U.S. patent application number 17/093710 was filed with the patent office on 2021-07-01 for mixing channel for an inhalation device and inhalation device.
The applicant listed for this patent is VECTURA GMBH. Invention is credited to MONIKA HARTMANN, MARTIN HUBER, TOBIAS KOLB, BERNHARD MUELLINGER.
Application Number | 20210196904 17/093710 |
Document ID | / |
Family ID | 1000005459209 |
Filed Date | 2021-07-01 |
United States Patent
Application |
20210196904 |
Kind Code |
A1 |
MUELLINGER; BERNHARD ; et
al. |
July 1, 2021 |
MIXING CHANNEL FOR AN INHALATION DEVICE AND INHALATION DEVICE
Abstract
The invention relates to a mixing channel for an inhalation
device, and in particular to a mixing channel with improved
injection and mixing properties for injecting and mixing a liquid
drug into an air flow streaming in the mixing channel, thereby
producing an aerosol to be inhaled by a patient. One aspect of the
invention relates to a mixing channel for an inhalation device,
comprising an inlet opening, an outlet opening, and an injection
zone located between the inlet opening and the outlet opening,
wherein the injection zone has a longitudinal center axis, wherein
the injection zone comprises (a) a built-in nebulizer, or (b) a
detachable nebulizer, or (c) a member adapted to receive a
detachable nebulizer, wherein the effective cross sectional area of
the mixing channel in a plane perpendicular to the longitudinal
center axis is smaller in the injection zone than upstream of the
injection zone.
Inventors: |
MUELLINGER; BERNHARD;
(MUNICH, DE) ; HUBER; MARTIN; (FURSTENFELDBRUCK,
DE) ; KOLB; TOBIAS; (NEURIED, DE) ; HARTMANN;
MONIKA; (KAUFERING, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
VECTURA GMBH |
GAUTING |
|
DE |
|
|
Family ID: |
1000005459209 |
Appl. No.: |
17/093710 |
Filed: |
November 10, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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14382392 |
Sep 2, 2014 |
10857310 |
|
|
PCT/EP2013/054705 |
Mar 8, 2013 |
|
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17093710 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 15/00 20130101;
A61M 2206/10 20130101; A61M 11/003 20140204; A61M 15/0086 20130101;
A61M 11/005 20130101; A61M 2205/75 20130101; A61M 15/009 20130101;
A61M 11/06 20130101; A61M 11/02 20130101; A61M 15/06 20130101; A61M
15/0021 20140204 |
International
Class: |
A61M 11/00 20060101
A61M011/00; A61M 15/00 20060101 A61M015/00; A61M 11/06 20060101
A61M011/06; A61M 15/06 20060101 A61M015/06; A61M 11/02 20060101
A61M011/02 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 9, 2012 |
EP |
12158852.9 |
Oct 26, 2012 |
EP |
12190139.1 |
Claims
1-15. (canceled)
16. An inhalation device comprising: a mixing channel having a
longitudinal center axis, the mixing channel comprising: a first
channel portion, comprising: an upstream end comprising an inlet
opening, and a downstream end comprising a transition opening, a
second channel portion, comprising: an upstream end comprising the
transition opening, and a downstream end comprising an outlet
opening, wherein the downstream end of the first channel portion
comprises a wall that is orthogonal to the longitudinal center axis
of the mixing channel, so that a step is formed between the first
channel portion and the second channel portion; and a vibrating
mesh nebulizer comprising a perforated membrane, wherein the
vibrating mesh nebulizer protrudes into the first channel portion
adjacent to the wall from a side of the mixing channel so that the
perforated membrane is flush with the upstream end of the second
channel portion on the side adjacent to the vibrating mesh
nebulizer.
17. The inhalation device of claim 16, wherein the wall obstructs
about 50% of a cross-sectional area of the first channel
portion.
18. The inhalation device of claim 16, wherein the vibrating mesh
nebulizer obstructs about 50% of a cross-sectional area of the
first channel portion.
19. The inhalation device of claim 16, wherein there is a step-free
transition between the first channel portion and the second channel
portion on a side opposite the vibrating mesh nebulizer.
20. The inhalation device of claim 16, wherein the vibrating mesh
nebulizer is positioned to emit an aerosol at, or near and towards
the longitudinal center axis of the mixing channel at an angle of
90.degree. or an angle from 45.degree. to 135.degree. with respect
to the longitudinal center axis of the mixing channel.
21. The inhalation device of claim 16, wherein the vibrating mesh
nebulizer further comprises: a main member that is connectable with
a liquid drug reservoir; and a ring member made of piezoelectric
material, wherein the main member comprises a tubular portion
comprising an outer area exhibiting a ring-shaped widening onto
which the ring member is attached such that the main member extends
through the ring member.
22. The inhalation device of claim 16, wherein an opening angle of
the second channel portion immediately downstream of the step is
constant.
23. The inhalation device of claim 16, wherein the opening angle of
the second channel portion immediately downstream of the step is
not more than 8.degree..
24. The inhalation device of claim 16, wherein the inlet opening of
the mixing channel is connectable with an inlet channel of the
inhalation device.
25. The inhalation device of claim 16, wherein the vibrating mesh
nebulizer protrudes into the first channel portion adjacent to the
wall from the side of the mixing channel so that a cross-sectional
area of the second channel portion immediately downstream of the
nebulizer is smaller than a cross-sectional area of the first
channel portion immediately upstream of the nebulizer.
26. An inhalation device comprising: a mixing channel having a
longitudinal center axis, the mixing channel comprising: a first
channel portion, comprising: an upstream end comprising an inlet
opening, and a downstream end comprising a transition opening, a
second channel portion, comprising: an upstream end comprising the
transition opening, and a downstream end comprising an outlet
opening, wherein the downstream end of the first channel portion
comprises a wall that is orthogonal to the longitudinal center axis
of the mixing channel, so that a step is formed between the first
channel portion and the second channel portion; and a vibrating
mesh nebulizer comprising a perforated membrane, wherein the
vibrating mesh nebulizer protrudes into the first channel portion
adjacent to the wall from the side of the mixing channel so that a
cross-sectional area of the second channel portion immediately
downstream of the nebulizer is smaller than a cross-sectional area
of the first channel portion immediately upstream of the
nebulizer.
27. The inhalation device of claim 26, wherein the wall obstructs
about 50% of the cross-sectional area of the first channel
portion.
28. The inhalation device of claim 26, wherein the vibrating mesh
nebulizer obstructs about 50% of the cross-sectional area of the
first channel portion.
29. The inhalation device of claim 26, wherein there is a step-free
transition between the first channel portion and the second channel
portion on a side opposite the vibrating mesh nebulizer.
30. The inhalation device of claim 26, wherein the vibrating mesh
nebulizer is positioned to emit an aerosol at, or near and towards
the longitudinal center axis of the mixing channel at an angle of
90.degree. or an angle from 45.degree. to 135.degree. with respect
to the longitudinal center axis of the mixing channel.
31. The inhalation device of claim 26, wherein the vibrating mesh
nebulizer further comprises: a main member that is connectable with
a liquid drug reservoir; and a ring member made of piezoelectric
material, wherein the main member comprises a tubular portion
comprising an outer area exhibiting a ring-shaped widening onto
which the ring member is attached such that the main member extends
through the ring member.
32. The inhalation device of claim 26, wherein an opening angle of
the second channel portion immediately downstream of the step is
constant.
33. The inhalation device of claim 26, wherein the opening angle of
the second channel portion immediately downstream of the step is
not more than 8.degree..
34. The inhalation device of claim 26, wherein the inlet opening of
the mixing channel is connectable with an inlet channel of the
inhalation device.
Description
[0001] This application a continuation of U.S. application Ser. No.
14/382,392, filed Sep. 2, 2014, which is the United States national
stage of International Application No. PCT/EP2013/054705, filed
Mar. 8, 2013, which was published as International Publication No.
WO 2013/132056 A1, and which claims benefit of European Application
No. 12158852.9 filed, Mar. 9, 2012 and European Application No.
12190139.1 filed Oct. 26, 2012. All applications are incorporated
by reference in their entirety herewith.
[0002] The invention relates to a mixing channel for an inhalation
device, and in particular to a mixing channel with improved
injection and mixing properties for injecting and mixing liquid
droplets of a drug formulation into an air flow streaming in the
mixing channel, thereby producing an aerosol to be inhaled by a
patient.
