U.S. patent application number 12/380956 was filed with the patent office on 2009-09-17 for inhaler.
This patent application is currently assigned to Ventura Delivery Devices Limited. Invention is credited to Howard William Biddle, Duncan James Bradley, Nicholas John Campling, Stephen William Eason, Graham Gibbins, Matthew Sarkar, Tristian Roger Thornhill.
Application Number | 20090229608 12/380956 |
Document ID | / |
Family ID | 38739365 |
Filed Date | 2009-09-17 |
United States Patent
Application |
20090229608 |
Kind Code |
A1 |
Eason; Stephen William ; et
al. |
September 17, 2009 |
Inhaler
Abstract
An inhaler is disclosed. It comprises a housing to receive an
elongate strip of blisters each containing a dose of medicament and
being sequentially movable into alignment with means for breaching
a blister to enable a user to inhale said dose contained therein.
The device comprises a spiral wound element within the housing that
receives and coils said strip of blisters that have been
breached.
Inventors: |
Eason; Stephen William;
(Diss, GB) ; Sarkar; Matthew; (Cambridge, GB)
; Gibbins; Graham; (Fakenham, GB) ; Campling;
Nicholas John; (Bretton, GB) ; Biddle; Howard
William; (Histon, GB) ; Thornhill; Tristian
Roger; (Peterborough, GB) ; Bradley; Duncan
James; (Ewhurst, GB) |
Correspondence
Address: |
Davidson, Davidson & Kappel, LLC
485 7th Avenue, 14th Floor
New York
NY
10018
US
|
Assignee: |
Ventura Delivery Devices
Limited
Chippenham
GB
|
Family ID: |
38739365 |
Appl. No.: |
12/380956 |
Filed: |
March 5, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12217609 |
Jul 7, 2008 |
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12380956 |
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11881582 |
Jul 27, 2007 |
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12217609 |
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Current U.S.
Class: |
128/203.15 ;
128/203.12 |
Current CPC
Class: |
A61M 15/0058 20140204;
A61M 15/0045 20130101; A61M 15/0056 20140204; A61M 2202/064
20130101; A61M 15/0051 20140204; A61M 15/0041 20140204; A61M
15/0055 20140204; A61M 15/0035 20140204; A61M 15/0081 20140204 |
Class at
Publication: |
128/203.15 ;
128/203.12 |
International
Class: |
A61M 16/10 20060101
A61M016/10 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 6, 2007 |
EP |
07111998.6 |
Claims
1. An inhaler comprising a housing to receive a strip of blisters
each containing a dose of medicament and means to sequentially move
each blister into alignment with means for opening a blister to
enable a user to inhale said dose and, a spiral wound element to
coil the strip.
2. An inhaler according to claim 1, wherein the spiral wound
element is configured so that a used portion of the strip formed
from blisters which have been aligned with said means for opening a
blister, is gradually coiled within the spiral wound element.
3. An inhaler according to claim 1, wherein the spiral wound
element is rigid.
4. An inhaler according to claim 1, wherein the spiral wound
element is formed from a flexible material.
5. An inhaler according to claim 4, wherein the spiral wound
element is formed from a deformable non-resilient material.
6. An inhaler according to claim 5, wherein the spiral wound
element is formed from a resiliently deformable material.
7. An inhaler according to claim 6, wherein the resiliency of the
spiral wound element is selected in dependence on the stiffness of
a blister strip so that a first closed coil of a used portion of a
blister strip is formed in the spiral wound element prior to any
substantial deformation or expansion of the spiral wound
element.
8. An inhaler according to claim 4, wherein the spiral wound
element is configured so that it expands as the length of the used
portion of the blister strip coiled within it increases.
9. An inhaler according to claim 1, wherein the spiral wound
element has at least one winding that extends over 360 degrees.
10. An inhaler according to claim 1, wherein the stiffness of the
spiral wound element varies along at least a portion of its
length.
11. An inhaler according to claim 10, wherein the spiral wound
element has an outer end that is connected to the housing and an
inner end remote from the outer end, the stiffness of the spiral
wound element decreasing towards at least a portion of the inner
end.
12. An inhaler according to claim 11, wherein the thickness of the
spiral wound element gradually reduces towards the inner end.
13. An inhaler according to claim 11 wherein the section of the
spiral wound element gradually reduces towards the inner end.
14. An inhaler according to claim 11, wherein holes are formed in
the spiral wound element close to its inner end.
15. An inhaler according to claim 1, wherein the spiral wound
element is formed from phosphor bronze, stainless steel, nylon,
acetal or polypropylene.
16. An inhaler according to claim 1, wherein the spiral wound
element is a coil spring.
17. An inhaler according to claim 1, wherein the housing comprises
a first compartment to contain unused blisters and a second
compartment to receive used blisters, the first and second
compartments being separated by a flexible or movable dividing
wall.
18. An inhaler according to claim 17 comprising a passage between
the first and second compartments, and blocking means in said
passage to prevent the egress of powdered medicament from the first
blister compartment into the second blister compartment through the
passage.
19. An inhaler according to claim 18 wherein the blocking means is
shaped to conform to the shape of the blister strip.
20. An inhaler according to claim 19 wherein said blocking means
includes a resilient member to effect a seal against the blister
strip.
21. An inhaler according to claim 20 wherein the blocking means is
disposed such that it is aligned with a blister of the blister
strip when another blister is aligned with said means for opening a
blister.
22. An inhaler according to claim 1 any preceding claim, including
means to crush and/or tear opened blisters prior to entry into the
spiral wound element.
23. An inhaler comprising a housing to receive a strip of blisters
each containing a dose of medicament and means to sequentially move
each blister into alignment with means for opening a blister to
enable a user to inhale said dose, the inhaler having first
compartment to contain unused blisters and a second compartment to
receive used blisters, the first and second compartments being
separated by a flexible or movable dividing wall.
24. An inhaler according to claim 23, comprising an aperture in the
dividing wall for the passage of the blister strip from the first
compartment into the second compartment, said aperture including
means to prevent the egress of powdered medicament from the used
blister compartment into the unused blister compartment through the
aperture.
25. An inhaler according to claim 24 wherein said means to prevent
egress of powdered medicament includes a portion of the housing
which is shaped to conform to the shape of the blister strip.
26. An inhaler according to claim 24 wherein said means to prevent
egress of powdered medicament includes a resilient member to effect
a seal against the blister strip.
27. An inhaler according to claim 26 wherein said resilient member
is shaped to conform to the shape of the blister strip.
28. An inhaler according to claim 27 wherein the resilient member
is formed integrally with the dividing wall.
29. An inhaler according to claim 24, wherein said means to prevent
egress of powdered medicament is disposed such that it is aligned
with a blister of the blister strip when another blister is aligned
with said means for opening a blister.
30. An inhaler according to claim 24, wherein said means includes a
brush or elastomeric element extending at least partially across
the aperture in the dividing wall.
31. An inhaler according to claim 1, wherein the housing comprises
a common chamber to receive both unused and used portions of the
blister strip.
32. An inhaler according to claim 26, wherein the chamber is
configured so that the used portion of the blister strip occupies a
region of the chamber initially occupied by an unused portion of
the blister strip as the size of the used portion of the strip
increases.
33. An inhaler according to claim 32, wherein the common chamber is
separated into a unused blister compartment and a used blister
compartment by a flexible and/or movable dividing wall.
34. An inhaler according to claim 33, wherein the dividing wall is
rigid but configured so as to be slidable within the housing so
that the relative sizes of the unused and used blister compartments
can be altered.
35. An inhaler according to claim 33, wherein the flexible and/or
movable dividing wall is fixed to the housing at one or both
ends.
36. An inhaler according to claim 33, wherein the dividing wall is
movable and fixed to the housing at one end so as to pivot about
said end within the housing.
37. An inhaler according to claim 33, wherein the dividing wall is
flexible and configured so that it extends across said space
between facing sidewalls of the inhaler to prevent passage of
powdered dose between the unused and used blister compartments.
38. An inhaler according to claim 37, wherein the width of the
flexible dividing wall in a direction extending between the
sidewalls is greater than the distance between the sidewalls so
that the flexible dividing wall is held in compression between the
sidewalls.
39. An inhaler according to claim 33, wherein the dividing wall is
movable and fixed to the housing at one end so as to pivot about
said end within the housing, wherein the dividing wall is flexible
and configured so that it extends across said space between facing
sidewalls of the inhaler to prevent passage of powdered dose
between the unused and used blister compartments, wherein the
flexible dividing wall comprises a foam strip.
40. An inhaler according to claim 39, wherein the foam strip
includes a stiffening element.
41. An inhaler according to claim 33, wherein said flexible
dividing wall is at least partially attached to the spiral wound
element.
42. An inhaler according to claim 22, including means to crush,
cut-up and/or tear a used portion of the blister strip.
43. An inhaler according to claim 1, comprising a second spiral
wound element, the unused blister strip being coiled up within said
second spiral wound element and located within the housing during
assembly, the arrangement being such that, during use of the
inhaler, the second spiral wound element retracts as the first
spiral wound element expands, as the size of the coil formed from a
used portion of the strip increases and the size of the coil formed
from an unused portion of the strip decreases.
44. An inhaler comprising a housing to receive a strip of blisters
each containing a dose of medicament and means to sequentially move
each blister into alignment with means for opening a blister to
enable a user to inhale said dose, wherein the housing comprises a
common chamber to receive an unused blister strip and a used
portion of that strip, wherein a flexible and/or movable dividing
wall separates the chamber into an unused and a used blister
compartment.
45. An inhaler according to claim 1, wherein the housing includes a
common chamber to receive an unused blister strip and an a used
portion of that strip, wherein a flexible and/or movable dividing
wall separates the chamber into a used and unused blister
compartment.
46. An inhaler according to claim 44, wherein the flexible dividing
wall is fixed to the housing at both ends.
47. An inhaler according to claim 44, wherein the dividing wall is
flexible and configured so that it extends across said space
between sidewalls of the inhaler to prevent passage of powdered
dose between the unused and used blister compartments.
48. An inhaler according to claim 47, wherein the width of the
flexible dividing wall is greater than the distance between the
sidewalls so that the flexible dividing wall is held in compression
between the sidewalls.
49. An inhaler according to claim 44, wherein the flexible dividing
wall comprises a foam strip.
50. An inhaler according to claim 49, wherein the foam strip
includes a stiffening element.
51. An inhaler according to claim 45, comprising a second spiral
wound element to receive an unused blister strip for insertion into
the housing during assembly, the arrangement being such that the
second spiral wound element retracts as the first spiral wound
element expands as the size of the coil formed from a used portion
of the strip increases and the size of the coil formed from an
unused portion of the strip decreases.
52. An inhaler according to claim 1, wherein the spiral wound
element is configured so that it is partially unrolled or unwound
by a used portion of a blister strip on initial contact of the
leading edge of the used portion of the strip against the spiral
wound element, prior to any substantial deformation of the used
portion of the strip caused by the spiral wound element.
53. An inhaler according to claim 52, wherein the spiral wound
element is configured so that it partially unrolls or unwinds
across an inner wall forming part of the housing.
54. An inhaler according to claim 52, including means to steady the
spiral wound element to prevent over-expansion as the length of the
used portion of the strip received within the spiral wound element
increases.
55. An inhaler according to claim 54, wherein said means is the
flexible dividing wall separating the common chamber into unused
and used blister compartments.
56. An inhaler according to claim 55, wherein the flexible dividing
wall is at least partially attached to the spiral wound
element.
57. An inhaler according to claim 1, wherein the spiral wound
element is configured so that its diameter increases by a factor of
at least 3 when filled with a used portion of a strip of blisters
relative to when the spiral wound element is empty.
58. An inhaler according to claim 1, wherein the housing contains a
coiled strip of blisters.
59. An inhaler according to claim 58, wherein at least some of the
coiled strip of blisters have past the means for opening a blister
to form a used portion, said used portion of the strip being coiled
within said spiral wound element.
60. A method of controlling a strip of blisters within an
inhalation device in which unused blisters are sequentially movable
into alignment with means for opening a blister to enable a user to
inhale said dose, the method including the step of feeding a used
portion of the strip into a spiral wound element to coil said used
portion of the strip.
61. A method according to claim 60, wherein the method includes the
step of forming the spiral wound element such that it is partially
unrolled or unwound by the used portion of the blister strip on
initial contact of the leading edge of the used portion of the
blister strip against the spiral wound element prior to any
substantial deformation of the used portion of the strip caused by
the spiral wound element.
62. A method of forming a coiled strip of blisters for insertion
into an inhalation device, the method including the steps of
feeding an end of a strip of blisters into a spiral wound element
such that the strip is coiled up within said spiral wound
element.
63. A method according to claim 62, including the step of
separating the coiled strip of blisters from the spiral wound
element prior to insertion of the strip into the device.
64. An inhaler comprising a housing to receive a strip of blisters
each containing a dose of medicament and means to sequentially move
each blister into alignment with means for opening a blister to
enable a user to inhale said dose, the housing including a chamber
to receive used blisters and means to compress, crush, tear, cut-up
and/or fold said used blisters.
65. An inhaler according to claim 64, including an indexing
mechanism for advancing the blisters, the indexing mechanism
including a wheel around which empty blisters are fed and which
rotates in response to movement of an actuator to draw the blister
strip through the device, wherein the wheel is positioned relative
to a wall of the housing such that blister cavities are partially
squashed between the indexing wheel and the wall as they pass
around the indexing wheel.
66. An inhaler according to claim 65, wherein the indexing wheel
comprises a plurality of pockets to receive blister cavities, the
maximum depth of each pocket being less than the maximum depth of a
blister cavity such that the cavities protrude from the pockets by
a distance which is greater than a gap between a top of the pockets
and said wall, such that the cavities are squashed as they pass
through said gap.
67. An inhaler according to claim 23, including means to crush,
cut-up and/or tear a used portion of the blister strip.
68. An inhaler according to claim 45, wherein the flexible dividing
wall is fixed to the housing at both ends.
69. An inhaler according to claim 45, wherein the dividing wall is
flexible and configured so that it extends across said space
between sidewalls of the inhaler to prevent passage of powdered
dose between the unused and used blister compartments.
70. An inhaler according to claim 45, wherein the flexible dividing
wall comprises a foam strip.
71. An inhaler according to claim 70, wherein the foam strip
includes a stiffening element.
Description
[0001] The present invention relates to an inhalation device for
oral or nasal delivery of medicament in powdered form and to an
inhaler containing a strip of blisters each having a breachable lid
and/or base that contains a dose of medicament for inhalation by a
user of the device.
[0002] Oral or nasal delivery of a medicament using an inhalation
device is a particularly attractive method of drug administration
as these devices are relatively easy for a patient to use
discreetly and in public. As well as delivering medicament to treat
local diseases of the airway and other respiratory problems, they
have more recently also been used to deliver drugs to the
bloodstream via the lungs thereby avoiding the need for hypodermic
injections.
[0003] It is common for dry powder formulations to be pre-packaged
in individual doses, usually in the form of capsules or blisters
which each contain a single dose of the powder which has been
accurately and consistently measured. A blister is generally cold
formed from a ductile foil laminate or a plastics material and
includes a puncturable or peelable lid which is heat-sealed around
the periphery of the blister during manufacture and after
introduction of the dose into the blister. A foil blister is
preferred over a polymer blister or gelatine capsule as each dose
is protected from the ingress of water and penetration of gases
such as oxygen in addition to being shielded from light and UV
radiation all of which can have a detrimental effect on the
delivery characteristics of the inhaler if a dose becomes exposed
to them. Therefore, a blister offers excellent environmental
protection to each individual drug dose.
