U.S. patent application number 16/270204 was filed with the patent office on 2019-06-06 for inhalers and related methods.
This patent application is currently assigned to Norton (Waterford) Limited. The applicant listed for this patent is Norton (Waterford) Limited. Invention is credited to Daniel Buck, Paul Prendergast, Declan Walsh.
Application Number | 20190167926 16/270204 |
Document ID | / |
Family ID | 58461953 |
Filed Date | 2019-06-06 |
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United States Patent
Application |
20190167926 |
Kind Code |
A1 |
Buck; Daniel ; et
al. |
June 6, 2019 |
Inhalers and Related Methods
Abstract
A nasal inhaler for the inhalation of inhalable substances
comprise: a canister having an interior reservoir containing
pressurised inhalable substances including fluid; a metering valve
including a metering chamber and a valve stem defining a
communication path between the metering chamber and the interior
reservoir, the communication path including an opening configured
to permit flow between a transfer space inside the valve stem and
the interior reservoir, the interior reservoir being arranged for
orientation above the metering chamber whereby gas located within
the metering chamber is replaced with liquid from the interior
reservoir.
Inventors: |
Buck; Daniel; (Co.
Waterford, IE) ; Prendergast; Paul; (Co. Carlow,
IE) ; Walsh; Declan; (Co. Kilkenny, IE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Norton (Waterford) Limited |
Waterford |
|
IE |
|
|
Assignee: |
Norton (Waterford) Limited
Waterford
IE
|
Family ID: |
58461953 |
Appl. No.: |
16/270204 |
Filed: |
February 7, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16129162 |
Sep 12, 2018 |
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16270204 |
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15881372 |
Jan 26, 2018 |
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16129162 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/06 20130101;
A61M 15/0026 20140204; A61M 15/009 20130101; A61M 15/0066 20140204;
A61M 15/0071 20140204; A61M 15/0091 20130101; A61M 15/08 20130101;
A61K 31/569 20130101; A61M 15/0078 20140204; A61M 15/0095 20140204;
B65D 83/386 20130101; A61M 2205/18 20130101; A61P 11/00 20180101;
B65D 83/54 20130101; A61M 15/0025 20140204; A61P 11/06 20180101;
A61M 2205/276 20130101; A61K 31/439 20130101; A61K 9/007
20130101 |
International
Class: |
A61M 15/00 20060101
A61M015/00; A61K 9/00 20060101 A61K009/00; A61P 11/06 20060101
A61P011/06; A61P 11/00 20060101 A61P011/00; A61M 15/08 20060101
A61M015/08; A61K 47/06 20060101 A61K047/06; A61K 31/569 20060101
A61K031/569; A61K 31/439 20060101 A61K031/439 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 14, 2017 |
GB |
17 02406.8 |
Claims
1. A nasal inhaler for the inhalation of inhalable substances, the
inhaler comprising: a canister having an interior reservoir
containing pressurized inhalable substances including fluid; a
metering valve including a metering chamber and a valve stem
defining a communication path between the metering chamber and the
interior reservoir, the communication path including an opening
configured to permit flow between a transfer space inside the valve
stem and the interior reservoir, the interior reservoir being
arranged for an orientation above the metering chamber whereby gas
located within the metering chamber is replaceable with liquid from
the interior reservoir.
2. The nasal inhaler of claim 1, in which the opening is configured
to permit flow in a direction with an axial component along the
valve stem directly between the transfer space inside the valve
stem and the interior reservoir.
3. The nasal inhaler of claim 1 in which the communication path is
configured to permit liquid to flow under pressure along the
communication path to the metering chamber and gas to flow in a
reverse direction therealong from the metering chamber into the
interior reservoir.
4. The nasal inhaler of claim 1 in which the opening comprises an
elongated opening.
5. The nasal inhaler of claim 1 further comprising at least one
additional opening into the communication path.
6. The nasal inhaler of claim 5 in which the at least one
additional opening is diametrically opposed to the first said
opening.
7. The nasal inhaler of claim 1 in which the valve stem has at
least one opening into the interior reservoir with an axially
oriented portion facing directly axially along a longitudinal axis
of the valve stem into the interior reservoir for the flow of fluid
directly into the communication path in an axial direction along
the valve stem.
8. The nasal inhaler of claim 1 further comprising a metering
chamber exit port for venting the metering chamber to atmosphere
via a stem block and/or nozzle.
9. The nasal inhaler of claim 8, further comprising a canister fire
system for ejecting inhalable substances from the inhaler in
response to air flow by closing communication between the metering
chamber and the interior reservoir and opening communication
between the metering chamber and atmosphere.
10. The nasal inhaler of claim 9 further comprising a drive for
driving the canister relative to the valve stem, the drive
including a drive spring.
11. The nasal inhaler of claim 10 further comprising an actuator
system for operating the drive, wherein the actuator system is
actuatable by air flow.
12. The nasal inhaler of claim 9 in which the canister fire system
is adapted to depress the valve stem into the canister to cause
inhalable substances to be ejected from the inhaler and to hold the
valve stem depressed with the metering chamber communicating with
atmosphere.
13. The nasal inhaler of claim 12 in which the canister fire system
includes a reset actuator which is operable so as to extend the
valve stem relative to the canister in order to close communication
between atmosphere and the metering chamber and to open
communication between the metering chamber and the interior
reservoir.
14. The nasal inhaler of claim 1 which includes inhalable
substances in the interior reservoir which include at least one
propellant.
15. The nasal inhaler of claim 14 in which the at least one said
propellant comprises a hydrofluoroalkane comprising
1,1,1,2-tetrafluoroethane.
16. The nasal inhaler of claim 14 in which the at least one said
propellant has a surface tension at 25.degree. C. of about 6 to 10
mN/m, about 7 to 9 mN/m, or about 8 mN/m.
17. The nasal inhaler of claim 1 which includes at least one
inhalable substance in the interior reservoir as an active
ingredient, wherein the active ingredient comprises beclomethasone
dipropionate or tiotropium bromide in suspension or in
solution.
18. The nasal inhaler of claim 1 which includes a dose counter for
counting doses, wherein the dose counter is configured to make one
count with each inhalation of a dose.
19. The nasal inhaler of claim 1 in which the dose counter
includes: (a) a tape bearing dose indicia for displaying counts
and/or (b) an actuator pin for contact with the canister, or a body
movable therewith, for counting doses, and preferably a dose
counter chamber separated by a barrier from an inner space of the
inhaler for containing the canister, the actuator pin extending out
of the dose counter chamber through an aperture in the wall for
contact during counting with the canister or the body movable
therewith.
20. The nasal inhaler of claim 1 which is a breath actuated
inhaler.
21. The nasal inhaler of claim 1 which is a metered dose
inhaler.
22. The nasal inhaler of claim 1 which includes a reset actuator
which when actuated prevents exposure of the metering chamber to
atmosphere, wherein the inhaler provides 75 to 125% of a dose
following exposure of the metering chamber to atmosphere for a time
period which is more than one minute.
23. The nasal inhaler of claim 1 in which the inhaler provides 75
to 125% of a dose following exposure of the metering chamber to
atmosphere for a time period which is more than two minutes.
24. The nasal of claim 1 in which the inhaler provides 75 to 125%
of a dose following exposure of the metering chamber to atmosphere
for a time period which is one hour, more than one hour, 24 hours
or more than 24 hours.
25. The nasal of claim 1 which includes a metering valve spring and
an opposing canister spring for drivingly firing the canister, the
metering valve spring, canister spring and metering valve being
arranged in the inhaler such that an equilibrium of various forces
is achieved in at least one ready-to-fire configuration of the
inhaler.
26. The nasal inhaler of claim 25 which is adapted to operate
including at least one suction force; the suction force configured
to operate against the canister spring.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority of
Application No. GB1702406.8, filed Feb. 14, 2017, which application
is incorporated by reference herein, in its entirety and for all
purposes.
FIELD OF THE INVENTION
[0002] The present invention relates to inhalers, including breath
actuated and metered dose inhalers. The invention relates to oral
and nasal inhalers. The invention also relates to methods of
metering inhalable substances in metering valves of canisters for
medicament inhalers, inhaler housings and inhaler valve stem and
valve stem block interfaces.
BACKGROUND OF THE INVENTION
[0003] A known inhaler, which is a breath actuated inhaler, has a
pressurised canister and a metering valve for controlling the
ejection of inhalable substances from the canister. The canister is
operable by a force holding unit having a cap housing attachable to
a main housing of the inhaler. The metering valve includes a valve
stem for transferring substances from an interior reservoir of the
canister into the metering chamber and then out of the metering
chamber along the valve stem in the direction of a nozzle of the
inhaler. A radially directed capillary port is provided in the
valve stem for communicating substances out of the interior
reservoir for communication along the valve stem to the metering
chamber and a similar port is provided for communicating substances
out of the metering chamber and along the valve stem towards the
nozzle. In use, a mouthpiece cap is opened to ready the inhaler for
inhalation and then after inhalation the mouthpiece cap is closed
and resets a canister fire system. It has been found that the
inhaler can be left after inhalation with the mouthpiece dust cap
in the opened position with the metering chamber communicating with
atmosphere via the valve stem and nozzle. This can result in the
variance of active ingredients in at least one subsequent dose.
This means that users will sometimes remove a force holding unit
cap housing from the main body of the inhaler and try to ensure
that the metering chamber is sufficiently primed by firing a number
of doses and this is both wasteful and may result in damage to the
inhaler.
[0004] In some inhalers, when it is necessary to make changes to
internal components, it is difficult to provide space and good
guidance for all the necessary interior moving parts. Also, the
assembly of some inhaler dose counters can be difficult.
[0005] Furthermore, in some inhalers, despite a tight connection
between the valve stem and a valve stem block within the main body,
blowback can occur which is leakage of substances between the valve
stem block and valve stem. It can also be difficult in some
inhalers to achieve reliable dose counting to reflect the number of
doses actually provided by the inhaler.
[0006] The present invention aims to alleviate at least to a
certain extent at least one of the problems of the prior art.
[0007] Alternatively, the present invention aims to provide a
useful inhaler, method of metering substances in a metering valve
of a canister for a medicament inhaler and/or useful inhaler
parts.
SUMMARY OF THE INVENTION
[0008] According to one aspect, the present disclosure discloses a
method of metering inhalable substances in a metering valve of a
canister for a medicament inhaler, the method comprising: providing
the metering valve with a metering chamber and valve stem extending
from a metering chamber to an interior reservoir of the canister,
with the valve stem defining a communication path between the
metering chamber and the interior reservoir, the communication path
including an opening configured to permit flow between a transfer
space inside the valve stem and the interior reservoir; and
orienting the interior reservoir above the metering chamber and
replacing gas such as air located within the metering chamber with
liquid from the interior reservoir.