[0003] There are various medical applications for inhalation
devices allowing a patient to inhale an aerosol, e.g., the
treatment of asthma, cystic fibrosis, and a number of other
respiratory diseases. An aerosol is a dispersion of small solid
particles or liquid droplets in a continuous gas phase. For medical
inhalation treatment, it is usually required to provide an aerosol
with fine droplets of a liquid formulation of a bioactive agent or
drug, e.g. an aqueous solution of the drug and suitable excipients.
Since, in the ideal case, the droplets of the liquid formulation
comprising said medical agent should reach even the smallest
branches of the lungs, it is particularly desirable to provide an
aerosol with the droplets being equally and homogeneously
distributed in the gas. Therefore, the liquid formulation of a
bioactive agent or drug is often atomised by means of a nebulizer;
i.e., an aerosol generator capable of converting a liquid into a
respirable aerosol in a continuous manner.
[0004] It is noted that inhalation devices comprising nebulizers as
aerosol generator are sometimes also referred to as nebulizers.
Consequently, it is the context which determines whether the
expression "nebulizer" should be interpreted so as to refer to the
aerosol generator only or the complete inhalation device.
[0005] As defined herein, common nebulizers are, for instance,
ultrasonic nebulizers, jet nebulizers and vibrating mesh
nebulizers. These devices operate continuously over the course of a
few breaths up to about 45 min (or longer if the patient requires
breaks during an inhalation treatment). During this time, they emit
aerosol either constantly or in pulses which are adapted to the
user's breathing pattern; e.g., triggered by the onset of
inhalation.
[0006] Further inhalation devices capable of dispersing small
droplets of liquid drug formulation in air are, for example,
pressurized metered dose inhalers, soft mist inhalers (such as
Respimat.RTM. by Boehringer Ingelheim) and other aerosol generators
with micro-machined silicon chip-type spray nozzles. These
inhalation devices are not commonly considered to represent
nebulizers, because they are designed (e.g., by the use of tension
springs) to deliver, upon actuation, only a single pulse of
aerosolised liquid. Therefore, if more than one breath was required
to administer a desired dose, repeated manual actuations would be
necessary when using e.g. pressurized metered dose inhalers and/or
soft mist inhalers. Moreover, pressurised metered dose inhalers
generate aerosol from pressurised liquids comprising propellants,
whereas nebulizers generate aerosols from unpressurised liquid
containing no propellants.
[0007] In order to ensure reproducible drug administration to the
lungs, with regard to the dose as well as the region of deposition
within the lungs, it is vital that the droplets of aerosolised
liquid formulation are as monodisperse as possible and
homogeneously distributed in the gas phase. Coalescence of droplets
and/or impaction with the inner walls of the inhalation device (or
the patient's mouth) would result in losses of drug formulation and
irreproducible dosing and deposition. Thus, sufficient mixing of
the nascent aerosol with the patient's inhalation air flow
streaming through the inhalation device is required, as well as
optimized flow properties of the "diluted" aerosol on its way from
the inhalation device into the patient's mouth and lungs.
[0008] With vibrating mesh nebulizers or ultrasonic nebulizers, the
nascent aerosol is typically rather dense, with an output rate
sometimes being in the region of about 1 ml aerosol per minute.
Hence, avoiding droplet coalescence and impaction at the inner
walls, for instance, of the vibrating mesh inhaler is more
challenging than with other inhalation devices such as the
traditional jet nebulizers with typical output rates of about 0.3
to 0.4 ml/min.
[0009] Currently available vibrating mesh nebulizers, for instance,
typically comprise a liquid reservoir, an aerosol generator
comprising the vibrating membrane (or vibrating mesh) and a
mouthpiece. These components are typically assembled so that the
nebulizer membrane is either arranged approximately vertical or
horizontal.
[0010] The benefit of horizontally arranged nebulizer membranes is
that they allow for an easy, gravity-driven and thus less variable
flow of the liquid from a reservoir positioned above said membrane.
However, the nascent aerosol is then introduced into the air flow
channel from the top and mostly perpendicular to it, so that
typically mixing chambers are required in order to avoid particle
collision with each other and/or the device's inner walls and to
homogeneously mix and slow down the aerosolized droplets within the
inspiratory air flow before inhalation by the user. Unfortunately,
these mixing chambers are rather spacious and increase the
dimensions of such inhalation devices unfavourably. Furthermore,
owing to longer residence times of the aerosol in the mixing
chamber and potential turbulences within said mixing chamber,
sedimentation and impaction of the aerosolized droplets may occur;
increasing wastage of the aerosolized formulation and decreasing
dose reproducibility. Also, such vertically stacked arrangements of
liquid reservoir, aerosol generator (with horizontal membrane) and
mixing chamber leads to devices which are rather high compared to
their width. This could lead to handling problems; e.g., devices
may tilt, especially upon filling of the reservoir or in filled
state.
[0011] With vertically arranged membranes, on the other hand, the
nascent aerosol can be introduced horizontally into the airflow
channel, and the aerosol generator can be positioned at an angle to
the direction of the air flow without changing the vertical
arrangement of the membrane. Depending on the selected angle
between the aerosol generator and the air flow channel, it is
possible to introduce the aerosol roughly in parallel or even
completely in parallel with the direction of the air flow. This
approach is, for example, chosen in WO 2009/135871 A1. However,
since the liquid has to be supplied to a vertically positioned
nebulizer membrane (rather than simply flowing onto it as it does
with horizontal membranes), even minor handling deviations, such as
tilting the device during inhalation, can lead to distinct
variations in liquid supply and aerosol output. Also, the residual
volume remaining in the liquid reservoir at the end of the
inhalation treatment is typically higher than for inhalation
devices with horizontally arranged membranes.
[0012] Another approach, as described in DE 10 2005 029 498 B4, is
the use of an annular air stream surrounding the aerosol generator
and/or the nascent aerosol, so that the aerosol plume is engulfed
in an "air jacket" to avoid particle collision with the inner walls
of the mouthpiece. This often has practical limitations. It
increases the dimensions of the device unfavourably, because the
aerosol cone broadens quickly once emitted from the membrane.
Beyond that, the annular ring slit has to be comparatively large in
order to not create turbulences. In addition, inhalation devices
using the "air jacket" approach require more components.
[0013] An approach slightly similar to said "air jacket" is the use
of air slits in the mouthpiece through which ambient air is drawn
by reduced pressure when the aerosol is passing the mouthpiece at
high speed. Such air slits are, for example, provided with the
Respimat.RTM. soft mist inhaler. While requiring far less space and
no extra components than the above mentioned annular ring slits,
the air slits in the mouthpiece are also less efficient and cannot
prevent droplet deposition within the mouthpiece and/or reduction
of the aerosol speed satisfactorily.
[0014] U.S. Pat. No. 4,592,348 B discloses a pressurized metered
dose inhaler comprising the medication canister and a dispenser
housing with an air passage running through it. The air channel of
the dispensing aid is tapered from the air inlet opening towards
the position of the dispensing port of the medication canister and
then widens from there towards the aerosol outlet opening. Like
this, a venturi throat is formed in the air passage. From the
dispensing port, aerosol is dispensed into the center of the air
stream in the direction of flow. U.S. Pat. No. 4,592,348 B
discloses that the reduced air pressure within the venturi passage
helps to atomise the liquid droplets of medication which enter the
air passage through the dispensing port. No other function is
described in the document. It does not provide any indication that
its teachings may also be applied to nebulizers.
[0015] WO 2010/065616 A1 discloses a therapeutic treatment system
comprising a delivery device for a cooled breathing gas mixture and
an injection device positioned near a distal end of said delivery
device. More specifically, the document discloses a respirator
capable of forming and emitting a mist of fine ice particles for
inhalation. The specific embodiment depicted in FIG. 3A shows a
delivery device which is also shaped as a venturi element with a
reduced cross-sectional area, so that the breathing gas mixture
increases velocity and decreases pressure when flowing through said
venturi element and over the fluid source. The lower pressure
within the venturi element is described to draw fluid from the
fluid source/the injection device into the venturi to mix it with
air, thereby causing formation of droplets or a fine mist, which
freeze to fine ice particles in the cooled gas mixture. Beyond
this, WO 2010/065616 A1 does not disclose any further function.
Moreover, it appears that a mixing channel is not necessary in the
system of WO 2010/065616 A1. The injection device is positioned
near a distal end of the therapeutic system (as can be seen in FIG.