[0004] Inhalation devices that receive a blister pack comprising a
number of blisters each of which contain a pre-metered and
individually packaged dose of the drug to be delivered are known.
Actuation of the device causes a mechanism to breach or rupture a
blister, such as by puncturing it or peeling the lid off, so that
when the patient inhales, air is drawn through the blister
entraining the dose therein that is then carried out of the blister
through the device and via the patient's airway down into the
lungs. Pressurized air or gas or other propellants may also be used
to carry the dose out of the blister. Alternatively, the mechanism
that punctures or opens the blister may also push or eject the dose
out of the blister into a receptacle from which the dose may
subsequently be inhaled.
[0005] It is advantageous for the inhaler to be capable of holding
a number of doses to enable it to be used repeatedly over a period
of time without the requirement to open and/or insert a blister
into the device each time it is used. Therefore, many conventional
devices include means for storing a number or strip of blisters
each containing an individual dose of medicament. When a dose is to
be inhaled, an indexing mechanism moves a previously emptied
blister away from the opening mechanism so that a fresh one is
moved into a position ready to be opened for inhalation of its
contents.
[0006] An inhaler of the type described above is known from the
Applicant's own co-pending international application no.
PCT/GB2004/004416 filed on 18.sup.th Oct. 2004 and claiming
priority from GB application no. 0324358.1 filed 17.sup.th Oct.
2003. This international application has been published as WO
2005/037353 A1.
[0007] According to one embodiment described and claimed in WO
2005/037353 A1, and illustrated in FIGS. 1a and 1b of the
accompanying drawings, an inhaler 1 has a housing 2 containing a
coiled strip of blisters 3. An indexing mechanism 4 comprising a
single actuating lever 5 unwinds the coil 3 one blister at a time
so that they pass over a blister locator chassis 6 and successively
through a blister piercing station 7, when the actuator 5 is
pivoted in a direction indicated by arrow "A" in FIG. 1b. The
blister 3a located at the blister piercing station 7 on each
movement of the actuator 5 is pierced on the return stroke of the
actuator 5 (in the direction indicated by arrow "B" in FIG. 1b) by
piercing elements 8 on the actuator 5 itself so that, when a user
inhales through a mouthpiece 9, an airflow is generated within the
blister 3a to entrain the dose contained therein and carry it out
of the blister 3a via the mouthpiece 9 and into the user's
airway.
[0008] Although the inhalation device referred to above and
described in the aforementioned publication has addressed many of
the known problems associated with these types of devices, it is
designed so as to store only a small number of used blisters within
the device so that, when that number of blisters is exceeded, they
extend out of the housing of the device so that the user must
separate those used blisters from those unused blisters that remain
within the device and discard the detached portion of the strip.
The direction of movement of the used blisters is indicated by
arrow "C" in FIGS. 1a and 1b. The blister strip 3 may be perforated
or weakened between each or a number of blisters to facilitate the
tearing of used blisters from the strip 3.
[0009] Although devices that eject used blisters have the advantage
of being particularly small and lightweight, it is desirable to
provide a fully integrated device in which all the used blisters
are retained within the device so that separation of used blisters
from those that remain in the device is no longer necessary. Not
only would this make the device simpler to use because the user no
longer has to concern themselves with periodic detachment and
disposal of a used portion of the blister strip but any potential
contamination of the fingers by residual drug remaining on the used
blisters can be avoided because there is no need for the user to
come into contact with any of the used blisters. Therefore, the
entire strip can be effectively sealed within the housing of the
device.
[0010] Used blisters can be simply wound around a take-up spool
within the device. However, such devices are large and require
means to rotate the spool to wind up the used blisters. The leading
end of the strip must also be pre-attached to the spool so that the
strip starts to wind around the spool as the spool is rotated.
[0011] WO 2005/037353 also discloses an embodiment in which all the
blisters are retained within the device and in which the blister
strip takes the form of an endless loop that is wrapped around
itself. Such a device 10 is shown in FIG. 2. If suitable low
friction materials are used, the two centre spools 11,12 need not
be driven, the drive being solely provided by the indexing
mechanism 4 that is concentric with the actuator pivot and which
rotates in response to pivotal movement of the actuator 13 by the
user, as described with reference to the device shown in FIGS. 1a
and 1b. Although this device provides a compact arrangement, if the
strip 14 is too long it tends to jam on the walls 15 separating the
elements of the strip 14 in the manner of a wrap-spring clutch or a
rope passed around a cylinder preventing proper indexing of the
strip 14.
[0012] A previously undisclosed version of a loop type device 20 is
shown in FIGS. 3a and 3b in which the inherent potential for
jamming is minimised by providing drive to successive parts 21 of
the strip 22 at several points along its length. As shown in the
rear view of FIG. 3a, the loop 22 follows a serpentine path around
a number of wheels 7, at least some of which are driven from the
main indexing wheel 4, the remaining wheels being idler wheels 8
which guide the successive parts of the strip 21 of the loop 22. In
the front view of FIG. 3b, it can be seen that the indexing
mechanism 4 and the three secondary driving wheels 7 are toothed
and are geared to a single larger toothed gear wheel 23 mounted for
rotation on a central spindle 24 on the rear of the housing 25.
[0013] The present invention seeks to provide an inhalation device
that retains a used strip of blisters within the housing of the
device whilst maintaining simplicity and compactness of the device,
as well as ease of use.
[0014] Although the device may be disposable after all the blisters
contained within it have been exhausted, it is envisaged that it
may be possible to open the housing to enable the old strip to be
removed and a fresh one inserted. It is also envisaged that
blisters may be retained within a portion of the housing of the
device which is detachable from the remainder of the housing in
which the indexing and piercing mechanism is located, thereby
forming a replaceable cartridge. This would enable an exhausted
blister strip to be removed without direct contact by the
patient.
[0015] A potential complication with inhalation devices that
retains used blisters is that a small amount of the powdered dose,
typically between 1%-5%, may remain in each blister after
inhalation. Furthermore, if a patient indexes the strip without
having previously inhaled the dose in a blister that has been
pierced or breached, the amount of residual powder will be
substantial. It is therefore important to prevent the unused
blisters from becoming contaminated with loose powder that could
have a detrimental effect on the operation of the device and also
result in the patient exceeding an intended dose as they may inhale
some of the residual powder as well as the contents of a pierced
blister. Furthermore, if the residual powder has been exposed to
the atmosphere, it may have also degraded making it unsuitable for
inhalation.
[0016] In view of the foregoing, the present invention also seeks
to address the problem of residual powder containment to prevent
residual powder from contaminating unused blisters remaining in the
device and from being inhaled by a user of the device.
[0017] According to one aspect of the invention, there is provided
an inhaler comprising a housing to receive a strip of blisters each
containing a dose of medicament and means to sequentially move each
blister into alignment with means for opening a blister to enable a
user to inhale said dose and, a spiral wound element or former to
coil said strip.
[0018] Preferably, the spiral wound element is configured so that a
used portion of the strip, which is made up of blisters which have
been aligned with the means for opening a blister, is gradually
coiled within the spiral wound element as the device is used.
[0019] In one embodiment, the spiral wound element is rigid.
However, in a more preferable embodiment, the spiral wound element
is formed from a flexible material.
[0020] The spiral wound element may be formed from a deformable
non-resilient material.
[0021] However, in a preferred embodiment it is formed from a
resilient deformable material.
[0022] The resiliency of the spiral wound element is preferably
selected in dependence on the stiffness of a used portion of a
blister strip so that a first closed coil of a used portion of a
blister strip is formed in the spiral wound element prior to any
substantial deformation or expansion of the spiral wound element.
Alternatively the configuration of a more resilient spiral wound
element can be arranged such that a first closed coil is formed
during initial deflection of the element. In one preferred
embodiment, the spiral wound element is configured so that it
expands radially as the length of the used blister strip coiled
within it increases as more blisters are breached.
[0023] Conveniently, the spiral wound element has at least one
winding that extends over 360 degrees.
[0024] The stiffness of the spiral wound element may advantageously
vary along at least a portion of its length. In particular, the
stiffness of the spiral wound element may decrease towards its
inner end.
[0025] One approach to achieving the reduction in stiffness is for
the thickness of the spiral wound element to gradually reduce
towards its inner end and/or its width to gradually reduce towards
its inner end.
[0026] In one embodiment, holes, slots or other apertures are
formed in the spiral wound element close to or at its inner
end.
[0027] The spiral wound element may be formed for example from
phosphor bronze, stainless steel, titanium, spring steel, shape
memory alloy, nylon, acetal, PTFE or polypropylene.
[0028] The spiral wound element may also be coated with a low
friction material to aid smooth winding of the breached blister
strip, for example, a PTFE coating. Alternatively the surface
finish or texture of the spiral wound element can be selected to
provide a low friction surface.
[0029] The spiral wound element can be formed from flat strip
material, or from square, circular or rectangular section material.
Alternatively, the spiral may be formed from one or more wire
elements wound into a spiral. This reduces the contact area with
the strip and therefore reduces friction.
[0030] The materials and components may be used separately or in
combination to give the desired characteristics.
[0031] In a preferred embodiment, the spiral wound element is a
coil spring formed from a thin sheet of material.
[0032] One embodiment may comprise a passage between the first and
second compartments, and blocking means in said passage to prevent
the egress of powdered medicament from the first blister
compartment into the second blister compartment through the
passage.
[0033] The blocking means may be shaped to conform to the shape of
the blister strip, and may include a resilient member to effect a
seal against the blister strip. The blocking means may be disposed
such that it is aligned with a blister of the blister strip when
another blister is aligned with said means for opening a
blister.
[0034] According to one aspect of the invention, there is provided
a housing to receive a strip of blisters each containing a dose of
medicament and means to sequentially move each blister into
alignment with means for opening a blister to enable a user to
inhale said dose, the inhaler having a first compartment to contain
unused blisters and a second compartment to receive used blisters,
the first and second compartments being separated by a flexible
and/or movable dividing wall.
[0035] Preferably, an aperture is provided in the flexible and/or
movable dividing wall for the passage of the blister strip from the
first compartment into the second compartment, said aperture
including means to prevent the egress of powdered medicament from
the used blister compartment in to the unused blister compartment
through the aperture. The means may be a brush or elastomeric
element.
[0036] Preferably, said means to prevent egress of powdered
medicament includes a portion of the housing which is shaped to
conform to the shape of the blister strip. Alternatively, said
means to prevent egress of powdered medicament may include a
resilient member to effect a seal against the blister strip.
[0037] Said resilient member may be shaped to conform to the shape
of the blister strip, and the resilient member may be formed
integrally with the dividing wall.
[0038] The means to prevent egress of powdered medicament may be
disposed such that it is aligned with a blister of the blister
strip when another blister is aligned with said means for opening a
blister.
[0039] Although the unused blister strip and the breached blisters
may be housed in separate compartments, in one embodiment the
housing comprises a common chamber to receive both an unused and a
used portion of the blister strip.
[0040] Advantageously, the chamber is configured so that the used
portion of the strip occupies a region of the chamber-initially
occupied by an unused portion of the blister strip as the size of
the used portion of the strip increases.
[0041] In one embodiment, the dividing wall may be rigid but
configured so as to be slideable within the housing so that the
relative sizes of the unused and used blister compartments can be
altered.
[0042] The flexible dividing wall may be fixed to the housing at
one or both ends and may comprise a foam strip which can include a
stiffening element. In one embodiment, the flexible dividing wall
is movable and fixed to the housing at one end so as to pivot about
said end within the housing.
[0043] In one embodiment, the flexible and/or movable dividing wall
is flexible and configured so that it extends across said space
between said sidewalls of the inhaler to prevent passage of
powdered dose between the unused and used blister compartments. In
one embodiment, the flexible dividing wall is at least partially
attached to the spiral wound element.
[0044] The flexible dividing wall can also be designed to exert a
constraining or steadying force on one or both of the blister
coils. This constraining force can be achieved by, for example, the
stiffness of the dividing wall or by the friction created as the
dividing wall slides relative to the walls of the housing. This can
be particularly beneficial if the spiral wound element containing
the used portion of the blister coil is selected to be very
resilient, and can help to ensure that the coil of used blisters is
kept as small as possible.
[0045] In one embodiment, the inhaler may comprise a second spiral
wound element within which an unused blister strip may be coiled up
within said housing such that the second spiral wound element
retracts as the first spiral wound element expands, as the size of
the coil formed from a used portion of the strip increases and the
size of the coil forming the unused portion of the strip
decreases.
[0046] According to another aspect of the invention, there is
provided an inhaler comprising a housing to receive a strip of
blisters each containing a dose of medicament and means to
sequentially move each blister into alignment with means for
opening a blister to enable a user to inhale said dose, wherein the
housing comprises a common chamber to receive an unused blister
strip and, a used portion of that strip, a flexible and/or movable
dividing wall separating the chamber into an unused and a used
blister compartment
[0047] The flexible dividing wall may be fixed to the housing at
each end.
[0048] In one embodiment, the dividing wall is flexible and
configured so that it extends across said space between the
sidewalls of the inhaler to prevent passage of powdered dose
between the unused and used blister compartments.
[0049] Preferably, the width of the dividing wall is greater than
the distance between the sidewalls so that the flexible dividing
wall is held in compression between the sidewalls so as to prevent
passage of powder between the two regions of the chamber around the
edges of the dividing wall and the walls of the chamber.
[0050] The flexible dividing wall preferably comprises a foam
strip.
[0051] In one embodiment, the inhalation device comprises a second
spiral wound element to receive an unused blister strip prior to
insertion of the strip into the housing such that the second spiral
wound element retracts as the first spiral wound element expands as
the size of the coil formed from a used portion of the strip
increases and the size of the coil formed from an unused portion of
the strip decreases.
[0052] Preferably, the spiral wound element is configured so that
it is partially unrolled or unwound by the leading edge of a used
portion of a blister strip on initial contact of the leading edge
of the strip against the spiral wound element, prior to any
substantial deformation of the strip caused by the spiral wound
element.
[0053] According to the invention, there is also provided a method
of controlling a strip of blisters within an inhalation device in
which unused blisters are sequentially movable into alignment with
means for opening a blister to enable a user to inhale a dose, the
method including the step of feeding a used portion of the strip
into a spiral wound element to coil said used portion of the
strip.
[0054] According to the invention, there is also provided a method
of forming a coiled strip of blisters for insertion into an
inhalation device, the method including the steps of feeding an end
of the strip of blisters into a spiral wound element such that the
strip is coiled within said spiral wound element.
[0055] According to another aspect of the invention, there is
provided an inhaler comprising a housing to receive a strip of
blisters each containing a dose of medicament and means to
sequentially move each blister into alignment with means for
opening a blister to enable a user to inhale said dose, the housing
including a chamber to receive used blisters and means to compress,
crush, tear, cut-up and/or fold said used blisters.
[0056] It will be appreciated that different aspects of the
invention may be used independently or in any combination with
other aspects of the invention. For example, the spiral wound
element can be used in conjunction with the flexible wall and/or a
device to crush used blisters.
[0057] It will be appreciated that the inhaler of the invention may
be either a passive or active device. In a passive device, the dose
is entrained in a flow of air caused when the user inhales through
the mouthpiece. However, in an active device, the inhaler would
include means for generating a pressurised flow of gas or air
through the blister to entrain the dose and carry it out of the
blister through the mouthpiece and into the user's airway. In one
embodiment, the inhaler may be provided with a source of
pressurised gas or air within the housing.