[0009] The present inventors have worked out that the reasons why
inaccurate dosing can occur include that when the metering chamber
is left vented to atmosphere in some prior inhalers for as little
as 2 minutes, a gas or air lock can form in the metering chamber
and when the metering chamber is next connected for communication
with the interior reservoir, due to the radial capillary port, the
gas or air is trapped within the metering chamber and liquid does
not enter the metering chamber reliably as the next dose. The air
may enter the metering chamber from the atmosphere in the prior
art. This may happen as propellant in the metering chamber
evaporates and diffuses into the atmosphere. Using the presently
disclosed method which involves the use of the opening configured
to permit flow in a direction with an axial component along the
valve stem directly between a transfer space inside the valve stem
and the interior reservoir, when the interior reservoir is oriented
above the metering chamber, this enables liquid from the interior
reservoir to replace gas such as air located within the metering
chamber and an accurate dose can be administered at the next
dose.
[0010] The opening may be configured to permit flow in a direction
with an axial component along the valve stem directly between the
transfer space inside the valve stem and the interior
reservoir.
[0011] The replacing gas located in the metering chamber with
liquid from the interior reservoir may include flowing liquid under
pressure through the opening, along the valve stem to a portion of
the communication path communicating with the metering chamber.
[0012] The method may include flowing gas from the metering
chamber, in a direction counter to a direction of liquid flow from
the interior reservoir, along the communication path into the
interior chamber.
[0013] The method may include providing the opening as an elongated
opening.
[0014] The method may include providing a second opening to the
communication path diametrically opposed to the first said
opening.
[0015] The method may include providing the valve stem with at
least one said opening into the interior reservoir as having an
axially oriented opening portion which is oriented facing directly
axially along a longitudinal axis of the valve stem into the
interior reservoir, and which includes flowing liquid into the
metering chamber via said axially oriented opening portion.
[0016] The method may include venting the metering chamber to
atmosphere via a valve stem block and/or nozzle.
[0017] The method may include operating the metering valve and
canister within a medicament inhaler and holding the valve stem
depressed relative to the canister with the metering chamber vented
to atmosphere so as at least partially to permit substances within
the metering chamber to vaporise and to permit atmospheric air to
enter the metering chamber.
[0018] Advantageously, the inhaler can be left for a long period
such as 24 hours with the metering chamber communicating with
atmosphere and then when the metering chamber is reconnected to the
interior reservoir and the interior reservoir is oriented above the
metering chamber the metering chamber can fully fill with liquid
for the next dose. Advantageously, in a breath actuated inhaler,
the features of the method mean therefore that any force holding
unit and/or cap housing for the inhaler can be permanently secured
or locked on to the inhaler so that users cannot tamper with the
interior and there is no need to perform manual priming of the
metering valve, which is a necessity in prior art inhalers, before
the next dose is taken.
[0019] The method may include providing the medicament inhaler as a
breath actuated inhaler, and may include, in response to air flow,
firing the canister by closing communication between the metering
chamber and interior reservoir and opening communication between
the metering chamber and atmosphere, the valve stem being held
depressed after firing.
[0020] The method may include resetting the inhaler to a reset
configuration with a reset actuator so as to close communication
between the metering chamber and atmosphere and open communication
between the metering chamber and the interior reservoir, and
carrying out the orienting of the interior reservoir above the
metering chamber while the inhaler is in the reset
configuration.
[0021] The method may include providing the reset actuator as a
lever, press button, hinged or rotatable piece, dust cap, nasal
outlet cap or mouthpiece cap for the inhaler. Closing the actuator
may reset the inhaler. In the case of an oral inhaler the reset
actuator may be a dust cap mouthpiece cap. In the case of a nasal
inhaler, the reset actuator may take a variety of forms, including
but not limited to a dust cap or a movable lever, cap or button. In
this case, the carrying out of the orienting of the interior
reservoir above the metering chamber being carried out once the
reset actuator has been opened to a configuration suitable for
inhalation or otherwise operated. Therefore, it can be ensured that
right before inhalation, the metering chamber is full of liquid and
any gas which may have been in the metering chamber has been drawn
into the interior reservoir due to the free flowing communication
pathway between metering chamber and interior reservoir.
[0022] In an alternative embodiment, the inhaler may include a dust
cap or mouthpiece cap which closes communication between the
metering chamber and atmosphere but does not reset the inhaler. In
these cases, optionally, a separate reset actuator may be
provided.
[0023] The method may include providing the medicament inhaler as a
metered dose inhaler and may include applying a force to the
canister to hold the valve stem depressed; and may include
subsequently releasing the canister to extend the valve stem and
carrying out the orienting of the interior reservoir above the
metering chamber.
[0024] The method may include providing the inhalable substances as
including at least one propellant.
[0025] The method may include providing at least one said
propellant as a hydrofluoroalkane, such as
1,1,1,2-tetrafluoroethane.
[0026] The method may include providing at least one said
propellant with a surface tension at 25.degree. C. of about 6 to 10
mN/m, typically about 7 to 9 mN/m, about 8 mN/m being one
example.
[0027] Advantageously, it has been found that fluid with this
surface tension is capable of avoiding gas or air lock in the
metering chamber by flowing into the metering chamber when the
features of the presently disclosed method are used.
[0028] The method may include providing the inhalable substances as
including an active ingredient in suspension or in solution, such
as beclomethasone dipropionate (BDP) or tiotropium bromide.
[0029] According to a further aspect, the present disclosure
discloses a breath actuated inhaler for the inhalation of inhalable
substances, the inhaler comprising: a canister having an interior
reservoir containing pressurised inhalable substances including
fluid; a metering valve including a metering chamber and a valve
stem defining a communication path between the metering chamber and
the interior reservoir, the communication path including an opening
configured to permit flow between a transfer space inside the valve
stem and the interior reservoir, the interior reservoir being
arranged for orientation above the metering chamber whereby gas
such as air located within the metering chamber is replaced with
liquid from the interior reservoir.
[0030] Advantageously, with this configuration of metering valve
there is no need to manually prime the metering chamber by
repeatedly firing the canister manually and an accurate next dose
can be provided to the metering chamber since a gas or air lock can
be avoided. This also means, advantageously, that in a breath
actuated inhaler having a force holding unit or cap housing secured
to a main body of the inhaler, these components may be locked
together so that it is relatively difficult for a user to remove
the force holding unit or cap housing and tamper with the interior
components. Instead, there is no need to perform manual priming and
the inhaler main housing and the cap housing can be permanently
locked together enclosing the internal moving parts of the inhaler
where they cannot easily be damaged.
[0031] The opening may be configured to permit flow in a direction
with an axial component along the valve stem directly between a
transfer space inside the valve stem and the interior
reservoir.
[0032] The communication path may be configured to permit liquid to
flow under pressure along the communication path to the metering
chamber and gas to flow in a reverse direction therealong from the
metering chamber into the interior reservoir.
[0033] The opening may comprise an elongated opening.
[0034] The inhaler may include a second opening or further openings
into the communication path.
[0035] The second opening may be diametrically opposed to the first
said opening.
[0036] The valve stem may have at least one opening into the
interior reservoir with an axially oriented portion facing directly
axially along a longitudinal axis of the valve stem into the
interior reservoir for the flow of fluid directly into the
communication path in an axial direction along the valve stem.
[0037] The inhaler may include a metering chamber exit port for
venting the metering chamber to atmosphere via a stem block and/or
nozzle.
[0038] The inhaler may include a canister fire system for ejecting
inhalable substances from the inhaler in response to air flow by
closing communication between the metering chamber and the interior
reservoir and opening communication between the metering chamber
and atmosphere. The canister fire system preferably includes a
drive such as a spring for driving the canister relative to the
valve stem. The inhaler may have an actuator system for operating
the drive, the actuator system optionally including a vacuum
chamber having a vacuum release system operable to permit the drive
to drive movement of the canister relative to the valve stem. The
vacuum release system may be air flow actuatable.
[0039] The actuator and/or drive may include or operate as a latch,
trigger or switch and may take other forms in other embodiments
such as being electromechanical.
[0040] The canister fire system may be adapted to depress the valve
stem into the canister to cause inhalable substances to be ejected
from the inhaler and to hold the valve stem depressed with the
metering chamber communicating with atmosphere.
[0041] The canister fire system may include a reset actuator which
is operable so as to extend the valve stem relative to the canister
in order to close communication between atmosphere and the metering
chamber and to open communication between the metering chamber and
the interior reservoir.
[0042] In the case of a nasal inhaler, the reset actuator may, for
example, comprise a dust cap or a lever, cap or button. In the case
of an oral inhaler, the reset actuator may comprise a dust cap or
mouthpiece cap for a mouthpiece of the inhaler. The mouthpiece cap
may be closable to permit extension of the valve stem relative to
the canister, the mouthpiece cap optionally being hingedly
connected to a main housing of the inhaler for camming engagement
with at least one drive rod. The drive rod may be associated with a
yoke for pushing on a drive element to compress a spring of the
drive.
[0043] In an alternative embodiment, the inhaler may include a dust
cap or mouthpiece cap which closes communication between the
metering chamber and atmosphere but does not reset the inhaler. In
these cases, optionally, a separate reset actuator may be
provided.
[0044] The inhaler may include a preventer adapted, after an
inhalation has taken place, to prevent a further inhalation until
the reset actuator has been operated to extend the valve stem. In
the case of a mouthpiece or other cap, this may comprise closing
the cap.
[0045] Advantageously, the preventer may therefore ensure that the
user closes the cap at some time before each inhalation and this in
turn means that reliable dosing can be achieved.
[0046] The preventer may comprise a warning signaller, such as an
audible or visual alarm, dose counter or warning notice, quick
reference guide or instructions.
[0047] The inhaler may include inhalable substances in the interior
reservoir which include at least one propellant.
[0048] At least one said propellant may comprise a
hydrofluoroalkane, such as 1,1,1,2-tetrafluoroethane.
[0049] At least one said propellant may have a surface tension at
25.degree. C. of about 6 to 10 mN/m, typically about 7 to 9 mN/m,
about 8 mN/m being on example.
[0050] The inhaler may include at least one inhalable substance in
the interior reservoir as an active ingredient, for example in
suspension or in solution, such as beclomethasone dipropionate or
tiotropium bromide.
