U.S. patent application number 14/051975 was filed with the patent office on 2014-04-10 for entraining powder in an airflow.
This patent application is currently assigned to AstraZeneca AB. The applicant listed for this patent is AstraZeneca AB. Invention is credited to Per Arne KJELLGREN, Orest LASTOW, Johan REMMELGAS, Marten SVENSSON.
Application Number | 20140096771 14/051975 |
Document ID | / |
Family ID | 40801454 |
Filed Date | 2014-04-10 |
United States Patent
Application |
20140096771 |
Kind Code |
A1 |
REMMELGAS; Johan ; et
al. |
April 10, 2014 |
ENTRAINING POWDER IN AN AIRFLOW
Abstract
A device for inhalation of at least one air stream carrying a
dose of medicament powder. The device comprises a powder-containing
cavity which opens into a flow passage. The flow passage is
arranged to direct an inhalation air flow across the cavity
opening. A circulating flow is thereby induced in the cavity by the
phenomenon of shear driven cavity flow. Powder is entrained in the
circulating flow and deaggregated before exiting the cavity and
becoming entrained in the flow of air along the flow passage.
Inventors: |
REMMELGAS; Johan;
(Torslanda, SE) ; KJELLGREN; Per Arne; (Drammen,
NO) ; LASTOW; Orest; (Torna Hallestad, SE) ;
SVENSSON; Marten; (Sodra Sandby, SE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AstraZeneca AB |
Sodertalje |
|
SE |
|
|
Assignee: |
AstraZeneca AB
Sodertalje
SE
|
Family ID: |
40801454 |
Appl. No.: |
14/051975 |
Filed: |
October 11, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12496525 |
Jul 1, 2009 |
8578933 |
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14051975 |
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PCT/SE2008/051488 |
Dec 18, 2008 |
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12496525 |
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61015383 |
Dec 20, 2007 |
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Current U.S.
Class: |
128/203.15 |
Current CPC
Class: |
A61M 2206/10 20130101;
A61M 2202/064 20130101; A61M 15/0025 20140204; A61M 15/0045
20130101; A61M 15/0065 20130101; A61M 15/0048 20140204 |
Class at
Publication: |
128/203.15 |
International
Class: |
A61M 15/00 20060101
A61M015/00 |
Claims
1. A dry powder inhaler device for dispensing an air stream
carrying a dose of medicament powder, the device defining a flow
passage and a powder storage cavity having a cavity opening,
wherein the cavity opening is disposed in a wall of the flow
passage with the flow passage arranged to direct a flow of air
across the cavity opening, wherein the cavity opening has a length
in the flow direction, and has a depth, the cavity opening length
being between 50% and 150% of the cavity depth, and at least 80% of
a maximum length of the cavity in the flow direction, and wherein
the flow passage has a maximum height immediately adjacent the
cavity, the maximum height being between 0.5 mm and 4 mm.
2.-35. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part application of
and claims priority to PCT Application Serial No.
PCT/SE2008/051488, filed on Dec. 18, 2008, which claims priority to
U.S. Ser. No. 61/015,383 filed on Dec. 20, 2007.
TECHNICAL FIELD
[0002] The present invention relates to a device and method for
entraining in an airflow a medicament powder contained in a cavity.
The present invention also relates to a medical dispenser that
includes a powder-containing cavity.
BACKGROUND
[0003] There are many devices for administering powdered
medicaments to the lungs, which employ propellants, such as
compressed gases, e.g. air, or liquefied gas propellants, to
dispense and disperse the medicament.
[0004] There are also a number of known breath actuated inhalation
devices for administering powdered medicaments to the lungs, which
have mouthpieces through which the medicament is inhaled. British
Patent Specification Nos. 1 521 000, 1 520 062, 1 472 650 and 1 502
150 disclose devices where a capsule is inserted into the device,
which mitigates spillage of medicament prior to inhalation. Access
to the medicament is gained by piercing the capsule or cutting it
in half inside the dispensing device. On inhalation the air flows
into or through the capsule and the powder within is released into
the air stream and flows towards the mouth.
[0005] U.S. Pat. No. 4,210,140 discloses a device in which access
to the powdered medicament is gained by pulling the halves of the
capsule apart so that the medicament is emptied to a suitable
position for entrainment in the airflow caused by inhalation.
[0006] U.S. Pat. No. 6,655,381 relates to a pre-metered dose
assembly for consistently supplying precise doses of medicament for
a breath-actuated dry powder inhaler. The assembly includes a cap
defining a dry powder delivery passageway for providing air to a
dry powder supply port of a swirl chamber of a breath-actuated dry
powder inhaler, and a magazine including a plurality of reservoirs
for holding pre-metered doses of dry powder. One of the magazine
and the cap is movable with respect to the other of the magazine
and the cap for sequentially positioning the reservoirs within the
delivery passageway of the cap. A breath-induced low pressure at an
outlet port of the inhaler causes an airflow through the dry powder
delivery passageway of the assembly and into the dry powder supply
port that entrains dry powder from the reservoir positioned in the
passageway for inhalation by a patient using the inhaler. The
passageway is provided with a venturi in the passageway by the
reservoir to create a flow through the reservoir and bring the
powder there from.
[0007] U.S. Pat. No. 4,446,862 to Baum et al. describes an inhaler
device in which access to the powdered medicament is gained by
pulling the halves of a capsule apart, leaving the lower half of
the capsule retained in an upright position in the device, with its
open end flush with the lower surface of a disc shaped inhalation
chamber. Spaced around half the circumference of the chamber are a
number of air inlets and, opposite these, a larger air outlet
leading to a mouthpiece. On inhalation, air is drawn through the
chamber and across the open mouth of the capsule. It is stated that
this may create a resonance effect in the capsule, similar to the
effect which causes a sound to be produced by blowing across the
opening of a bottle.
[0008] US published patent application number 2009114220 to
Boehringer discloses a powder inhaler device in which a powder
cavity is provided with an air outlet opening into the lower
surface of an air flow path which narrows in the region of the
outlet opening. The cavity also has an air inlet which does not
open into the flow path. A venturi is created by the narrowing flow
path adjacent the outlet, giving rise to low pressure in this area
when flow is generated by a user inhaling. Air is thereby drawn
through the cavity from the inlet to the outlet and then into the
flow path.
[0009] In spite of the numerous prior art devices there is a need
for a device which is simple in design and therefore inexpensive,
compact in size and also simple to operate, but which also allows
for efficient emptying of a cavity of powder. Consistent and
efficient emptying is important to avoid wastage of expensive
medicament by leaving it in the device and to avoid residual powder
contaminating the device and being inadvertently inhaled on
subsequent uses of the device.
[0010] There is also a need for a device which efficiently
deaggregates powder before being administered. It is desirable for
the deaggregation process to result in a significant proportion of
the powder particles being in a certain aerodynamic size range.
This is often referred to as classifying the powder particles.
Various ways of enabling deaggregation are described in the prior
art. For example, tortuous flow paths can cause deaggregation as
particles impact the walls of the flow path. Alternatively,
obstructions can be placed in the flow path downstream of the
powder cavity or reservoir. Vibrating or shaking is another
possibility. U.S. Pat. No. 4,446,862, discussed above, provides for
the capsule to be moved rapidly on inhalation to loosen the powder
contents and thereby aid deaggregation of highly cohesive or
compacted powders.
[0011] Devices employing deaggregation features in the downstream
flow passage may become clogged or contaminated in use, since
medicament powder may accumulate on these downstream features. It
is of course desirable to reduce or avoid the risk of administering
an inaccurate amount of medicament powder. Where powder accumulates
on downstream deaggregation features, a risk is that accumulated
powder from several doses may dislodge suddenly from these
downstream features (e.g. if the device is dropped) resulting in
the patient receiving a significant over-dose. Accordingly, there
is a need to mitigate or eliminate downstream powder
accumulation.
SUMMARY
[0012] We have discovered that the phenomenon of shear-driven
cavity flow may be employed to produce a compact and simple device
for efficiently entraining and deaggregating medicament powder.
[0013] A trend in dry powder inhaler devices is to have shallow
cavities into which flow is directed in order to entrain particles
and empty the cavity efficiently. Especially for larger doses of
powder, the use of shallow cavities can result in devices which are
relatively large, since such a cavity may occupy a relatively large
area. We have found, however, that a relatively deep cavity may be
emptied very efficiently by designing the device so as to take
advantage of the phenomenon of shear driven cavity flow in the
powder cavity.
[0014] The concept of shear driven cavity flow as known in the
field of fluid dynamics is that a rotating flow in a cavity may
result from passing a fluid stream across the opening of the cavity
(distinct from directing flow into the cavity or using an airflow
to create low pressure by the venturi effect above an opening of
the cavity to draw a fluid stream through it). The flow tends to
rotate in a cylindrical pattern.