3A), therefore the formed mist exits the device almost immediately,
creating only a minor risk of droplet impaction on walls. In
addition, the cooled breathing gas mixture provided by the
respirator freezes said mist into fine ice particles, so that there
is actually no risk of droplet coalescence as there is in an
inhalation device comprising a nebulizer.
[0016] DE 10 2005 010 965 B3 and US 2009/0050137 A1 describe an
inhalation device which employs a mixing channel. The inhalation
device provided therein has a mixing channel that is especially
adapted for supplying an aerosol to a patient's mouth in such a way
that the droplets of liquid which are contained in the aerosol
remain separated until they enter the mouth, throat, and lungs
without being deposited on the wall of the mixing channel. The
mixing channel comprises an air inlet and an aerosol outlet as well
as an injection zone therebetween, for supplying a liquid drug
through at least one nozzle orifice, which forms a part of the
channel wall and is largely flush (height difference max. 1 mm)
with the channel wall's inner surface, at least at the side facing
the air inlet. This avoids any projecting edges in the mixing
channel, which would cause turbulences and increase the risk of
droplets coalescence or deposition on the channel walls. The
inhalation device uses one or more nozzle orifice(s) in order to
inject jet(s) of droplets into the mixing channel at a certain
angle .alpha. relative to the longitudinal axis of the channel.
[0017] The cross section of the channel is either constant or
tapered from the air inlet to the injection zone. In a particular
embodiment of US 2009/0050137 A1, the cross section of the mixing
channel continuously decreases in successive longitudinal sections
from a rectangular shape at the inlet to a rectangular shape with
rounded corners across the injection zone, and then makes a
transition from rectangular shapes with rounded corners and
outwardly arched sides to a circular shape; see e.g. FIG. 13. The
increased air velocity breaks up the initially continuous fluid
jet(s) ejected from the nozzle orifice(s) into monodisperse
droplets at a short distance from the nozzle and keeping them
separated from one another and from the walls of the channel behind
the so called mixing zone.
[0018] As described, the mixing channel of the device is formed
such that its inner circumferential wall is smooth and continuous
with respect to the intended direction of flow of the air stream.
Thus, when being injected into the mixing channel, the droplets of
agent are at first concentrated in the jet spilling out of the
nozzle orifice. This is to say that the mixing process is then
mainly performed by a diffusion process, i.e. the droplets diffuse
into the air stream surrounding the jet. However, as the aerosol
only remains a restricted time in the mixing channel, there is not
enough time to achieve a spatially homogenous mixture of droplets
and air. Indeed, since the jet is injected with a certain angle
.alpha. into the air stream, e.g. .alpha.=90.degree. (or any other
angle between 10 and 170.degree.), also small turbulences occur.
However, they are relatively small due to the small size of the jet
compared with the air stream; the jet rather bends in the air
stream instead of being swirled, as depicted in FIG. 10 taken from
US 2009/0050137 A1.
[0019] US 2009/0050137 A1 does not provide any teachings as to how
their mixing channel (or, for instance, which particular shape out
of the various ones suggested), could work with a continuously
operating high output nebulizer such as a vibrating mesh nebulizer.
In fact, it should be noted here that the nozzle plate described in
DE 10 2005 010 965 B3 or US 2009/0050137 A1 with nozzle orifices
arranged in a straight line perpendicular to the direction of the
air stream is substantially different from perforated membranes of
vibrating mesh nebulizers, which typically have .about.300 up to
.about.9000 orifices, often arranged in circular or polygonal
arrays.
[0020] The problem of insufficient mixing and/or deposition within
the device is even more pronounced and important when using slow
flow rates because these offer less dispersing and entraining
qualities for the dense nascent aerosol emitted rapidly from the
vibrating mesh. However, as described in various earlier
publications by the inventors (e.g., WO 2010/089330 A1 or Griese et
al.; Am. J. Resp. Critical Care Medicine, Vol. 169, 2004, pg.
822-828), it is exactly these slow inspiratory flow rates, such as
below 20 L/min, preferably about 15 L/min, which are advantageous
for drug delivery to the deeper lungs.
[0021] For the reasons discussed above, the mixture of the droplets
into the air stream may remain incomplete when using a
state-of-the-art mixing channel in combination with a continuously
operating high output nebulizer such as a vibrating mesh nebulizer
or an ultrasonic nebulizer, which results in an inhomogeneous
distribution of droplets in the aerosol. Thus, there is a need for
a mixing channel that allows for an improved mixing process
resulting in a homogenous distribution of droplets in the
aerosol.
[0022] Therefore, the object of the present invention is to provide
a mixing channel that allows for an improved mixing process
resulting in a homogenous distribution of droplets in the aerosol.
Another object of the invention is to provide an inhalation device
comprising such a mixing channel. A further object is to reduce the
loss of aerosol droplets in an inhalation device due to coalescence
and/or deposition within the device. A yet further object is to
provide a mixing channel of comparatively small outer dimension,
which render it suitable for an optional application in small,
mobile (i.e., portable), handheld inhalation devices. This object
is achieved by a mixing channel for an inhalation device and an
inhalation device with the features according to the claims
attached hereto.
[0023] The idea of the mixing channel of the present invention is
to provide a step in the mixing channel's inner wall, or any other
means which abruptly decrease the effective cross sectional area of
the mixing channel. In contrast to the prior art, wherein--as
described above--the mixing channel comprises a smooth and
continuous inner circumferential surface, thereby avoiding the
occurrence of swirling processes, the mixing channel according to
the present invention comprises a step on its inner circumferential
surface, i.e. a discontinuity in the direction of flow. As used
herein, a step is a substantial or abrupt change in the cross
sectional area at a longitudinal locus or within a short
longitudinal section of the mixing channel. According to the
invention, the cross sectional area decreases more or less abruptly
within or at the downstream end of the injection zone. For example,
the step may be formed so as to obstruct about 50% of the cross
section of the mixing channel. The injection zone, as used herein,
is that part of the mixing channel where the injection of the
nascent aerosol occurs and/or where the aerosol emitted from the
nebulizer is initially mixed with air. The injection zone, as well
as other features of the invention, will be defined in further
detail, also in combination with the figures. Herein, a step is
understood as an offset or change in the level of the inner surface
of the mixing channel, the step being formed by three successive
surface portions. The angle between two neighboring surface
portions is in a range from 80.degree.-100.degree., preferably
85.degree.-95.degree., more preferably essentially 90.degree., and
most preferably 90.degree..
[0024] The process of equally distributing the droplets into the
air stream is further supported by the fact that the mixing channel
is restricted to a smaller effective cross section (compared to the
inlet opening) through the step, and immediately behind the step,
and only gradually increases again towards the outlet opening. That
is to say that the reduced cross sectional area is owed to an
actual step rather than just a baffle-type wall protruding from an
inner wall; as can be seen in FIG. 1A. Here, the term "effective
cross section" shall denote that part of the cross section that is
actually open to the air stream, i.e. that part of the cross
section that is confined by the inner circumferential wall of the
mixing channel, independently of the mixing channel's outer
circumferential wall that may not reflect the step. Further, the
wording "behind the step" as well as all similar terms designating
a position, orientation or direction shall be related here and in
the following to the intended direction of flow of the air stream
in the mixing channel, i.e., from inlet opening to outlet
opening.
[0025] Due to the restricted cross section, the flow profile and
the flow rate, more precisely the velocity, of the air flow changes
at the position of the step in that the air and the aerosol undergo
an acceleration there. According to the invention, as will be
described later in detail, the nebulizer is placed directly
adjacent to, i.e. in front of, the step in the mixing channel or
forms the step itself, as can e.g. be seen in FIG. 11B. Typically,
only a part of the nebulizer is actually inserted and protruding
into the mixing channel, not the whole nebulizer. In the specific
embodiment depicted in FIGS. 11A and B, this inserted part
comprises the downstream end of a vibrating mesh nebulizer which
has affixed the vibrating mesh at its bottom from where the nascent
aerosol is emitted. Consequently, the jet of droplets is injected
at or directly behind the step into the mixing channel, i.e. at a
position with high air velocity. As the air is accelerated here
compared with upstream or in front of the step, the density of the
nascent aerosol in the air stream is kept small (in comparison to
the case that the droplets were injected into an air stream with a
lower velocity--like, e.g., before the step) because the droplets
are rapidly entrained and diluted in the fast air stream. A
decreased density is of the advantage that the average distance
between the droplets is increased and so an unwanted coalescing of
the droplets--that would lead to larger average diameters of the
droplets--can be largely avoided or reduced.