[0051] The inhaler may include a dose counter for counting doses,
preferably for making one count with each inhalation of a dose.
[0052] The dose counter may include: (a) a tape bearing dose
indicia for displaying counts and/or (b) an actuator pin for
contact with the canister, or a body movable therewith, for
counting doses, and preferably a dose counter chamber separated by
a barrier from an inner space of the inhaler for containing the
canister, the actuator pin optionally extending out of the dose
counter chamber through an aperture in the wall for contact during
counting with the canister (or the body movable therewith).
[0053] The inhaler may be a breath actuated inhaler.
[0054] The inhaler may be a metered dose inhaler.
[0055] The inhaler may be an oral inhaler.
[0056] The inhaler may be a nasal inhaler.
[0057] The inhaler may include a reset actuator which when actuated
prevents exposure of the metering chamber to atmosphere, wherein
the inhaler provides 75 to 125% of labelled claim for a dose
following exposure of the metering chamber to atmosphere for a time
period which is more than one minute.
[0058] In this case, the reset actuator may be a mouthpiece cap
that, when closed, prevents exposure of the metering chamber to
atmosphere.
[0059] The inhaler may provide 75 to 125% of labelled claim for a
dose following exposure of the metering chamber to atmosphere for a
time period which is more than two minutes.
[0060] The inhaler may provide 75 to 125% of labelled claim for a
dose following exposure of the metering chamber to atmosphere for a
time period which is one hour, more than one hour, 24 hours or more
than 24 hours.
[0061] Operation of the inhaler may include, subsequent to closing
the mouthpiece, opening the mouthpiece.
[0062] The inhaler may include a metering valve spring and an
opposing canister spring for drivingly firing the canister, the
metering valve spring, canister spring and metering valve being
arranged in the inhaler such that an equilibrium of various forces
is achieved in at least one ready-to-fire configuration of the
inhaler.
[0063] In that case, the operation of the inhaler may include at
least one suction force, e.g. provided by a pneumatic chamber; the
suction force preferably operating against the canister spring.
[0064] In another aspect, the present application discloses use of
a metering valve for preventing gas lock within a metering chamber
of an inhaler having a pressurised canister, the metering valve
having a metering chamber and a valve stem extending from the
metering chamber to an interior reservoir of the canister, with the
valve stem defining a communication path between the metering
chamber and the interior reservoir, the communication path
including an opening configured to permit flow between a transfer
space inside the valve stem and the interior reservoir, in use the
interior reservoir being oriented above the metering chamber so as
to cause movement through the opening and gas such as air located
within the metering chamber to be replaced with liquid from the
interior reservoir.
[0065] The use may be performed in a breath actuated inhaler. The
inhaler may be oral. Nasal inhalers of this type are also
envisaged.
[0066] The use may be performed in a metered dose inhaler. The
metered dose inhaler may be oral or nasal.
[0067] According to a further aspect, the present disclosure
discloses an inhaler housing for an inhaler for inhalable
substances, the inhaler housing being arranged to contain a
pressurised canister for sliding motion within a tubular body
portion thereof, the inhaler housing having a valve stem block for
connection to a valve stem of a pressurised canister, the valve
stem block having a top surface, the tubular body portion having at
least two mutually opposed guide ribs for guiding canister position
within the tubular body portion, the guide ribs having
substantially straight guide edges extending substantially parallel
to and spaced from one another, each straight guide edge having an
upper corner where the straight guide edge meets a further surface
of the rib leading outwardly towards an upper rib section near an
inner wall of the tubular body portion, at least one of the ribs
having its straight guide edge's upper corner positioned a distance
D2 in a direction parallel to an axis of the valve stem block along
away from the top surface of the valve stem block, a distance
between the straight guide edges of the ribs perpendicular to the
axis being ID2, and in which the ratio D2/ID2 is less than 0.8.
[0068] It has been surprisingly found that ratios below this value
enable very efficient and smooth guidance of the canister relative
to the inhaler housing in some configurations.
[0069] The ratio D2/ID2 may be less than 0.75, about 0.7 being one
example.
[0070] The further surface of at least one guide rib may extend
away from the valve stem block and terminate at a distance D3 from
the top surface of the valve stem block in the direction parallel
to the axis, the ratio D3/ID2 being less than 0.9 or less than
0.85, about 0.8 being one example.
[0071] Each guide rib meets the upper rib section near the inner
wall of the tubular body portion at outer rib positions wherein the
outer rib positions are a distance ID1 apart in a direction
perpendicular to the axis, and in which the ratio ID2/ID1 is
between 0.7 and 0.9, typically between 0.75 and 0.85, about 0.78 or
0.8 being two examples.
[0072] According to a further aspect, the present disclosure
discloses an inhaler housing for an inhaler for inhaling inhalable
substances, the inhaler having: a body and a dose counter with an
actuation member adapted to drive a dose indication portion of the
dose counter against a return spring, the body including a recess
for location of an end of the return spring; the recess having a
substantially flat reaction surface, a shoulder surface adjacent
the reaction surface and an entrance mouth into the reaction
surface; wherein a distinct guide surface is provided for guiding
the end of the return spring into the recess, the distinct guide
surface being wider than the entrance mouth in a direction across
the mouth.
[0073] This feature of the distinct guide surface being wider than
the entrance mouth advantageously assists in assembly of the dose
counter into the inhaler since when the return spring is being
fitted as part of the dose counter installation it can slide along
the distinct guide surface relatively easy into the recess.
[0074] The entrance mouth may have at least one chamfered entrance
lip, the distinct guide surface having a slanted edge which is an
extension of the lip.
[0075] The distinct guide surface may be substantially planar. The
distinct guide surface may have an edge which intersects with an
adjacent curved surface of the body.
[0076] At least a portion of the distinct guide surface may
comprise a portion of the body which is recessed relative to an
adjacent portion of the body.
[0077] A further aspect of the present disclosure discloses an
inhaler housing for an inhaler for inhaling inhalable substances,
the inhaler housing having a tubular portion defining a tubular
interior space for containing a pressurised canister containing
inhaler substances, a valve stem block for engagement with a valve
stem of such a pressurised canister, and a dose counter chamber for
containing a dose counter assembly, the dose counter chamber being
separated from the tubular interior space by a barrier, the barrier
including a stepped upper wall area including at least three steps
at different levels.
[0078] This configuration advantageously permits enough room for
the dose counter in the dose counter chamber and enough room for
the movable parts inside the inhaler housing including the
pressurised canister and in at least one arrangement has been found
to be particularly effective in space saving.
[0079] The inhaler may include four said steps.
[0080] The steps may be arcuate.
[0081] The arcuate steps may have substantially flat areas aligned
substantially perpendicular to an axis of the valve stem block as
well as part-cylindrical riser surfaces between the substantially
flat areas.
[0082] The steps may be substantially concentric with an axis of
the valve stem block.
[0083] The steps may extend around the valve stem block a distance
of about 180 degrees.
[0084] The material forming the barrier may be of substantially
constant thickness substantially throughout the steps.
[0085] The dose counter chamber may be formed with at least one
heat staking pin for mounting of a dose counter system, the heat
staking pin being directly attached to at least two of the
steps.
[0086] The heat staking pin may be attached to at least one step
surface that is oriented substantially perpendicular to an axis of
the valve stem block and to at least one and preferably two step
risers.
[0087] An aperture for a drive pin for actuating the dose counter
may be formed through a second furthest step away from the valve
stem block.
[0088] According to a further aspect, the present disclosure
discloses an inhaler valve stem and valve stem block interface for
a breath actuated inhaler having a dose counter, a pressurised
canister containing inhaler substances including a medicament,
which may be in solution or suspension, the valve stem block having
a cylindrical inner bore with an inner diameter which is a first
diameter, the cylindrical inner bore being for accepting a valve
stem with an outer diameter, the valve stem block having a seal in
the inner bore with a second diameter which is smaller than the
first diameter.
[0089] It has been found with this configuration that,
surprisingly, better sealing is achieved than with a simple
interference fit between a cylindrical outer wall of a valve stem
and a cylindrical inner wall of a valve stem block with a larger
interference fit. This new configuration has been found to be
particularly effective at sealing and avoiding blowback leakage.
Especially with regard to the dose counter, the seal permits a
relatively low insertion force to be needed to insert the valve
stem into the valve stem block and enables very accurate
positioning of the valve stem relative to the valve stem block in
an axial direction of the valve stem, while at the same time
providing a surprisingly effective seal bearing in mind the low
insertion force.
[0090] The first diameter may be about 3.22 mm.
[0091] The first diameter may be about 3.5% larger than the second
diameter.
[0092] An outer diameter of the valve stem may be smaller than the
first diameter but larger than the second diameter prior to
introduction of the valve stem into the inner bore, preferably
about 0.75% to 1.5% larger, for example about 1% larger.
[0093] The valve stem block may include an annular recess
concentric with and extending around the inner bore at least
partially around the circumference thereof, the inner diameter of
the annular recess being about 25 to 50% larger than the inner
diameter of the cylindrical inner bore, for example about 40%
larger.
[0094] The seal may be inwardly convex.
[0095] The seal may have an inner surface which is part of a
toroid.
[0096] The seal may be located at or near an entrance to the inner
bore.
[0097] The seal may be formed integrally with, e.g. of the same
material as, the material defining the inner bore which may, for
example, be moulded plastics.
[0098] A further aspect of the present disclosure discloses a
breath actuated inhaler having a drive adapted to drive a
pressurised canister so as to retract a metering valve stem into
the canister to fire the canister, the canister being adapted to
move during operation between 1 and 4 mm between end positions of
its length of travel relative to the valve stem, the drive being
arranged to apply a firing force of between 15N and 60N of force to
the canister at a position of the canister relative to the valve
stem at which the canister fires.
[0099] With this configuration of drive and canister travel, it has
been surprisingly found possible to have very accurate and reliable
firing of the canister, as well as accurate counting when a dose
counter is provided. Furthermore, a long extent of travel of the
canister to retract the valve stem can be provided to ensure that
both count and fire very reliably occur.
[0100] The drive may comprise a drive spring.
[0101] The canister may be arranged to move between 1 and 3 mm
between the end positions. In one example the movement between the
end positions is 3 mm.
[0102] The drive may be adapted to provide the firing force as more
than 40N, preferably also less than 60N.
[0103] The drive may be adapted to provide the firing force as more
than 35N.
[0104] The firing force may be greater than the sum at the point of
firing of opposing forces applied to the canister by a valve stem
spring in the canister and a return spring for an actuator pin of a
dose counter of the inhaler.