[0058] Embodiments of the invention will now be described, by way
of example only, with reference to FIGS. 4 to 20 of the
accompanying drawings, in which:--
[0059] FIGS. 1a and 1b are side sectional views of a conventional
inhalation device to show how the blisters of a strip are
sequentially moved into alignment with a blister piercing station
by movement of an actuator from the position shown in FIG. 1a to
the position shown in FIG. 1b which drives an indexing wheel. A
piercing head on the actuator pierces the lid of an aligned blister
when the actuator is returned to its normal position as shown in
FIG. 1a.
[0060] FIG. 2 is a sectional view of an inhalation device in which
all the blisters are retained within the device and in which the
blister strip takes the form of an endless loop which is wrapped
around itself;
[0061] FIGS. 3a and 3b show front and rear sectional views of
another version of a previously undisclosed endless loop device in
which the strip is driven at several locations along its
length;
[0062] FIGS. 4a to 4c shows an embodiment according to one aspect
of the invention in which the used portion of a strip of blisters
are folded in a zig-zag or concertina fashion and the blister
cavities are crushed so that the used blisters form a neat stack
within an enclosed chamber in the housing of the device;
[0063] FIGS. 5a and 5b show another embodiment according to one
aspect of the invention in which the used portion of the blister
strip is driven through a nip between at least one pair of rollers
to crush the blister cavities and impart a curvature to the strip
so that it coils up within an enclosed chamber in the housing of
the device;
[0064] FIGS. 5c and 5d shows a simplified embodiment of a mechanism
for tearing or otherwise detaching used blisters, which may have
been crushed, from remaining blisters;
[0065] FIG. 6a to 6d shows a sequence of drawings to show how the
used portion of the blister strip may be fed into a rigid spiral
wound element so as to cause the used portion of the strip to coil
up as it is guided by the surface of the spiral wound element,
according to an embodiment of the invention;
[0066] FIG. 7a to 7c shows a sequence of drawings to show how the
used portion of the blister strip may be fed into a flexible spiral
wound element that expands as the used portion of the coiled
blister strip grows within it, according to an embodiment of the
invention;
[0067] FIG. 8 shows an embodiment of an inhalation device
incorporating a coil such as that shown in FIG. 7;
[0068] FIG. 9a to 9d shows a sequence of drawings to show how the
unused portion of a coiled strip of blisters gradually unwinds as
the blisters pass the blister piercing station and the used portion
of the blister strip is coiled up within the spiral wound
element;
[0069] FIG. 9e shows an embodiment similar to that shown in FIG. 8
but in which a blocking element is secured to the end of the
blister strip;
[0070] FIG. 10 shows an embodiment of an inhalation device having a
housing defining an interior chamber containing a coiled, unused
strip of blisters and a spiral wound element to receive a used
portion of that blister strip, the chamber is divided into two
between the unused blisters and the spiral wound element by a
flexible dividing wall to form an unused and a used blister
compartment;
[0071] FIG. 11 shows a partial side sectional view across the
housing to illustrate how the flexible dividing wall is held in
compression between the sidewalls of the housing;
[0072] FIG. 12a to 12d shows a sequence of drawings to shown how
the flexible dividing wall moves as the spiral wound element
expands as it fills up with used portion of the blister strip;
[0073] FIGS. 13a and 13b show a modified version of the inhalation
device illustrated in FIG. 11a and in which the flexible dividing
wall surrounds, and is at least partially attached to, the outer
surface of the spiral wound element. In FIG. 13a, none of the
blisters have been used and so the spiral wound element is empty.
However, in FIG. 13b, all the blisters have been used and the
spiral wound element has expanded to its maximum extent together
with the flexible dividing wall;
[0074] FIGS. 14a, 14b and 14c show three perspective views of a
spiral wound element which have notches close to its outer end for
attachment to the internal wall of the housing of an inhaler;
[0075] FIGS. 15a and 15b show two perspective views of a moulded
spiral wound element;
[0076] FIGS. 16a and 16b shows a spiral wound element formed from a
wire or from a material having a rectangular section,
respectively;
[0077] FIGS. 17a and 17b show a twin spiral wound element prior to
and after insertion into an inhalation device, respectively;
[0078] FIG. 18a to 18c show a sequence of drawings to illustrate
how a fresh strip of unused blisters may be coiled within a spiral
wound element prior to insertion into the housing of an inhalation
device;
[0079] FIG. 19(a) to 19(j) are a sequence of drawings to show how a
coil of used portion of a blister strip is formed in a spiral wound
element according to another embodiment;
[0080] FIG. 20(a) to 20(f) show how a coil of a used portion of a
blister strip is formed with the spiral wound element of FIG. 18
when located in an inhalation device;
[0081] FIG. 21(a) to 21(c) shows a perspective view, an unrolled
plan view and, a side view of the more flexible spiral wound
element shown in FIGS. 19 and 20;
[0082] FIG. 22 shows another embodiment of an inhalation device
similar to that of FIG. 10, but including means to prevent residual
powdered medicament passing from a used blister compartment to the
unused blister compartment through the passage between the two
through which the blister strip passes;
[0083] FIG. 23 shows a partial sectional plan view from above of
the area within circle L in FIG. 22;
[0084] FIG. 24 shows an alternative embodiment of an inhalation
device similar to that of FIG. 22;
[0085] FIG. 25 shows a partial sectional plan view from above of
the area within circle M in FIG. 24;
[0086] FIGS. 26A-26C show alternative configurations of resilient
members of the embodiment of FIGS. 24 and 25;
[0087] FIG. 27 shows an alternative embodiment of an inhalation
device similar to that of FIGS. 22 and 24;
[0088] FIG. 28 shows a partial sectional plan view from above of
the area within circle N in FIG. 26;
[0089] FIGS. 29A-29C show alternative configurations of resilient
members of the embodiment of FIGS. 28 and 28;
[0090] FIG. 30 shows an alternative embodiment of an inhalation
device similar to that of FIGS. 22, 24 and 27; and
[0091] FIG. 31 shows a partial sectional plan view from above of
the area within circle O in FIG. 30
[0092] Reference is made throughout this specification to both
"unused" and "used" blisters. It will be appreciated that "unused"
blisters refer to those blisters that have not passed the blister
piercing station and which remain intact with the dose contained
therein. "Used" blisters refer to those blisters which have passed
the blister piercing station in response to movement of the
actuator by a user and which have been pierced to enable access to
the dose contained therein to be obtained. Although in general, a
"used" blister refers to a blister from which a dose has been
inhaled, it should also be taken to include blisters which have
passed the blister piercing station and have been pierced but which
still contain either some or all of the dose contained therein.
This may happen, for example, when a user moves the actuator to
move the blister strip without inhaling the dose from a previously
pierced blister.
[0093] An alternative to both the conventional approach of spooling
used blisters, and the loop drive described above, is to employ a
mechanism to impart folds to a used strip so that it is encouraged
to form a concertina. The device can, alternatively or in addition
to a folding mechanism, also include means for crushing the used
blister cavities so as to reduce their volume and so that a
compacted stack of used blisters is formed, thereby minimising the
volume of space occupied by the used blisters.
[0094] One way in which the concertina folds and crushing of the
used blister cavities can be carried out is shown in FIGS. 4a to
4c, from which it can be seen that two lobed rollers 30,31 are
configured so as to intermesh with a small gap between them which
is less than the depth of a blister cavity. The lobed rollers 30,31
may be connected by integral toothed gear wheels (not shown) so
that both are driven, possibly in response to movement of the
actuator 5. As a used blister strip 51 passes between the lobed
rollers 30,31, the lobes 30a, 31a produce a zig-zag or fold in
alternate directions into the flattened strip so as to form a
concertina. Each roller has the same construction but they are
mounted so the lobes 30a on one roller are 90 degrees out of phase
with the lobes 31a on the other roller so that, as the rollers
30,31 rotate, the lobes 30a,31a on one roller 30,31 engage the
strip and press it against the other roller between the lobes
30,31a of that roller 30,31. As shown in FIGS. 4b and 4c, if the
concertina is forced into an enclosed space 32 within the housing
33 of the inhaler, a compacted stack 34 (see FIG. 4(c)) of used
blisters is created. The enclosed space 32 may be provided with a
wall or piston (not shown) slidable against a bias provided by a
spring (not shown) in response to pressure applied thereto by the
used blisters 51 entering the enclosed space 32, so as to minimise
the volume occupied by the blisters 51 and maintain the concertina
form.
[0095] It will also be appreciated that, in place of the lobes 30a,
31a, one or both of the rollers 30,31 may be provided with an arm
having a cutting blade (not shown) affixed to its tip so that
rather than fold the strip, the cutting blade engages the strip 51
to cut it or chop it up into sections or individual blisters.
[0096] In another modification, illustrated in FIGS. 5a and 5b, the
blister cavities of the used blister strip 51 can simply be crushed
without imparting any fold to the strip 51. If the strip 51 is
passed around a roller 41 and through a nip 42 between that roller
41 and at least one other roller 43, 44, the rollers 41,43,44 will
crush the cavities and will also tend to form a curvature in the
strip 51 such that a coil is formed which can be directed into an
enclosed space 45 within the housing 40, as shown in FIG. 5b.
[0097] It will be appreciated that techniques other than rollers
can be used to crush or flatten the blisters in order to reduce
their size. They may be compressed between moving parts, or between
a moving part and an anvil. The moving part may be driven by the
actuator or by separate means. The blister form may be weakened in
manufacture to reduce the force needed to crush the blister, for
example by scoring the blister form.
[0098] In one unillustrated embodiment, the indexing wheel forming
part of the indexing mechanism and which rotates to draw the
blister strip through the device past the piercing station may be
itself be used to squeeze the used blister cavities as they pass
around it, thereby at least partially crushing them. This is
achieved by enlarging the axle or hub of the indexing wheel so that
the distance between the hub and the casing of the device, or a
component fixed to the casing, is less than the maximum height of a
blister cavity. As the blister cavities are entrained between the
spokes of the indexing wheel, onward rotation of the wheel causes
the cavities to be at least partially squashed or sandwiched
between the enlarged hub of the indexing wheel and the casing of
the device.
[0099] In FIGS. 5c and 5d, a mechanism for tearing or separating a
used blister 51a from the strip 51 is shown. The used blisters may
or may not have been crushed prior to being separated. As can be
seen from FIG. 5a, the strip 51 passes through a "letterbox" shaped
opening 201 in a rotatably mounted tearing wheel 200. Means (not
shown) are provided to keep the strip in a fixed position upstream
from the point at which it passes through the tearing wheel 200 so
that, when the tearing wheel 200 rotates a section of the strip 51
is torn off. The tearing wheel 200 may be driven by gear wheels
that rotate in response to movement of the actuator 5. The detached
blisters 51a are allowed to fall into a containment section or
enclosed space within the housing 2.
[0100] Referring now to FIG. 6, there is shown a rigid spiral wound
element 50 and a used portion of a strip of blisters 51. As the
used portion of the strip of blisters 51 sequentially move through
the device in response to successive actuation of an indexing
mechanism by the user, the used portion of the strip 51 moves in
the direction of arrow "D" as the size of the used portion of the
blister strip gradually increases. As shown in FIG. 6(a), the
leading end 51a of the used portion of the strip is about to enter
the mouth 52 of the spiral wound element 50. In FIG. 6(b), the used
portion of the strip 51 has entered the mouth 52 and has been
deflected by the surface of the spiral wound element 50 so that it
begins to follow a curved path guided by the surface of the spiral
wound element 50. In FIG. 6(c), the used portion of the strip 51
has passed further into the spiral wound element 50 so as to form a
complete coil. Further movement of the used portion of the strip 51
into the spiral wound element 50 results in the formation of
multiple coils from the used portion of the blister strip, as shown
in FIG. 6(d). As the spiral wound element 50 is rigid, no more
blisters can be received within the spiral wound element when the
leading end 51a of the used portion of the blister strip 51 reaches
the centre of the spiral, as shown in FIG. 6(d).
[0101] It will be appreciated that when the leading end 51a of the
used portion of the strip 51 reaches the centre of the spiral, no
more can be inserted as the spiral wound element 50 shown in FIG. 6
is rigid. Therefore, in a more preferable configuration, the spiral
wound element 60 is formed from a flexible, preferably resilient,
material so that it expands as the number of coils of used blisters
61 increase, as shown in the sequence of drawings of FIG. 7. Once a
coil of blisters 61 has been formed within the spiral wound element
60, further movement of the used portion of the strip 61 into the
spiral wound element 60 causes it to expand as the coiled used
portion of the blister strip 61 grows, as shown in FIG. 7c. The
initial size and rigidity of the spiral wound element 60 may be
selected in dependence on the stiffness of the used portion of the
blister strip 61 such that, as the used portion of the strip 61 is
received in the spiral wound element 60, it is guided by the spiral
wound element 60 until it forms a first closed coil, as shown in
FIG. 7b. Only once this first closed coil has been formed does any
expansion of the spiral wound element 60 take place. In practice, a
blister strip 61 consisting of 16, 30 or 60 or more blisters can be
successfully formed into a coil in this way. It will of course be
appreciated that there may be some initial expansion of the spiral
wound element 60 during formation of the first closed coil.
[0102] In both versions of the spiral wound element shown in FIGS.
6 and 7, the outer end of the spiral has a hook 53, 63 to
facilitate the attachment of the spiral wound element 50,60 to a
suitable formation on the inner wall of a housing of a device.
Other means of providing corresponding locating features to secure
the element may be used. FIG. 14(a), (b) and (c) show a spiral
wound element 60 with notches 110 formed in it close to its outer
end for location on corresponding formations on the housing.
[0103] Although the blister strip 51, 61, in the embodiments of
FIGS. 6 and 7, is shown coiling up within the spiral wound element
50,60 with the pierced upper surface of the blister strip facing
outward, i.e. facing the surface of the spiral wound element 51,
61, it will also be appreciated that the blister strip can be
encouraged to coil with the pierced upper surface facing the centre
of the spiral wound element. In this way, the strip itself serves
as a flexible wall to prevent the passage of residual powder around
the strip. To assist in this, the blister strip can be made
slightly wider than the distance between the walls of the device
and more flexible so that it constantly engages with the walls of
the device with sufficient force to prevent the passage of residual
powder around the strip but still enabling coiling and indexing of
the strip. The coil thereby effectively becomes a self-sealing
enclosure preventing escape of residual powder out of the coil.
[0104] An embodiment of an inhalation device 70 incorporating a
spiral wound element 60 to form a coil from a used portion of a
blister strip 61 in the way described with reference to FIG. 7 is
illustrated in FIGS. 8 and 9. It will be appreciated that the
general construction and operation of the device shown in FIG. 8 is
similar to that of the device shown in FIGS. 1a and 1b, except that
the used part of the blister strip 61 is retained within the device
70 and formed into a coil by a spiral wound element 60 located
within the housing 71 of the device, rather than being ejected from
it. Accordingly, the indexing mechanism 4 pushes the used portion
of the strip 61 into the spiral wound element 60 as well as drawing
the unused portion of the strip 61a from the starting coil over the
blister location chassis 6 and past the blister piercing station 7.
The indexing mechanism 4 moves the strip 61 incrementally one
blister at a time, i.e. activation of the indexing mechanism
sequentially moves a blister into alignment with the blister
piercing station so that access to the contents of each blister may
be obtained one by one.
[0105] As can be seen most clearly from FIG. 8, the hook 63 on the
spiral wound element 60 hooks over a protrusion 72 formed within
the wall of the housing to attach the spiral wound element 60
thereto.
[0106] It will be appreciated that the dimensions of the device
shown in FIG. 8 are generally the same as that of the device shown
in FIG. 1, except that the housing 71 is elongated by the starting
diameter of the spiral wound element 60, which is typically 20 mm
or less.