[0026] Furthermore, as the shape of the mixing channel behind the
step is preferably a truncated cone that widens towards its
downstream end, a deposition of the droplets on the inner wall of
the mixing channel can be avoided or reduced. These depositions can
be further reduced by a suitable anti-static coating material.
[0027] Moreover, the accelerated air stream behind the step becomes
decelerated again due to the trumpet-like shape of the truncated
cone. This way, at the outlet of the mixing channel, the flow is
reduced so that it attains a value suitable for the inflow into the
patient's mouth without impaction and for the transport into the
deeper lung areas. Thus, the mixing channel behind the step is
shaped such as to act as a diffusor.
[0028] Unexpectedly, it was found by the inventors that the mixing
channel of the invention achieves a sufficiently large acceleration
of the air flowing inside the channel at a moderate flow rate (of
e.g. 15 l/min) to ensure that an aerosol, even when emitted by a
nebulizer having a high output rate (such as about 0.5 ml/min or
more, or about 0.8 or more, or even about 1 ml/min or more) from
the top into the mixing zone at an angle of about 90 relative to
the longitudinal center axis of the mixing channel, is rapidly
mixed with the air and diluted without substantial impaction on the
wall of the mixing channel and without substantial coalescence. It
was also surprising to find that the mixing channel as described
herein could be miniaturised and still be effective to achieve
these results. It is noted that the conditions mentioned above,
i.e. the incorporation of a highly efficient nebulizer in an
inhalation device adapted for a slow inspiratory flow rate are
particularly challenging with respect to the propensity of the
nascent aerosol to coalesce and become deposited within the
device.
[0029] Depending on the flow rate within the mixing channel, it was
observed that the abrupt decrease of the effective cross sectional
area at the step may lead to a rapid deflection and acceleration of
the flowing air even without substantially interfering with a
laminar flow. This was confirmed by computational flow
simulations.
[0030] One aspect of the invention relates to a mixing channel for
an inhalation device, comprising an inlet opening, an outlet
opening, and an injection zone located between the inlet opening
and the outlet opening. The injection zone has a longitudinal
center axis and comprises (a) a built-in nebulizer, or (b) a
detachable nebulizer, or (c) a member adapted to receive a
detachable nebulizer. Furthermore, the effective cross sectional
area of the mixing channel in a plane perpendicular to the
longitudinal center axis is smaller in the injection zone than
upstream of the injection zone. More specifically, the effective
cross sectional area of the mixing channel in a plane perpendicular
to the longitudinal center axis decreases abruptly in the direction
of air flow within or at the downstream end of the injection zone
such that said cross sectional area is smaller in the injection
zone than upstream of the injection zone. The abrupt decrease in
cross sectional area preferably forms a step in the mixing
channel.
[0031] Optionally, the shape of the cross sectional area is
circular or elliptical, alternatively rectangular, at the upstream
end of the injection zone and becomes semi-circular or
semi-elliptical at the downstream end of the injection zone.
[0032] As defined herein, the shape of cross sectional areas with
an aspect ratio (i.e., the ratio between the largest diameter and
the smallest diameter orthogonal to it) of not more than
.about.1.3:1 are considered circular or approximately circular,
whereas those with aspect ratios larger than .about.1.3:1 will be
considered elliptical. In analogy, the terms "approximately
semi-circular" or "approximately semi-elliptical" refers to shapes
which resemble circular or elliptic ones cut in halves; optionally
with rounded edges and/or the circumferential lines slightly
arching outwards.
[0033] Depending on the precise shape of the approximately
semi-circular or semi-elliptical cross section, the size of the
cross sectional area is decreased abruptly at the downstream side
of the injection zone to about half the area, or slightly less,
compared to the area on the upstream side of the injection zone.
One example of an approximately semi-circular cross section
according to the invention is depicted in FIG. 11C.
[0034] Throughout the following, the term "direction of flow" shall
be understood as the direction from the inlet opening to the outlet
opening of the mixing channel.
[0035] One aspect of the invention relates to a mixing channel
comprising a first channel portion and a second channel portion
downstream of the first channel portion. The first channel portion
comprises the inlet opening and the injection zone. The built-in
nebulizer, detachable nebulizer or member adapted to receive a
detachable nebulizer is in, or extends from, a lateral position
relative to the longitudinal center axis of the injection zone.
Preferably, the built-in nebulizer, or the detachable nebulizer, or
the member adapted to receive a detachable nebulizer are arranged
or located on a longitudinal side portion or side wall of the
mixing channel. Thus, the built-in nebulizer, or the detachable
nebulizer may be arranged in a direction transversal to the
longitudinal direction or axis of the mixing channel.
[0036] One aspect of the invention relates to a mixing channel,
wherein the built-in nebulizer protrudes into the mixing channel.
Alternatively, the detachable nebulizer protrudes into the mixing
channel. Such "protruding" or extension is preferably not beyond
the longitudinal center axis of the mixing channel.
[0037] A further aspect of the invention relates to a mixing
channel, wherein the built-in nebulizer or the detachable nebulizer
is arranged in the injection zone such that the effective cross
sectional area of the mixing channel in a plane perpendicular to
the longitudinal center axis is smaller in the injection zone, or
at the downstream end of the injection zone, than upstream of the
injection zone. More specifically, the built-in nebulizer or the
detachable nebulizer extends from a lateral position relative to
the longitudinal center axis (A) of the injection zone (3) and
protrudes into the injection zone (3) such that the size of the
effective cross sectional area of the mixing channel in a plane
perpendicular to the longitudinal center axis (A) decreases
abruptly in the direction of air flow within or at the downstream
end of the injection zone (3).
[0038] A further aspect of the invention relates to a mixing
channel, wherein upon the detachable nebulizer being received in
said member, the effective cross sectional area of the mixing
channel in a plane perpendicular to the longitudinal center axis is
smaller in the injection zone than upstream of the injection zone.
More specifically, this aspect of the invention relates to a mixing
channel, wherein upon the detachable nebulizer being received in
said member, the size of the effective cross sectional area of the
mixing channel in a plane perpendicular to the longitudinal center
axis is decreased abruptly within or at the downstream end of the
injection zone (3).
[0039] In other words, while the step may be formed by the size and
shape of the walls of the mixing channel and its openings as such,
the inserted nebulizer which protrudes into the mixing channel may
also be understood as forming a step.
[0040] As already described, the mixing channel comprises a first
channel portion and a second channel portion downstream of the
first channel portion. Preferably, the inner surface of the wall of
the mixing channel forms a continuous or step-free transition
between the downstream end of the first channel portion and the
upstream end of the second channel portion on the side opposite to
the built-in nebulizer, detachable nebulizer or member adapted to
receive a detachable nebulizer. In other words, the step is
primarily formed on that side of the mixing channel where the
nebulizer or member adapted to receive the nebulizer is located,
whereas the opposite side is shaped in such a way that it does not,
or not significantly, contribute to the step.
[0041] The first channel portion preferably comprises the inlet
opening forming an air inlet, and a member adapted to receive a
detachable nebulizer, which may be realized by a through-hole. The
first channel portion may be shaped as a preferably circular, but
optionally also elliptic or rectangular, cylinder with a
longitudinal center axis A. This cylinder is preferably confined at
its upstream end by the inlet opening, which can be considered as a
cut through the cylinder along a cross sectional plane, which is
not necessarily orthogonal to the longitudinal center axis A.
[0042] The inlet opening may thus be shaped as a preferably
circular, but optionally also elliptic. Alternatively, the inlet
opening is rectangular, for example with right-angled corners or
with rounded corners.
[0043] The through-hole may be arranged at the very downstream end
of the first channel portion on one side of the circumferential
wall of the cylinder. At its downstream end, the first channel
portion may be partially closed by a wall that is arranged on a
cross sectional plane orthogonal to the longitudinal center axis A;
i.e. the step. Thereby, the wall may be arranged so as to cover
approximately 50% of the cross sectional size at downstream end of
the first channel portion on the side of the through-hole. The
remaining opening of the downstream end of the first channel
portion may be formed as an approximate semi-circle. Alternatively,
the remaining opening of the downstream end of the first channel
portion may be formed approximately semi-elliptical, such as e.g.
when the first segment of the mixing channel is shaped as an
elliptical cylinder.