[0105] A further aspect of the present disclosure discloses a
breath actuated inhaler having a main body for accommodating a
medicament reservoir, a canister fire system for moving the
canister to release a dose in response to air flow, a cap housing
for enclosing the canister fire system and canister within an
interior chamber defined by the main body and the cap housing,
wherein a lock system is provided for locking the cap housing on
the main body.
[0106] Advantageously, a user can be prevented from tampering with
and damaging the interior components of the inhaler. In the case of
a breath actuated inhaler, this is particularly advantageous
because prior inhalers have required the ability to remove the cap
housing for manual priming of the metering chamber. But, when a
metering valve is provided with an opening configured to permit
flow in a direction with an axial component along the valve stem
directly between the transfer space inside the valve stem and the
interior reservoir, and when the interior reservoir is arranged for
orientation above the metering chamber whereby gas such as air
located within the metering chamber is replaced with liquid from
the interior reservoir, it is no longer necessary to be able to
open the inhaler for manual priming of the metering chamber by
manually pushing and firing the canister.
[0107] Helical threads may be provided for rotational attachment of
the cap housing on the main body and for resisting relative
longitudinal movement therebetween without rotation.
[0108] The lock system may include a protrusion in the region of a
helical thread on one of the main body and the cap housing which is
lockable in a recess in the region of a helical thread on the other
of the main body and the cap housing.
[0109] Two said protrusions may be engageable in two said recesses
formed at opposing locations on the inhaler.
[0110] Each protrusion may have a leading ramp surface and a
trailing ramp surface, the included angle between the ramp and
trailing surfaces being about 95.degree. to 120.degree.; the
included angle of the protrusion preferably being larger than that
of the recess.
[0111] The main body may have a central axis and the ramp surfaces
are inclined at an angle of about 45.degree. plus or minus
15.degree. (or plus or minus 10.degree.) to tangential.
[0112] The lock system may include a first lock member on one of
the main body and the cap housing which is adapted to engage a
second lock member at a lock interface formed by respective
engagement faces thereof, the lock interface being oriented
substantially perpendicular to tangential.
[0113] The main body may have a central axis and the first lock
member has a radial extent of 0.25 to 0.75 mm, preferably about
0.35 to 0.45 mm; the first lock member preferably having a
longitudinal extent of about 10 mm.
[0114] The main body and the cap housing may be formed of plastics
material and the lock system may be configured so that a release
torque required to overcome the locking provided by the plastics
main body and cap housing is more than 1 Nm.
[0115] The lock system may be configured such that the release
torque is between 2 and 5 Nm, preferably between 2.5 and 3 Nm,
about 2.7 Nm being one example.
[0116] When the present disclosure is implemented in a metered dose
inhaler, this may comprise a press and breathe metered dose
inhaler, for example in which a canister is pushed by hand to fire,
normally directly although indirect operation is an alternative,
normally using finger and/or thumb operation of the canister.
BRIEF DESCRIPTION OF THE DRAWINGS
[0117] The present invention may be carried out in various ways and
a number of preferred embodiments will now be described by way of
example with reference to the accompanying drawings, in which:
[0118] FIGS. 1A and 1B show respective isometric views of a
preferred inhaler;
[0119] FIG. 2 shows an exploded view of the inhaler shown in FIGS.
1A and 1B;
[0120] FIG. 3 is an enlarged view of the dose counter assembly
shown in FIG. 2;
[0121] FIG. 4 is an isometric sectional view of a metering valve of
the inhaler and part of the canister shown in FIG. 2;
[0122] FIGS. 5A, 5B, 5C and 5D show various details of the inhaler
and parts of it in a closed configuration thereof.
[0123] FIGS. 6A, 6B, 6C and 6D show various details of the inhaler
in an opened configuration thereof;
[0124] FIGS. 7A, 7B, 7C and 7D show various details of the inhaler
in an actuated configuration thereof;
[0125] FIGS. 8A, 8B, 8C and 8D show various details of the inhaler
in a closing configuration thereof;
[0126] FIG. 9 schematically shows forces and ports within the
inhaler in the closed configuration of FIGS. 5A to 5D;
[0127] FIG. 10 schematically shows forces and ports within the
inhaler in the opened configuration of FIGS. 6A to 6D;
[0128] FIG. 11 schematically shows forces and ports within the
inhaler in the actuated configuration of FIGS. 7A to 7D;
[0129] FIG. 12 is a sectional elevational view of part of the
inhaler shown in FIG. 1A with long dash lines denoting the top of
ribs used in an earlier prototype;
[0130] FIG. 13 shows a portion of the inhaler of FIG. 1A with the
dose counter and dose counter door removed;
[0131] FIG. 14A is a sectional isometric view of part of the
inhaler shown in FIG. 1A;
[0132] FIG. 14B shows part of the inhaler with a dose counter not
yet installed, showing heat stake pins;
[0133] FIGS. 15A and 15B show respective side elevation and
isometric views of the valve stem block of the inhaler of FIG.
1A;
[0134] FIGS. 16A, 16B, 17A, 17B, 17C, 17D, 18A, 18B and 18C show
various views of part of the inhaler, including components showing
the interlocking interaction of the main body of the inhaler with a
cap housing thereof;
[0135] FIG. 19 shows a modified form of the inhaler of FIG. 1A in
which the force holding unit and cap housing are removed and the
modified inhaler takes up the form of a metered dose inhaler;
and
[0136] FIG. 20 shows a side view of the inhaler shown in FIG. 1A;
and
[0137] FIG. 21 shows a comparative graph of delivered dose recovery
at various time delays post previous actuation for the inhaler of
FIG. 1A and an inhaler having a metering valve with radial
capillary metering chamber inlet and outlet ports.
DETAILED DESCRIPTION OF THE INVENTION
[0138] The following detailed description of embodiments of the
inhaler and accompanying methods will be better understood when
read in conjunction with the appended drawings of exemplary
embodiments. It should be understood, however, that the invention
is not limited to the precise arrangements and instrumentalities
described in the following detailed description.
[0139] As shown in FIGS. 1A and 1B, a breath actuated inhaler which
is merely an example of an inhaler in accordance with the present
invention, includes a force holding unit or cap housing 12, a main
body 14, a mouthpiece dust cap 16 and a dose counter door 18 having
a dose counter window 20.
[0140] As shown by the exploded view of FIG. 2, a dose counter
chamber 22 includes a dose counter system 24 closed within it by
the dose counter door 18.
[0141] The dose counter system is shown in enlarged detail in FIG.
3 and includes an actuating pin 26 and return spring 28. The dose
counter can take various forms and may, for example, be as
described in EP2135199A or EP2514464A.
[0142] As also shown in FIG. 2, the inhaler 10 includes a force
holding unit 30 which includes: a filter 32, flap valve housing 34,
flap valve 36, flap valve spring 38, main compression spring 40,
retaining ring 42, diaphragm 44 and lower cap 46. The inhaler also
includes a canister 50 with a metering valve 52 and a valve stem
54; as well as a yoke 56 with drive rods or legs 58 having distal
ends 59 which are driven by respective cams 60 on the
hingedly-connected mouthpiece dust cap. The valve stem 54 is fitted
into an inner bore 61 (FIG. 15B) of a valve stem block 62 which
communicates with a nozzle 64 for ejection of inhalable substances
through a central bore 68 (FIG. 12) of a mouthpiece 66 (FIG. 12 and
FIG. 2) of the main body 14 of the inhaler 10.
[0143] The force holding unit 30 operates substantially as
disclosed with reference to FIGS. 1 to 3 of EP1289589A and the yoke
56 and mouthpiece dust cap 16 substantially as described in
EP2514465A, including but not limited to FIG. 22 thereof.
[0144] In particular, with reference to FIGS. 5A to 5D, starting
from a configuration in which the mouthpiece dust cap 16 is closed
in this configuration the liquid 201 in an interior reservoir 84 of
canister 50 communicates with a metering chamber 82 which does not
communicate with atmosphere through an interior bore 88 of the
valve stem 54. An opening rotation of the mouthpiece dust cap 16 to
the configuration of FIGS. 6A to 6D enables the distal ends 59 of
the drive rods 58 and indeed the whole yoke 56 to be moved away
from the cap housing 12 under the influence of the main compression
spring 40, the main compression spring 40 being reacted against as
equilibrium is reached for the canister position by friction forces
as well as forces provided by partial vacuum at the diaphragm, the
dose counter return spring 28, and metering valve spring 70 (FIG.
4) which forms part of the metering valve 52. In this
configuration, the metering chamber 82 is isolated from both of the
interior reservoir 84 and atmosphere.
[0145] As the next step, the user (not shown) inhales through the
mouthpiece 66 and the drawing out of air through the central bore
68 in turn draws air into the enclosure formed by the main body 14
and cap housing 12 through the series of approximately ten air
inlets 72 formed on the cap housing 12. The incoming air impinges
upon the flap 74 which releases vacuum (i.e. a partial vacuum) from
the vacuum chamber formed by the diaphragm 44 due to flap seal 76
rising off port 78 on diaphragm top plate 80. With the vacuum
released, as shown in FIGS. 7A to 7D, as the user is inhaling air
through the inhaler 10, i.e. through the apertures 72 and all of
the way along inside the cap housing 12 and main body 14 past the
canister 50 and out through the central bore 68, the main
compression spring 40 drives the lower cap 46, yoke 56 and canister
50 away from the cap housing 12 and towards the main body 14 and
valve stem block 62 whereby the valve stem 54 is retracted into the
canister 50. This places the pressurised metering chamber 82 in
communication with valve stem block nozzle 64 so fires the canister
and ejects inhalable substances from the metering chamber 82
through the nozzle 64 and mouthpiece 66 towards the lungs (not
shown) of the user. The dose counter system 24 also registers a
count by movement of the actuating pin 26 by the canister ferrule
220. At this time after opening and firing, the metering chamber 82
communicates with atmosphere. With the mouthpiece 66 left open such
that the atmosphere communicates through the bore 88 and exit port
90 with the metering chamber 82, the metering chamber 82 can become
at least partially or fully filled with gas such as air from the
atmosphere.
[0146] In other embodiments comprising nasal inhalers, the
mouthpiece 66 may be replaced with a nose piece.
[0147] As shown in FIGS. 8A to 8D, during closing, the mouthpiece
dust cap 16 is rotated back to its closed position and the cams 60
push on the distal ends 59 of the drive rods 58 so as to push the
yoke 56 towards the cap housing 12 so as to compress the main
compression spring 40 again and the vacuum is formed again at the
diaphragm 44. At the same time, the canister is pushed back to its
original configuration of FIGS. 5A to 5D by the metering valve
return spring 70.