[0015] It is somewhat counter-intuitive that generating a
cylindrical rotating flow in a powder-containing cavity may result
in fast and effective emptying of the cavity, rather than simply
causing powder to be entrained in the rotating flow. However, we
have found that powder may be quickly transferred from the rotating
flow to the linear flow over the cavity, rather than remaining for
a long period entrained in the rotating flow.
[0016] We have found that the shear driven cavity flow effect,
preferably in a relatively deep cavity, may be enhanced by
manipulating one or more parameters such as flow path design,
cavity shape, pressure drop, flow velocity or volume flow rate. We
have found that not only fast cavity emptying but also
deaggregation or classifying of powder in the cavity can be
achieved very effectively in a deep cavity by employing the shear
driven cavity flow phenomenon.
[0017] One aspect of the invention features a dry powder inhaler
device for dispensing an air stream carrying a dose of medicament
powder. The inhaler device defines a flow passage and a powder
storage cavity having a cavity opening. The cavity opening is
disposed in a wall of the flow passage and the flow passage is
arranged to direct a flow of air across the cavity opening. The
cavity opening has a length in the flow direction and has a depth.
The cavity opening length is (i) between 50% and 150% of the cavity
depth, and (ii) at least 80% of a maximum length of the cavity in
the flow direction. The flow passage has a maximum height
immediately adjacent the cavity. The maximum height is between 0.5
mm and 4 mm.
[0018] The flow passage can be contoured to avoid directing flow
into the cavity. For example, the cavity opening can be formed in a
flat wall of the flow passage with a parallel wall opposite the
cavity opening. In some embodiments, the geometry and dimensions
may generate airflow of the correct characteristics to result in
efficient emptying and deaggregation of powder contained in the
cavity. In some embodiments, the maximum height of the flow passage
adjacent the cavity can be between 0.5 mm and 3 mm, more preferably
between 1 mm and 2 mm. The flow passage can be arranged to create a
substantially unidirectional flow across the cavity opening. This
would be in contrast, for example, to the flow across the cavity
described in U.S. Pat. No. 4,446,862 which is (in plan view) fan
shaped: although this flow has an overall direction which could be
said to be along the line of symmetry of the fan shape, it could
not be described as "unidirectional". Furthermore, the height of
the flow passage adjacent the cavity in U.S. Pat. No. 4,446,862,
being 10 mm or more, may allow for substantial vertical deviations
in the flow.
[0019] The maximum width (see definition below) of the flow passage
in the region of the cavity can be between 2 mm and 6 mm. The cross
sectional area of the passage adjacent the cavity may therefore be
in the range 1 mm.sup.2 to 20 mm.sup.2, preferably 3 mm.sup.2 to 10
mm.sup.2.
[0020] The cavity opening can be generally of quadrilateral shape,
such as rectangular or trapezoidal. The fillet radii may be 0.001
mm to 0.5 mm, preferably 0.01 mm to 0.3 mm. In some embodiments, a
cavity opening of this shape may promote the cylindrical flow
pattern characteristic of shear driven cavity flow more effectively
than, say, a circular opening. The opening can have an aspect ratio
in the range 1.5 to 4.0, more preferably 1.8 to 3.5, still more
preferably 2.6 to 3.2. The larger dimension can be aligned with the
direction of flow in the flow passage.
[0021] The length of the cavity opening in the flow direction can
be between 75% and 140% of the cavity depth, more preferably
between 90% and 135%. In some embodiments, this may promote shear
driven flow in the cavity.
[0022] The geometry of the lower front and/or rear edges of the
cavity may be another factor that promotes shear driven cavity flow
with respect to the flow direction. The lower front and/or rear
edges can have a radius of between 1 mm and 3 mm, preferably
between 1.5 mm and 2.5 mm. This is distinct from the fillet radii
of the cavity opening and vertical corners/edges of the cavity, as
mentioned above.
[0023] The cavity itself can have a depth as defined below between
3 mm and 10 mm, preferably between 4 mm and 6 mm. The maximum
length in the flow direction can be between 3 mm and 10 mm,
preferably between 4 mm and 7 mm. The average width of the cavity
can be between 1.5 mm and 5 mm, preferably between 2 mm and 3 mm.
As well as defining an appropriate volume for containing medicament
powder in a dry powder inhaler, the dimensions may promote
effective emptying and deaggregation.
[0024] An initial study used a simple cuboid shaped cavity (see
e.g. FIG. 1). Physical models of such cavities were constructed,
filled with powder and tested, the results being recoded using high
speed video techniques. Cavity emptying similar to that shown in
FIGS. 3a to 3d was observed. In an attempt to improve the
performance, the cavity shape was modified to include a large
radius (of the order of 2 mm) on the lower upstream edge since this
reflected the erosion pattern of the powder during the emptying
process. This was found to improve the emptying of the cavity.
Further work using computational fluid dynamics techniques
(described in more detail below) has resulted in the development of
shapes for the cavity which have a large radius on the both the
upstream and downstream lower edges of the cavity.
[0025] A flow-perturbing member can project from a flow passage
wall. The flow perturbing member can be located with its most
upstream extent between 1 mm and 20 mm upstream of the cavity,
preferably between 2 mm and 10 mm, more preferably between 3 mm and
7 mm. This flow perturbing member or members may increase the
turbulence in the flow across the cavity, which in turn may
increase the turbulence of the induced rotating flow in the cavity.
This may increase the efficiency with which the cavity is emptied
of powder.
[0026] Work using computational fluid dynamics techniques with
different designs of flow-perturbing member has confirmed that a
markedly increased performance can be obtained. The exact shape and
lateral position of the member may also have an effect.
[0027] The flow-perturbing member can project from a wall in which
the cavity opening is formed (i.e. from the "floor" of the
passage). The member can extend across the full height of the
passage or across the full width of the passage. In some
embodiments, the member only extends over from 1% to 50%, more
preferably from 1% to 20%, of the width and/or height of the
passage. The cross sectional area of the member in the direction of
the flow can be from 1 to 25% of the cross section of the flow
passage (perpendicular to the flow) in the vicinity of the member.
In some embodiments, the cross section of the member is from 3 to
20%, more preferably 5 to 15%, of the cross section of the flow
passage in the vicinity of the member.
[0028] A lid member can be associated with the cavity. The lid can
be movable between a first position, in which the cavity is closed,
and a second position, in which the cavity is open. The lid member
can provide part of the boundary of the flow passage.
[0029] In some embodiments, the device can include a second powder
storage cavity opening into the flow passage downstream of the
first said cavity. This arrangement can be used to administer two
separate medicaments in the same inhalation. In some embodiments, a
lid member can be used to close or open both cavities as it moves
between its first and second positions.
[0030] The device can have a plurality of flow passages arranged
around the circumference of a circle. The flow passages can be
arranged such that the flow direction is radial with respect to the
said circle. The device can include at least one said powder
storage cavity being associated with each flow passage. In this
way, a conveniently shaped multi-dose inhaler may be provided. The
cavities can be provided in a disc member, which can be arranged to
be rotatable with respect to an inhaler mouthpiece, in order
sequentially to bring into registry with the mouthpiece unused
powder-containing cavities. In some embodiments, a disc member can
include a cavity opening having a trapezium shape with the line of
symmetry located along the direction of flow in the flow passage. A
trapezium shaped cavity opening in a disc member may help to
maximise the number of cavities which can be fitted into a given
size of disc.
[0031] A multi-dose device can have a radially outward flow
direction, with an inlet near the centre of the device and a
mouthpiece located at the periphery. For example, if the multi-dose
device has cavities with trapezium shaped openings, the direction
of flow can be from the smaller to the larger end of the opening.
In other embodiments, a multi-dose device can have an inlet at the
periphery and a centrally located mouthpiece, in which case the
flow across any trapezium shaped cavities can be from the larger to
the smaller end.
[0032] According to another aspect of the invention, a device for
dispensing an air stream carrying a dose of medicament powder
defines a flow passage and a powder storage cavity having a cavity
opening and a lid member movable between a first position in which
the cavity is closed and a second position in which the cavity is
open. The lid member provides part of the boundary of a flow
passage (e.g., when the lid member is in the second position). The
cavity opening is in a wall of the flow passage and the flow
passage is arranged to direct a flow of air across the cavity
opening. The length of the cavity opening in the flow direction is
between 50% and 150% of the cavity depth and the maximum height of
the flow passage adjacent the cavity is between 0.5 mm and 4 mm. In
some embodiments, the length of the cavity opening in the flow
direction is at least 80% of the maximum length of the cavity in
the flow direction.