[0107] For obvious reasons, it is desirable to ensure that the
dimensions of the device are kept within reasonable limits. This
enhances patient acceptability and portability of the device.
Therefore, the housing has a common chamber 80 within it that
receives both unused and used portions of the blister strip. Prior
to use of the inhaler 70, a large proportion of the chamber 80 is
occupied by the coil of unused blisters 61a, the remaining, much
smaller portion, being occupied by the spiral wound element 60. As
the diameter or size of the unused portion of the strip 61a reduces
during use, the coil formed from the used portion of the strip 61
increases in diameter causing the spiral wound element 60 to expand
and increase in diameter as more and more of the blisters are used
and coil up within it. As the size of the coil formed from the used
portion of the strip 61 increases, and the spiral wound element 60
expands and grows, it occupies the space previously occupied by the
unused portion of the strip of blisters 61a. Therefore, the chamber
80 is common to both used 61 and unused 61a portions of the strip,
as opposed to having a separate chamber for each. Consequently, the
overall size of the device 70 can be kept to a minimum.
[0108] It is desirable for the coil formed from the used portion 61
of the blister strip in its initial state to occupy as little space
as possible and in its final state to occupy as much of the space
previously occupied by the unused portion 61a of the blister strip
as possible. Preferably the unfilled spiral wound element 60 has a
diameter less than 50% of the diameter of the coil of the unused
portion 61a of the blister strip and more preferably less than 40%.
In yet further preferred embodiments, the unfilled spiral wound
element 60 has a diameter less than 20-40% of the diameter of the
coil of the unused portion 61a of the blister strip and more
preferably still less than 25%. In the embodiment of FIG. 8 it has
a diameter of 38% of the diameter of the coil of the unused
blisters 61a. Preferably the coil of used blisters 61 in its final
state occupies greater than 50% of the space previously occupied by
the unused portion 61a of the blister strip.
[0109] It can be advantageous for the outer surface of the spiral
wound element 60 to press against or contact the coil formed from
the unused portion 61a of the blister strip, as generally indicated
by arrow "X" in FIGS. 8 and 9, as the unused portion 61a of the
blister strip reduces in diameter and the used portion 61 of the
blister strip increases in diameter. This can assist in steadying
the spiral wound element 60 as it expands and also helps maintain a
tighter coil formed from the unused portion 61a of the blister
strip.
[0110] The spiral wound element 60 for coiling up the used portion
61 of the blister strip has been found to work with blister strips
of varying degrees of thickness. The strip is required to have at
least a certain degree of rigidity and stiffness otherwise it
cannot withstand the compressive force exerted on it by the
indexing mechanism 4 and buckles. Devices with spiral wound
elements 60 have been proven to work with blister strips formed
from a base layer of either 25 .mu.m nylon/45 .mu.m aluminium/30
.mu.m PVC or 25 .mu.m nylon/45 .mu.m aluminium/60 .mu.m PVC,
containing over 60 blisters and over 660 mm in length. Spiral wound
springs, such as a coil spring, have been formed from phosphor
bronze, stainless steel, nylon, acetal and polypropylene. It will
be appreciated that the device 70 will function adequately with a
wide range of materials and dimensions for both the blister strip
and the spiral wound element 60.
[0111] The spiral wound element 60 is generally formed from a thin
sheet of material (as shown, for example, in FIGS. 14a and 14b) or,
it can be moulded in the form of a spiral (see FIGS. 15(a) and
15(b). When moulded, the surface of the element 60 may be provided
with raised regions 111 to facilitate ejection of the element from
the mould. It can be also be formed from wire or a thicker
rectangular section material, as shown in FIGS. 16(a) and 16(b), so
that friction between the blister strip and the surface of the
spiral wound element 60 is reduced due to a smaller region of
contact between the strip and the element 60. As described earlier
a range of materials can be used in the construction of the spiral
60.
[0112] Although the spiral wound element 60 preferably has a degree
of resilience, it is also envisaged that the spiral wound element
60 could be constructed from a material, such as a polymer, which
creeps and relaxes as it expands thereby relieving the load on the
wound blister coil. Creep may occur to at least some extent even in
a resilient spiral wound element 60 as all polymers are subject to
at least some degree of creep.
[0113] The spiral wound element 60 preferably has at least one
complete spiral or coil extending over an angle that exceeds 360
degrees. However, it will be appreciated that it may also have a
plurality of coils or portion of a coil. FIGS. 14a and 14b show a
spiral wound element with one and a half turns, or 540 degrees. The
coil in FIG. 14a can be formed from stainless steel between 0.8 and
0.15 mm thick, preferably 0.12 mm thick. Such a coil can also be
formed from phosphor bronze between 0.1 mm and 0.18 mm thick,
preferably 0.15 mm thick. The coil in FIG. 13c can be moulded from
acetal with a nominal thickness of between 0.3 mm and 1.0 mm,
preferably 0.5 mm.
[0114] These thicknesses are selected to give a similar stiffness
irrespective of the material. Stiffness of a flat spring is
proportional to Young's Modulus and the cube of the material
thickness. The Young's Moduli of stainless steel, phosphor bronze
and acetal are 192, 103 and 3.1 GPa respectively. Hence nominal
thicknesses of 0.12, 0.15 and 0.5 mm will give similar
stiffness.
[0115] Coils with two or more turns can also be used. These perform
well with thinner material, for example stainless steel 0.05 mm
thick. This will have a stiffness approximately 7% of that of a
coil formed from material 0.12 mm thick, and it behaves in a
different way, as shown in FIGS. 19 and 20 and as will be explained
later. The increased flexibility of the thinner material also
allows a smaller coil to be used. In one example used to
accommodate a 60 blister coil, a coil of the type shown in FIG. 14a
with a nominal starting diameter of 20 mm could be replaced by a
longer thinner coil with a starting diameter of 12 mm. The more
flexible coil has the further advantage that it is more tolerant of
friction caused, for example, by waste powder rubbing between the
coil and the strip.
[0116] In any embodiment that employs a spiral wound element of the
type described, the stiffness of the spiral wound element may be
constant along its length. However, it can be advantageous to
provide the spiral wound element with a region of reduced stiffness
towards its inner end 60a as this helps the spiral wound element to
assume a rounder form as it expands and helps to prevent the end of
the spiral wound element from "clawing" against the surface of the
blister strip. The stiffness can easily be varied by changing the
thickness or width of the spiral wound element or forming it so
that it tapers towards its inner end 60a. In a preferred
arrangement, the spiral wound element tapers for a portion of its
length towards the inner end. A 50% reduction in section area over
the last 20 mm of the length of the spiral has been found to work
well. The spiral wound element can also be provided with a series
of holes or slots in it to reduce its stiffness.
[0117] It will be appreciated that any embodiment that employs a
spiral wound element for coiling up a used portion of a blister
strip can also employ means for crushing the blister cavities prior
to the used portion of the blister strip being received within the
spiral wound element, such as those means described previously.
[0118] When the end of the strip is reached, it passes through the
blister location chassis 6 and indexing mechanism 4. However, it
may be desirable to implement a blocking feature so that repeated
actuation of the device when the blister strip has been exhausted
is prevented. This would clearly indicate to the patient that all
doses have been taken. The blocking feature may take the form of an
enlargement attached to or formed from the end of the strip that is
physically too large to pass through the blister location chassis
6. For example, as illustrated in FIG. 9e, a cylindrical or
spherical plastic moulding 100 is securely clipped to the end of
the blister strip during assembly. The moulding 100 has no effect
on the operation of the device until the end of the strip reaches
the blister location chassis 6, where further movement of the strip
and actuator 5 is prevented. It will be appreciated that many other
methods of creating a blocking element on the end of the strip
could be used, including various shapes of plastic moulding or by
forming and/or folding the end of the strip itself. However, it
will be appreciated that a blocking element is not essential and,
once all the blisters of a strip have been used, continued
operation of the indexing mechanism will result in almost the
entire length of the strip being coiled within the spiral wound
element, the used portion of the strip will then comprise all the
blisters of that strip.
[0119] Although the housing of an inhalation device may be provided
with a common chamber 80 that stores the unused portion of the
blister strip 61a, powder contamination of the unused portion 61 of
the blister strip needs to be addressed for reasons that have
already been described.
[0120] The aforementioned problem is at least partially addressed
by the provision of the spiral wound element 60 because the opening
in at least some of the used blister cavities lies against the
inner surface of the element 60, thereby preventing escape of
residual powder from the blister cavities. It is also envisaged
that the edges of the spiral wound element 60 may be provided with
sealing elements, such as plastic strips formed in a U-shape to
create lip seals, brushes or wipers, where they contact adjacent
walls of the chamber to assist in retaining residual powder that
does escape from the blister cavities within the coils of the
spiral wound element 60. As long as the sealing elements are thin
and flexible, the strip can seal between the inner surfaces of the
housing without impeding expansion of the spiral wound element
60.
[0121] In another alternative arrangement, a spiral wound element
60 may be lined with a flexible tape that overlaps the edges of the
element so as to create a wiper seal against the surfaces of the
device walls. However, the sealing effect provided by the spiral
wound element 60 itself may not alone be sufficient to prevent
powder contamination of the unused portion of the blister strip
61a. Furthermore, to provide a complete barrier around the used
portion of the blister strip 61 requires a longer spiral wound
element 60 because, as the spiral wound element expands, a section
of the spent coil and its associated cavities becomes exposed.
[0122] To at least partially overcome the problem of contamination
of unused blisters with residual powdered dose, the Applicant's
have proposed the provision of a flexible, or inflexible but
movable, dividing wall so as to separate the interior of the
housing into a unused blister chamber and, a used blister chamber.
This wall constrains any residual powder within the used blister
portion of the housing.
[0123] To reduce the size of an inhalation device, the Applicants
have proposed allowing the space initially occupied by the unused
portion 61a of the blister strip to be being slowly taken up by the
used portion 61 of the blister strip as the size of the used
portion 61 of the blister strip increases and the size of the
unused portion 61a of the blister strip decreases. To address the
problem of powder contamination, a flexible and/or movable dividing
wall 90 is interposed between the unused portion 61a of the blister
strip and the part of the housing 71 that receives the used portion
61 of the blister strip so as to divide the chamber 80 into "clean"
and "contaminated" regions containing the unused blisters 61a and
the used blisters 61, respectively.
[0124] It will be appreciated that a flexible and/or movable
dividing wall 90 can be used in an inhaler 70 with, or without, the
spiral wound element 60 described previously, although particular
benefits have been obtained as a result of using both a flexible
dividing wall 90 and a spiral wound element 60 in combination as
the interaction between these components has some advantages, as
will become apparent from the following description.
[0125] In one unillustrated embodiment, the dividing wall may
simply be a rigid element which is fixed at one end so that it can
pivot about this point. Alternatively, it can be slideably fixed to
the housing so that it slides depending on the relative size of the
unused and used blister strips. However, in a preferred embodiment,
and as shown in FIGS. 10 to 13, the dividing wall 90 is flexible
and resilient in nature and has one or both ends immovably fixed in
place within the housing 71 of the device. It is also envisaged
that a flexible dividing wall 90 may be elastomeric in nature so
that it can expand and lengthen as pressure is applied to it by an
expanding spiral wound element 60 or used blister coil 61.
[0126] Although the flexibility of the dividing wall 90 may be such
as to allow the relative sizes of the unused and used blister strip
compartments to change as the device is used, the flexibility also
improves or assists in the sealing of the edges of the dividing
wall 90 against the walls 2a,2b of the device housing 71 against
which they rub. The width of the dividing wall 90 may be greater
than the width of the space, defining the unused and used blister
chamber, between the side walls 2a,2b so that the dividing wall 90
is always held in compression between the sidewalls 2a,2b in a
direction extending across its width so as to maintain the edges of
the dividing wall 90 in close contact with the sidewalls 2a,2b of
the housing, thereby minimising egress of powder from the used
blister strip compartment into the unused blister compartment
between the edges of the dividing wall 90 and the sidewalls 2a,2b
of the housing 71 against which they are held in contact. It is
also possible to provide the edges of the dividing wall 90 with
sealing elements (not shown), such as plastic strips formed in a
U-shape to create lip seals, brushes or wipers, where they contact
adjacent walls 2a,2b of the housing 71 to assist in retaining
residual powder that does escape from the blister cavities within
the contaminated compartment of the housing 71.
[0127] FIG. 10 illustrates an embodiment of the invention in which
a flexible movable dividing wall 90 extends over the spiral wound
element 60 and separates the used portion 61 of the blister strip
from the unused portion 61a from each other. The dividing wall 90
is fixed at each end 90a,90b to the walls of the device. FIG. 11
illustrates a partial sectional view to illustrate how the dividing
wall 90 is resiliently flexible in a direction across its width "X"
and is wider than the distance "Z" between the two facing sidewalls
2a,2b of the housing 2, so that the dividing wall 90 is slightly
deformed and held in compression between the two sidewalls 2a,2b in
a direction across its width so that the edges of the dividing wall
90 apply pressure to the sidewalls 2a,2b in the direction indicated
by "F" in FIG. 11. Although the pressure applied to the sidewalls
2a,2b by the dividing wall 90 needs to be sufficient to prevent
escape of powder from the used blister compartment to the unused
blister compartment, it is important to ensure that the pressure is
not so great that the friction between the dividing wall 90 and the
side walls 2a,2b is too great so as to disrupt or prevent fluid
movement of the dividing wall 90 as the used blister strip 61 or
spiral wound element 60 expands and pushes against it.
[0128] FIGS. 12a to 12d show how the flexible dividing wall 90 is
moved or resiliently deformed by a strip of used blisters or, the
expanding spiral wound element 60, during the life of the device 70
and as the unused portion 61a of the blister strip unwinds and the
used portion 61 of the blister strip winds up within the spiral
wound element 60 or is otherwise contained within the used blister
compartment.
[0129] In one embodiment, the flexible dividing wall 90 can be
formed from a flexible foam strip which is dimensioned so that it
is lightly compressed between the front and rear housing walls so
that an effective powder seal is maintained even as the foam strip
is moved by pressure applied to it by the expanding spiral wound
element 60. Foam provides a good balance between flexibility and
low frictional resistance. Foams can be produced from EVA, PVA, PU
and silicone, although it will be appreciated that many other
materials could be used instead.
[0130] Depending on the stiffness of the foam strip, a stiffening
strip (not shown), narrower than the foam strip, may be fixed to
the foam strip to increase stiffness. Alternatively, a strip formed
of linked rigid sections can be fixed to the flexible sealing strip
to control its movement. In another unillustrated embodiment, the
dividing wall 90 may itself be formed from a chain of individually
rigid segments pivotally linked to each other.
[0131] In another modified arrangement, a flexible dividing wall 91
or a portion of it can be at least partially fixed to the outer
surface of the spiral wound element 60, as shown in FIG. 13. As
with the embodiment of FIG. 12, at least one end of the dividing
wall 91a,b can be fixed to the walls of the device.
[0132] The provision of a spiral wound element 60 having a
stiffness which is sufficient to ensure that there is little or no
expansion until a first closed coil of a used portion of the
blister strip is formed has proved to successfully control the
coiling and storage of the used portion of the blister strip within
the device. However, it has been found that in circumstances where
a relatively large amount of residual drug remains within the
device, such as may occur when a blister is pierced but the dose is
not inhaled prior to indexing to the next blister, it can find its
way between the used portion 61 of the blister strip and the
surface of the spiral wound element 60 which can result in an
increase in friction between these components and ultimately cause
the used portion 61 of the blister strip to jam within the coil 60.