[0148] As shown in FIG. 9, with the inhaler 10 in the configuration
of FIGS. 5A to 5D, the metering valve spring 70 keeps the valve
stem 54 extended, the inlet port 86 open and the exit port 90
effectively closed, i.e. with the metering chamber 82 isolated from
atmosphere. At the same time the force F.sub.YL applied as
F.sub.YL/2 by each of the legs or rods 58 of the yoke 56 to the
lower cap 46 is greater than or equal to the force F.sub.FHUCS
applied in the opposite direction by the spring of the force
holding unit 12.
[0149] As shown in FIG. 10, with the inhaler then changed to the
configuration of FIGS. 6A to 6D, the canister is displaced to a
representative distance D.sub.valve from the canister position of
FIG. 9 where this displacement at D.sub.valve is less than the
displacement required to actuate and fire a dose. In this FIG. 10
configuration, the position of the canister 50 is determined by an
equilibrium between forces, which is:
F.sub.valve CS+F.sub.Dia=F.sub.FHU CS
where F.sub.valve CS is the force applied to the canister by the
metering valve spring 70, F.sub.Dia is the force applied by the
partial vacuum in the diaphragm 44 in the same direction and
F.sub.FHU CS is the opposing force applied by the compression
spring 40 of the force holding unit 30. The port 78 is noted to be
closed. The port 86 is open and the port 90 is closed.
[0150] As the user then inhales, the port 78 is opened by the
action of air entering through the apertures 72 impinging on the
flap 74, lifting flap seal 76. The equilibrium of FIG. 10 is
therefore lost. The canister 50 is therefore moved to displace the
valve stem 54 more, to the configuration of FIG. 11, so that the
canister is a representative distance D.sub.Actuated from the valve
stem block 62, and where the force balance is that F.sub.valve
CS.ltoreq.F.sub.FHUCS in which the force applied to the lower cap
46 is less than or equal to the opposing force applied by the
compression spring 40 of the force holding unit R. In this
configuration, the port 86 has closed to isolate the metering
chamber 82 from the interior reservoir 84 of the canister 50 and
after this closure the port 90 has opened, thereby firing the
canister 50 by venting pressurised contents within the metering
chamber 82 out through the nozzle 64 of the valve stem block 62 for
inhalation by the user.
[0151] The spring 40 is adapted such that the firing force
F.sub.FHU CS is more than 35 N, typically less than 60 N. This may
vary in other embodiments.
[0152] In most embodiments, the spring 40 is adapted in addition to
device geometry such that the force exerted by the spring 40 on the
valve/canister is equal to the sum of the opposing valve spring 70
and pneumatic resistance force in the FHU diaphragm 44 in the
prepared position. Nonetheless, the spring 40, unless otherwise
assisted, must be able to provide sufficient force once the
mechanism is triggered to actuate the canister on inhalation. The
specific force values will be dependent on the componentry of the
device, driven predominately by the force required to actuate the
canister at a specific displacement, thus the spring 40 will be
adapted to suit.
[0153] The metering valve 52 shown in FIG. 4 is similar to those
described in U.S. Pat. No. 7,959,042B, which is incorporated by
reference herein, and has the metering chamber 82 arranged for
selective communication with either the interior reservoir 84 of
the canister 50 via an inlet port 86, or with the interior bore 88
(FIGS. 5A to 5D) of the valve stem 54 which communicates via the
valve stem block 62 with the nozzle 64, the valve stem 54 being
provided with a radially configured capillary exit port 90 leading
to the bore 88. The metering chamber 82 is at least partly defined
by a cup-shaped inner metering body 92 and has an inner seal 94 and
outer seal 96, as well as a location member 98, a main canister
seal 100 and a crenelated valve stem driver 102 which has a through
bore 104 axially directed towards the inlet port 86. The inlet port
86 includes two elongate openings 106 diametrically opposed to one
another and which are defined by a pair of forked legs 108 which
are spaced apart from one another by the elongated openings 106 and
the open space forming the inlet port 86 between them. The forked
legs 108 have substantially constant cross-section all the way
along to their distal ends (not shown) which are located within the
crenelated valve stem driver 102. When the valve stem 54 is
depressed into the canister 50 so that the inlet port 86 permits
communication between the metering chamber 82 and the interior
reservoir 84, the communication into the interior reservoir 84 is
at an inner side 110 of the inner seal 94 and it will be
appreciated that this is a slot-shaped porting between the forked
legs 108 from where flow can travel directly axially into our out
of the interior reservoir 84.
[0154] According to an alternative embodiment, the arrangement of
openings in the metering valve of the present invention is similar
to those described in US2016/0084385, which is incorporated by
reference herein. In particular, the metering valve of the present
invention may be similar to the embodiment shown in FIG. 4 of
US2016/0084385, in which the valve body includes at least one first
opening (i.e., at least one first side hole 100 that is arranged in
a cylindrical portion of the valve body) and at least one second
opening (i.e., at least one second side hole 111 that, as with the
first hole(s), is arranged in a cylindrical portion of the valve
body), the second opening(s) being axially offset relative to the
first opening(s) along a longitudinal axis that extends between a
first axial end and a second axial end of the valve body. The first
opening(s) and second opening(s) that are axially offset from each
other along the valve body enable the metering chamber to be filled
and emptied.
[0155] The canister 50 includes inhalable substances including the
active ingredient beclomethasone dipropionate and the propellant
HHFA134a which has a surface tension of about 8 mN/m as liquid at
25.degree. C. Other active ingredients may be used in other
embodiments, such as tiotropium bromide.
[0156] If the mouthpiece dust cap 16 is left open such that the
atmosphere communicates through the bore 88 and exit port 90 with
the metering chamber 82, the metering chamber can become at least
partly or substantially fully filled with gas such as air from the
atmosphere. When the mouthpiece dust cap 16 is closed, however, and
when the interior reservoir 84 is oriented above the metering
chamber 82, the present inventors have discovered that the liquid
phase in the interior chamber can exchange places with gas in the
metering chamber 82, the fluid travelling either directly through
the openings 106 or through the throughbore 104, and along through
the inner seal 94 and into the metering chamber 82 and gas in the
metering chamber 82 can travel in the reverse direction along the
same path, exiting with an axial component through between the
forked legs 108 and through the elongated openings 106 into the
interior reservoir 84. It is believed that the particular surface
tension of the chosen propellant promotes this action and the
higher density of the liquid than that of any gas in the metering
chamber enabling the latter to rise up in and relative to the
liquid.
[0157] The full filling of the metering chamber 82 with a dose of
liquid from the interior reservoir 84 with any gas in the metering
chamber passing in the reverse direction from the metering chamber
82 into the interior reservoir 84 is highly advantageous since with
this one extension of the valve stem 54 from its retracted
configuration after inhalation to its extended configuration with
the mouthpiece dust cap 16 closed again ensures that the inhaler 10
is fully primed for use. This has overcome a significant
problem.
[0158] As shown in FIG. 20, the inhaler 10 may be provided with a
preventer 110 for preventing the user from taking a second or
further inhalation while the dust cap 16 is still open. The
preventer 110 may take the form of a warning signaller 102 such as
a warning notice as shown in the drawing stating "to reload: close
before each inhalation" although in other embodiments the preventer
110 could take various other forms such as an alarm or audible or
visual warning device to indicate that the mouthpiece dust cap 16
is open and needs to be closed prior to the next inhalation.
[0159] FIG. 21 is a graph showing a comparison of the inhaler of
FIG. 1A with delivered dose for a prior art breath actuated inhaler
with a different metering valve (not shown) in which the exit port
from the interior reservoir comprises a radially oriented capillary
bore which leads to an internal bore of the valve stem leading
axially towards a further radially extending capillary port, such
that the communication from the interior space is through the first
capillary port, along the internal bore and out through the second
radial capillary port into the metering chamber when the valve stem
is in its extended configuration. In all cases the inhalers were
held with the valve stems vertical and the canister interior
reservoir above the metering chamber. After inhalation, the valve
stem in each case was left in the retracted inhale configuration
with the metering chamber exposed to atmosphere through the valve
stem for the specified delay period and the inhaler was then reset
and readied for inhalation, in the case of the present inhaler 10
by closing and opening the mouthpiece cap again. As shown by the
graph of FIG. 21, with a target of 80 micrograms of BDP
(beclomethasone dipropionate) the diamond shaped plots 205 are for
the prior art inhaler which began to fail to reach 75% of the
labelled claim for the dose after a delay of 30 seconds after
inhalation in closing the mouthpiece cap to isolate the metering
chamber from atmosphere. At all delays of 2 minutes or over, the
prior inhaler failed to provide 75% of the labelled claim of dose
in 100% of cases. This, the present inventors have discovered, is
due to gas lock forming in the metering chamber after inhalation
due to the metering chamber's exposure to atmosphere, i.e. in that
when the mouthpiece cap is closed after a delay air is trapped in
the metering chamber and is not replaced by liquid in the interior
reservoir even when the metering chamber is connected to the
interior reservoir. In contrast, the plots of crosses 207 in FIG.
21 show the performance of the inhaler of FIG. 1A. Here, 100% of
the plots are in the range of 75 to 125% of labelled claim for the
dose, even when there is no appreciable delay or a delay of one
hour, twelve or twenty-four hours before closing the mouthpiece cap
after inhalation. Therefore, even if the metering chamber 82 has
been exposed to atmosphere for a relatively long time such that it
is after that delay substantially full of gas due to
evaporation/diffusion of substances after inhalation, this graph
clearly shows that by closing the mouthpiece fully and opening it
again, the gas in the metering chamber 82 is removed into the
interior reservoir 84 and replaced with a correct dose very
reliably.
[0160] Although FIG. 21 data is presented for 80 mcg (ex-actuator)
targeted BDP HFA product, the data is representative of any
formulation and formulation strength.
[0161] As shown in FIG. 12, the main body 14 has a tubular body
portion 120 arranged to contain the pressurised canister 50 for
sliding motion. As shown in FIG. 12, the valve stem block has a top
surface 122 and the tubular body portion 120 has at least two
mutually opposed guide ribs 124, 126. The guide ribs 124, 126 have
substantially straight guide edges 130, 132 extending parallel to
and spaced from one another, each straight guide edge 130, 132
having an upper corner 134, 136 where the straight guide edge meets
a further surface 138, 140 of the ribs 124, 126 leading outwardly
towards an upper rib section near an inner wall 146 of the tubular
body portion 120. At least one of the ribs 124, 126 has its
straight guide edge's upper corner 134, 136 positioned a distance
D2 in a direction parallel to an axis of the valve stem block 62
along away from the top surface 122 of the valve stem block 62, a
distance between the straight guide edges 130, 132 of the ribs 124,
126 perpendicular to the axis being ID2, and the ratio D2 divided
by ID2 is 0.7. This is smaller than in previous embodiments and can
surprisingly assist in providing smooth guiding of the canister
within the tubular body portion 120.