[0033] In some embodiments, the device can include a second powder
storage cavity opening into the flow passage. For example, the
device can be used to administer two separate medicaments in the
same inhalation. The second cavity can be closed when a lid member
in the first position and open when the lid member is in the second
position.
[0034] In another aspect, a dry powder inhaler device for
dispensing an air stream carrying a dose of medicament powder
defines a flow passage and a powder storage cavity having a cavity
opening. The cavity opening is in a wall of the flow passage and
the flow passage is arranged to direct a flow of air across the
cavity opening. The length of the cavity opening in the flow
direction is (i) between 50% and 150% of the cavity depth, and (ii)
at least 80% of the maximum length of the cavity in the flow
direction. The flow passage adjacent the cavity has a cross
sectional area in the range 1 mm.sup.2 to 15 mm.sup.2. In some
embodiments, the flow passage adjacent the cavity has a cross
sectional area in the range 3 mm.sup.2 to 10 mm.sup.2.
[0035] In an inhaler for use by human patients, the total pressure
drop across the device in use can be between 2 kPa and 6 kPa. The
pressure difference in the flow passage from one end of the cavity
to the other can be from 0.1 kPa to 5 kPa, preferably 0.5 kPa to 2
kPa. The flow passage dimensions referred to above may result in a
pressure drop in this range for an inhaler designed for use by a
human patient.
[0036] According to another aspect of the invention, a dry powder
inhaler device for dispensing an air stream carrying a dose of
medicament powder defines a flow passage and a powder storage
cavity having only a single opening The cavity opening is in a wall
of the flow passage and the flow passage is arranged to direct a
flow of air across the cavity opening. The length of the cavity
opening in the flow direction is between 50% and 150% of the cavity
depth. The maximum height of the flow passage immediately adjacent
the cavity is between 0.5 mm and 4 mm.
[0037] According to another aspect, a dry powder inhaler device for
dispensing an air stream carrying a dose of medicament powder
defines a flow passage and a powder storage cavity having only a
single opening. The cavity opening is in a wall of the flow passage
and the flow passage is arranged to direct a flow of air across the
cavity opening. The length of the cavity opening in the flow
direction is between 50% and 150% of the cavity depth. The flow
passage adjacent the cavity has a cross sectional area in the range
1 mm.sup.2 to 15 mm.sup.2. In some embodiments, the flow passage
adjacent the cavity has a cross sectional area in the range 3
mm.sup.2 to 10 mm.sup.2.
[0038] The device can be loaded with a dosage form including a
compound or combination selected from the list which appears
below.
[0039] The shape of the cavity may have an important effect on the
performance. Because the shear driven cavity flow phenomenon tends
to produce a cylindrical rotating flow pattern, a cavity of
generally rectangular or trapezoidal shape in plan view, at least
for some of its depth, e.g. at least the upper half of the cavity
(the half nearer the opening, based on the perpendicular distance
from the cavity opening to the furthest extent of the cavity), may
promote a rotating cavity flow. By plan view it is meant the view
looking at the cavity in a direction normal to the plane of the
cavity opening (as defined). The longitudinal line of symmetry of
the rectangular or trapezoidal opening preferably is oriented in
the direction of the airflow in the flow passage.
[0040] In order to generate shear driven cavity flow, the opening
of the cavity should may have a cross sectional area which is of
the same order as the maximum cross section of the cavity in a
plane parallel to the cavity opening, e.g. at least 80% of the
maximum cross section, preferably at least 90%, more preferably
about 100%.
[0041] The cavity is provided with a headspace between the powder
fill level (when the powder surface is level and parallel with the
cavity opening) and the cavity opening; the headspace can be from 1
mm to 6 mm.
[0042] Another aspect of the invention features a replacement
magazine configured to be received in a device as described in any
of the preceding paragraphs. The replacement magazine includes a
cavity or cavities charged with medicament powder for use in a
device as described in any of the preceding paragraphs.
[0043] Another aspect of the invention features a cavity disc for a
dry powder inhaler, the cavity disc defining a plurality of
powder-containing cavities arranged in a circular pattern on the
disc. The cavity disc is shaped generally as a solid disc or as an
annulus. The cavities each have a trapezoid-shaped opening. Each
cavity has a radial direction length that is from 50% to 150% of a
depth of the cavity. The openings can be covered by a removable
seal or lid.
[0044] In some embodiments, the length in a radial direction of
each cavity can be at least 80% of the maximum length of the cavity
in the said radial direction.
[0045] In some embodiments, the lower front and/or rear edges of
the cavity (33), with respect to the flow direction, can have a
radius of between 0.5 and 3 mm, preferably between 1.5 mm and 2.5
mm, more preferably between 1.75 mm and 2.25 mm.
[0046] A device as described in any of the preceding paragraphs can
be charged with medicament powder in the cavity or cavities.
[0047] The medicament powder can contain various active
ingredients. The active ingredient can be selected from any
therapeutic or diagnostic agent. For example, the active ingredient
can be an antiallergic, a bronchodilator (e.g. a beta2-adrenoceptor
agonist or a muscarinic antagonist), a bronchoconstrictor, a
pulmonary lung surfactant, an analgesic, an antibiotic, a mast cell
inhibitor, an antihistamine, an anti-inflammatory, an
antineoplastic, an anaesthetic, an anti-tubercular, an imaging
agent, a cardiovascular agent, an enzyme, a steroid, genetic
material, a viral vector, an antisense agent, a protein, a peptide,
a non-steroidal glucocorticoid Receptor (GR Receptor) agonist, an
antioxidant, a chemokine antagonist (e.g. a CCR1 antagonist), a
corticosteroid, a CRTh2 antagonist, a DP1 antagonist, an Histone
Deacetylase Inducer, an IKK2 inhibitor, a COX inhibitor, a
lipoxygenase inhibitor, a leukotriene receptor antagonist, an MPO
inhibitor, a p38 inhibitor, a PDE inhibitor, a PPAR.gamma. agonist,
a protease inhibitor, a statin, a thromboxane antagonist, a
vasodilator, an ENAC blocker (Epithelial Sodium-channel blocker)
and combinations thereof.
[0048] Examples of specific active ingredients that can be
incorporated in the medicament powder include: [0049] (i)
antioxidants:--Allopurinol, Erdosteine, Mannitol, N-acetyl cysteine
choline ester, N-acetyl cysteine ethyl ester, N-Acetylcysteine,
N-Acetylcysteine amide and Niacin; [0050] (ii) chemokine
antagonists:--BX471
((2R)-1-[[2-[(aminocarbonyl)amino]-4-chlorophenoxy]acetyl]-4-[(4-fluoroph-
enyl)methyl]-2-methylpiperazine monohydrochloride), CCX634,
N-{2-[((2S)-3-{[1-(4-chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2-methy-
lpropyl)oxy]-4-hydroxyphenyl}acetamide (see WO 2003/051839), and
2-{2-Chloro-5-{[(2S)-3-(5-chloro-1'H,3H-spiro[1-benzofuran-2,4'-piperidin-
]-1'-yl)-2-hydroxypropyl]oxy}-4-[(methylamino)carbonyl]phenoxy}-2-methylpr-
opanoic acid (see WO 2008/010765), 656933
(N-(2-bromophenyl)-N-(4-cyano-1H-1,2,3-benzotriazol-7-yl)urea),
766994
(4-({[({[(2R)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]-
-amino}methyl)benzamide), CCX-282, CCX-915, Cyanovirin N, E-921,
INCB-003284, INCB-9471, Maraviroc, MLN-3701, MLN-3897, T-487
(N-{1-[3-(4-ethoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl]et-
hyl}-N-(pyridin-3-ylmethyl)-2-[4-(trifluoromethoxy)phenyl]acetamide)
and Vicriviroc [0051] (iii) Corticosteroids:--Alclometasone
dipropionate, Amelometasone, Beclomethasone dipropionate,
Budesonide, Butixocort propionate, Ciclesonide, Clobetasol
propionate, Desisobutyrylciclesonide, Etiprednol dicloacetate,
Fluocinolone acetonide, Fluticasone Furoate, Fluticasone
propionate, Loteprednol etabonate (topical) and Mometasone furoate.