[0044] In this embodiment, the downstream opening, or end, of the
first channel portion is at the same time the upstream opening, or
end, of the second channel portion. That is, it forms a transition
opening between the first and the second channel portion. Thus, the
transition opening between the first channel portion and the second
channel portion forms a virtual section or plane distinguishing the
first channel portion from the second channel portion. Because of
said wall partially closing the downstream end of the first channel
portion, a step is formed at the site of the transition between
both channel portions.
[0045] The first channel portion may also be understood as a mixing
chamber. According to an aspect of the invention, a mixing chamber
for an inhalation device is provided which has a substantially
cylindrical or cylindroidal wall and a substantially first, for
example horizontal, orientation. The mixing chamber comprises an
inlet opening at its upstream end, a mixing chamber outlet opening
(which is identical with the transition opening mentioned above) at
its downstream end, and an injection zone for aerosol. Moreover, it
includes a built-in or detachable nebulizer extending from the top
of the mixing chamber such as to protrude into the injection zone
and to emit aerosol at or near the longitudinal center axis of the
injection zone at an angle of 90.degree. or an angle from 450 to
135.degree. with respect to the longitudinal center axis A of the
injection zone. The mixing chamber outlet opening may have a
substantially second, for example vertical, orientation and be
positioned between the longitudinal center axis and the wall of the
mixing chamber opposite of the position from which the nebulizer
extends into the mixing chamber.
[0046] As mentioned, the inlet opening may optionally be circular
or elliptic. Optionally, the diameter or, in the case of an
elliptic opening, the average diameter may be in the range from
about 5 to 15 mm, in particular from about 7 to about 12 mm, such
as from about 8 to about 10 mm.
[0047] The outlet opening of the mixing channel may be connectable
with a mouthpiece for inhalation by a user. The mouthpiece may
comprise an inner part and an outer part. The inner part of the
mouthpiece is connected to the downstream end of the second channel
portion, for example by means of an air tight pressfit. Thereby,
the inner part of the mouthpiece acts as or forms an extension of
the second channel portion. Furthermore, the connection between the
inner part of the mouthpiece and the second channel portion may be
formed as a continuous or step-free transition. This way, the
profile of an air stream propagating through the mixing channel is
not disturbed in the area of this connection. When being connected
to the mixing channel, the outer part of the mouthpiece may cover
approximately two thirds of the second channel portion of the
mixing channel on the downstream side. Thus, part of the outer part
of the mouthpiece surrounds the inner part of the mouthpiece in a
concentric manner.
[0048] Alternatively, the second channel portion and the mouthpiece
may be shaped as one single part.
[0049] One aspect of the invention relates to a mixing channel,
wherein the longitudinal center axis of the second channel portion
and the longitudinal center axis of the injection zone form an
angle of preferably 180.degree.; i.e. they are parallel to each
other.
[0050] One aspect of the invention relates to a mixing channel,
wherein the longitudinal center axis of the second channel portion
and the longitudinal center axis of the injection zone form an
angle of preferably not less than 172.degree.. In other words, if
the two axes are not parallel, they should form an obtuse angle of
not less than 172.degree., i.e. in the range of 172.degree. to
180.degree..
[0051] As described earlier, the built-in nebulizer or the
detachable nebulizer protrudes into the injection zone of the
mixing channel. One aspect of the invention relates to a mixing
channel, wherein the built-in nebulizer or detachable nebulizer is
positioned such as to emit the aerosol at the longitudinal center
axis of the injection zone, or near and towards the longitudinal
center axis of the injection zone. As used herein, the expression
"near the longitudinal center axis" should be understood to
describe that the downstream end of the nebulizer is substantially
closer to the longitudinal center axis than to a lateral wall of
the mixing channel.
[0052] One aspect of the invention relates to a mixing channel,
wherein the nebulizer (be it the built-in nebulizer or the inserted
detachable nebulizer) is flush with a part of the inner surface of
the wall of the mixing channel downstream of the injection zone. In
other words, the end of the downstream part of the nebulizer is
flush with the step, which is e.g. the case if both the downstream
end of the nebulizer and the highest point of the transition
opening (or of the mixing chamber outlet opening) are at or near
the longitudinal center axis of the mixing channel.
[0053] One aspect of the invention relates to a mixing channel,
wherein the shape of the cross sectional area of the mixing channel
downstream of the injection zone is inconstant. One aspect of the
invention relates to a mixing channel, wherein the size of the
cross sectional area of the mixing channel downstream of the
injection zone is inconstant. One aspect of the invention relates
to a mixing channel, wherein the shape and the size of the cross
sectional area of the mixing channel downstream of the injection
zone is inconstant.
[0054] More specifically, one aspect of the invention relates to a
mixing channel, wherein the cross sectional area of the mixing
channel downstream of the injection zone increases in size along
the direction of flow. Preferably, the cross sectional area
increases continuously. In this respect, the term continuously is
to be understood such that the increases in cross sectional area
are not stepwise but steadily, so as to leave the inner walls of
the second segment of the mixing channel (i.e. downstream of the
injection zone) smooth and free of edges, in order to avoid or
reduce turbulences and/or flow stalls here which could cause
deposition of aerosol droplets within the second segment.
[0055] The second channel portion may essentially be formed as a
truncated cone or tapered elliptical cylinder. Due to the step
mentioned above, the second channel portion may not be symmetrical
or coaxial with respect to the longitudinal center axis A of the
first channel portion.
[0056] The widening of the channel in the second segment serves to
decrease the velocity of the aerosol so that the decelerated
aerosol droplets are not deposited in the throat of the user, but
reach the lungs.
[0057] The second channel portion is preferably shaped as follows:
Taking a sequential series of cross sections of the second channel
portion from the upstream to the downstream end (each of the cross
sections being orthogonal to the longitudinal center axis A of the
first channel portion), the first cross section has an
approximately semi-circular or semi-elliptical shape corresponding
to the upstream opening, or transition opening, of the second
channel portion. Then, the shape of each of the subsequent cross
sections extends over the shape of the respective previous cross
section. The cross section having the largest size out of that
series corresponds to the downstream opening of the second channel
portion. The downstream opening of the second channel portion forms
at the same time the outlet opening of the mixing channel.
[0058] One aspect of the invention relates to a mixing channel,
wherein the opening angle, which is roughly twice the angle .alpha.
between the center axis of the second channel portion and any
tangential plane (i.e. that line of the tangential plane which is
also part of a longitudinal section) on the inner surface of the
second channel portion, is not more than about 8.degree..
[0059] Due to this limitation, stalls and turbulences potentially
causing aerosol deposition in the second segment can be largely
avoided.
[0060] One aspect of the invention relates to a mixing channel,
wherein the opening angle as described herein is not more than
about 6.degree.. For example, the opening angle may be about
5.degree., about 5.5.degree., or about 6.degree..
[0061] One such alternative of the invention relates to a mixing
channel, wherein the opening angle is constant or approximately
constant (i.e., in the form of a truncated cone).
[0062] With regard to the opening angle, and/or the angle .alpha.
which is roughly half of the opening angle, it should be noted that
these angles may differ slightly depending on the particular
longitudinal section under consideration. Since the shape of the
transition opening and the air outlet may differ somewhat, the
respective opening angle of the second segment along a horizontal
longitudinal section may also slightly differ from that of a
vertical longitudinal section. In this case, the opening angle
should be understood as the mean opening angle along any such
longitudinal section. For example, an opening angle of not more
than about 8.degree. (i.e., a not more than about 4.degree.) or
alternatively not more than about 6.degree. (i.e., a not more than
about 3.degree.) refers to the mean value of the respective angles
for different longitudinal sections.
[0063] Moreover, in case the downstream end of the second segment
at the outlet opening is rounded such as to avoid sharp edges, this
rounded downstream end should not be taken into consideration when
determining the mean angles.
[0064] The term "constant", when referring to the opening angle
and/or angle .alpha., is to be understood as meaning constant along
a longitudinal section on an inner surface of the second channel
portion from the transition opening nearly to the outlet opening
(not taking a rounded downstream end into account). In other words,
the line where the longitudinal section intersects the inner
surface of the second segment is a straight line, at least for most
of its length, such as over 80% of its length or more, or even over
90% of its length or more. For example, the opening angle could be
about 5.degree. at the upstream opening, or transition opening, of
the second mixing channel segment as well as about 5.degree.
further downstream.