The extent to which this may occur depends not only on the amount
of residual drug but also on the type of drug itself and the
particle size.
[0133] With the aim of minimising the occurrence of jamming, the
use of a much thinner, more flexible and so less stiff spiral wound
element is envisaged. In fact, the use of a foil sheet-like spiral
wound element has been found sufficient to adequately coil used
blisters. The coils of this element are closely wound, preferably
such that adjacent coils lie in contact with each other and there
is no space between them in the absence of a used portion of a
blister strip. As the spiral wound element is considerably more
flexible than the spiral wound elements of previous embodiments,
the frictional forces between the used portion of the blister strip
and the spiral wound element are considerably reduced.
[0134] The coil of a used portion of the blister strip is formed in
a different way with a more flexible spiral wound element as the
spiral wound element begins to move as soon as it is contacted by
the leading edge of the used portion of the blister strip. The
steps in the formation of a coil of blisters are shown in the
sequence of drawings of FIG. 19(a) to 19(j).
[0135] FIG. 19(a) shows a spiral wound element 150 in a stable
unstressed state according to this embodiment of the invention
which is formed from a flat elongate sheet of thin, flexible
foil-like material. The walls of the spiral wound element 150 may
all lie in contact although there may also be a space between the
walls, as shown in FIG. 1(a).
[0136] FIG. 19(b) shows the same spiral wound element 150 as the
leading edge 151a of a used portion of a blister strip 151 is
received within the mouth 152 of the spiral wound element 150. At
this point, the leading edge 151a has come into contact with the
curved surface of the spiral wound element 150 but there is
generally no flexing or deformation of the used portion of the
blister strip 151 or the spiral wound element 150.
[0137] FIG. 19(c) shows the spiral wound element 150 after the used
portion of the blister strip 151 has moved further towards the
spiral wound element 150 and from which it can be seen that the
strip 151 begins to flex as the leading edge 151a starts to travel
up the curved inner wall surface of the outer coil of the spiral
wound element 150, in the direction shown by arrow "A" in the
Figure, and the outer coil of the spiral wound element 150 begins
to move away from its adjacent inner coil and begin to straighten
out due to the force of the leading end 151a of the relatively
stiff used portion of the blister strip 151 against the flexible
spiral wound element 150.
[0138] FIG. 19(d) shows the spiral wound element 150 after the used
portion of the blister strip 151 has been moved further into or
towards the spiral wound element 150 and from which it can be seen
that the leading edge 151a of the blister strip 151 has traveled
further up the curved inner surface of the outer coil and the
blister strip 151 has deformed further pushing out and further
straightening the outer coil and effectively unwinding or unrolling
the spiral wound element 150, as can be seen from the position of
the trailing end 153 of the spiral wound element 150.
[0139] FIG. 19(e) shows the spiral wound element 150 after the used
portion of the blister strip 151 has been moved further towards the
spiral wound element 150 and from which it can be seen that the
leading edge 151a of the blister strip 151 has traveled yet further
up the curved inner surface of the outer coil, the blister strip
151 further deforming and assuming a curved shape close to its
leading edge 151a. Further unwinding or unrolling of the spiral
wound element 150 is apparent due to the load applied to the spiral
wound element 150 by the leading end 151a of the stiffer blister
strip 151.
[0140] FIG. 19(f) shows the spiral wound element 150 after the used
portion of the blister strip 151 has been moved even further
forward toward and into the spiral wound element 150 and from which
it can be seen that the leading edge 151a of the blister strip 151
is now almost parallel to the inner wall surface of the outer coil
of the spiral wound element 150 with the lower surface 151b of the
blister strip 151 generally in contact with the inner wall
surface.
[0141] It will be appreciated that in the transition from the
position shown in FIGS. 19(c) to 19(f), the direction of the force
applied to the spiral wound element 150 by the leading end 151a of
the used portion of the blister strip 151 changes. In FIG. 19(c),
the direction in which the primary component "X" of the load acts
against the spiral wound element 150 is at an angle ".alpha." to a
tangent extending along the wall surface of the spiral wound
element 150 from the point of contact of the leading edge 151a of
the strip 151 with the spiral wound element 150, which tends to
cause the spiral wound element 150 to unroll or unwind. However, in
FIG. 19(f) the primary component of the load acts at a much smaller
angle to a tangent extending along the wall surface of the spiral
wound element 150 from the point of contact of the leading edge
151a of the strip 151 with the spiral wound element 150 so that the
strip 151 tends to more closely follow the wall surface of the
spiral wound element 150 and slide along the wall surface so as to
coil up within the spiral wound element 150 rather than continue to
unroll or unwind it.
[0142] FIG. 19(g) to 19(i) shows the spiral wound element 150 after
the used portion of the blister strip 151 has advanced further
forward into the spiral wound element 150 and from which it can be
seen that the strip 151 generally assumes a curvature which is
similar to the curvature of the spiral wound element 150 and that
the spiral wound element 150 begins to expand as more of the strip
151 is fed into it.
[0143] In FIG. 19(j), a complete closed coil of a used portion of
the blister strip has been formed. As further blisters are used up,
the spiral wound element 150 expands to accommodate more blisters
and to form further coils.
[0144] The sequence of FIG. 19(a) to 19(j) demonstrates how
deformation occurs with the spiral wound element 150 in isolation,
i.e. without being acted on by any external forces resulting from,
for example, contact of the spiral wound element against the walls
of the housing of the device and/or against a flexible dividing
wall separating the chamber into two regions containing used and
unused portions of the blister strip, respectively.
[0145] FIGS. 20(a) to 20(f) show how deformation occurs in practice
and when the spiral wound element 150 is constrained between the
housing wall 160 below the spiral wound element 150 and a flexible
dividing wall 90 above the spiral wound element 150 or, if no
dividing wall 90 is present, the unused portion of the blister
strip. Generally, the spiral wound element 150 deforms in the same
way although, as can be seen from FIGS. 20(a) to 20(c), the spiral
wound element 150 unrolls or unwinds along the end wall surface 160
of the housing 170 prior to expansion. The resulting coil formed
from the used portion of the blister strip is also noticeably and
usefully smaller than the coil created by an unconstrained spiral
wound element.
[0146] In practice, it has been found that, when the spiral wound
element 150 has expanded to the extent shown in FIGS. 20(d) and
20(e), the coil formed from the used portion of the blister strip
becomes very loose due to the flexibility of the spiral wound
element 150 which places a load on the coil which is insufficient
to keep it close wound or tight. This problem can be mitigated by
using the flexible dividing wall 90, the unused portion of the
blister strip if no dividing wall is present, or some other
dedicated element, to steady the spiral wound element 150 and used
portion of the blister strip 151 as it expands, thereby preventing
over expansion and maintaining relative tightness between the
windings. As shown in FIGS. 20(a) to 20(f), expansion of the spiral
wound element 150 is controlled, supported or at least steadied by
its contact with the flexible dividing wall 90. As mentioned
previously, the spiral wound element and flexible dividing wall may
be at least partially attached to each other so that the dividing
wall expands together with the spiral wound element, thereby
providing additional control of expansion of the spiral wound
element.
[0147] FIGS. 21(a) to 21(c) show the spiral wound element according
to this embodiment of the invention. FIGS. 21(a) and 21(c) show the
spiral wound element in its normal relaxed coiled state from which
it can be seen that it has a generally planar or uncoiled leading
edge portion 160 with slots 161 to facilitate its connection to
corresponding lugs in the device housing. FIG. 21(b) shows a plan
view of the spiral wound element after it has been flattened out.
Table 1 shows preferred dimensions of the spiral wound element
according to one preferred embodiment of the invention. As the
diameter of a coiled strip of a used portion of a blister strip may
exceed 50 mm, the diameter of the spiral wound element prior to
receiving the strip may be less than 25% of its maximum diameter,
i.e. when filled with a used portion of a strip of blisters having
a diameter in the region of 50 mm.
TABLE-US-00001 TABLE 1 Length (a) ~104 mm Width (b) ~17.5 mm
Diameter (c) unstressed ~12.4 mm Length (d) of initial portion ~16
mm Thickness (e) of material ~0.0508 mm
[0148] Although embodiments of the invention have been described in
which a spiral wound element is provided only for coiling up a used
portion of a blister strip, it is also envisaged that a second
spiral wound element could be provided to contain the unused
blister strip. In this situation, the unused blister strip may be
wound into a coil within a spiral wound element that is then
located in the housing of the device during assembly. As the device
is used, the spiral wound element containing the coiled up strip of
unused blisters gradually retracts as the coil unwinds whereas the
spiral wound element that receives the used portion of the strip
expands as the used portion of the strip is coiled up within it.
The spiral wound elements 130a,130b may be formed integrally as a
single unit and be fixed to the housing 71 together, as shown in
FIG. 17a which illustrates a "twin coil" spiral wound element 130
together with a strip 61a of unused blisters received therein and,
FIG. 17b which illustrates the coil once loaded into an inhalation
device 70 so as to form an integral part of the device. Since
identical materials can be used for each spiral wound element
130a,130b, this reduces the overall component count and simplifies
the assembly process. It will be appreciated that an aperture (not
shown) may need to be made in the twin spiral wound element 130 at
the blister piercing station 7 to allow the piercing elements 8 to
extend through the aperture into a blister located beneath it.
[0149] In an alternative arrangement, it is envisaged that two
separate spiral wound elements may be used. Means to fix the twin
coil element to the device housing may take the same form as the
slots 161 illustrated in FIG. 21. These slots may be formed, for
example, in the spiral wound element between the two coils.
[0150] If a spiral wound element is used for the unused blister
strip, the assembly of the device is greatly simplified because the
coil of unused blisters is essentially preformed and held together
in its coiled formation by the spiral wound element ready for
insertion into the device during assembly. Preferably, the spiral
wound element containing the unused blister strip is loaded into
the housing of an inhaler together with the strip. However, it is
envisaged that the coiled strip could be pressed out of the spiral
wound element containing it immediately prior to or during
insertion into the housing so that the unused strip is maintained
in in its coiled state only by being constrained by the housing
walls.
[0151] Blister strips are typically produced by a form/fill/seal
machine which produces flat strips that must be wound into a coil
prior to insertion into the device housing. Conventionally, this is
achieved by gripping the end of a strip on a winding spindle and
rotating the spindle until the coil is formed. Although this
procedure works satisfactorily, the step of gripping the end of the
strip is intricate and complex to automate. Therefore, it is
advantageous to avoid having to locate and grip the strip. This is
achieved with the spiral wound element of the present invention
because the end of the strip can simply be fed into the mouth of
the spiral wound element. As more of the strip is fed into the
coil, it is wound up within it in the same way that the used
blister strip is wound up within the inhalation device during
use.
[0152] A sequence of drawings to show how a flat strip of unused
blisters 120 which have been produced using a form/fill/seal
blister strip forming machine (not shown) can be fed into and wound
up within a spiral wound element 123 ready for insertion into the
chamber of a device, is shown in FIGS. 18a to 18c. It will be
appreciated that the strip can either be pre-cut or be cut as part
of the winding process. The drive to the strip can be achieved with
a driving wheel 121 and a pinch wheel 122 to give positive grip to
the strip to drive it in the direction of the arrow "D" in the
drawings.
[0153] As mentioned above, when the strip is fully wound it can be
transferred into the device by sliding it axially out of the spiral
wound element and into the device housing. Alternatively, the
spiral wound element 123 ("former") can be loaded into the device
housing together with the strip 120 to become a component of the
device. The loaded spiral formers 123 can also be used to contain
and protect the strip 120 during assembly or storage operations, as
in this form it is more compact and more robust than a flat length
of strip.
[0154] FIG. 22 illustrates a further embodiment of the invention
which is similar to that shown and described in FIGS. 10-12d, and
comprises an inhalation device 270 having a housing 271 and a
flexible movable dividing wall 290 which extends over a spiral
wound element 260 and separates a used portion 261 of the blister
strip and an unused portion 261a from each other. The device 270
includes an indexing mechanism 274 comprising an actuating lever
275 which unwinds the coil one blister at a time so that they pass
over a blister locator chassis 276 and successively through a
blister piercing station 277, when the actuator 275 is pivoted as
described previously. When a user inhales through a mouthpiece 279,
an airflow is generated within the blister to entrain the dose
contained therein and carry it out of the blister via the
mouthpiece 279 and into the user's airway
[0155] The dividing wall 290 is fixed at each end 290a,290b to the
walls of the device. As with the embodiment shown in FIG. 10, the
dividing wall 290 may be resiliently flexible in a direction across
its width and wider than the distance between the two facing
sidewalls of the housing so that the dividing wall 290 is slightly
deformed and held in compression between the two sidewalls, as
described previously.
[0156] The first end 290a of the flexible dividing wall 290 is
mounted to a support rib 291 formed in the housing 271 and extends
between the side walls of the housing 271. Thereby, the side walls
and edge wall (on the left of FIG. 22) of the housing 271, together
with the support rib 291, define a passage 292 though which the
used portion 261 of the blister strip initially passes into the
used compartment from the unused compartment. Accordingly, it will
be appreciated that the passage 292 is the only path through which
it may be possible for residual powder to pass from the used
blister compartment to the unused blister compartment of the
housing. Therefore, the embodiment of the invention shown in FIG.
22 differs from that of FIG. 10 in that it includes means across
the passage to substantially close the passage around the blister
strip to minimise or substantially eliminate the possibility of
residual powder passing from the used blister compartment to the
unused blister compartment of the housing. Various configurations
of such means are envisaged within the scope of the invention, some
of which will be described hereafter.
[0157] FIGS. 22 and 23 show the passage 292 of the housing 271 is
provided with a first element 293 projecting from the support rib
291 towards the outer wall of the housing 271, and a second element
294 on the outer wall of the housing 271 opposite to and projecting
towards the first element 293. The first element 293 includes an
arcuate cut-out 295 and it may be formed integrally with the
support rib or a separate component mounted to the support rib 291.
The first and second elements 293,294 are spaced from each other,
such that an aperture 296 is formed therebetween in the shape of a
rectangular slot 296a with a segment or semi-circular portion 296b
with its flat edge against one long side of the slot 296a. The
resulting aperture 296 is thereby shaped such that the blister
strip can pass through the aperture 296 with the flat portion of
the blister strip located within the slot 296a and the blister
within the segment portion 296b. This is shown more clearly by the
enlarged partial cross-sectional view of FIG. 23. The aperture 296
is dimensioned such it is only very slightly larger than the
corresponding dimensions of the blister strip, so that the blister
strip and blister thereof form a close clearance through the
aperture 296. Thereby, the passage of powder from the used blister
compartment into the unused blister compartment is minimised or
substantially prevented.
[0158] It should be appreciated that the indexing mechanism 274 of
the inhaler 270 only causes the blister strip to be moved when the
user operated the actuating lever 275, and thus the blister strip
remains in the same position during piercing and inhalation, and
thereafter the same storage position until the actuating lever 275
is operated again. Furthermore, the regular spacing of the blisters
in the blister strip means that each operation of the actuating
lever 275 results in the blister strip being incrementally moved
such that next blister along in the blister strip is positioned in
the same location as the previous blister. Accordingly, the first
and second elements 293, 294 are located in the housing 271 such
that a blister of the blister strip is centrally located in the
aperture 296 in the piercing/inhalation/storage position of the
blister strip so that the close fit of the aperture 296 around the
blister and blister strip is maintained at all times except for the
very brief moment of operating the actuating lever 275 to index the
blister strip along.
[0159] A further variation of the embodiment shown in FIGS. 22 and
23, is shown in FIGS. 24 and 25. Like components retain the same
reference numerals and description thereof will not be repeated.