[0052] (iv) DP1 antagonisits:--L888839 and MK0525; [0053] (v)
Histone deacetylase inducers:--ADC4022, Aminophylline, a
Methylxanthine or Theophylline; [0054] (vi) IKK2
inhibitors:--2-{[2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carbonyl]-a-
mino}-3-(phenyl-pyridin-2-yl-amino)-propionic acid; [0055] (vii)
COX inhibitors:--Celecoxib, Diclofenac sodium, Etodolac, Ibuprofen,
Indomethacin, Meloxicam, Nimesulide, OC1768, OC2125, OC2184, OC499,
OCD9101, Parecoxib sodium, Piceatannol, Piroxicam, Rofecoxib and
Valdecoxib; [0056] (viii) Lipoxygenase inhibitors:--Ajulemic acid,
Darbufelone, Darbufelone mesilate, Dexibuprofen lysine
(monohydrate), Etalocib sodium, Licofelone, Linazolast, Lonapalene,
Masoprocol, MN-001, Tepoxalin, UCB-35440, Veliflapon, ZD-2138,
ZD-4007 and Zileuton
((.+-.)-1-(1-Benzo[b]thien-2-ylethyl)-1-hydroxyurea); [0057] (ix)
Leukotriene receptor antagonists:--Ablukast, Iralukast (CGP
45715A), Montelukast, Montelukast sodium, Ontazolast, Pranlukast,
Pranlukast hydrate (mono Na salt), Verlukast (MK-679) and
Zafirlukast; [0058] (x) MPO Inhibitors:--Hydroxamic acid derivative
(N-(4-chloro-2-methyl-phenyl)-4-phenyl-4-[[(4-propan-2-ylphenyl)sulfonyla-
mino]methyl]piperidine-1-carboxamide), Piceatannol and Resveratrol;
[0059] (xi) Beta2-adrenoceptor agonists:--metaproterenol,
isoproterenol, isoprenaline, albuterol, salbutamol (e.g. as
sulphate), formoterol (e.g. as fumarate), salmeterol (e.g. as
xinafoate), terbutaline, orciprenaline, bitolterol (e.g. as
mesylate), pirbuterol, indacaterol, salmeterol (e.g. as xinafoate),
bambuterol (e.g. as hydrochloride), carmoterol, indacaterol (CAS no
312753-06-3; QAB-149), formanilide derivatives e.g.
3-(4-{[6-({(2R)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)-
hexyl]oxy}-butyl)-benzenesulfonamide;
3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxy-methyl)phenyl]ethyl}ami-
no)-hexyl]oxy}butyl)benzenesulfonamide; GSK 159797, GSK 159802, GSK
597901, GSK 642444, GSK 678007; and a compound selected from
N-[2-(Diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzo-
thiazol-7-yl)ethyl]amino}ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide,
N-[2-(Diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzo-
thiazol-7-yl)ethyl]amino}ethyl)-3-[2-(3-chlorophenyl)ethoxy]propanamide,
7-[(1R)-2-({2-[(3-{[2-(2-Chlorophenyl)ethyl]amino}propyl)thio]ethyl}amino-
)-1-hydroxyethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-one, and
N-Cyclohexyl-N.sup.3-[2-(3-fluorophenyl)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo--
2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-.beta.-alaninamide
or a pharmaceutically acceptable salt thereof (e.g. wherein the
counter ion is hydrochloride (for example a monohydrochloride or a
dihydrochloride), hydrobromide (for example a monohydrobromide or a
dihydrobromide), fumarate, methanesulphonate, ethanesulphonate,
benzenesulphonate, 2,5-dichlorobenzenesulphonate,
p-toluenesulphonate, napadisylate (naphthalene-1,5-disulfonate or
naphthalene-1-(sulfonic acid)-5-sulfonate), edisylate
(ethane-1,2-disulfonate or ethane-1-(sulfonic acid)-2-sulfonate),
D-mandelate, L-mandelate, cinnamate or benzoate.) [0060] (xii)
Muscarinic antagonists:--Aclidinium bromide, Glycopyrrolate (such
as R,R-, R,S-, S,R-, or S,S-glycopyrronium bromide), Oxitropium
bromide, Pirenzepine, telenzepine, Tiotropium bromide,
3(R)-1-phenethyl-3-(9H-xanthene-9-carbonyloxy)-1-azoniabicyclo[2-
.2.2]octane bromide,
(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(2-phenoxyeth-
yl)-1-azoniabicyclo[2.2.2]actane bromide, a quaternary salt (such
as
[2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3--
phenoxy-propyl)-ammonium salt,
[2-(4-Chloro-benzyloxy)-ethyl]-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)--
oxazol-5-ylmethyl]-dimethyl-ammonium salt and
(R)-1-[2-(4-Fluoro-phenyl)-ethyl]-3-((S)-2-phenyl-2-piperidin-1-yl-propio-
nyloxy)-1-azonia-bicyclo[2.2.2]octane salt wherein the counter-ion
is, for example, chloride, bromide, sulfate, methanesulfonate,
benzenesulfonate (besylate), toluenesulfonate (tosylate),
napthalenebissulfonate (napadisylate or hemi-napadisylate),
phosphate, acetate, citrate, lactate, tartrate, mesylate, maleate,
fumarate or succinate) [0061] (xiii) p38 Inhibitors:--681323,
856553, AMG548
(2-[[(2S)-2-amino-3-phenylpropyl]amino]-3-methyl-5-(2-naphthalenyl)-6-(4--
pyridinyl)-4(3H)-pyrimidinone), Array-797, AZD6703, Doramapimod,
KC-706, PH 797804, R1503, SC-80036, SCIO469,
6-chloro-5-[[(2S,5R)-4-[(4-fluorophenyl)methyl]-2,5-domethyl-1-piperaziny-
l]carbonyl]-N,N,1-trimethyl-.alpha.-oxo-1H-indole-3-acetamide,
VX702 and VX745
(5-(2,6-dichlorophenyl)-2-(phenylthio)-6H-pyrimido[1,6-b]pyridazin--
6-one); [0062] (xiv) PDE Inhibitors:--256066, Arofylline
(3-(4-chlorophenyl)-3,7-dihydro-1-propyl-1H-Purine-2,6-dione), AWD
12-281
(N-(3,5-dichloro-4-pyridinyl)-1-[(4-fluorophenyl)methyl]-5-hydroxy-.alpha-
.-oxo-1H-indole-3-acetamide), BAY19-8004 (Bayer), CDC-801
(Calgene), Celgene compound
((.beta.R)-.beta.-(3,4-dimethoxyphenyl)-1,3-dihydro-1-oxo-2H-isoindole-2--
propanamide), Cilomilast
(cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-cyclohexanecarboxylic
acid),
2-(3,5-dichloro-4-pyridinyl)-1-(7-methoxyspiro[1,3-benzodioxole-2,-
1'-cyclopentan]-4-yl)ethanone (CAS number 185406-34-2)),
(2-(3,4-difluorophenoxy)-5-fluoro-N-[cis-4-[(2-hydroxy-5-methylbenzoyl)am-
ino]cyclohexyl]-)-3-pyridinecarboxamide),
(2-(3,4-difluorophenoxy)-5-fluoro-N-[cis-4-[[2-hydroxy-5-(hydroxymethyl)b-
enzoyl]amino]cyclohexyl]-3-pyridinecarboxamide), CT2820, GPD-1116,
Ibudilast, IC 485, KF 31334, KW-4490, Lirimilast
([2-(2,4-dichlorobenzoyl)-6-[(methylsulfonyl)oxy]-3-benzofuranyl])-urea),
(N-cyclopropyl-1,4-dihydro-4-oxo-1-[3-(3-pyridinylethynyl)phenyl]-)-1,8-n-
aphthyridine-3-carboxamide),
(N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amin-
o])-1-dibenzofurancarboxamide), ONO6126, ORG 20241
(4-(3,4-dimethoxyphenyl)-N-hydroxy-)-2-thiazolecarboximidamide),
PD189659/PD168787 (Parke-Davis), Pentoxifylline
(3,7-dihydro-3,7-dimethyl-1-(5-oxohexyl)-)-1H-purine-2,6-dione),
compound
(5-fluoro-N-[4-[(2-hydroxy-4-methyl-benzoyl)amino]cyclohexyl]-2-(thian-4--
yloxy)pyridine-3-carboxamide), Piclamilast
(3-(cyclopentyloxy)-N-(3,5-dichloro-4-pyridinyl)-4-methoxy-benzamide),
PLX-369 (WO 2006026754), Roflumilast
(3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)b-
enzamide), SCH 351591
(N-(3,5-dichloro-1-oxido-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-qui-
nolinecarboxamide), SelCID.TM. CC-10004 (Calgene), T-440 (Tanabe),
Tetomilast
(6-[2-(3,4-diethoxyphenyl)-4-thiazolyl]-2-pyridinecarboxylic acid),
Tofimilast
(9-cyclopentyl-7-ethyl-6,9-dihydro-3-(2-thienyl)-5H-pyrazolo[3,4-c]-1,2,4-
-triazolo[4,3-a]pyridine), TPI 1100, UCB 101333-3
(N,2-dicyclopropyl-6-(hexahydro-1H-azepin-1-yl)-5-methyl-4-pyrimidinamine-
), V-11294A (Napp), VM554/VM565 (Vernalis), and Zardaverine
(6-[4-(difluoromethoxy)-3-methoxyphenyl]-3(2H)-pyridazinone).