[0162] The further surface 138, 140 of at least one of the guide
ribs 124, 126 and in this case both of them extends away from the
valve stem block 62 and terminates at a distance D3--in the case of
guide rib 124--from the top surface 122 of the valve stem block 62
in the direction parallel to the axis, the ratio D3 divided by ID2
being 0.8, the equivalent ratio for the guide rib 126 being 1.0.
Each guide rib meets the upper rib section 142, 144 near the inner
wall 146 of the tubular body portion 120 at an outer rib position
148, 150 wherein the outer rib positions are a distance apart ID1
in a direction perpendicular to the axis 202 of the valve stem
block 62 and the ratio ID2 divided by ID1 is 0.8. This arrangement
assists beneficially in providing sufficient space for the canister
50 to move within the tubular body section 120.
[0163] With reference to FIG. 13, a portion of the main body 16 is
shown with the mouthpiece dust cap 16 and the dose counter door 18
and the dose counter system 24 not yet installed. As can be seen,
the dose counter chamber 22 includes a recess 152 for location of
an end 154 (FIG. 3) of the return spring 28. The recess 152 has a
substantially flat reaction surface for pushing on the end 154 of
the return spring 28. The recess 152 also has a shoulder surface
158 adjacent the reaction surface 156 and an entrance mouth 160
into the reaction surface 156. A distinct guide surface 162, which
is substantially planar is provided for guiding the end 154 of the
return spring 28 into the recess 152 during assembly. The distinct
guide surface 162 is wider than the entrance mouth 160 in a
direction across the mouth and this assists substantially in
assembling the spring 28 into the recess 152.
[0164] The entrance mouth 160 also has at least a chamfered
entrance lip 164, an extension 166 of which into the guide surface
forms a slanted edge 166 of the distinct guide surface 162. At
least a portion of the distinct guide surface 162 comprises a
portion of the body 14 which is recessed relative to the adjacent
and partially surrounding portion 164 of the body by an edge 168.
The edge 168 is particularly effective in catching the end 154 of
the return spring and the wide guide surface 162 is effective in
guiding the spring 28 past the chamfered entrance lip 164 and onto
the reaction surface 156 where it remains once installed. A further
edge 170 of the guide surface 162 is spaced from and generally
parallel to the edge 168. The edge 170 forms an intersection with
an adjacent portion 171 of the body 14.
[0165] As shown in FIG. 14A, the main body of the inhaler 10
includes a barrier 180 separating an interior space 182 defined at
least partly by the tubular body portion 120 from the dose counter
chamber 22. The barrier includes a stepped upper wall area 184
which has four steps 186, 188, 190, 192 at different levels. The
steps are arcuate and have substantially flat parts 194, 196, 198,
200 aligned substantially perpendicular to the axis 202 of the
valve stem block as well a part-cylindrical risers 204, 206, 208
between the substantially flat parts 194, 196, 198, 200.
[0166] The arcuate steps 186, 188, 190, 192 are substantially
concentric with the axis 202 of the valve stem block 62. The steps
186, 188, 190, 192 extend around the valve block 62 a
distance/angle of about 170.degree. although this is only
approximate and may be in the region of about 180 to 120.degree. in
various embodiments. The material forming the barrier 180 is of
substantially constant thickness throughout the steps 186, 188,
190, 192 which is advantageous for manufacturing techniques by
moulding.
[0167] As shown in FIG. 14B which is a view into the dose counter
chamber 22, the dose counter chamber 22 is formed with two heat
staking pins 212, 214 for attaching the dose counter system 24
permanently into position within the dose counter chamber 22. One
of the heat staking pins 214 is directly attached to two of the
steps 188, 190. The heat staking pin 214 is attached to one
substantially flat step part 198 and to two step risers 206, 208,
providing secure and advantageous location of the heat staking pin
214 in the stepped upper wall area 184 of the barrier 180. An
aperture 218 for the actuating pin 26 of the dose counter system 24
is formed through the second furthest step part 198 away from the
valve stem block 62.
[0168] The stepped upper wall area 184 is highly advantageous since
it enables the accommodation of a length of movement of the
canister 50 and in particular its ferrule 220 (FIG. 2) within the
main body 14. Therefore, even with a metering valve 70 as used in
the inhaler 10 which has a relatively long end-to-end travel of
approximately 4 mm, the internal components can be maintained
within a relatively small and compact inhaler 10, while also
allowing for space in the dose counter chamber 22 for the dose
counter system 24 and enabling the dose counter to be heat staked
firmly in place by the heat stake pins 212, 214 including the pin
214 which is attached to the stepped upper wall area 84 of the
barrier 180.
[0169] As shown in FIGS. 15A and 15B, the valve stem block 62 has
the cylindrical inner bore 61 which has an inner diameter BD1 which
has a first diameter, a seal 224 at an entrance to the inner bore
61 having a second diameter BD2 which is smaller than the first
diameter. The seal 224 is inwardly convex and/or is toroidal. The
first diameter BD1 is about 3.22 mm and is about 3.5% larger than
the second diameter BD2. The valve system 54 has a cylindrical
outer surface 226 (FIG. 2) with a diameter which is smaller than
the first diameter BD1 but larger than the second diameter BD2
prior to introduction of the valve stem 54 into the inner bore 61
and is about 1% larger. The valve stem block 62 also includes an
annular recess 228 which extends more than half way around the
periphery of the inner bore 61, in this embodiment about
350.degree. or more. The annular recess 228 has an inner diameter
which is about 40% larger than the inner diameter BD1 of the
cylindrical inner bore 61. This arrangement has been found to
provide extremely effective sealing against blowback which has
occurred in prior designs which have a substantially greater
interference fit between the exterior diameter of the valve stem
and the interior diameter of the inner bore of the valve stem.
Surprisingly, and advantageously, using the inwardly convex seal
224 to the bore 61, very effective sealing without any blowback can
be achieved even with a relatively small interference fit between
the valve stem 54 and the seal 224, the annular recess 228
assisting in providing resilience to the valve stem block 62 for
this purpose. The small interference fit allows for good sealing
even when the inhaler 10 is subjected to high temperatures for long
periods since there is little stress to relieve. Furthermore, the
seal 224 permits a relatively low insertion force for inserting the
valve stem 54 into the valve stem block 62 and this enables
accurate positioning of these two components relative to one
another in an axial direction of the valve stem 54 so that the dose
counter system 24 can count reliably by way of accurate actuation
of its actuator pin 26 by the canister ferrule 220.
[0170] As shown in the various sectional views of FIGS. 16A through
to 18C, a lock system 250 is provided for locking the cap housing
or force holding unit housing 12 on the main body 14. Helical
threads 252, 254 are provided, with male threads 252 on the cap
housing 12 and female threads 254 on the main body 14, for
rotational attachment of the cap housing 12 on the main body 14 and
for resisting relative longitudinal movement therebetween without
rotation.
[0171] The lock system 250 includes a protrusion 256 in the region
of the helical thread 254 on the main body 14 which is lockable in
a recess 258 in the region of the helical thread 252 on the cap
housing. As shown in FIG. 17C, the inhaler 10 includes two of the
protrusions 256 in two of the recesses 258 formed at opposing
locations on the inhaler, i.e. diametrically opposite to one
another. As shown in FIG. 18A, each protrusion 256 has a leading
ramp surface 260 and a trailing ramp surface 266, the included
angle A between the ramp and trailing surfaces 260, 266 being
115.degree., although a range of about 95 to 120.degree. is
envisaged. The recesses have a similar included angle which is
smaller than the angle of the protrusion 256 at about 100.degree..
This ensures that the protrusion 256 will fit securely in the
recess 258 without any play rotationally.
[0172] The main body 14 has a central axis 202 coincident with that
202 of the valve stem block 62 and the ramp surfaces 266 are
inclined at an angle of about 45.degree..+-.15.degree. to
tangential.
[0173] The lock system 250 also includes a first lock member 270 on
the cap housing 12 which is adapted to engage a second lock member
272 at a lock interface 274 formed by respective engagement faces
thereof, the lock interface 274 being oriented substantially
perpendicular to tangential. This therefore assists in preventing
rotation. The first lock member 270 has a radial extent of 0.39 mm,
although about 0.35 to 0.45 mm is envisaged in other embodiments or
0.25 to 0.75 mm. The second lock member 272, it will be
appreciated, has a greater radial extent. The first lock member 270
has a longitudinal extent parallel to the axis 202 of about 10
mm.
[0174] The main body 14 and cap housing 12 are formed of plastics
material and the lock system 250 is configured so that a release
torque required to overcome the locking provided by the plastics
main body and cap housing at the lock interface 274 and at the
protrusions 256 and recesses 258 is more than 1 Nm. In the
described example, the release torque is about 2.75 Nm. When an
information sticker is applied over the top of the interface
between the main body 14 and cap housing 12 the release torque may
rise to about 3.5 Nm. This has been found to be lower than 4 Nm and
this is low enough that a laboratory is capable of opening up the
inhaler 10 for inspection without significant destruction. However,
this level of torque is significantly higher than likely to be
tried by a user in an attempt to open the inhaler 10 which might
result in tampering and damage to the components of the inhaler
10.
[0175] In an alternative design, the radial extent of the first
locking member 270 is significantly greater at about 0.73 mm and
this has been found, surprisingly, to provide a removal torque
which is considered too high at 4.6 Nm for laboratory disassembly
without destruction. In contrast, a design omitting the first lock
member 270 was found to provide a removal torque of only 0.7 Nm
which is considerably too low and likely to result in users
rotating the cap housing 12 off the main body 14 and potentially
damaging the inhaler by investigating the contents. In fact, this
was the first design attempted by the present inventors and the
next step was to double up the number of protrusions 256 and
recesses 258 so that there are four in total in an attempt to
double the torque, at least, from 0.7 Nm. However, surprisingly,
with this design, the removal torque was only increased by about
10% to 0.8 Nm. The ideal remove torque was surprisingly achieved
with only one protrusion 256 on each thread 254 and with a locking
member 270 with only a small radial extent of 0.39 mm. The locking
member 270 advantageously also includes a lead ramp 290 for
achieving a smooth snap lock of the cap housing 12 onto the main
body 14 when the cap housing 12 is twisted into the locked
position.
