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline
[0185]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carb-
onylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline [0186]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]--
piperidin-4-yloxy}-7-methoxy-quinazoline [0187]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piper-
idin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline [0188]
4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quin-
azoline [0189]
4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quin-
azoline [0190]
4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-me-
thoxy-quinazoline [0191]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-me-
thoxy-ethoxy)-quinazoline [0192]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-
-yloxy)-7-methoxy-quinazoline [0193]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-ylo-
xy)-7-methoxy-quinazoline [0194]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-meth-
yl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline [0195]
4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline
[0196]
4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yl-
oxy]-7-methoxy-quinazoline [0197]
4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-y-
loxy}-7-methoxy-quinazoline [0198]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-y-
l)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline [0199]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbon-
yl]-piperidin-4-yloxy}-7-methoxy-quinazoline [0200]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo
[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline
[0201]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyeth-
yl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline [0202]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-metho-
xy-quinazoline [0203]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline [0204]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbony-
l]-piperidin-4-yloxy}-7-methoxy-quinazoline [0205]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-
-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline [0206]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cy-
clohexan-1-yloxy]-7-methoxy-quinazoline [0207]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-y-
loxy)-7-methoxy-quinazoline [0208]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-meth-
yl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline [0209]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-
-yloxy)-7-methoxy-quinazoline [0210]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbon-
yl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline
[0211]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4--
yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline
[0212]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-ylo-
xy)-7-methoxy-quinazoline [0213]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-metho-
xy-quinazoline optionally in the form of the racemates,
enantiomers, diastereomers thereof and optionally in the form of
the pharmacologically acceptable acid addition salts, solvates or
hydrates thereof. According to the invention these acid addition
salts are preferably selected from among the hydrochloride,
hydrobromide, hydriodide, hydrosulphate, hydrophosphate,
hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,
hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,
hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
[0214] The dopamine agonists used are preferably compounds selected
from among bromocriptin, cabergoline, alpha-dihydroergocryptine,
lisuride, pergolide, pramipexol, roxindol, ropinirol, talipexol,
tergurid and viozan, optionally in the form of the racemates,
enantiomers, diastereomers thereof and optionally in the form of
the pharmacologically acceptable acid addition salts, solvates or
hydrates thereof. According to the invention these acid addition
salts are preferably selected from among the hydrochloride,
hydrobromide, hydriodide, hydrosulphate, hydrophosphate,
hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,
hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,
hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
[0215] H1-Antihistamines which may be used are preferably compounds
selected from among epinastine, cetirizine, azelastine,
fexofenadine, levocabastine, loratadine, mizolastine, ketotifen,
emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine,
pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate,
diphenhydramine, promethazine, ebastine, desloratidine and
meclozine, optionally in the form of the racemates, enantiomers,
diastereomers thereof and optionally in the form of the
pharmacologically acceptable acid addition salts, solvates or
hydrates thereof. According to the invention these acid addition
salts are preferably selected from among the hydrochloride,
hydrobromide, hydriodide, hydrosulphate, hydrophosphate,
hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,
hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,
hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
[0216] In addition, inhalable macromolecules may be used as
disclosed in EP 1 003 478.
[0217] In addition, the compound may from the group of the
derivatives of ergot alkaloids, triptanes, CGRP-inhibitors,
phosphodiesterase-V inhibitors, optionally in the form of the
racemates, enantiomers or diastereomers thereof, optionally in the
form of the pharmacologically acceptable acid addition salts,
solvates and/or hydrates thereof.
[0218] Examples of ergot alkaloid derivatives are:
dihydroergotamine, ergotamine.
[0219] Examples of substances suitable for inhalation include
medicaments, medicament formulations and mixtures containing the
above-mentioned active substances, and the salts and esters thereof
and combinations of these active substances, salts and esters.