[0063] (xv) PDE5
Inhibitors:--Gamma-glutamyl[s-(2-iodobenzyl)cysteinyl]glycine,
Tadalafil, Vardenafil, sildenafil,
4-phenyl-methylamino-6-chloro-2-(1-imidazolyl)-quinazoline,
4-phenyl-methylamino-6-chloro-2-(3-pyridyl)-quinazoline,
1,3-dimethyl-6-(2-propoxy-5-methanesulphonylamidophenyl)-1,5-dihydropyraz-
olo[3,4-d]pyrimidin-4-one and
1-cyclopentyl-3-ethyl-6-(3-ethoxy-4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-o-
ne; [0064] (xvi) PPAR.gamma. agonists:--Pioglitazone, Pioglitazone
hydrochloride, Rosiglitazone Maleate, Rosiglitazone Maleate
((-)-enantiomer, free base), Rosiglitazone maleate/Metformin
hydrochloride and Tesaglitizar; [0065] (xvii) Protease
Inhibitors:--Alpha1-antitrypsin proteinase Inhibitor, EPI-FINE4,
UT-77, ZD-0892, DPC-333, Sch-709156 and Doxycycline; [0066] (xviii)
Statins:--Atorvastatin, Lovastatin, Pravastatin, Rosuvastatin and
Simvastatin [0067] (xix) Thromboxane Antagonists: Ramatroban and
Seratrodast; [0068] (xx) Vasodilators:--A-306552, Ambrisentan,
Avosentan, BMS-248360, BMS-346567, BMS-465149, BMS-509701,
Bosentan, BSF-302146 (Ambrisentan), Calcitonin Gene-related
Peptide, Daglutril, Darusentan, Fandosentan potassium, Fasudil,
Iloprost, KC-12615 (Daglutril), KC-12792 2AB (Daglutril), Liposomal
treprostinil, PS-433540, Sitaxsentan sodium, Sodium Ferulate,
TBC-11241 (Sitaxsentan), TBC-3214
(N-(2-acetyl-4,6-dimethylphenyl)-3-[[(4-chloro-3-methyl-5-isoxazolyl)amin-
o]sulfonyl]-2-thiophenecarboxamide), TBC-3711, Trapidil,
Treprostinil diethanolamine and Treprostinil sodium; [0069] (xxi)
ENACs:--Amiloride, Benzamil, Triamterene, 552-02, PSA14984,
PSA25569, PSA23682 and AER002.
[0070] The medicament powder can contain a combination of two or
more active ingredients, for example a combination of two or more
of the specific active ingredients listed in (i) to (xxi) herein
above.
[0071] In some embodiments, the medicament powder contains an
active ingredient selected from mometasone, ipratropium bromide,
tiotropium and salts thereof, salemeterol, fluticasone propionate,
beclomethasone dipropionate, reproterol, clenbuterol, rofleponide
and salts, nedocromil, sodium cromoglycate, flunisolide,
budesonide, formoterol fumarate dihydrate, terbutaline, terbutaline
sulphate, salbutamol base and sulphate, fenoterol,
3-[2-(4-Hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino]-N-[2-[2-(4-met-
hylphenyl)ethoxy]ethyl]propane-sulphonamide, hydrochloride,
indacaterol, aclidinium bromide,
N-[2-(Diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzo-
thiazol-7-yl)ethyl]amino}ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide
or a pharmaceutically acceptable salt thereof (e.g.
dihydrobromide);
N-Cyclohexyl-N.sup.3-[2-(3-fluorophenyl)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo--
2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-.beta.-alaninamide
or a pharmaceutically acceptable salt thereof (e.g.
di-D-mandelate); a
[2-(4-Chloro-benzyloxy)-ethyl]-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)--
oxazol-5-ylmethyl]-dimethyl-ammonium salt (e.g.
hemi-naphthalene-1,5-disulfonate); a
(R)-1-[2-(4-Fluoro-phenyl)-ethyl]-3-((S)-2-phenyl-2-piperidin-1-yl-propio-
nyloxy)-1-azonia-bicyclo[2.2.2]octane salt (e.g. bromide or
toluenesulfonate); or a combination of any two or more thereof.
[0072] Specific combinations of active ingredients which may be
incorporated in the medicament powder include:-- [0073] (a)
formoterol (e.g. as fumarate) and budesonide; [0074] (b) formoterol
(e.g. as fumarate) and fluticasone; [0075] (c)
N-[2-(Diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzo-
thiazol-7-yl)ethyl]amino}ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide
or a pharmaceutically acceptable salt thereof (e.g. dihydrobromide)
and a
[2-(4-Chloro-benzyloxy)-ethyl]-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)--
oxazol-5-ylmethyl]-dimethyl-ammonium salt (e.g.
hemi-naphthalene-1,5-disulfonate); [0076] (d)
N-[2-(Diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzo-
thiazol-7-yl)ethyl]amino}ethyl)-3-[2-(1-naphthyl)ethoxy]propanamide
or a pharmaceutically acceptable salt thereof (e.g. dihydrobromide)
and a
(R)-1-[2-(4-Fluoro-phenyl)-ethyl]-3-((5)-2-phenyl-2-piperidin-1-yl-propio-
nyloxy)-1-azonia-bicyclo[2.2.2]octane salt (e.g. bromide or
toluenesulfonate); [0077] (e)
N-Cyclohexyl-N.sup.3-[2-(3-fluorophenyl)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo--
2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-.beta.-alaninamide
or a pharmaceutically acceptable salt thereof (e.g. di-D-mandelate)
and
[2-(4-Chloro-benzyloxy)-ethyl]-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)--
oxazol-5-ylmethyl]-dimethyl-ammonium salt (e.g.
hemi-naphthalene-1,5-disulfonate); [0078] (f)
N-Cyclohexyl-N.sup.3-[2-(3-fluorophenyl)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo--
2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-.beta.-alaninamide
or a pharmaceutically acceptable salt thereof (e.g. di-D-mandelate)
and a
(R)-1-[2-(4-Fluoro-phenyl)-ethyl]-3-((5)-2-phenyl-2-piperidin-1-yl-propio-
nyloxy)-1-azonia-bicyclo[2.2.2]octane salt (e.g. bromide or
toluenesulfonate).
[0079] In some embodiments, the medicament powder is formulated as
an ordered mixture, with fine powder active ingredient particles
adhered to larger carrier particles of e.g. lactose.
[0080] Another aspect of the invention features a method of
dispensing an air stream carrying a dose of medicament powder. The
method includes passing a flow of air across the opening of a
powder-containing cavity having, the length of the cavity opening
in the flow direction being (i) between 50% and 150% of the cavity
depth, and (ii) at least 80% of the maximum length of the cavity in
the flow direction. The maximum velocity of the flow immediately
adjacent the cavity opening is at least 15 m/s. In some
embodiments, the maximum velocity of the flow immediately adjacent
the cavity opening is at least 20 m/s, more preferably at least 30
m/s, more preferably at least 40 m/s or as much as 50 m/s. In some
embodiments, the flow is in the range 15 m/s to 100 m/s, more
preferably 20 m/s to 80 m/s.
[0081] By generating a flow of this velocity across the opening of
the cavity, a rotating flow in the cavity may be created which may
give rise to effective emptying and deaggregation. There may, of
course, be a variation of flow across the cross section of the
passage. The expression "immediately adjacent the cavity opening"
includes the plane of the cavity opening as defined below.
[0082] In some embodiments, the mass of residual active
pharmaceutical ingredient (API) in the cavity after dispensing
amounts to between 0.1% and 10% by mass of the total mass of API in
the cavity prior to dispensing, preferably between 1% and 8%, more
preferably between 1% and 5%. It is normal to measure retention by
the mass of API rather than the total powder mass. The term
"medicament powder" is used in this specification to mean the
complete powder formulation, including API, carrier particles and
any other ingredients.
[0083] The device is intended to be a platform for delivery of a
wide range of powder formulations. Although emptying will vary
between different formulations, higher surface shear stress in the
lower half of the cavity would normally result in more efficient
emptying.