[0176] FIG. 19 shows a modification of the inhaler 10 to form an
inhaler 1000 which is a metered dose inhaler having a main body
1002 and mouthpiece dust cap 1004 for the mouthpiece 1006 for
stopping foreign objects entering the central bore 1008 of the
mouthpiece 1006 and for protecting the mouthpiece generally. This
metered dose inhaler 1000 does not include the cap housing 12 or
the force holding unit 30 or yoke 56 but it does include the same
dose counter chamber 22, dose counter system 24, canister 50 and
metering valve 52 and valve stem 54 and valve stem block 62 as that
in the inhaler 10. If this metered dose inhaler is left with the
canister 50 accidentally depressed, for example while squashed in
luggage or clothing by mistake, such that the metering chamber is
left exposed to the atmosphere for a considerable period of time,
then when the inhaler 1000 is located and turned upright for use
with respective gravity with the canister allowed to extend to its
rest position in which the metering chamber communicates with the
interior reservoir, any gas such as air which has entered the
metering chamber is easily expelled up into the interior reservoir
of the canister just as in the inhaler 10 such that an accurate
next dose is applied and the problem of gas lock is therefore
avoided.
[0177] Inhalers in accordance with preferred embodiments of the
present invention are suitable for the delivery of many classes of
active ingredients by inhalation, and may be used for the treatment
of various diseases and disorders. According to preferred
embodiments, the inhaler is used for the treatment of respiratory
disorders (e.g., COPD, asthma and/or cystic fibrosis). The inhaler
may also be used to treat non-respiratory disorders, such as
migraine. According to an embodiment, a method of treating a
respiratory disease or disorder comprises actuating the inhaler to
administer a therapeutically effective amount of one or more active
ingredients. As described herein, the canister of the inhaler
contains a drug formulation comprising one or more active
ingredients in suspension or in solution. Preferably, the drug
formulation comprises one or more active ingredients in propellant
(e.g., HFA). The drug formulation may optionally comprise one or
more excipients in combination with the active ingredient(s) and
propellant.
[0178] In certain embodiments, the inhaler described herein can be
used to treat patients suffering from a disease or disorder
selected from asthma, chronic obstructive pulmonary disease (COPD),
exacerbation of airways hyper reactivity consequent to other drug
therapy, allergic rhinitis, sinusitis, pulmonary vasoconstriction,
inflammation, allergies, impeded respiration, respiratory distress
syndrome, pulmonary hypertension, pulmonary vasoconstriction, and
any other respiratory disease, condition, trait, genotype or
phenotype that can respond to the administration of, for example, a
long-acting muscaric antagonist (LAMA), long-acting
.beta.2-adrenergic agonist (LABA), corticosteroid, or other active
agent as described herein, whether alone or in combination with
other therapies. In certain embodiments, the compositions, systems
and methods described herein can be used to treat pulmonary
inflammation and obstruction associated with cystic fibrosis. As
used herein, the terms "COPD" and "chronic obstructive pulmonary
disease" may encompass chronic obstructive lung disease (COLD),
chronic obstructive airway disease (COAD), chronic airflow
limitation (CAL) and chronic obstructive respiratory disease (CORD)
and include chronic bronchitis, bronchiectasis, and emphysema. As
used herein, the term "asthma" refers to asthma of whatever type or
genesis, including intrinsic (non-allergic) asthma and extrinsic
(allergic) asthma, mild asthma, moderate asthma, severe asthma,
bronchitic asthma, exercise-induced asthma, occupational asthma and
asthma induced following bacterial infection. Asthma is also to be
understood as embracing wheezy-infant syndrome.
[0179] A range of classes of active ingredients have been developed
to treat respiratory disorders and each class has differing targets
and effects.
[0180] Bronchodilators are employed to dilate the bronchi and
bronchioles, decreasing resistance in the airways, thereby
increasing the airflow to the lungs. Bronchodilators may be
short-acting or long-acting. Typically, short-acting
bronchodilators provide a rapid relief from acute
bronchoconstriction, whereas long-acting bronchodilators help
control and prevent longer-term symptoms.
[0181] Different classes of bronchodilators target different
receptors in the airways. Two commonly used classes are
anticholinergics and .beta.2-agonists.
[0182] Anticholinergics (or "antimuscarinics") block the
neurotransmitter acetylcholine by selectively blocking its receptor
in nerve cells. On topical application, anticholinergics act
predominantly on the M3 muscarinic receptors located in the airways
to produce smooth muscle relaxation, thus producing a
bronchodilatory effect. Non-limiting examples of long-acting
muscarinic antagonists (LAMA's) include tiotropium (bromide),
oxitropium (bromide), aclidinium (bromide), ipratropium (bromide)
glycopyrronium (bromide), oxybutynin (hydrochloride or
hydrobromide), tolterodine (tartrate), trospium (chloride),
solifenacin (succinate), fesoterodine (fumarate), darifenacin
(hydrobromide) and umeclidinium (bromide). In each case,
particularly preferred salt/ester forms are indicated in
parentheses.
[0183] .beta.2-Adrenergic agonists (or ".beta.2-agonists") act upon
the .beta.2-adrenoceptors and induce smooth muscle relaxation,
resulting in dilation of the bronchial passages. Non-limiting
examples of long-acting .beta.2-adrenergic agonists (LABA's)
include formoterol (fumarate), salmeterol (xinafoate), indacaterol
(maleate), bambuterol (hydrochloride), clenbuterol (hydrochloride),
olodaterol (hydrochloride), carmoterol (hydrochloride), tulobuterol
(hydrochloride) and vilanterol (triphenylacetate). Non-limiting
examples of short-acting .beta.2-agonists (SABA's) include
albuterol (sulfate) and levalbuterol (tartrate). In each case,
particularly preferred salt/ester forms are indicated in
parentheses.
[0184] According to one embodiment, the formulation comprises
albuterol (sulfate).
[0185] Another class of active ingredients employed in the
treatment of respiratory disorders are inhaled corticosteroids
(ICS's). ICS's are steroid hormones used in the long-term control
of respiratory disorders. They function by reducing the airway
inflammation. Non-limiting examples of inhaled corticosteroids
include budesonide, beclomethasone (dipropionate), fluticasone
(propionate), mometasone (furoate), ciclesonide and dexamethasone
(sodium).
[0186] According to one embodiment, the formulation comprises
beclomethasone dipropionate.
[0187] According to an embodiment, the inhaler delivers one or more
active ingredients selected from the group consisting of tiotropium
(bromide), oxitropium (bromide), aclidinium (bromide), ipratropium
(bromide) glycopyrronium (bromide), oxybutynin (hydrochloride or
hydrobromide), tolterodine (tartrate), trospium (chloride),
solifenacin (succinate), fesoterodine (fumarate), darifenacin
(hydrobromide), umeclidinium (bromide), formoterol (fumarate),
salmeterol (xinafoate), indacaterol (maleate), bambuterol
(hydrochloride), clenbuterol (hydrochloride), olodaterol
(hydrochloride), carmoterol (hydrochloride), tulobuterol
(hydrochloride), vilanterol (triphenylacetate), albuterol
(sulfate), levalbuterol (tartrate), budesonide, beclomethasone
(dipropionate), fluticasone (propionate), mometasone (furoate),
ciclesonide, dexamethasone (sodium) and a combination thereof.
[0188] According to particular embodiments, the inhaler delivers a
combination of at least two different active ingredients (two,
three, four, etc.) which belong to the same or different classes.
According to one embodiment, the inhaler delivers a "triple
combination" of three different active ingredients. The three
active ingredients may belong to three different active ingredient
classes (e.g., LAMA, LABA, ICS); alternatively, two or three of the
active ingredients may belong to the same class.
[0189] According to additional embodiments, the inhaler delivers
one or more active ingredients selected from the group consisting
of a long-acting muscarinic antagonist (LAMA), a long-acting
.beta.2-adrenergic agonist (LABA), an inhaled corticosteroid (ICS)
and a combination thereof. Thus, the inhaler may deliver a
formulation comprising one or more LAMA's, one or more LABA's and
one or more ICS's. That is, the device may deliver a double
combination of a LAMA and a LABA, a LAMA and an ICS, or a LABA and
an ICS; or a triple combination of a LAMA, a LABA and an ICS.
[0190] According to an alternative embodiment, the inhaler delivers
one or more active ingredients for the treatment of a headache
disorder, such as migraine. For example, the inhaler may deliver
dihydroergotamine (DHE) or a pharmaceutically acceptable salt
thereof, such as dihydroergotamine mesylate.
[0191] In one embodiment the inhaler comprises a reservoir,
particularly a pressurized canister, comprising an active
ingredient.
[0192] Preferably the active ingredient is presented in a
pharmaceutical formulation comprising a propellant, optionally a
co-solvent and optionally other pharmaceutically acceptable
excipients.
[0193] Preferred propellants include hydrofluroalkanes, in
particular 1,1,1,2-tetrafluoroethane (HFA134a),
1,1,1,2,3,3,3-heptafluoropropane (HFA227), or combinations thereof.
Most particular propellant is HFA134a. Most particular HFA134a
concentration is from about 91.8% w/w to 92.9% w/w.
[0194] HFA134a has a low boiling point (-26.1.degree. C.) and
correspondingly high vapor pressure (572 kpa) at 20.degree. C.
[0195] Particular co-solvents are selected from the list of
aliphatic alcohols (particularly ethanol), glycerols and glycols.
Most particular co-solvent is ethanol. Most particular ethanol
concentration is about 8% w/w.
[0196] Ethanol is well known to be compatible with HFA-134a and
increases the solubility of BDP.
[0197] Ethanol (anhydrous) is used as a co-solvent to aid
solubility of BDP in HFA134a. A concentration of around 8% w/w of
ethanol is known to provide necessary stability, preventing
precipitation and achieving correct aerosol performance.
[0198] Other pharmaceutically acceptable excipients include
surfactants, particularly oleic acid.
[0199] Preferably, the active ingredient is suspended in the
propellant. Alternatively the active ingredient is dissolved in the
propellant. The active ingredient may also be partly suspended and
partly dissolved in the propellant.
[0200] A particular active ingredient is selected from the group
consisting of anti-inflammatory agents, .beta.2-adrenoreceptor
agonists, anti-cholinergic agents, anti-histamines, serotonin
agonists, and combinations thereof.
[0201] A particular corticosteroid is beclomethasone dipropionate
(BDP).