The embodiment of FIGS. 24 and 25 differs from that of FIGS. 22 and
23 in that the first element 293' is made of a resilient material,
such as foam or rubber for example, and is secured to the support
rib 291. The arcuate cut out 295' and first element 293' is
dimensioned so that the aperture 296 is the same size as or
slightly smaller than, the cross-sectional dimensions of the
blister strip and blister, such that the resilient material forms a
contact fit thereagainst and may deform slightly, to achieve an
effective seal between the used and unused blister
compartments.
[0160] With the embodiment shown in FIGS. 24 and 25, it is intended
that alternative configurations of resilient first elements 293'',
293''' may also be included within the scope of the invention, and
are shown in FIGS. 26A-26C. FIG. 26A shows a first alternative
where there is no concave cut-out portion 295' and instead, the end
is just flat. In this embodiment, the resilient member 293'' would
simply be deflected around the shape of the blisters as the blister
strip was indexed along. FIG. 26B shows a second alternative 293'''
in which there is no cut-out portion 295', but instead of having a
solid flat end as with the resilient element 293'' of FIG. 26A, the
flat end has a plurality of cuts 295'' extending into the resilient
element 293''' to form a comb or brush structure. This would enable
the blisters to deform each `finger` of the comb/brush structure as
necessary as the blister strip is advanced, thereby creating less
resistance to movement of the blister strip than the solid
flat-ended embodiment of FIG. 26A, whilst also maintaining a seal
against the blister. FIG. 26C shows the first resilient element
293' of the embodiment of FIGS. 24 and 25 having the arcuate
cut-out 295'.
[0161] In all of the embodiments shown in FIGS. 22-26C, the first
element 293,293',293'',293''' is either formed as part of the
support rib 291, or is a separate element mounted to the support
rib 291. However, it is envisaged that the first element may
instead be formed as part of the dividing wall 290. Such an
embodiment is shown in FIGS. 27 and 28. Again, like components
retain the same reference numerals and description thereof will not
be repeated. The flexible dividing wall 290 extends over the top of
the support rib 291 and the end portion 290a extends towards the
second element 294. The end 290a of the dividing wall 290 is spaced
from the second element 294 and shaped with an arcuate cut-out as
with the embodiment shown in FIGS. 24 and 25, and so performs the
same function as described above for that embodiment. In addition,
the end 290a of the dividing wall 290 may alternatively be shaped
with a flat end 290a' or a comb/brush structure end 290a'', as
described above with reference to FIGS. 26A and 26B. These
alternatives are shown in FIGS. 29A and 29B and have the same
function and advantages as described previously FIG. 29C shows the
end 290a of the dividing wall of FIGS. 27 and 28.
[0162] All of the embodiments shown and described in FIGS. 27-29C
include the second element 294 as a separate element to the
dividing wall 290, formed integrally with or mounted to the wall of
the housing 271. However, an alternative embodiment is shown in
FIGS. 30 and 31, in which no separate second element is provided.
Instead, the dividing wall 290 extends over the top of the support
rib 291 and the end portion 290a all the way to the wall of the
housing 271 where it is secured, for example, by being bonded
thereto. To allow the blister strip to pass through the passage 292
from the unused compartment to the used compartment, an aperture
297 is formed in the dividing wall 290 between the support rib 291
and the wall of the housing 271, and is shaped as a slit 297a with
a segment-shaped portion 297b, to accommodate the blister strip and
blister as shown in FIG. 31. As above, the aperture 297 may be
dimensioned to be the same size or slightly smaller than the
cross-sectional dimensions of the blister strip and blister, such
that the resilient material forms a contact fit thereagainst and
may deform slightly, to achieve an effective seal between the used
and unused blister compartments. The dividing wall also includes a
slit 298 extending from the aperture 297 to the edge of the
dividing wall 290. This enables a blister strip to be loaded in the
inhaler 270 and positioned in the aperture 297 in the dividing wall
290 by sliding it though the slit 298, without having to feed one
remote end of the blister strip though the aperture 297.
[0163] In a further un-illustrated embodiment of the invention, the
inhaler could be provided as shown in FIGS. 30 and 31, except that
the end 290a of the dividing wall may not be secured to the wall of
the housing 271, and would not have an aperture 297 formed therein.
Instead, a remote end of the dividing wall 290 would include an
arcuate cut out and be configured to bias towards the wall of the
housing 271 away from the support rib 291. In use, the end of the
dividing wall would bias the blister strip against the wall of the
housing 271, with the arcuate cut-out conforming around the
blister, to effect the seal in the passage 292 between the used and
unused blister compartments. Also, the end of the dividing wall may
be flat ended or have a comb/brush configuration as described above
with reference to other embodiments, instead of having an arcuate
cut-out portion.
[0164] It should be appreciated that in the above-described
embodiments that include a second element 294, this may be made
from a resilient material secured to the wall of the housing 271,
to effect a snug fit against the blister strip, as well as being a
solid element formed integrally with or secured to the housing
271.
[0165] A variety of medicaments may be administered alone by using
inhalers of the invention. Such medicaments include those that are
suitable for the treatment of asthma, chronic obstructive pulmonary
diseases (COPD), respiratory infections, rhinitis, allergic
rhinitis, nasal diseases and disorders; general and specific
conditions, and systemic diseases with the lung or nasal cavity as
the site of delivery. Such medicaments include, but are not limited
to, .beta..sub.2-agonists, eg carmoterol, fenoterol, formoterol,
levalbuterol, pirbuterol, reproterol, metaproterenol, rimiterol,
salbutamol, salmeterol, indacaterol, terbutaline, orciprenaline,
clenbuterol, bambuterol, procaterol, broxaterol, picumeterol, and
bitolterol; non-selective .beta.-stimulants such as ephedrine and
isoprenaline; phosphodiesterase (PDE) inhibitors, eg
methylxanthines, theophylline, aminophylline, choline
theophyllinate, and selective PDE isoenzyme inhibitors, PDE 3
inhibitors, eg milrinone and motapizone; PDE 4 inhibitors, eg
rolipram, cilomilast, roflumilast, oglemilast, and ONO 6126; PDE
3/4 inhibitors, eg zardaverine and tolafentrine; inducers of HDAC2
eg theophylline; anticholinergics including muscarinic receptor
(M1, M2, and M3) antagonists eg atropine, hyoscine, glycopyrrolate,
ipratropium, tiotropium, oxitropium, NVA237, pirenzepine, and
telenzepine; mast cell stabilisers, eg cromoglycate and ketotifen;
bronchial anti-inflammatory agents, eg nedocromil; steroids, eg
beclometasone, dexamethasone, fluticasone, budesonide, flunisolide,
rofleponide, triamcinolone, butixocort, mometasone, and
ciclesonide; disease modifying agents such as methotrexate,
leflunomide, teriflunomide, and hydroxychloroquine; histamine type
1 receptor antagonists, eg cetirizine, loratadine, desloratadine,
fexofenadine, acrivastine, terfenadine, astemizole, azelastine,
levocabastine, chlorpheniramine, promethazine, cyclizine, and
mizolastine; antibacterial agents and agents for cystic fibrosis
and/or tuberculosis treatment, eg Pseudomonas aeruginosa infection
vaccines (eg Aerugen.RTM.), mannitol, denufosol, glutathione,
N-acetylcysteine, amikacin duramycin, gentamycin, tobramycin,
dornase alfa, alpha 1-antitrypsin, heparin, dextran, capreomycin,
vancomycin, meropenem, ciprofloxacin, piperacillin, and rifampicin;
mucolytic agents for the treatment of COPD and cystic fibrosis, eg
N-acetylcysteine, and ambroxol; histamine type 2 receptor
antagonists; tachykinin neurokinin antagonists; triptans, eg
almotriptan, rizatriptan, naratriptan, zolmitriptan, sumatritpan,
eletriptan, and frovatriptan; neurological agents eg apomorphine,
dronabinol, dihydroergotamine, and loxapine; antiviral agents eg
foscarnet, acyclovir, famciclovir, valacyclovir, ganciclovir,
cidofovir; amantadine, rimantadine; ribavirin; zanamivir and
oseltamavir and pleconaril, protease inhibitors (eg ruprintrivir,
indinavir, nelfinavir, ritonavir, and saquinavir), nucleoside
reverse transcriptase inhibitors (eg didanosine, lamivudine,
stavudine, zalcitabine, and zidovudine), and non-nucleoside reverse
transcriptase inhibitors (eg nevirapine and efavirenz);
.alpha.-1/.alpha.-2 adrenoceptor agonists, eg propylhexedrine,
phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine,
naphazoline, oxymetazoline, tetrahydrozoline, xylometazoline,
tramazoline, and ethylnorepinephrine; platelet aggregation
inhibitors/anti-inflammatory agents, eg bemiparin, enoxaparin,
heparin; anti-infectives, eg cephalosporins, penicillins,
tetracyclines, macrolides, beta-lactams, fluoroquinolones,
streptomycin, sulphonamides, aminoglycosides (eg tobramycin),
doripenem, pentamidine, colistimethate, and aztreonam; agents for
sexual health, sexual dysfunction including premature ejaculation;
eg. apomorphine, VR776, agents that acts via 5HT- and
noradrenergic-mediated pathways in the brain, leuprolide, and PDE 5
inhibitors eg, sildenafil, tadalafil, and vardenafil; leukotriene
modifiers, eg zileuton, fenleuton, tepoxalin, montelukast,
zafirlukast, ontazolast, ablukast, pranlikast, verlukast, and
iralukast; inducible nitric oxide synthase (iNOS) inhibitors;
antifungals, eg amphotericin B, natamycin, and nystatin;
analgesics, eg codeine, dihydromorphine, ergotamine, fentanyl,
cannabinoids, and morphine; anxiolytic/antidepressive agents, eg
benzodiazepines and benzodiazepine derivatives, diazepam,
midazolam, chlordiazepoxide, lorazepam, oxazepam, clobazam,
alprazolam, clonazepam, flurazepam, zolazepam; tryptase and
elastase inhibitors; beta-2 integrin antagonists; adenosine
receptor agonists or antagonists, eg adenosine 2a agonists; calcium
channel blockers, eg gallopamil, and diltiazem; prostacyclin
analogues, eg iloprost; endothelin-receptor antagonists, eg
LU-135252; cytokine antagonists, eg chemokine antagonists and
inhibitors and modifiers of cytokine synthesis including modifiers
and inhibitors of the pro-inflammatory transcription factor, NFkB;
interleukins and inhibitors of interleukins, eg aldesleukin;
therapeutic proteins and peptides, eg insulin, insulin aspart,
insulin glulisine; insulin lispro, neutral, regular and soluble
insulins, isophane insulins, insulin zinc, protamine zinc insulin,
insulin analogues, acylated insulin, insulin glargine, insulin
detemir, glucagon, glucagon-like peptides, and exendins; enzymes,
eg dornase alfa; systemically active macromolecules, eg human
growth hormone, leuprolide, alpha-interferon, growth factors (eg
insulin-like growth factor type 1), hormones, eg epinephrine,
testosterone, and parathyroid hormone and analogues (eg
Ostabolin-C); osteoporosis agents, eg bisphosphonates; anticancer
agents, eg anthracyclines, doxorubicin, idarubicin, epirubicin,
methotrexate, taxanes, paclitaxel, docetaxel, ciplatin, vinca
alkaloids, vincristine, and 5-fluorouracil; anticoagulants, eg
blood factors and blood factor constructs, eg FVIII-Fc and FIX-Fc;
eg FV111-Fc; immunomodulators, eg cyclosporine, sirolimus, and
tacrolimus; antiproliferative immunosuppressants, eg azathioprine,
and mycophenolate mofetil; cytokines (eg interferons, interferon
.beta., interleukins, and interleukin antagonists and inhibitors);
nucleic acids; vaccines, eg flumist; anti-obesity agents;
diagnostics and gene therapies. It will be clear to a person
skilled in the art that, where appropriate, the medicaments may be
linked to a carrier molecule or molecules and/or used in the form
of prodrugs, salts, as esters, or as solvates to optimise the
activity and/or stability of the medicament.
[0166] Inhalers according to the invention may also be used to
deliver combinations of two or more different medicaments. Specific
combinations of two medicaments which may be mentioned include
combinations of steroids and .beta..sub.2-agonists. Examples of
such combinations are beclomethasone and formoterol; beclomethasone
and salmeterol; fluticasone and formoterol; fluticasone and
salmeterol; budesonide and formoterol; budesonide and salmeterol;
flunisolide and formoterol; flunisolide and salmeterol; ciclesonide
and salmeterol; ciclesonide and formoterol; mometasone and
salmeterol; and mometasone and formoterol. Specifically inhalers
according to the invention may also be used to deliver combinations
of three different medicaments.
[0167] It will be clear to a person skilled in the art that, where
appropriate, the medicaments may be linked to a carrier molecule or
molecules and/or used in the form of prodrugs, salts, as esters, or
as solvates to optimise the activity and/or stability of the
medicament.
[0168] It is also envisaged that the pharmaceutical composition may
comprise one or more, preferably one, anticholinergic 1, optionally
in combination with a pharmaceutically acceptable excipient.