[0084] Yet another aspect of the invention features a method of
dispensing an air stream carrying a dose of medicament powder
includes passing a flow of air across the opening of a
powder-containing cavity, the length of the cavity opening in the
flow direction being (i) between 50% and 150% of the cavity depth,
and (ii) at least 80% of the maximum length of the cavity in the
flow direction. The average surface shear stress over the lower
half of the cavity is at least 0.5 Pa. In some embodiments, the
average surface shear stress over the lower half of the cavity is
at least 1 Pa, more preferably at least 1.5 Pa. In some
embodiments, the average surface shear stress can be less than or
equal to 20 Pa, more preferably less than or equal to 15 Pa. This
is based computer modeling of the flow in the cavity, with Reynolds
averaged Navier-Stokes (RAND), turbulent, three dimensional, steady
computational fluid dynamics (CFD) calculations using the
ANSYS.RTM. software Fluent, version 6.3.26.
[0085] In another aspect, the invention features a method of
dispensing an air stream carrying a dose of medicament powder
includes passing a flow of air across the opening of a
powder-containing cavity having only a single opening. The length
of the cavity opening in the flow direction is between 50% and 150%
of the cavity depth. The maximum velocity of the flow immediately
adjacent the cavity opening is at least 15 m/s. In some
embodiments, the flow immediately adjacent the cavity opening is at
least 20 m/s, more preferably at least 30 m/s, more preferably at
least 40 m/s or as much as 50 m/s. The flow can be in the range 15
m/s to 100 m/s, more preferably 20 m/s to 80 m/s.
[0086] Yet another aspect of the invention features a method of
dispensing an air stream carrying a dose of medicament powder that
includes passing a flow of air across the opening of a
powder-containing cavity having only a single opening. The cavity
opening has a length in the flow direction of between 50% and 150%
of the cavity depth. The average surface shear stress over the
lower half of the cavity is at least 0.5 Pa, preferably at least 1
Pa. In some embodiments, the average surface shear stress over the
lower half of the cavity is at least 1.5 Pa, the upper end of these
ranges being 20 Pa or preferably 15 Pa. This is based on computer
modeling of the flow in the cavity, with Reynolds averaged
Navier-Stokes (RAND), turbulent, three dimensional, steady
computational fluid dynamics (CFD) calculations using the
ANSYS.RTM. software Fluent, version 6.3.26.
[0087] There are also a number of other parameters of the flow in
the cavity that are possible to calculate using the computational
fluid dynamics technique referred to above. The parameters referred
to below are also derived from a computer model with RAND,
turbulent, three dimensional, steady CFD calculations using the
ANSYS.RTM. software Fluent, version 6.3.26.
[0088] According to another aspect of the invention, a method of
dispensing an air stream carrying a dose of medicament powder
includes passing a flow of air across the opening of a
powder-containing cavity. The length of the cavity opening in the
flow direction being (i) between 50% and 150% of the cavity depth,
and (ii) at least 80% of the maximum length of the cavity in the
flow direction. The average turbulent kinetic energy in the lower
half of the cavity is at least 3 m.sup.2/s.sup.2. In some
embodiments, the average turbulent kinetic energy in the lower half
of the cavity is at least 4 m.sup.2/s.sup.2, more preferably at
least 5 m.sup.2/S.sup.2. In some embodiments, the average turbulent
kinetic energy in the lower half of the cavity is less than or
equal to 50 m.sup.2/s.sup.2, preferably less than or equal to 20
m.sup.2/s.sup.2.
[0089] According to another aspect of the invention, a method of
dispensing an air stream carrying a dose of medicament powder
includes passing a flow of air across the opening of a
powder-containing cavity. The length of the cavity opening in the
flow direction being (i) between 50% and 150% of the cavity depth,
and (ii) at least 80% of the maximum length of the cavity in the
flow direction. The average vorticity in the lower half of the
cavity is at least 2,000 l/s. In some embodiments, the average
vorticity in the lower half of the cavity is at least 4,000 l/s,
more preferably at least 10,000 l/s. In some embodiments, the
average vorticity in the lower half of the cavity is less than or
equal to 100,000 l/s, preferably less than or equal to 50,000 l/s,
more preferably less than or equal to 20,000 l/s.
[0090] According to another aspect, a method for dispensing an air
stream carrying a dose of medicament powder includes passing a flow
of air across the opening of a powder-containing cavity. The length
of the cavity opening in the flow direction is (i) between 50% and
150% of the cavity depth, and (ii) at least 80% of the maximum
length of the cavity in the flow direction. The average flow
velocity in the lower half of the cavity is at least 1.5 m/s. In
some embodiments, the average flow velocity in the lower half of
the cavity is at least 3 m/s, more preferably at least 4 m/s. In
some embodiments, the average flow velocity in the lower half of
the cavity is less than or equal to 30 m/s, preferably less than or
equal to 20 m/s, more preferably less than or equal to 10 m/s.
[0091] According to another aspect of the invention, a method of
dispensing an air stream carrying a dose of medicament powder
includes passing a flow of air across the opening of a
powder-containing cavity having only a single opening. The cavity
opening having length in the flow direction of between 50% and 150%
of the cavity depth. The average turbulent kinetic energy in the
lower half of the cavity is at least 3 m.sup.2/s.sup.2. In some
embodiments, the average turbulent kinetic energy in the lower half
of the cavity is at least 4 m.sup.2/s.sup.2, more preferably at
least 5 m.sup.2/s.sup.2. In some embodiments, the average turbulent
kinetic energy in the lower half of the cavity is less than or
equal to 50 m.sup.2/s.sup.2, preferably less than or equal to 20
m.sup.2/s.sup.2.
[0092] According to another aspect of the invention, a method of
dispensing an air stream carrying a dose of medicament powder
includes passing a flow of air across the opening of a
powder-containing cavity having only a single opening. The cavity
opening has a length in the flow direction of between 50% and 150%
of the cavity depth. The average vorticity in the lower half of the
cavity is at least 2,000 l/s. In some embodiments, the average
vorticity in the lower half of the cavity is at least 4,000 l/s,
more preferably at least 10,000 l/s. In some embodiments, the
average vorticity in the lower half of the cavity is less than or
equal to 100,000 l/s, preferably less than or equal to 50,000 l/s,
more preferably less than or equal to 20,000 l/s.
[0093] According to another aspect of the invention, a method of
dispensing an air stream carrying a dose of medicament powder
includes passing a flow of air across the opening of a
powder-containing cavity having only a single opening. The cavity
opening has a length in the flow direction of between 50% and 150%
of the cavity depth. The average flow velocity in the lower half of
the cavity is at least 1.5 m/s. In some embodiments, the average
flow velocity in the lower half of the cavity is at least 3 m/s,
more preferably at least 4 m/s. In some embodiments, the average
flow velocity in the lower half of the cavity is less than or equal
to 30 m/s, preferably less than or equal to 20 m/s, more preferably
less than or equal to 10 m/s.
[0094] Flow in the cavity as defined in any of the paragraphs above
can, in some embodiments, be created solely by the phenomenon of
shear driven cavity flow.
[0095] In some embodiments, in a method as defined above, the
medicament powder includes a compound or combination selected from
the list which appears above.
DEFINITIONS
[0096] The aspect ratio of the cavity opening is defined as the
perpendicular length (in the case of a trapezoidal shape being the
length of the line of symmetry) of the opening divided by the mean
width.
[0097] The term "height", referring to the flow passage shall mean
the perpendicular distance from the wall of the passage in which
the cavity opening is formed to the opposite wall of the
passage.
[0098] The term "width", referring to the flow passage, at any
given location in the flow passage, shall mean the shortest
distance between the two side walls at that location.
[0099] The term "floor" shall mean the wall of the flow passage in
which the cavity opening is formed. The term "ceiling" shall mean
the wall of the flow passage opposite the floor.
[0100] The term "side wall" in relation to the flow passage shall
mean a flow passage wall which extends between the floor and the
ceiling.
[0101] The plane of the cavity opening shall mean the plane defined
by the rim of the cavity, the rim being the interface between the
cavity and the flow passage. If the rim does not lie completely in
one plane, then the plane of the cavity opening shall mean the
plane which is the best fit to the rim.
[0102] The term "depth" in connection with the cavity shall mean
the perpendicular distance from the plane of the cavity opening to
the deepest point of the cavity.
[0103] The maximum length of the cavity shall be defined as the
greatest length of the cavity in the flow direction, measured in a
plane parallel to the plane of the cavity opening
[0104] Where expressions such as "up" and "down" are used with
respect to a device in this specification, it is assumed that the
orientation of the device is such that the opening of the cavity or
cavities faces upwards.
[0105] The term "medicament powder" shall mean all of a powder
formulation, including without limitation any carrier, diluent or
coating in addition to any active pharmaceutical ingredients.