[0065] Another alternative of the invention relates to a mixing
channel, wherein the angle between the center axis of the second
channel portion and a tangential plane on the inner surface of the
second channel portion is increasing along the direction of flow.
For example, the (mean) opening angle could be about 5.degree. at
the upstream opening, or transition opening, of second segment and
increase to about 6.degree. towards the outlet opening of second
mixing channel segment.
[0066] One aspect of the invention relates to a mixing channel,
wherein the built-in nebulizer or detachable nebulizer is
positioned such as to emit the aerosol into the mixing channel at
an angle of 90.degree. or at an angle within a range from 450 to
135.degree., preferably 60.degree. to 120.degree., more preferably
85.degree. to 95.degree. with respect to the longitudinal center
axis A of the injection zone. This is of particular importance for
vibrating mesh nebulizers, where the liquid is supposed to flow
freely and gravity-driven from a reservoir to a horizontally
arranged vibrating mesh, and more pronounced tilting of the
nebulizer could result in spillage, deceleration of aerosol output,
and/or incomplete aerosolization of the liquid formulation.
[0067] One aspect of the invention relates to a mixing channel,
wherein the inlet opening of the mixing channel forms the inlet
opening of the inhalation device.
[0068] One aspect of the invention relates to a mixing channel,
wherein the inlet opening of the mixing channel is connectable with
an inlet channel of the inhalation device.
[0069] One aspect of the invention relates to a mixing channel,
wherein the reduction of the cross section area of the mixing
channel in the area of the injection zone is configured such as to
cause a change in the flow profile of a medium when the medium is
streaming through the mixing channel.
[0070] One aspect of the invention relates to a mixing channel,
comprising a filter positioned upstream of the injection zone,
preferably near the inlet opening. The filter is preferably a
hydrophobic filter with a low flow resistance. The filter may be
made from polyester. "Low flow resistance" preferably means that it
effects a pressure drop of not more than 5 mbar at a flow of 15
L/min. The use of such a filter may be valuable for retaining air
borne particles which could introduce uncontrollable turbulences
and interfere with the laminar flow of the air stream within the
mixing channel.
[0071] One aspect of the invention relates to a mixing channel,
wherein the inner surface of the wall of the mixing channel is at
least partially coated with a layer of a biocompatible material,
wherein said biocompatible material is preferably antistatic and/or
made from poly(p-xylylene).
[0072] In a further aspect, the built-in nebulizer or detachable
nebulizer is an ultrasonic nebulizer or a vibrating mesh nebulizer.
As used herein, a nebulizer means an aerosol generator, or
atomiser, capable of converting a non-pressurised liquid into an
inhalable aerosol in a continuous manner. In particular, the
built-in or detachable nebulizer is a vibrating mesh nebulizer,
i.e. a nebulizer with a mesh, or perforated membrane, through which
the liquid which is to be nebulised is extruded by means of
vibration. Typically, the perforated membrane is vibrated by a
piezo element (thus the expression, vibrating mesh nebulizer);
however, it may also be possible to vibrate the liquid rather than
the membrane and thereby generate the aerosol.
[0073] It is particularly useful to practise the invention by using
a nebulizer with a high output rate. In this context, the output
rate of the nebulizer means the amount of liquid which is converted
into an aerosol per time unit. Optionally, a nebulizer with an
output rate of at least about 0.5 ml/min is selected. The output
rate may also be at least about 0.8 ml/min, or at least about 1.0
ml/min, respectively.
[0074] One aspect of the invention relates to a mixing channel,
wherein the built-in nebulizer or detachable nebulizer comprises a
main member, preferably a turned part, a ring member made of
piezoelectric material, and a perforated membrane, wherein the main
member comprises a tubular portion comprising an outer area
exhibiting a ring-shaped widening onto which the ring member is
attached such that the main member extends through the ring member,
and the perforated membrane being connected into or onto the front
part of the main member; and the main member being connectable with
a liquid drug reservoir.
[0075] One aspect of the invention relates to a mixing channel,
wherein the built-in nebulizer or detachable nebulizer is connected
to the mixing channel in an air-tight manner, and preferably by
means of a sealing lip. The sealing lip is preferably produced by
two component molding.
[0076] A further aspect of the invention relates to an inhalation
device comprising one embodiment of the mixing channel according to
the invention. The inhalation device may comprise a case or housing
and a mouthpiece. The mouthpiece may be connected with the second
channel portion of the mixing channel, as described above, or it
may itself represent the second channel portion.
[0077] One aspect of the invention relates to an inhalation device,
wherein the mixing channel according to the invention is connected
with the inhalation device in an air-tight manner, and preferably
by means of a sealing lip, wherein the sealing lip is preferably
produced by two component molding.
[0078] The inhalation device may comprise a main body which may be
covered by or received in a base piece of the housing. The main
body may comprise a chamfer or recess into which the mixing channel
may be detachably placed. Thereby, the mixing channel is placed so
into the main body that the through-hole is located on the side
opposite to the main body or opposite to the base piece of the
housing. Onto the through-hole may be placed a reservoir member
holding a drug reservoir, configured to receive a liquid drug
formulation. Furthermore, a nebulizer may be either comprised
within the reservoir member or attached thereto. An exemplary
inhalation device suitable for incorporating a mixing channel
according to the invention is described, for instance, in the
co-pending European patent application number 12 19 0139.1 or the
international application PCT/EP2012/076963.
[0079] In a further aspect, the inhalation device is adapted for,
or configured to, allowing the user to inhale air and/or aerosol
through the mouthpiece at an inspiratory flow rate of not more than
about 20 l/min, such as from about 10 to 20 l/min, or from about 12
to 18 l/min, such as about 15 l/min. Optionally, the inhalation
device may comprise a feature which restricts the air flow, e.g. by
means of a responsive flow restrictor, to a particular maximum flow
rate, of e.g. 20 l/min or 18 l/min. Alternatively, or in addition,
the inhalation device may provide the use with visible, audible or
tactile feedback or guidance such as to enable the user to inhale
at the desired inspiratory flow rate.
[0080] Other aspects, features, and advantages will be apparent
from the summary above, as well as from the description that
follows, including the figures and the claims.
LIST OF FIGURES
[0081] FIG. 1A shows a vertical section through the longitudinal
center axis of an embodiment of the mixing channel 1 according to
the invention.
[0082] FIG. 1B shows a cross section of the first channel portion
2a of mixing channel 1 according to B-B in FIG. 1.
[0083] FIG. 2 shows a bottom view of the mixing channel 1 according
to the invention.
[0084] FIG. 3A shows a side view of the mixing channel 1 according
to the invention.
[0085] FIG. 3B shows the mixing channel 1 seen from side of the
outlet opening 5.
[0086] FIG. 3C shows the mixing channel 1 from the side of the
inlet opening 4.
[0087] FIG. 4 shows a top view of the mixing channel 1 according to
the invention.
[0088] FIG. 5 shows a vertical section through the longitudinal
center axis of another embodiment of the mixing channel 1.
[0089] FIG. 6 shows a perspective view of the mixing channel 1
connected to the mouthpiece 20.
[0090] FIG. 7 shows an inhalation device comprising the mixing
channel 1.
[0091] FIG. 8 is an exploded view of the inhalation device shown in
FIG. 7.
[0092] FIG. 9 shows an exploded view of a nebulizer configured to
be inserted into the through-hole 3a of the mixing channel 1.
[0093] FIG. 10 shows a channel according to the prior art.
[0094] FIG. 11A shows a vertical section through the longitudinal
center axis of an embodiment of the mixing channel 1 according to
the invention prior to insertion of a nebulizer
[0095] FIG. 11B shows a vertical section through the longitudinal
center axis of an embodiment of the mixing channel 1 according to
the invention with a nebulizer inserted
[0096] FIG. 11C shows an enlarged cross section of the mixing
channel at the transition opening 7 between first channel portion
2a and second channel portion 2b along the line B-B depicted in
FIG. 11B
[0097] FIG. 12 shows the angle .alpha. between the center axis of
the second channel portion and one exemplary tangential plane on
the inner surface of the second channel portion, i.e., the line of
the tangential plane which is also part of a longitudinal
section
[0098] Embodiments of the invention are explained below with the
help of FIGS. 1A to 9, FIGS. 11 and 12. FIG. 10 refers to prior
art.