[0169] The anticholinergic 1 can be selected from the group
consisting of
a) tiotropium salts 1a, b) compounds of formula 1c
##STR00001##
wherein A denotes a double-bonded group selected from among
##STR00002## [0170] X.sup.- denotes an anion with a single negative
charge, preferably an anion selected from the group consisting of
fluoride, chloride, bromide, iodide, sulphate, phosphate,
methanesulphonate, nitrate, maleate, acetate, citrate, fumarate,
tartrate, oxalate, succinate, benzoate and p-toluenesulphonate,
[0171] R.sup.1 and R.sup.2 which may be identical or different
denote a group selected from among methyl, ethyl, n-propyl and
iso-propyl, which may optionally be substituted by hydroxy or
fluorine, preferably unsubstituted methyl; [0172] R.sup.3, R.sup.4,
R.sup.5 and R.sup.6, which may be identical or different, denote
hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine,
chlorine, bromine, CN, CF.sub.3 or NO.sub.2; [0173] R.sup.7 denotes
hydrogen, methyl, ethyl, methyloxy, ethyloxy, --CH.sub.2--F,
--CH.sub.2--CH.sub.2--F, -0-CH.sub.2--F, -0-CH.sub.2--CH.sub.2--F,
--CH.sub.2--OH, --CH.sub.2--CH.sub.2--OH, CF.sub.3,
--CH.sub.2--OMe, --CH.sub.2--CH.sub.2-OMe, --CH.sub.2--OEt,
--CH.sub.2--CH.sub.2-OEt, --O--COMe, --O--COEt, -Q-COCF.sub.3,
-Q-COCF.sub.3, fluorine, chlorine or bromine; c) compounds of
formula 1d
[0173] ##STR00003## [0174] wherein [0175] A, X.sup.-1, R.sup.1 and
R.sup.2 may have the meanings as mentioned hereinbefore and wherein
R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11 and R.sup.12, which
may be identical or different, denote hydrogen, methyl, ethyl,
methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN,
CF.sub.3 or NO.sub.2, with the proviso that at least one of the
groups R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11 and R.sup.12
is not hydrogen, d) compounds of formula 1e
[0175] ##STR00004## [0176] wherein A and X.sup.- may have the
meanings as mentioned hereinbefore, and wherein [0177] R.sup.15
denotes hydrogen, hydroxy, methyl, ethyl, --CF.sub.3, CHF.sub.2 or
fluorine; [0178] R.sup.1' and R.sup.2' which may be identical or
different denote C.sub.1-C.sub.5-alkyl which may optionally be
substituted by C.sub.3-C.sub.6-cycloalkyl, hydroxy or halogen, or
[0179] R.sup.1' and R.sup.2' together denote a
--C.sub.3-C.sub.5-alkylene-bridge; [0180] R.sup.13, R.sup.14,
R.sup.13' and R.sup.14' which may be identical or different denote
hydrogen, --C.sub.1-C.sub.4-alkyl, --C.sub.1-C.sub.4-alkyloxy,
hydroxy, --CF.sub.3, --CHF.sub.2, CN, NO.sub.2 or halogen, e)
compounds of formula 1f
[0180] ##STR00005## [0181] wherein X.sup.- may have the meanings as
mentioned hereinbefore, and wherein [0182] D and B which may be
identical or different, preferably identical, denote --O, --S,
--NH, --CH.sub.2, --CH.dbd.CH, or --N(C.sub.1-C.sub.4-alkyl)-;
[0183] R.sup.16 denotes hydrogen, hydroxy, --C.sub.1-C.sub.4-alkyl,
--C.sub.1-C.sub.4-alkyloxy, --C.sub.1-C.sub.4-alkylene-Halogen,
--O--C.sub.1-C.sub.4 alkylene-halogen,
--C.sub.1-C.sub.4-alkylene-OH, --CF.sub.3, CHF.sub.2,
--C.sub.1-C.sub.4-alkylene-C.sub.1-C.sub.4 alkyloxy,
--O--COC.sub.1-C.sub.4-alkyl,
--O--COC.sub.1-C.sub.4-alkylene-halogen,
--C.sub.1-C.sub.4-alkylene-C.sub.3-C.sub.6-cycloalkyl,
--O--COCF.sub.3 or halogen;
[0184] R.sup.1'' and R.sup.2'' which may be identical or different,
denote --C.sub.1-C.sub.5-alkyl, which may optionally be substituted
by --C.sub.3-C.sub.6-cycloalkyl, hydroxy or halogen, or [0185]
R.sup.1'' and R.sup.2'' together denote a --C3-C5-alkylene bridge;
[0186] R.sup.17, R.sup.18, R.sup.17' and R.sup.18', which may be
identical or different, denote hydrogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkyloxy, hydroxy, --CF.sub.3, --CHF.sub.2, CN,
NO.sub.2 or halogen; [0187] R.sup.x and R.sup.x' which may be
identical or different, denote hydrogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkyloxy, hydroxy, --CF.sub.3, --CHF.sub.2, CN,
NO.sub.2 or halogen or [0188] R.sup.x and R.sup.x' together denote
a single bond or a bridging group selected from among the bridges
--O, --S, --NH, --CH.sub.2, --CH.sub.2--CH.sub.2--,
--N(C.sub.1-C.sub.4-alkyl), --CH(C.sub.1-C.sub.4-alkyl)- and
--C(C.sub.1-C.sub.4-alkyl).sub.2, and f) compounds of formula
1g
[0188] ##STR00006## [0189] wherein X.sup.- may have the meanings as
mentioned hereinbefore, and wherein [0190] A' denotes a
double-bonded group selected from among
[0190] ##STR00007## [0191] R.sup.19 denotes hydroxy, methyl,
hydroxymethyl, ethyl, --CF.sub.3, CHF.sub.2 or fluorine; [0192]
R.sup.1''' and R.sup.2''' which may be identical or different
denote C.sub.1-C.sub.5-alkyl which may optionally be substituted by
C.sub.3-C.sub.6-cycloalkyl, hydroxy or halogen, or [0193]
R.sup.1''' and R.sup.2''' together denote a
--C.sub.3-C.sub.5-alkylene-bridge; [0194] R.sup.20, R.sup.21,
R.sup.20' and R.sup.21' which may be identical or different denote
hydrogen, --C.sub.1-C.sub.4-alkyl, --C.sub.1-C.sub.4-alkyloxy,
hydroxy, --CF.sub.3, --CHF.sub.2, CN, NO.sub.2 or halogen. [0195]
The compounds of formula 1c are known in the art (WO 02/32899).
[0196] In a preferred embodiment of the invention the method
comprises administration of compounds of formula 1c, wherein [0197]
X.sup.- denotes bromide; [0198] R.sup.1 and R.sup.2 which may be
identical or different denote a group selected from methyl and
ethyl, preferably methyl;
[0199] R.sup.3, R.sup.4, R.sup.5 and R.sup.6, which may be
identical or different, denote hydrogen, methyl, methyloxy,
chlorine or fluorine;
[0200] R.sup.7 denotes hydrogen, methyl or fluorine, optionally
together with a pharmaceutically acceptable excipient.
[0201] Of particular importance are compounds of general formula
1c, wherein A denotes a double-bonded group selected from among
##STR00008##
[0202] The compounds of formula 1c, may optionally be administered
in the form of the individual optical isomers, mixtures of the
individual enantiomers or racemates thereof.
[0203] Of particular importance within a method according to the
invention are the following compounds of formula 1c: [0204]
tropenol 2,2-diphenylpropionic acid ester methobromide, [0205]
scopine 2,2-diphenylpropionic acid ester methobromide, [0206]
scopine 2-fluoro-2,2-diphenylacetic acid ester methobromide and
[0207] tropenol 2-fluoro-2,2-diphenylacetic acid ester
methobromide.
[0208] The compounds of formula 1d are known in the art (WO
02/32898).
[0209] In a preferred embodiment of the invention the method
comprises administration of compounds of formula 1d, wherein
[0210] A denotes a double-bonded group selected from among
##STR00009##
[0211] X.sup.- denotes bromide;
[0212] R.sup.1 and R.sup.2 which may be identical or different
denote methyl or ethyl, preferably methyl;
[0213] R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11 and R.sup.12,
which may be identical or different, denote hydrogen, fluorine,
chlorine or bromine, preferably fluorine with the proviso that at
least one of the groups R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11 and R.sup.12 not hydrogen, optionally together with a
pharmaceutically acceptable excipient.
[0214] Of particular importance within the method according to the
invention are the following compounds of formula 1d: [0215]
tropenol 3,3',4,4'-tetrafluorobenzilic acid ester methobromide,
[0216] scopine 3,3',4,4'-tetrafluorobenzilic acid ester
methobromide, [0217] scopine 4,4'-difluorobenzilic acid ester
methobromide, [0218] tropenol 4,4'-difluorobenzilic acid ester
methobromide, [0219] scopine 3,3'-difluorobenzilic acid ester
methobromide, and [0220] tropenol 3,3'-difluorobenzilic acid ester
methobromide.
[0221] The pharmaceutical compositions according to the invention
may contain the compounds of formula 1d optionally in the form of
the individual optical isomers, mixtures of the individual
enantiomers or racemates thereof.
[0222] The compounds of formula 1e are known in the art (WO
03/064419).
[0223] In a preferred embodiment of the invention the method
comprises administration of compounds of formula 1e, wherein
[0224] A denotes a double-bonded group selected from among
##STR00010##
[0225] X.sup.- denotes an anion selected from among chloride,
bromide and methanesulphonate, preferably bromide;
[0226] R.sup.15 denotes hydroxy, methyl or fluorine, preferably
methyl or hydroxy;
[0227] R.sup.1' and R.sup.2' which may be identical or different
represent methyl or ethyl, preferably methyl;
[0228] R.sup.13, R.sup.14, R.sup.13' and R.sup.14' which may be
identical or different represent hydrogen, --CF.sub.3, --CHF.sub.2
or fluorine, preferably hydrogen or fluorine, optionally together
with a pharmaceutically acceptable excipient.
[0229] In another preferred embodiment of the invention the method
comprises administration of compounds of formula 1e, wherein
[0230] A denotes a double-bonded group selected from among
##STR00011##
[0231] X.sup.- denotes bromide;
[0232] R.sup.15 denotes hydroxy or methyl, preferably methyl;
[0233] R.sup.1' and R.sup.2' which may be identical or different
represent methyl or ethyl, preferably methyl;
[0234] R.sup.13, R.sup.14, R.sup.13' and R.sup.14' which may be
identical or different represent hydrogen or fluorine, optionally
together with a pharmaceutically acceptable excipient.
[0235] Of particular importance within the method according to the
invention are the following compounds of formula 1e: [0236]
tropenol 9-hydroxy-fluorene-9-carboxylate methobromide; [0237]
tropenol 9-fluoro-fluorene-9-carboxylate methobromide; [0238]
scopine 9-hydroxy-fluorene-9-carboxylate methobromide; [0239]
scopine 9-fluoro-fluorene-9-carboxylate methobromide; [0240]
tropenol 9-methyl-fluorene-9-carboxylate methobromide; [0241]
scopine 9-methyl-fluorene-9-carboxylate methobromide.
[0242] The pharmaceutical compositions according to the invention
may contain the compounds of formula 1e optionally in the form of
the individual optical isomers, mixtures of the individual
enantiomers or racemates thereof.
[0243] The compounds of formula 1f are known in the art (WO
03/064418)
[0244] In another preferred embodiment of the invention the method
comprises administration of compounds of formula if wherein
[0245] X.sup.- denotes chloride, bromide, or methanesulphonate,
preferably bromide; D and B which may be identical or different,
preferably identical, denote --O, --S, --NH or --CH.dbd.CH--;
[0246] R.sup.16 denotes hydrogen, hydroxy, --C.sub.1-C.sub.4-alkyl,
--C.sub.1-C.sub.4 alkyloxy, --CF.sub.3, --CHF.sub.2, fluorine,
chlorine or bromine;
[0247] R.sup.1'' and R.sup.2'' which may be identical or different,
denote C.sub.1-C.sub.4-alky, which may optionally be substituted by
hydroxy, fluorine, chlorine or bromine, or
[0248] R.sup.1'' and R.sup.2'' together denote a
--C.sub.3-C.sub.4-alkylene-bridge;
[0249] R.sup.17, R.sup.18, R.sup.17' and R.sup.18', which may be
identical or different, denote hydrogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkyloxy, hydroxy, --CF.sub.3, --CHF.sub.2, CN,
NO.sub.2, fluorine, chlorine or bromine;
[0250] R.sup.x and R.sup.x' which may be identical or different,
denote hydrogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyloxy,
hydroxy, --CF.sub.3, --CHF.sub.2, CN, NO.sub.2, fluorine, chlorine
or bromine or
[0251] R.sup.x and R.sup.x' together denote a single bond or a
bridging group selected from among the bridges --O, --S, --NH-- and
--CH.sub.2--, optionally together with a pharmaceutically
acceptable excipient.
[0252] In another preferred embodiment of the invention the method
comprises administration of compounds of formula 1f, wherein
[0253] X.sup.- denotes chloride, bromide, or methanesulphonate,
preferably bromide; D and B which may be identical or different,
preferably identical, denote --S or --CH.dbd.CH--;
[0254] R.sup.16 denotes hydrogen, hydroxy or methyl;
[0255] R.sup.1'' and R.sup.2'' which may be identical or different,
denote methyl or ethyl;
[0256] R.sup.17, R.sup.18, R.sup.17' and R.sup.18', which may be
identical or different, denote hydrogen, --CF.sub.3 or fluorine,
preferably hydrogen;
[0257] R.sup.x and R.sup.x' which may be identical or different,
denote hydrogen, --CF.sub.3 or fluorine, preferably hydrogen or
[0258] R.sup.x and R.sup.x' together denote a single bond or the
bridging group --O--, optionally together with a pharmaceutically
acceptable excipient.
[0259] In another preferred embodiment of the invention the method
comprises administration of compounds of formula 1f wherein
[0260] X.sup.- denotes bromide;
[0261] D and B denote --CH.dbd.CH--;
[0262] R.sup.16 denotes hydrogen, hydroxy or methyl;
[0263] R.sup.1'' and R.sup.2'' denote methyl;
[0264] R.sup.17, R.sup.18, R.sup.17' and R.sup.18', which may be
identical or different, denote hydrogen or fluorine, preferably
hydrogen;
[0265] R.sup.x and R.sup.x' which may be identical or different,
denote hydrogen or fluorine, preferably hydrogen or
[0266] R.sup.x and R.sup.x' together denote a single bond or the
bridging group --O--, optionally together with a pharmaceutically
acceptable excipient.
[0267] Of particular importance within the method according to the
invention are the following compounds of formula 1f: [0268]
cyclopropyltropine benzilate methobromide; [0269]
cyclopropyltropine 2,2-diphenylpropionate methobromide;
cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide;
cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide;
cyclopropyltropine 9-methyl-xanthene-9-carboxylate methobromide;
cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide;
cyclopropyltropine methyl 4,4'-difluorobenzilate methobromide.
[0270] The pharmaceutical compositions according to the invention
may contain the compounds of formula 1f optionally in the form of
the individual optical isomers, mixtures of the individual
enantiomers or racemates thereof.
[0271] The compounds of formula 1g are known in the art (WO
03/064417).
[0272] In another preferred embodiment of the invention the method
comprises administration of compounds of formula 1g wherein
[0273] A' denotes a double-bonded group selected from among
##STR00012##
[0274] X.sup.- denotes chloride, bromide or methanesulphonate,
preferably bromide;
[0275] R.sup.19 denotes hydroxy or methyl; [0276] R.sup.1''' and
R.sup.2''' which may be identical or different represent methyl or
ethyl, preferably methyl;
[0277] R.sup.20, R.sup.21, R.sup.20' and R.sup.21' which may be
identical or different represent hydrogen, --CF.sub.3, --CHF.sub.2
or fluorine, preferably hydrogen or fluorine, optionally together
with a pharmaceutically acceptable excipient.
[0278] In another preferred embodiment of the invention the method
comprises administration of compounds of formula 1g wherein
[0279] A' denotes a double-bonded group selected from among
##STR00013## [0280] X.sup.- denotes bromide;
[0281] R.sup.19 denotes hydroxy or methyl, preferably methyl;
[0282] R.sup.1''' and R.sup.2''' which may be identical or
different represent methyl or ethyl, preferably methyl;
[0283] R.sup.3, R.sup.4, R.sup.3' and R.sup.4' which may be
identical or different represent hydrogen or fluorine, optionally
together with a pharmaceutically acceptable excipient.
[0284] Of particular importance within the method according to the
invention are the following compounds of formula 1g: [0285]
tropenol 9-hydroxy-xanthene-9-carboxylate methobromide; [0286]
scopine 9-hydroxy-xanthene-9-carboxylate methobromide; [0287]
tropenol 9-methyl-xanthene-9-carboxylate methobromide; [0288]
scopine 9-methyl-xanthene-9-carboxylate methobromide; [0289]
tropenol 9-ethyl-xanthene-9-carboxylate methobromide; [0290]
tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide;
[0291] scopine 9-hydroxymethyl-xanthene-9-carboxylate
methobromide.
[0292] The pharmaceutical compositions according to the invention
may contain the compounds of formula 1g optionally in the form of
the individual optical isomers, mixtures of the individual
enantiomers or racemates thereof.
[0293] The alkyl groups used, unless otherwise stated, are branched
and unbranched alkyl groups having 1 to 5 carbon atoms. Examples
include: methyl, ethyl, propyl or butyl. The groups methyl, ethyl,
propyl or butyl may optionally also be referred to by the
abbreviations Me, Et, Prop or Bu. Unless otherwise stated, the
definitions propyl and butyl also include all possible isomeric
forms of the groups in question. Thus, for example, propyl includes
n-propyl and iso-propyl, butyl includes iso-butyl, sec. butyl and
tert.-butyl, etc.