BRIEF DESCRIPTION OF THE DRAWINGS
[0106] The present invention will now be described, for exemplary
purposes, in more detail by way of embodiments and examples and
with reference to the enclosed drawings, in which:
[0107] FIG. 1 is a schematic cross sectional view of a flow passage
region of a first embodiment;
[0108] FIG. 2 is a schematic cross sectional view of a flow passage
region of a second embodiment;
[0109] FIGS. 3a-3d are schematic perspective views of part of the
flow passage region of FIG. 1, showing a sequence of operation;
[0110] FIG. 4 is a plan view of the entire first embodiment;
[0111] FIG. 5 is an exploded perspective view of a cavity disc and
support of the first embodiment;
[0112] FIG. 6 is a side sectional view of part of a third
embodiment, showing the cavity disc and two cavities;
[0113] FIG. 7 is a perspective view of a computer model of the flow
path of the inhaler of U.S. Pat. No. 4,446,862, used in Example
1;
[0114] FIG. 8 is a side view of the computer flow path model of
FIG. 7;
[0115] FIG. 9 is a perspective view of a computer model of the flow
path of an inhaler, used in Example 2;
[0116] FIG. 10 is a graph showing the results of computer modeling
of powder entrainment in the flow path of FIGS. 7 and 8 and also in
a flow path;
[0117] FIGS. 11a and 11c are side views of computer models of flow
paths;
[0118] FIGS. 11b and 11d are plan views of the cavities shown in
FIGS. 11a and 11c;
[0119] FIG. 12 is a bar chart showing powder retention for four
different shapes of cavity;
[0120] FIG. 13 is a graph showing the degree of powder retention
for two alternative designs of cavity and for nine different powder
formulations;
[0121] FIGS. 14a and 14b are side and perspective views,
respectively, of an alternative flow path model of a device;
and
[0122] FIGS. 15a and 15b are side and perspective views,
respectively, of an alternative flow path model of a device with
increases channel height.
EXAMPLE 1 (PRIOR ART)
[0123] FIGS. 7 and 8 show a computer model of the flow path of the
device described in U.S. Pat. No. 4,446,862 (referred to above).
This model is based on the main embodiment described in U.S. Pat.
No. 4,446,862, FIGS. 1 to 4a. The device includes a flat
cylindrical flow chamber 101, in the base of which is located a
separated part 102 of a standard size 4 pharmaceutical capsule
containing a powder for inhalation. Evenly spaced around half of
the circumference of the chamber and located towards the lower end
are six air inlets 103. Symmetrically opposite the inlets 103 is a
mouthpiece 104 of rather larger diameter than the inlets 103.
[0124] Some dimensions are specified in U.S. Pat. No. 4,446,862.
For example the inlet diameter is said to be 2 mm, see col. 6, line
19, and the use of standard size 4 capsules is specified in col. 7,
line 15. Size 4 capsules have a capsule base inner diameter of
approximately 5 mm and a capsule base length of approximately 7 mm.
The remaining dimensions have been taken from FIG. 4a, scaled
according to the values which are specified in the text.
[0125] The model was used to simulate flow in the device using
computational fluid dynamics techniques, specifically Reynolds
averaged Navier-Stokes (RANS), turbulent, three-dimensional, steady
computational fluid dynamics (CFD) using the ANSYS.RTM. software
Fluent.RTM., version 6.3.26.
[0126] In U.S. Pat. No. 4,446,862, the pressure drop across the
device is said to be 4.7 cm H.sub.2O (about 0.46 kPa) to produce a
flow rate of 28.3 l/min. In the CFD simulation, this pressure drop
produced a flow rate of 21.9 l/min, which represents a fairly good
correlation of simulated result to the result reported in U.S. Pat.
No. 4,446,862. To get a flow rate nearer the target rate according
to U.S. Pat. No. 4,446,862, a pressure drop of 0.76 kPa was needed
in the model.
[0127] The current standard pressure difference for testing inhaler
designs is 4 kPa, which is what a normal patient will tend to
generate. A weak patient may generate about 2 kPa, whilst a very
fit one will generate about 6 kPa.
[0128] The table below shows four sets of results for different
pressures and corresponding volume flow rates. 4 kPa pressure has
been used since it is a modern day standard test condition. 0.46
kPa and 0.76 kPa have been used for reasons discussed above, and
0.17 kPa has been used for reasons which will be explained below in
the discussion of Example 2. A number of parameters were computed
for each case, labeled 1-8 in Table 1 below, as follows:
Parameter 1: Average shear stress at the cavity surface (Pa) over
the whole cavity; Parameter 2: Average shear stress at the cavity
surface (Pa) over lower half of cavity; Parameter 3: Average flow
velocity (ms.sup.-1) over the whole cavity; Parameter 4: Average
flow velocity (ms.sup.-1) over lower half of cavity; Parameter 5:
Average vorticity (1/s) over the whole cavity; Parameter 6 Average
vorticity (1/s) over lower half of cavity; Parameter 7: Average
turbulent kinetic energy (m.sup.2/s.sup.2) over the whole cavity;
and Parameter 8: Average turbulent kinetic energy (m.sup.2/s.sup.2)
over lower half of cavity.
[0129] The average surface shear stress at the wall of the cavity,
for the lower half of the cavity (based on half the perpendicular
distance from the plane of the cavity opening to the bottom of the
cavity), is considered to represent the best indicator of emptying
efficiency for this model. The wall shear stress is defined as:
.tau. w = .mu. .differential. v .differential. n ##EQU00001##
where
[0130] .mu. is the molecular viscosity and
.differential. v .differential. n ##EQU00002##
the normal velocity gradient at the wall.
[0131] In Table 1, .DELTA.P is the pressure difference in kPa and Q
is the volume flow rate in l/min.
TABLE-US-00001 TABLE 1 .DELTA.P Q PARAMETER (kPa) (l/min) 1 2 3 4 5
6 7 8 4.00 66.53 1.72 0.43 2.73 1.18 5000 1800 32.00 3.10 0.46
21.90 0.28 0.06 0.39 0.85 1637 592 2.49 0.26 0.17 12.96 0.10 0.02
0.45 0.19 876 288 0.69 0.06 0.76 28.58 0.45 0.08 1.11 0.49 2133 724
4.70 0.45
EXAMPLE 2
CFD Modeling of Devices
[0132] A computer model of a device designed as an example of one
embodying our concepts was created using the same software that was
used in Example 1. The entire inhaler device has more automated
functions. There are also two flow paths in the inhaler, one which
passes over the powder cavity and a bypass passage. The flow path
which passes over the cavity is slightly more tortuous than that of
the prior art and there may be a moderately significant pressure
drop before the flow passage reaches the cavity. For example, there
may be a pressure drop in normal use of between 0.01 and 2.0 kPa
over the portion of the total flow path leading up to the cavity.
This is preferably at the lower end of that range, e.g. 0.1 to 1.0
kPa.
[0133] For these reasons, a straight comparison based on overall
pressures and volume flows, etc, between the two inhalers is not
really the best test. Nonetheless, the whole inhaler was analyzed
at 4 kPa pressure difference between air inlet and mouthpiece, with
the results shown in row 1 of Table 2 below. The remaining results
in Table 2 are for a section of the flow path which corresponds
better with the very simple flow path of the device described in
U.S. Pat. No. 4,446,862.
[0134] The modeled flow path is shown in FIG. 9. This path
accurately represents the critical part of the flow as regards
emptying of the powder cavity. The cavity is shown at 41 and the
flow passage over the cavity at 42. The dimensions of the cavity
are given in Table 3 below under column "A". The flow passage
adjacent the cavity has height 1.5 mm and the width is 3.1 mm at
the upstream end and 5.1 mm at the downstream end, with respect to
the flow direction F. Part 43 of the floor of the flow passage 42
on the upstream side of the cavity is sloping. Projecting from this
floor is a turbulence-inducing obstruction or projection 44--a
so-called "turbulator". The purpose of this feature is to promote
turbulence in the flow in the passage 42 which is then imparted to
the shear driven flow in the cavity 41. In this example, results
were obtained both with and without a turbulator 44 in the flow
path; this is indicated in the Table.
[0135] The same eight parameters used in Example 1 were computed
for the device and the numbered columns in Table 2 below correspond
to those of Table 1.
[0136] Four of the eight results are parameters average over the
whole cavity, whilst the other four are averaged over only the
lower half of the cavity. The line 45 half way down the cavity in
FIG. 9 shows the division between the upper and lower halves of the
cavity: it is located at half the perpendicular distance from the
plane of the cavity opening to the bottom of the cavity.