[0099] FIG. 1A shows a vertical section through the longitudinal
center axis of an embodiment of the mixing channel 1 according to
the invention. The mixing channel 1 comprises a first channel
portion 2a and a second channel portion 2b. The first channel
portion 2a comprises an inlet opening 4 forming an air inlet, and a
member adopted to receive a detachable nebulizer, which is realized
here by a through-hole 3a. Thereby, the first channel portion 2a is
shaped as a cylinder with a longitudinal center axis A. This
cylinder is confined at its upstream end by the inlet opening 4,
which can be considered as a virtual cut through the cylinder along
a cross sectional plane, which is not necessarily orthogonal to the
longitudinal center axis A. The through-hole 3a is arranged at the
very downstream end of the first channel portion 2a on one side of
the circumferential wall of the cylinder. At its downstream end,
the first channel portion 2a is partially closed by a wall that is
arranged on a cross sectional plane orthogonal to the longitudinal
center axis A. Thereby, the wall is arranged so as to cover
approximately 50% of the downstream end of the first channel
portion 2a on the side of the through-hole 3a. The remaining
opening of the downstream end of the first channel portion 2a is
formed as an approximate semi-circle, as shown in detail in FIGS.
3B and 3C as well as FIG. 11C (therein, cf. reference numeral 7
labelling the transition opening explained below).
[0100] The downstream opening of the first channel portion 2a is at
the same time the upstream opening of the second channel portion
2b; in other words, it forms a transition opening 7 between the
first and the second channel portion. Thus, the transition opening
7 between the first channel portion 2a and the second channel
portion 2b forms a virtual section or plane distinguishing the
first channel portion 2a from the second channel portion 2b.
Because of said wall partially closing the downstream end of the
first channel portion 2a, a step 18 is formed at the site of the
transition between channel portions 2a and 2b. The second channel
portion 2b is essentially formed as a truncated cone or tapered
elliptical cylinder. Due to the step 18, the second channel portion
2b is not symmetrical or coaxial with respect to the longitudinal
center axis A of the first channel portion 2a.
[0101] The second channel portion 2b is formed as follows (cf.
FIGS. 1 and 3B together): Taking a sequential series of cross
sections of the second channel portion 2b from the upstream to the
downstream end (each of the cross sections being orthogonal to the
longitudinal center axis A of the first channel portion 2a), the
first cross section has a semi-circular shape corresponding to the
upstream opening of the second channel portion 2b. Then, the shape
of each of the subsequent cross sections extends over the shape of
the respective previous cross section. The cross section having the
largest size out of that series corresponds to the downstream
opening of the second channel portion 2b. The downstream opening of
the second channel portion 2b forms at the same time the outlet
opening 5 of the mixing channel 1. The outlet opening 5 may be
connectable with a mouthpiece for inhalation by a user.
[0102] FIG. 1B shows a cross section of the first channel portion
2a mixing channel 1 along the line B-B depicted in FIG. 1A. The
circumferential wall of the first channel portion 2a is essentially
formed as a, preferably circular, cylinder. On one side of the
cylinder, a through-hole 3a is arranged, which acts as a member 6
adapted to receive a detachable nebulizer.
[0103] FIGS. 2, 3A, and 4 show, respectively, a bottom view, a side
view, and a top view of an embodiment of the mixing channel 1
according to the invention. The first channel portion 2a comprises
at its upstream end the inlet or rear opening 4. At or near or
adjacent to the downstream end of the first channel portion 2a, a
through-hole 3a is arranged. Directly behind (with respect to the
direction from the upstream to the downstream end) the through-hole
3a, a step 18 is formed by a wall arranged perpendicular to the
longitudinal center axis A of the first channel portion 2a, the
wall partially closing the downstream end of the first channel
portion 2a. Downstream of the first channel portion 2a, the mixing
channel 1 comprises the second channel portion 2b formed as a
tapered elliptical cylinder with the outlet opening 5 at its
downstream end.
[0104] FIG. 3B shows an embodiment of the mixing channel 1 as seen
from the side of the outlet or front opening 5, i.e. a front view,
wherein the second channel portion 2b formed as a tapered
elliptical cylinder. A number of concentric ellipsoidal contour
lines 17 visualize the tapered shape of the second channel portion
2b. The approximately semi-circular contour line 7 depicts the
transition opening between the first channel portion 2a and the
second channel portion 2b. In this context, please be also referred
to the description of FIG. 1 given above.
[0105] FIG. 3C shows the same mixing channel 1 as in FIG. 3B now
from the side of the inlet opening 4, i.e. a rear view. Seen from
this side, the first channel portion 2a appears as a circle. Inside
the inlet opening 4, the transition opening 7 between the first
channel portion 2a and the second channel portion 2b is visible as
a semi-circular shape. The contour of the second channel portion 2b
is visible behind the inlet opening 4 as an ellipsoidal
profile.
[0106] FIG. 5 shows the view of a vertical section through the
longitudinal center axis of another embodiment of the mixing
channel 1 according to the invention similar to FIG. 1a, which is
connected to a mouthpiece 20. The mouthpiece 20 comprises an inner
part 20a and an outer part 20b. The inner part 20a of the
mouthpiece 20 is connected to the outlet opening 5 at the
downstream end of the second channel portion 2b, for example by
means of an air tight press-fit 21. Thereby, the inner part 20a of
the mouthpiece 20 acts as or forms an extension of the second
channel portion 2b. Furthermore, the connection between the inner
part 20a of the mouthpiece 20 and the second channel portion 2b is
formed as a continuous or step-free transition. This way, the
profile of an air stream propagating through the mixing channel 1
is not disturbed in the area of this connection. When being
connected to the mixing channel 1, the outer part 20b of the
mouthpiece 20 may cover, for example, approximately two thirds of
the second channel portion 2b of the mixing channel 1 on the
downstream side.
[0107] FIG. 6 shows a perspective view of the mixing channel 1
connected to the mouthpiece 20. The connection site is located
inside the outer circumferential wall of the mouthpiece 20 and
therefore not visible. The upstream end of the second channel
portion 2b extends out of the mouthpiece 20 and is therefore
visible. FIG. 6 gives also a three dimensional view of the first
channel portion 2a comprising the inlet opening 4 and the
through-hole 3a and connected to the upstream end of second channel
portion 2b. Through-hole 3a is surrounded by a sealing lip 12.
[0108] FIG. 7 shows an inhalation device comprising the mixing
channel 1 according to the invention. The inhalation device
comprises a case or housing 23 and the mouthpiece 20. However, the
mixing channel 1 itself is not visible from this perspective, since
its upstream part is located inside the inhalation device, and the
downstream part is covered by the mouthpiece 20.
[0109] FIG. 8 is an exploded view of the inhalation device shown in
FIG. 7. A main body 26 is covered or received in a base piece 27 of
a housing. The main body 26 comprises a chamfer 28, into which the
mixing channel 1 (preferably) connected to a mouthpiece 20 is
placed. Thereby, the mixing channel 1 is placed so into the chamfer
28 that the through-hole 3a is located on the side opposite to the
main body 26 or opposite to the base piece 27. Onto the
through-hole 3a is placed a reservoir member 25 including a
reservoir for a liquid drug formulation (not shown). Furthermore, a
nebulizer (not shown in FIG. 8, cf. FIG. 9) may be comprised within
the reservoir member 25, optionally in direct contact with the drug
reservoir.
[0110] FIG. 9 shows an exploded view of a nebulizer 16 configured
to be inserted into the through-hole 3a of the mixing channel 1.
The depicted nebulizer 16 may be a built-in nebulizer or a
detachable nebulizer. The nebulizer comprises a main member 8
formed as a turned part. The main member 8 comprises a tubular
portion comprising an outer area exhibiting a ring-shaped widening
11. A ring member 9 made of piezoelectric material is attached to
the ring-shaped widening 11 such that the main member 8 extends
through the ring member 9. Further, a perforated membrane 10 is
connected into or onto the downstream part, or front part, 15a of
the main member 8. The main member 8 is connectable with a drug
reservoir (not shown) for a liquid drug at its upstream end 15b.
Typically, only the downstream part 15a of the nebulizer 16 is
inserted in the through-hole 3a, not the whole nebulizer 16.
[0111] FIG. 10 shows a channel according to the prior art.