[0202] A particular .beta.2-adrenoreceptor agonist is salbutamol
sulphate.
[0203] In a particular embodiment of the invention, the active
ingredient is selected from beclomethasone dipropionate (BDP),
salbutamol sulphate and dihydroergotamine.
[0204] In a particular embodiment the inhaler comprises a
pressurized canister comprising beclomethasone dipropionate as
active ingredient, HFA134a as propellant and ethanol as
co-solvent.
[0205] In a particular embodiment the inhaler comprises a
pressurized canister comprising beclomethasone dipropionate as
active ingredient at about 1.0 mg/ml, HFA134a as propellant at
about 1090.20 mg/ml and ethanol as co-solvent at about 94.80
mg/ml.
[0206] In a particular embodiment the inhaler comprises a
pressurized canister comprising beclomethasone dipropionate as
active ingredient at about 0.084% w/w, HFA134a as propellant at
about 91.9% w/w and ethanol as co-solvent at about 8.0% w/w.
[0207] In a particular embodiment the inhaler comprises a
pressurized canister comprising beclomethasone dipropionate as
active ingredient at about 0.169% w/w, HFA134a as propellant at
about 91.8% w/w and ethanol as co-solvent at about 8.0% w/w.
[0208] In a particular embodiment the inhaler comprises a
pressurized canister comprising salbutamol sulphate as active
ingredient, HFA134a as propellant and ethanol as co-solvent.
[0209] In a particular embodiment the inhaler comprises a
pressurized canister comprising about 0.1098 mg of salbutamol
sulphate as active ingredient, about 27.8 mg of HFA134a as
propellant and about 3.6 mg of ethanol as co-solvent.
[0210] One embodiment relates to an inhaler as described herein
comprising an active ingredient.
[0211] One embodiment relates to an inhaler as described herein
comprising an active ingredient for therapeutic use.
[0212] One embodiment relates to an inhaler as described herein
comprising an active ingredient for use in the treatment or
prevention of a respiratory disease, particularly COPD or
Asthma.
[0213] One embodiment relates to an active ingredient for use in
the treatment or prevention of a respiratory disease, particularly
COPD or Asthma, wherein the active ingredient is delivered to a
patient using an inhaler as described herein.
[0214] One embodiment relates to a method for the treatment or
prevention of respiratory diseases, particularly COPD or Asthma,
which method comprises administering an active ingredient to a
human being or animal using an inhaler as described herein. One
embodiment relates to the use of an inhaler as described herein
comprising an active ingredient for the treatment or prevention of
respiratory diseases, particularly COPD or Asthma.
[0215] Embodiments of the present invention may be further
understood by reference to the Example provided below.
EXAMPLE
[0216] According to the following example, a method of using the
inhaler of the present invention comprises delivering a
therapeutically effective amount of beclomethasone dipropionate HFA
for the treatment of asthma, particularly for the maintenance
treatment of asthma as prophylactic therapy in patients 4 years of
age and older, wherein the inhaler is a breath-actuated inhaler
(BAI) as described herein and the step of actuating the inhaler
comprises inhaling through the inhaler. The breath-actuated inhaler
may be used by patients to deliver at least about 40 mcg
beclomethasone dipropionate upon each actuation, preferably twice
daily, e.g., it may be used by patients 4 to 11 years old to
deliver 40 mcg or 80 mcg beclomethasone dipropionate twice daily,
or may be used by patients 12 years of age and older to deliver 40
mcg, 80 mcg, 160 mcg or 320 mcg beclomethasone dipropionate twice
daily. Actuation of the breath-actuated inhaler is preferably
triggered by an inspiratory flow rate of at least about 20 liters
per minute (L/min), and includes a primeless valve so that no
priming actuations are required before use. A method of treating
asthma may comprise inhaling through the BAI at a flow rate of at
least about 20 L/min without priming the inhaler before use,
wherein the inhaler comprises a primeless valve as described herein
and wherein the mean change from baseline for FEV.sub.1 between 2-6
weeks or between 2-12 weeks or between 4-12 weeks of using the BAI
is greater than about 0.150 L or greater than about 0.200 L.
Preferably, the mean peak plasma concentration (Cmax) of BDP is
between about 6000 pg/mL and about 7000 pg/mL or between about 6200
pg/mL and about 6800 pg/mL at 2 minutes after inhalation of 320 mcg
using the BAI (4 inhalations of the 80 mcg/inhalation strength).
The mean peak plasma concentration of the metabolite 17-BMP is
preferably between about 1000 pg/mL and about 2000 pg/mL or between
about 1200 pg/mL and about 1700 pg/mL at 10 minutes after
inhalation of 320 mcg of the BAI.
[0217] The breath-actuated inhaler (BAI) in this example included a
canister having an interior reservoir containing pressurised
inhalable substances including fluid; a "primeless" metering valve
including a metering chamber and a valve stem defining a
communication path between the metering chamber and the interior
reservoir, the communication path including an opening configured
to permit flow between a transfer space inside the valve stem and
the interior reservoir, the interior reservoir being arranged for
orientation above the metering chamber whereby gas such as air
located within the metering chamber is replaced with liquid from
the interior reservoir. Preferably, the primeless metering valve is
the embodiment shown in FIG. 4 and described in U.S. Pat. No.
7,959,042B. Alternatively, the primeless metering valve is similar
to the embodiment shown in FIG. 4 of US2016/0084385, as described
herein.
[0218] Two confirmatory Phase 3 clinical trials were conducted
comparing the above-described breath-actuated inhaler with placebo
in adult and adolescent patients with persistent asthma (Trial 1
and Trial 2).
[0219] Trial 1: This randomized, double-blind, parallel-group,
placebo-controlled, 12-week, efficacy and safety trial compared the
breath-actuated inhaler 40 and 80 mcg given as 1 inhalation twice
daily with placebo in adult and adolescent patients with persistent
symptomatic asthma despite low-dose inhaled corticosteroid or
non-corticosteroid asthma therapy. Patients aged 12 years and older
who met the entry criteria including FEV.sub.1 40-85 percent of
predicted normal, reversible bronchoconstriction of 15% with
short-acting inhaled beta-agonist entered a 14-21 day run-in
period. 270 patients (104 previously treated with inhaled
corticosteroids) who met all the randomization criteria including
asthma symptoms and rescue medication use were discontinued from
asthma maintenance medication and randomized equally to treatment
with the breath-actuated inhaler (BAI) 80 mcg/day BDP, the
breath-actuated inhaler 160 mcg/day BDP or placebo. Baseline
FEV.sub.1 values were similar across treatments. The primary
endpoint for this trial was the standardized baseline-adjusted
trough morning forced expiratory volume in 1 second (FEV.sub.1)
area under the effect curve from time zero to 12 weeks [FEV.sub.1
AUEC(0-12 wk)]. Patients in both treatment groups had significantly
greater improvements in trough FEV.sub.1 compared to placebo (BAI
80 mcg/day, LS mean change of 0.124 L and BAI 160 mcg/day, LS mean
change of 0.116 L over 12 weeks). In addition, the mean change from
baseline for FEV.sub.1 was greater than about 0.150 L between week
4 through week 12 (generally between about 0.150 L and about 0.250
L). Both doses of BAI were effective in improving asthma control
with significantly greater improvements in FEV.sub.1 and morning
PEF when compared to placebo. Reduction in asthma symptoms was also
supportive of the efficacy of the BAI.
[0220] Trial 2: This randomized, double-blind, parallel-group,
placebo-controlled, 6-week, efficacy and safety trial compared BAI
40 and 80 mcg BDP given as 4 inhalations twice daily and placebo in
adult and adolescent patients with persistent symptomatic asthma
despite treatment with non-corticosteroid, inhaled corticosteroids
(with or without a long acting beta agonist [LABA]), or combination
asthma therapy. The study also included a reference treatment
group, QVAR.RTM. Inhalation Aerosol (QVAR MDI) 40 mcg, 4
inhalations twice daily. Patients aged 12 years and older who met
the entry criteria including FEV.sub.1 50-90% predicted normal,
reversible bronchoconstriction of at least 10% with short-acting
inhaled beta-agonist discontinued baseline asthma treatment and
entered a 2-4 week run-in period. 425 patients (257 previously
treated with ICS with or without LABA) who met all the
randomization criteria including FEV.sub.1 of 40-85% predicted and
15% reversibility with short-acting inhaled beta-agonist, and
asthma symptoms were randomized equally to the BAI 320 mcg/day, BAI
640 mcg/day, QVAR MDI 320 mcg/day or placebo. Baseline FEV.sub.1
values were similar across treatments. The primary endpoint for
this trial was the standardized baseline-adjusted trough morning
forced expiratory volume in 1 second (FEV.sub.1) area under the
effect curve from time zero to 6 weeks [FEV.sub.1 AUEC(0-6 wk)].
Patients in both treatment groups had significantly greater
improvements in trough FEV.sub.1 compared to placebo (BAI 320
mcg/day, LS mean change of 0.144 L and BAI 640 mcg/day, LS mean
change of 0.150 L over 12 weeks). Treatment with QVAR MDI was
similar. The change from baseline in morning FEV1 during the trial
was greater than 0.150 L or 0.200 L between week 2 through week 6
(generally between about 0.150 L and about 0.250 L). Both doses of
the BAI were effective in improving asthma control with
significantly greater improvements in FEV.sub.1, morning PEF,
weekly average of daily trough morning FEV.sub.1, reduced rescue
medication use and improved asthma symptom scores than with
placebo. Similar results were demonstrated with QVAR MDI.
[0221] The inhaler of the present disclosure has broad application.
The apparatuses and associated methods in accordance with the
present disclosure have been described with reference to particular
embodiments thereof in order to illustrate the principles of
operation. The above description is thus by way of illustration and
not by way of relative and directional references (including:
upper, lower, upward, downward, left, right, leftward, rightward,
top, bottom, side, above, below, front, middle, back, vertical,
horizontal, height, depth, width, and so forth) are normally given
by way of example to aid the reader's understanding of the
particular embodiments described herein. They should not be read to
be requirements or limitations, particularly as to the position,
orientation, or use of the invention unless specifically set forth
in the claims. Connection references (e.g., attached, coupled,
connected, joined, secured and the like) are to be construed
broadly and may include intermediate members between a connection
of elements and relative movement between elements. As such,
connection references do not necessarily infer that two elements
are directly connected and in fixed relation to each other, unless
specifically set forth in the claims.
[0222] Various modifications may be made to the embodiments
described without departing from the scope of the invention as
defined by the accompanying claims.
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