[0220] The invention is hereinafter described in more detail by
means of examples. In the drawings:
[0221] FIG. 1 shows a detail of a powder inhaler with the removal
principle,
[0222] FIG. 2 shows the removal principle, in simplified view,
[0223] FIG. 3 shows a medicament magazine as an annular disc,
[0224] FIG. 4 shows the medicament magazine with the medicament
chamber open,
[0225] FIG. 5 shows the entire medicament magazine,
[0226] FIG. 6 shows a scale representation of the medicament
magazine according to FIG. 3-5,
[0227] FIG. 7 shows a medicament chamber for different opening
mechanisms,
[0228] FIG. 8 shows a double annular magazine with a combined air
channel,
[0229] FIG. 9 shows a double annular magazine with separate air
channels,
[0230] FIG. 10 shows a blister with internal structure and
preliminary chamber as a medicament magazine,
[0231] FIG. 11 shows two embodiments of a blister with internal
structure.
[0232] FIG. 1 and FIG. 2 show the removal principle for a powder 6
containing a medicament and contained in a medicament chamber, such
as may be used in a powder inhaler. The medicament chamber is in
the form of a cavity 7 in a plastics part preferably produced by
injection moulding or thermoforming. The medicament chamber has, on
an upper side, a removal opening 2 which is connected directly to
an air channel 4. The air channel is constructed as a Venturi tube.
When the inhaler is used, sucking on a mouthpiece 9 produces a
drive current 5 in the air channel and a vacuum current in the
region of the constriction of the air channel (Venturi effect). The
powder in the cavity is sucked out into the air channel 4 through
the removal opening and together with the drive current 5 is
carried towards the mouthpiece and the person using the inhaler. As
a result of the Venturi effect the maximum pressure difference and
the maximum velocity in the air current are found at the removal
opening. This guarantees efficient detachment of a medicament from
its support (dispersion of the powder). The medicament chamber also
has on its upper side, the same side as the removal opening, a
control opening 3 through which air flows into and through the
cavity and forms an emptying current. Some of this emptying current
flows away over the powder 6 and can produce an additional Venturi
effect with a turbulence element 15 located in the cavity between
the turbulence element and the powder or the base of the cavity.
The turbulence element may also have structures, e.g. projections
pointing into the medicament chamber, which intensify the
turbulence of the air and powder.
[0233] Every one of these measures and effects increases the
formation of turbulence in the cavity and hence the dispersion. Any
clumps in the powder can also be broken up in this way. The shape
of the removal opening and the combining of the vacuum and emptying
currents also influence the dispersion of the powder.
[0234] The medicament chamber comprises a fill opening 13 on the
bottom, opposite the top. The fill opening 13 extends substantially
over the entire lower surface of the cavity and is closed off with
a sealing film 12 once the powder has been placed in the
cavity.
[0235] With this removal concept the removal of the medicament can
be adapted very sensitively and in versatile manner to all kinds of
medicaments, dosages and user requirements. This can be done by
varying and adapting the emptying flow, which is affected by
several parameters: the diameter of the air channel above the
removal opening, the dimensions of the removal opening, the
configuration of the cavity, and the dimensions of the control
opening. The special configuration of the medicament magazine also
allows easy adaptation to different amounts, compositions or
consistencies of medicaments, e.g. by enlarging the cavity and/or
changing the opening diameter. The separate fill opening also
allows this to be made as large as possible, so that a powder can
be poured in very quickly and without having to be tailored to a
special (small) fill opening. Also, because of the direct
connection of a removal opening to the air channel and the vacuum
flow prevailing therein, no powder is lost along lengthy passages
or ducts.
[0236] If required, the air channel 4 has additional sidestream or
bypass openings which terminate in the air channel and are arranged
offset downstream of a removal opening, towards the mouthpiece 9.
This reduces the suction force needed or creates crosscurrents in
the air channel to assist with the dispersion of a powder contained
therein.