[0112] FIG. 11A shows a vertical section through the longitudinal
center axis of an embodiment of the mixing channel 1 according to
the invention, similar to FIG. 1A, prior to insertion of a
nebulizer 16 similar to that of FIG. 9. The mixing channel 1
comprises a first channel portion 2a, or mixing chamber 13,
confined by a substantially cylindrical or cylindroidal wall (14),
with an inlet opening 4, a member 6 adopted to receive a detachable
nebulizer 16 and its through-hole 3a; a second channel portion 2b
with outlet opening 5 and a transition opening 7 at the step 18
where the cross sectional diameter of the mixing channel 1
decreases abruptly, such that the cross sectional area is smaller
at the step 18 in the injection zone 3 than upstream of the
injection zone 3. The nebulizer 16 is to be positioned in such a
way that its downstream end 15a with the perforated membrane 10 is
inserted through through-hole 3a, while the piezoelectric
ring-member 9 and the ring shaped widening 11 (which holds the
piezoelectric ring-member 9 in place) remain on the outside of the
mixing channel 1. The upstream end 15b of the nebulizer 16 is open
and connectable to a liquid reservoir. Optionally, the nebulizer 16
may be fixed within reservoir member 25 (not shown), so that proper
insertion of the nebulizer is assured by the correct assembly of
reservoir member 25 onto the inhalation device as depicted in FIGS.
7 and 8.
[0113] FIG. 11B shows a vertical section through the longitudinal
center axis of an embodiment of the mixing channel 1 according to
the invention as depicted in FIG. 11A, now with the nebulizer 16
inserted and positioned such that the downstream part 15a of the
nebulizer 16 with the perforated membrane 10 is positioned
approximately flush with the upper part of the inner surface of the
wall of the mixing channel 1 downstream of the injection zone 3. In
other words, the end of the downstream part 15a of the nebulizer 16
is flush with the step 18.
[0114] FIG. 11C shows an enlarged cross section of the mixing
channel at the transition opening 7 between first channel portion
2a and second channel portion 2b along the line B-B depicted in
FIG. 11B.
[0115] FIG. 12 shows the angle .alpha. between the center axis of
the second channel portion 2b and an exemplary tangential plane on
the inner surface (or, in this case, the line at the intersection
of a vertical longitudinal section and the inner surface) of the
second channel portion 2b.
EXAMPLE 1
[0116] Five prototype mixing channels (nos. 1 to 5) with different
geometries were designed and prepared. The second channel portions
were approx. 80 mm long and slightly tapered, i.e. shaped as
truncated, roughly circular, cones. The prototypes differed with
respect to the diameter of the inlet opening and the opening angle
of the cone (which is twice the angle between the center axis of
the second channel portion and any tangential plane on the inner
surface of the second channel portion). In prototypes nos. 1 to 3,
the opening angles increased from a smaller angle at the proximal
(or upstream) end to a larger angle at the distal (or downstream)
end of the second channel portion. The dimensions of the transition
opening at the step between first and second mixing channel portion
were selected according to the inlet diameter, in that the radius
was not changed but the shape was altered from circular to
semi-circular with rounded edges, as depicted in FIG. 11C. The
respective parameters are given in table 1.
TABLE-US-00001 TABLE 1 Mixing channel no. 1 2 3 4 5 Inlet diameter
(mm) 10 9 8 9 9 Opening angle 5.degree. to 6.degree. 5.degree. to
6.degree. 5.degree. to 6.degree. 5.degree. 6.degree.
[0117] Two aerosol generators (A and B) as described in US
2010/0044460 A1 were used to aerosolise isotonic saline solution
(0.9%) in pulses of 5 seconds of aerosolization time followed by
pauses of 5 seconds. The experiments were conducted first without
any mixing channel, and subsequently with each of the five mixing
channels at a flow rate of 15 L/min. In each configuration, the
aerosol droplet size distribution was determined using laser
diffraction. The volume median diameters (VMD) and the geometric
standard deviations (GSD) are given in table 2 for aerosol
generator A and in table 3 for aerosol generator B.
TABLE-US-00002 TABLE 2 Mixing channel no. None 1 2 3 4 5 VMD
(pulsed mode) 5.3 5.0 5.2 4.9 5.0 5.1 GSD (pulsed mode) 6.4 1.6 1.6
1.6 1.6 1.6
TABLE-US-00003 TABLE 3 Mixing channel no. None 1 2 3 4 5 VMD
(pulsed mode) 5.5 4.7 4.8 4.7 4.7 4.7 GSD (pulsed mode) 3.6 1.6 1.6
1.6 1.6 1.6
[0118] In result, a remarkable and--especially in its magnitude
completely unexpected--effect of all tested mixing channels was
observed in that the geometric standard deviation, i.e. the
polydispersity of the aerosol droplets, was dramatically reduced
from 6.4 or 3.6 to 1.6, indicating that these aerosol generators,
which emit substantially heterogeneous aerosols without any mixing
channel can, by means of the mixing channel of the invention, be
configured to deliver substantially homogeneous aerosols.
EXAMPLE 2
[0119] Using the same five prototype mixing channels as in example
1 and aerosol generator A, and an additional mixing channel (no. 6,
with an inlet diameter of 10 mm and a constant opening angle of
6.degree.), the deposition of the aerosolised isotonic saline
solution (0.9%) within the mixing channels at a flow rate of 15
L/min was evaluated. An exactly measured quantity of isotonic
saline solution (i.e., NaCl.sub.total) was filled into the
reservoir of the aerosol generator and aerosolised while a
breathing pump (ASL 5000 by IngMar Medical) simulated 20 breathing
manoeuvres. Subsequently, the reservoir and the mixing channel were
rinsed with distilled water and their sodium chloride content
measured conductometrically. Deposition within the mixing channel
(NaCl.sub.deposited) was calculated in percent based on the emitted
dose (NaCl.sub.emitted=NaCl.sub.total-NaCl.sub.left in reservoir).
The results are given in Table 4.
TABLE-US-00004 TABLE 4 Mixing channel no. 1 2 3 4 5 6 Inlet
diameter (mm) 10 9 8 9 9 10 Opening angle 5.degree. to 6.degree.
5.degree. to 6.degree. 5.degree. to 6.degree. 5.degree. 6.degree.
6.degree. Deposition 9.7 16.7 27.2 19.2 10.9 10.3 (% of emitted
dose)
[0120] In all cases, an acceptable low degree of deposition in the
mixing channel was observed. This is remarkable as the nebulizer
itself had not been especially adapted to, or optimised for, the
inhalation device or the mixing channel, which is normally
required.
[0121] A particularly low aerosol deposition in the device was
found for an inlet diameter of 9 or 10 mm and an opening angle of
6.degree., or from 5.degree. to 6.degree..
[0122] These experiments demonstrate the effectiveness of the
mixing channels in deflecting the vast majority of the aerosol
droplets emitted by the nebulizer, such that they can be delivered
through the mouthpiece to the user. A relatively small fraction of
droplets--probably those having the relatively largest
diameter--impacted within the device. Their removal may contribute
to the reduction of the geometric standard deviation of the aerosol
droplet diameter, as observed in Example 1.
[0123] In addition, computational flow simulations of the prototype
mixing channels indicated that the length of the second mixing
channel portion of approx. 80 mm is efficient in slowing down the
velocity of the aerosol droplets to a value very similar to the
velocity upstream of the injection zone and thus suitable for
inhalation into the deeper lung areas without impaction in the
mouth and/or throat region.
[0124] The computational flow simulations of the prototype mixing
channels further indicated that these effects may be achieved by
means of the step in the mixing channel (i.e. an abrupt decrease of
the effective cross sectional area), e.g. through an abrupt
increase in air velocity caused by the step, without interfering
with a laminar flow.
[0125] While the invention has been illustrated and described in
detail in the drawings and foregoing description, such illustration
and description are to be considered illustrative or exemplary and
not restrictive. It will be understood that changes and
modifications may be made by those of ordinary skill within the
scope of the following claims. In particular, the present invention
covers further embodiments with any combination of features from
different embodiments described above and below.
[0126] Furthermore, in the claims the word "comprising" does not
exclude other elements or steps, and the indefinite article "a" or
"an" does not exclude a plurality. A single unit may fulfil the
functions of several features recited in the claims. The terms
"essentially", "about", "approximately" and the like in connection
with an attribute or a value particularly also define exactly the
attribute or exactly the value, respectively. Any reference signs
in the claims should not be construed as limiting the scope.
* * * * *