[0294] The cycloalkyl groups used, unless otherwise stated, are
alicyclic groups with 3 to 6 carbon atoms. These are the
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
According to the invention cyclopropyl is of particular importance
within the scope of the present invention.
[0295] The alkylene groups used, unless otherwise stated, are
branched and unbranched double-bonded alkyl bridges with 1 to 5
carbon atoms. Examples include: methylene, ethylene, propylene or
butylene.
[0296] The alkylene-halogen groups used, unless otherwise stated,
are branched and unbranched double-bonded alkyl bridges with 1 to 4
carbon atoms which may be mono-, di- or trisubstituted, preferably
disubstituted, by a halogen. Accordingly, unless otherwise stated,
the term alkylene-OH groups denotes branched and unbranched
double-bonded alkyl bridges with 1 to 4 carbon atoms which may be
mono-, di- or trisubstituted, preferably monosubstituted, by a
hydroxy.
[0297] The alkyloxy groups used, unless otherwise stated, are
branched and unbranched alkyl groups with 1 to 5 carbon atoms which
are linked via an oxygen atom. The following may be mentioned, for
example: methyloxy, ethyloxy, propyloxy or butyloxy. The groups
methyloxy, ethyloxy, propyloxy or butyloxy may optionally also be
referred to by the abbreviations MeO, EtO, PropO or BuO. Unless
otherwise stated, the definitions propyloxy and butyloxy also
include all possible isomeric forms of the groups in question.
Thus, for example, propyloxy includes n-propyloxy and
iso-propyloxy, butyloxy includes iso-butyloxy, sec. butyloxy and
tert.-butyloxy, etc. The word alkoxy may also possibly be used
within the scope of the present invention instead of the word
alkyloxy. The groups methyloxy, ethyloxy, propyloxy or butyloxy may
optionally also be referred to as methoxy, ethoxy, propoxy or
butoxy.
[0298] The alkylene-alkyloxy groups used, unless otherwise stated,
are branched and unbranched double-bonded alkyl bridges with 1 to 5
carbon atoms which may be mono-, di- or trisubstituted, preferably
monosubstituted, by an alkyloxy group.
[0299] The --O--CO-alkyl groups used, unless otherwise stated, are
branched and unbranched alkyl groups with 1 to 4 carbon atoms which
are bonded via an ester group. The alkyl groups are bonded directly
to the carbonylcarbon of the ester group. The term
--O--CO-alkyl-halogen group should be understood analogously. The
group --O--CO--CF.sub.3 denotes trifluoroacetate.
[0300] Within the scope of the present invention halogen denotes
fluorine, chlorine, bromine or iodine. Unless otherwise stated,
fluorine and bromine are the preferred halogens. The group CO
denotes a carbonyl group.
[0301] One aspect of the invention is directed to an inhalation
device, in which the plural of doses are contained in one
reservoir. In another aspect of the invention, the inhalation
device comprises the plural of doses in a multi-dose blister pack.
In another aspect of the invention the inhalation device comprises
the multi-dose blister pack in form of blister strip.
[0302] The inhalation device according to the invention comprises
the compounds of formula 1 preferably in admixture with a
pharmaceutically acceptable excipient to form a powder mixture. The
following pharmaceutically acceptable excipients may be used to
prepare these inhalable powder mixtures according to the invention:
monosaccharides (e.g. glucose or arabinose), disaccharides (e.g.
lactose, saccharose, maltose, trehalose), oligo- and
polysaccharides (e.g. dextrane), polyalcohols (e.g. sorbitol,
mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate)
or mixtures of these excipients with one another. Preferably, mono-
or disaccharides are used, while the use of lactose or glucose is
preferred, particularly, but not exclusively, in the form of their
hydrates. For the purposes of the invention, lactose and trehalose
are the particularly preferred excipients, while lactose,
preferably in form of its monohydrate is most particularly
preferred.
[0303] The compounds of formula 1 may be used in the form of their
racemates, enantiomers or mixtures thereof. The separation of
enantiomers from the racemates may be carried out using methods
known in the art (e.g. by chromatography on chiral phases,
etc.).
[0304] Optionally, the inhalation device according to the invention
contains plural of doses of a medicament in powder form that
contains, beside one compound of formula 1, another active
ingredient.
[0305] Preferably the additional active ingredient is a beta.sub.2
agonists 2 which is selected from the group consisting of
albuterol, bambuterol, bitolterol, broxaterol, carbuterol,
clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol,
isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine,
metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol,
rimiterol, ritodrine, salmeterol, salmefamol, soterenot,
sulphonterol, tiaramide, terbutaline, tolubuterol, CHF-1035,
HOKU-81, KUL-1248,
3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyl-
oxy}-butyl)-benzenesulfoneamide,
5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-
-2-one,
4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-ami-
no}ethyl]-2(3H)-benzothiazolone,
1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamin-
o]ethanol,
1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimida-
zolyl)-2-methyl-2-butylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminoph-
enyl)-2-methyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-me-
thyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-OXO-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-
-methyl-2-propylamino]ethanol,
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,
5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-on-
e, 1-(4-amino-3-chloro-5-trifluormethylphenyl)-2-tert.-butylamino)
ethanol and
1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)-
ethanol, optionally in the form of the racemates, the enantiomers,
the diastereomers and optionally the pharmacologically acceptable
acid addition salts and the hydrates thereof.
[0306] According to the instant invention more preferred beta.sub.2
agonists 2 are selected from the group consisting of bambuterol,
bitolterol, carbuterol, clenbuterol, fenoterol, formoterol,
hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol,
salmeterol, sulphonterol, terbutaline, tolubuterol,
3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyl-
oxy}-butyl)-benzenesulfoneamide,
5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-
-2-one,
4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-ami-
no}ethyl]-2(3H)-benzothiazolone,
1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamin-
o]ethanol,
1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimida-
zolyl)-2-methyl-2-butylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminoph-
enyl)-2-methyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-me-
thyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-OXO-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-
-methyl-2-propylamino]ethanol,
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,
5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-on-
e, 1-(4-amino-3-chloro-5-trifluormethylphenyl)-2-tert.-butylamino)
ethanol and
1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)
ethanol, optionally in the form of the racemates, the enantiomers,
the diastereomers and optionally the pharmacologically acceptable
acid addition salts and the hydrates thereof.
[0307] More preferably, the betamimetics 2 used as within the
compositions according to the invention are selected from among
fenoterol, formoterol, salmeterol,
3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyl-
oxy}-butyl)-benzenesulfoneamide,
5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-
-2-one,
1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazol-
yl)-2-methyl-2-butylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminoph-
enyl)-2-methyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-me-
thyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-
-methyl-2-propylamino]ethanol,
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, optionally in the
form of the racemates, the enantiomers, the diastereomers and
optionally the pharmacologically acceptable acid addition salts
thereof, and the hydrates thereof. Of the betamimetics mentioned
above the compounds formoterol, salmeterol,
3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyl-
oxy}-butyl)-benzenesulfoneamide, and
5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-
-2-one are particularly preferred, optionally in the form of the
racemates, the enantiomers, the diastereomers and optionally the
pharmacologically acceptable acid addition salts thereof, and the
hydrates thereof. Of the betamimetics mentioned above the compounds
formoterol and salmeterol are particularly preferred, optionally in
the form of the racemates, the enantiomers, the diastereomers and
optionally the pharmacologically acceptable acid addition salts
thereof, and the hydrates thereof.
[0308] Examples of pharmacologically acceptable acid addition salts
of the betamimetics 2 according to the invention are the
pharmaceutically acceptable salts which are selected from among the
salts of hydrochloric acid, hydrobromic acid, sulphuric acid,
phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid,
succinic acid, lactic acid, citric acid, tartaric acid,
1-hydroxy-2-naphthalenecarboxylic acid, 4-phenylcinnamic acid,
5-(2,4-difluorophenyl)salicylic acid or maleic acid. If desired,
mixtures of the abovementioned acids may also be used to prepare
the salts 2.
[0309] According to the invention, the salts of the betamimetics 2
selected from among the hydrochloride, hydrobromide, sulphate,
phosphate, fumarate, methanesulphonate, 4-phenylcinnamate,
5-(2,4-difluorophenyl)salicylate, maleate and xinafoate are
preferred. Particularly preferred are the salts of 2 in the case of
salmeterol selected from among the hydrochloride, sulphate,
4-phenylcinnamate, 5-(2,4-difluorophenyl)salicylate and xinafoate,
of which the 4-phenylcinnamate, 5-(2,4-difluorophenyl)salicylate
and especially xinafoate are particularly important. Particularly
preferred are the salts of 2 in the case of formoterol selected
from the hydrochloride, sulphate and fumarate, of which the
hydrochloride and fumarate are particularly preferred. Of
exceptional importance according to the invention is formoterol
fumarate.
[0310] Salts of salmeterol, formoterol,
3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyl-
oxy}-butyl)-benzenesulfoneamide, and
5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-
-2-one, are preferably used as the betamimetics 2 according to the
invention. Of particular importance according to the invention are
salmeterol and formoterol salts. Any reference to the term
betamimetics 2 also includes a reference to the relevant
enantiomers or mixtures thereof. In the pharmaceutical compositions
according to the invention, the compounds 2 may be present in the
form of their racemates, enantiomers or mixtures thereof. The
separation of the enantiomers from the racemates may be carried out
using methods known in the art (e.g. by chromatography on chiral
phases, etc.) If the compounds 2 are used in the form of their
enantiomers, it is particularly preferable to use the enantiomers
in the R configuration at the C--OH group.
[0311] Optionally, the inhalation device according to the invention
contains plural of doses of a medicament in powder form, that
contains beside one compound of formula 1 a steroid 3 as another
active ingredient.
[0312] In such medicament combinations the steroid 3 is preferably
selected from among prednisolone, prednisone, butixocortpropionate,
RPR-166541, flunisolide, beclomethasone, triamcinolone, budesonide,
fluticasone, mometasone, ciclesonide, rofleponide, ST-126,
dexamethasone, (S)-fluoromethyl
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11[beta]-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioate,
(S)-(2-oxo-tetrahydro-furan-3S-yl)6.alpha.,9.alpha.-difluoro-l 1
.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alpha.-propionyloxy-androsta-1,4-
-diene-17.beta.-carbothionate, and etiprednol-dichloroacetate
(BNP-166), 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.
[0313] In particularly preferred medicament combinations the
steroid 3 is selected from the group comprising flunisolide,
beclomethasone, triamcinolone, budesonide, fluticasone, mometasone,
ciclesonide, rofleponide, ST-126, dexamethasone, (S)-fluoromethyl
6.alpha.,9.alpha.-difluoro-1 Ia-[(2-furanylcarbonyl)oxy]-11
.beta.-hydroxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carboth-
ionate, (S)--
(2-oxo-tetrahydro-furan-3S-yl)6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-
-16.alpha.-methyl-3-oxo-17.alpha.-propionyloxy-androsta-1,4-diene-17.beta.-
-carbothionate, and etiprednol-dichloroacetate, 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.
[0314] In particularly preferred medicament combinations the
steroid 3 is selected from the group comprising budesonide,
fluticasone, mometasone, ciclesonide, (S)-fluoromethyl
6.alpha.,9.alpha.-difluoro-1 Ia-[(2-furanylcarbonyl)oxy]-11
.beta.-hydroxy-16.alpha.-methyl-3-oxo-androsta-1,
A-diene-17.beta.-carbothionate, and etiprednol-dichloroacetate,
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.
[0315] Any reference to steroids 3 includes a reference to any
salts or derivatives, hydrates or solvates thereof which may exist.
Examples of possible salts and derivatives of the steroids 3 may
be: alkali metal salts, such as for example sodium or potassium
salts, sulphobenzoates, phosphates, isonicotinates, acetates,
propionates, dihydrogen phosphates, palmitates, pivalates or
furcates.
[0316] Optionally, the inhalation device according to the invention
contains plural of doses of a medicament on powder form, that
contains beside one compound of formula 1 additionally both, one of
the betamimetics 2 mentioned hereinbefore and one of the steroids 3
mentioned hereinbefore.
[0317] Accordingly, in a preferred embodiment the invention relates
to an inhalation device comprising a housing and a blister strip,
the strip being movable to sequentially align each blister with
means for opening a blister to enable a user to inhale said dose
and, a spiral wound element to receive and coil the strip, wherein
each blister contains a pharmaceutical composition in powder form
wherein the pharmaceutical composition comprises one or more,
preferably one, compound of formula 1.
[0318] In another embodiment, the invention relates to an
inhalation device comprising a housing and a blister strip, the
strip being movable to sequentially align each blister with means
for opening a blister to enable a user to inhale said dose, the
housing comprising a common chamber to receive the blister strip
and a coil of breached blisters of that strip, the chamber being
configured so that the coil of breached blisters occupies more of
the space in the chamber initially occupied by the blister strip as
more of the blisters of the strip are breached, wherein each
blister contains a pharmaceutical composition in powder form
wherein the pharmaceutical composition comprises one or more,
preferably one, compound of formula 1.
[0319] Within the scope of the inhalable powders according to the
invention the excipients have a maximum average particle size of up
to 250 .mu.m, preferably between 10 and 150 .mu.m, most preferably
between 15 and 80 .mu.m. It may sometimes seem appropriate to add
finer excipient fractions with an average particle size of 1 to 9
.mu.m to the excipients mentioned above. These finer excipients are
also selected from the group of possible excipients listed
hereinbefore. Finally, in order to prepare the inhalable powders
according to the invention, micronised active substance I--, and
optionally 2 and/or 3, preferably with an average particle size of
0.5 to 10 .mu.m, more preferably from 1 to 6 .mu.m, is added to the
excipient mixture. Processes for producing the inhalable powders
according to the invention by grinding and micronising and finally
mixing the ingredients together are known from the prior art.
[0320] For the methods of preparing the pharmaceutical compositions
in powder form reference may be made to the disclosure of WO
02/30390, WO 03/017970, or WO 03/017979 for example. The disclosure
of WO 02/30390, WO 03/017970, and WO 03/017979 is hereby
incorporated by reference into the instant patent application in
its entirety.
[0321] As an example, the pharmaceutical compositions according to
the invention may be obtained by the method described below.
[0322] First, the excipient and the active substance are placed in
a suitable mixing container. The active substance used has an
average particle size of 0.5 to 10 .mu.m, preferably 1 to 6 .mu.m,
most preferably 2 to 5 .mu.m. The excipient and the active
substance are preferably added using a sieve or a granulating sieve
with a mesh size of 0.1 to 2 mm, preferably 0.3 to 1 mm, most
preferably 0.3 to 0.6 mm. Preferably, the excipient is put in first
and then the active substance is added to the mixing container.
During this mixing process the two components are preferably added
in batches. It is particularly preferred to sieve in the two
components in alternate layers. The mixing of the excipient with
the active substance may take place while the two components are
still being added. Preferably, however, mixing is only done once
the two components have been sieved in layer by layer.
[0323] If after being chemically prepared the active substance used
in the process described above is not already obtainable in a
crystalline form with the particle sizes mentioned earlier, it can
be ground up into the particle sizes which conform to the
above-mentioned parameters (so-called micronising).
[0324] Many modifications and variations of the invention falling
within the terms of the following claims will be apparent to those
skilled in the art and the foregoing description should be regarded
as a description of the preferred embodiments of the invention
only. Furthermore, reference to an aperture formed in the wall to
allow passage of a blister strip from the unused side of the device
to the used side in the description above, may comprise an aperture
formed between the end of the wall and the housing of the inhaler,
as well as an aperture within the wall spaced from a remote end
thereof, and such variations are intended to fall within the scope
of the invention and claims hereafter.
* * * * *