[0237] FIG. 5 shows a multi-dose medicament magazine constructed as
an annular magazine 1, of the kind that may be used in a disc-type
inhaler, for example. In the annular magazine 1 the upper sealing
film has been removed from five medicament chambers. The plan view
shows one removal and one control opening for each medicament
chamber. An annular magazine of this kind may be made in one piece
by injection moulding, for example. The upper sealing film is
applied first. After filling, the cavity is closed off by means of
the lower sealing film. Examples of preferred injection-moulding
materials are PE, PP and PVC.
[0238] FIGS. 3 and 4 each show a diagonal view of a medicament
chamber, shown cut away. FIG. 3 shows a filled medicament chamber
in which there is powder 6 in the cavity 7. The removal and control
openings are covered by the upper sealing film 14 and are closed
off thereby in airtight and watertight manner. The lower fill
opening, one of which is preferably provided for each cavity, is
closed off by a lower sealing film 12. FIG. 4 shows the same
diagonal view of a medicament chamber after use. The upper sealing
film 14 has been removed. The air flow 5 over the removal opening
is guided through a constriction in the channel (cf. FIGS. 1 and
2), thereby producing a vacuum above this opening. The dimensions
of the removal and control opening are preferably such that the
cavity is emptied as continuously as possible.
[0239] FIG. 6 shows a cross-section through a cavity, and a plan
view of an annular magazine, drawn to scale, such as might be
produced for a powder volume of about 10 mm.sup.3 and 30 cavities,
i.e. single doses, in an annular magazine.
[0240] The quantity of fill volume of a single dose may be varied
relatively easily by changing the depth and/or length of the
cavity. As only the removal opening can be connected to a vacuum
flow, the control opening can be arranged virtually anywhere in the
magazine. It must not be adjacent to the removal opening on the
same side of the annular magazine but it could, for example, be
arranged on an inner diameter of the magazine.
[0241] FIG. 7 diagrammatically shows a section through the
structure of a medicament chamber, as it might be designed in order
to be opened by different opening mechanisms, such as peeling,
scraping off or piercing, without affecting the control openings,
i.e. the control and removal opening. FIG. 7 shows a cavity 7 with
the removal and control opening 2, 3 spaced apart from each other.
The openings are set into a recess. The height V and width B of the
recess can be adapted to the particular opening mechanism. If the
openings are exposed by peeling off a sealing film applied earlier,
the height V of the recess is preferably zero and the width B (or
area) of the recess corresponds to the width of the chamber. In
known piercing processes, a sealing film would be pierced and the
size and shape of a removal opening and a control opening would be
determined by the piercing tools. These are generally inexact and a
throttled flow would not be defined and in particular would not be
reproducible. In order to be able to use piercing as the opening
mechanism and thereby make use of the precisely defined openings
that can be made when the product is manufactured by the injection
moulding technique, the recess depth V>0 and the width B is
chosen to be greater than the chamber width. As a result, piercing
takes place independently of the actual removal and control
opening. The piercing tool is selected such that the foil is
pierced over one or more areas which are greater than the area of
the removal and control opening, such that any influence of the
pierced opening(s) is negligibly small in relation to the control
openings.
[0242] FIGS. 8 and 9 each show a section through a double
medicament magazine, e.g. an annular magazine. The magazine
substantially corresponds to two annular magazines according to
FIG. 3 which are arranged with their reverse sides, i.e. the sides
containing the fill openings 13, touching in mirror image and are
attached to one another or only pressed together. The two parts of
the magazine are pushed together such that the individual
medicament chambers 7 are not precisely opposite one another (the
offset chamber is shown by dotted lines). In this way, a multi-dose
inhaler of for example 30 doses can be converted into a preferred
60-dose inhaler. In FIG. 8 two air channels 4, 4', which belong to
an upper and lower part of the magazine, open into the same
mouthpiece 89. The mouthpiece and air channels are made in one
piece. Because of the offset arrangement of the medicament chambers
7 (shown by dotted lines in FIG. 7) powder can only be taken from
one chamber, even when the chambers are open. The air channel 4'
which is not in use can be used for an additional air supply
(bypass). However, it is also possible to arrange the chambers so
that they are not offset from one another, so that two different
medicaments, for example, can be taken from two chambers. FIG. 9
shows a mouthpiece 99 which subdivides the two air channels 4,4' so
that no air can pass through a non-selected channel into the
mouthpiece 99. The mouthpiece may be rotated for example from an
upper part to a lower part of the magazine.
[0243] FIG. 10 shows another embodiment of the invention by
reference to a medicament magazine which is constructed as a foil
blister with an internal structure 101. This internal structure 106
has opening means, for example, in the form of piercing points or
cutting edges by means of which a sealing foil that closes off a
medicament chamber is opened by pressing the internal structure
outwards. The internal structure is preferably also constructed so
that it gives a degree of stability to the medicament chamber. In
this way, a powder contained therein is protected from mechanical
influences from the outside or, in particular, when the chamber is
opened. This is important for powdered medicament carriers for
inhalers, as the inhaling or dosing of a compacted powder is no
longer possible, or is no longer possible in a defined manner.
[0244] The foil blister 101 has, in the region of the actual
medicament chamber, a preliminary chamber 105. The preliminary
chamber 105 has a removal opening 2 and a control opening 3. The
delivery of the powder 6 from the blister is preferably effected as
follows: the contents of the blister are emptied or introduced into
the preliminary chamber 105 with the aid of the internal structure,
preferably directly during the action of loading an inhaler. The
preliminary chamber has a removal opening 2 which may be in the
form of a through-bore and is connected to a Venturi suction tube
104. As a result of the Venturi effect, the maximum pressure
difference is present at the through-bore, enabling the powder to
be drawn out of the preliminary chamber 105 in metered amounts. At
this point the air current 5 reaches its maximum speed, thus
allowing efficient detachment (dispersion) of an active substance
from the carrier.
[0245] Preferably a blister with an integrated preliminary chamber
is produced, such that a medicament magazine with a fill opening,
removal opening and control opening in turn forms a unit, while the
openings are matched to one another, depending on the application.
One advantage of this variant is that a fresh preliminary chamber
is provided for each inhalation. Another variant in which a fresh
suction tube or part of a suction tube is available for each
removal is when the blister is formed with an integrated
preliminary chamber and suction tube. Any medicament residues on
the walls of the suction tube, which in particular occur directly
in the region of the removal opening would thus not affect
subsequent removals. In another variant the preliminary chamber is
in turn an integral part of the suction tube, but is independent of
the foil blister and the actual medicament chamber.
[0246] To illustrate blisters with an internal structure 101 FIG.
11 shows two examples on a larger scale. The Figure shows one
medicament chamber in the filled, unused state in each case. Powder
6 is at least partly enclosed by the internal structure 3 and
protected from external mechanical effects, but particularly from
being compressed as the internal structure is pressed out of the
medicament chamber. The internal structures have piercing points or
cutting edges 109 with which a sealing foil 107 is pierced or cut
open and torn or cut away as the chambers are opened.
[0247] The internal structure may be connected to the blister, e.g.
sealed on its reverse side with a film so as not to fall into the
preliminary chamber depending on the position of the blister.
However, if the preliminary chamber is an integral part of the
blister or each individual medicament chamber located therein, this
measure may not be necessary. An internal structure of this kind
may also serve as a turbulence element as well or in particular if
it is freely positioned in the preliminary chamber. The internal
structure may also provide additional turbulence by means of an
emptying current passing through the preliminary chamber and thus
additionally contribute to the disaggregation and dispersion of the
powder. The internal structure is preferably very open in design,
so that an air current can penetrate into and through the internal
structure is possible from many sides. This contributes to emptying
a medicament chamber as completely as possible and additional air
turbulence.
[0248] The internal structure, preliminary chamber and suction tube
are preferably formed by injection moulding a plastic. However, it
is also possible to produce individual parts thereof by a
thermoforming process or, in the case of internal structures, to
stamp and form them from a foil, e.g. a metal foil.
* * * * *