[0137] The first row of results is for a standard pressure drop of
4 kPa over a computer model of the entire inhaler. Approximately 1
kPa of this pressure drop was "lost" over other parts of the
inhaler model. For the first row results, therefore, the pressure
drop across the flow path shown in FIG. 9 may be assumed to be
approximately 3 kPa. The model used for the row 1 results includes
a bypass passage, which means that the volume flow rate is very
high in comparison with the other results which are for the short
section of flow path shown in FIG. 9. The volume flow rate through
the FIG. 9 flow passage only is shown in brackets.
[0138] The remaining results are for a given pressure drop across
only the flow path of FIG. 9. This section of flow path was chosen
to be as fair a comparison to the U.S. Pat. No. 4,446,862 device as
possible. In three of these cases, the turbulator is included in
the flow path. In one case, the turbulator was omitted.
TABLE-US-00002 TABLE 2 PARAMETER .DELTA.P (kPa) Q (l/min) 1 2 3 4 5
6 7 8 Whole inhaler - 4.00 57.50 3.46 2.00 5.14 4.44 15800 10400
9.67 5.96 no turbulator (12.1) With turbulator 1.50 12.26 4.17 1.87
5.38 4.36 17661 11012 10.23 5.19 Without turbulator 1.50 12.86 3.57
1.65 4.73 3.98 15563 10498 8.05 4.58 With turbulator 0.46 6.16 1.26
0.37 2.43 1.63 8108 4106 3.08 1.11 With turbulator 7.00 29.70 19.77
14.10 15.51 15.09 49053 39056 45.96 32.49
[0139] In Table 1, .DELTA.P is the pressure difference in kPa and Q
is the volume flow rate in l/min.
[0140] Comparing the results, it is immediately apparent that a
much more energetic flow is induced in the cavity in the device
according to this disclosure than in the cavity of U.S. Pat. No.
4,446,862. In line four of Tables 1 & 2, the 0.46 kPa pressure
drop specified in U.S. Pat. No. 4,446,862 is applied. The average
surface shear stress (Parameter 2) in the lower half of the cavity
is 0.37 Pa in the device according to this disclosure and only 0.06
Pa in the device according to U.S. Pat. No. 4,446,862. This
difference is more than a factor of 6 in a parameter which, as
discussed above, is considered to be the best indicator of cavity
emptying efficiency.
[0141] Comparing row 1 of the respective tables, where in each case
a pressure drop of 4 kPa was applied across the whole inhaler, the
values of Parameter 2 are 3.46 Pa and 1.72 Pa, respectively, for
the inhaler of this disclosure and the device according to U.S.
Pat. No. 4,446,862--a factor of more than 2, despite the fact that
pressure losses would have occurred in other parts of the inhaler,
and much of the flow would have been through the bypass
channel.
[0142] In row 3 of Table 2, a pressure drop of 1.5 kPa is applied
across the flow path without the turbulator feature; this results
in a flow rate of about 12.9 l/min and an average surface shear
stress in the lower half of the cavity of 3.57 Pa. A similar flow
rate in the device of U.S. Pat. No. 4,446,862 produces an average
surface shear stress in the lower half of the cavity of a mere 0.02
Pa.
EXAMPLE 3
[0143] A different CFD modeling technique, RANS turbulent,
three-dimensional, transient multiphase CFD using the ANSYS.RTM.
software CFX.RTM., release 11.0, was employed to model the movement
of powder in the airflow in the cavities, specifically to obtain
results relating to the emptying of the cavities. The software
simulated inter-phase momentum transfer using a dispersed particle
model with a particle size of 50 micron.
[0144] The flow path of Example 2/FIG. 9, without turbulator, was
compared to the flow path of Example 1 (the CFD model of the device
of U.S. Pat. No. 4,446,862). The same flow rate of 12 l/min was
applied to each flow path and, in the model, the cavity was
initially filled with powder to 2/3 of the total cavity volume.
[0145] The simulation was made for the first 100 mS after
initiation of airflow. As can be seen from the graph of the results
in FIG. 10, after 100 mS, the cavity in the flow path according to
this disclosure was substantially empty, whilst the cavity of the
U.S. Pat. No. 4,446,862 device still contained more than 90% of the
original mass of powder. More powder may subsequently have been
entrained in the air flow in the U.S. Pat. No. 4,446,862 device if
the simulation had been extended, but this Example demonstrates at
least that the rate of emptying of a cavity in a device or flow
path according to this disclosure appears to be markedly superior
to that of U.S. Pat. No. 4,446,862. It is generally considered
desirable in the inhaler art to entrain powder in as short a time
period as possible.
EXAMPLE 4
[0146] Referring to FIGS. 11a and 11b, a flow path in accordance
with this disclosure is shown. Various dimensions of the cavity
were altered in the CFD model referred to in Example 2. These
dimensions are shown in FIGS. 11a and 11b and also in Table 3
below. Fillet radius is shown at 207 in FIG. 11b, Rear radius at
203 in FIG. 11a, Front (downstream) radius at 204, Length at 201
and depth at 202. Rear half-width is shown at 205 in FIG. 11b and
Front half-width at 206. The flow passage passing over the cavity
is shown at 210 and cavity at 211. The direction of flow is
indicated by arrow F. One alternative shape of cavity, with
corresponding reference numerals indicating equivalent features of
the geometry, is shown in FIGS. 11c and 11d. Six designs were
tested in total.
[0147] Analysis was performed using the same software as in
Examples 1 and 2. The model included a turbulator (reference 212 in
FIG. 11a). For each geometry, the average surface shear stress over
the lower half of the cavity was computed. The results are shown in
Table 3 below.
TABLE-US-00003 TABLE 3 Cavity design A B C D E F Fillet Radius [mm]
0.3 0.2 0.22 0.2 0.2 0.201 Rear Radius (lower upstream edge) [mm] 2
2.2 2.09 2.16 2.14 2.17 Front Radius (lower downstream edge) [mm] 1
2.2 1.8 2.1 2.06 1.8 Length in flow direction [mm] 4.5 5.5 4.95
5.43 5.5 5.19 Depth [mm] 4.5 4.2 4.58 4.95 5.5 4.46 Length/depth
1.00 1.31 1.08 1.10 1.00 1.16 Rear Half Width [mm] 0.958 0.8 1.03
1.1 1.3 1.1 Front Half Width [mm] 1.35 1.1 0.7 0.67 0.65 0.72 Area
Cavity [mm2] 58.3 57.6 56.9 67.1 79 59 Area Lower Half of Cavity
[mm2] 30.4 29.4 28.9 34.3 40.6 30.1 Volume Cavity [mm3] 39.13 35.3
32.8 40.5 51.4 35.5 Shear stress Lower Half of Cavity [Pa] 2.08
3.46 4.16 4.34 4.32 4.6
[0148] It can be seen from the results that changing the cavity
shape can have a significant effect on the average shear stress.
Design A is shown in FIGS. 11a and 11b. This is also the design
shown in FIG. 9. This design had been developed using high speed
imaging of powder flow in physical models of cavities--it had been
determined that this shape produced considerably better emptying of
the cavity than a simple cuboid shape of approximately equivalent
overall proportions (length, depth, width). However, the CFD
results shown in Table 3 unexpectedly show that considerably better
performance is possible by refining the geometry further. Changing
Design A to increase the aspect ratio in plan view--that is to say
increasing the length relative to the width--appeared to result in
substantially greater surface shear stress in the lower half of the
cavity. Furthermore, increasing the size of the front radius (that
is to say, the downstream radius) appeared to have a marked effect.
These changes can be seen, for example, in Design B which is shown
in FIGS. 11c and 11d. For example, the both front and rear radii
can be between 1.75 mm and 2.25 mm.
EXAMPLE 5
[0149] Physical prototypes of Designs A, B C and F in Example 4
were created using rapid prototyping techniques. These models were
then tested using by filling them with two different powder
formulations, one very challenging and the other less so. A
pressure of 1.5 kPa was applied to each design to generate airflow
through the prototypes equivalent to a very weak human patient
inhaling. Figures for emptying expressed as the percentage mass of
active pharmaceutical ingredient (API) remaining the cavity were
determined for each design.
[0150] The results are shown in FIG. 12. The shaded columns
represent results for the more challenging formulation, whilst the
plain columns represent the less challenging formulation. A marked
reduction in retention of API powder can be seen between Design A
and Design B, consistent with the CFD results in Table 3. However,
an increase in retention is seen from Design B to Design C, despite
the fact that the average surface shear stress value in the CFD
work for Design C was higher than for Design B. Design F showed
retention broadly similar to Design B, although the surface shear
stress from the CFD work was higher. It is believed that the main
reason for the increased retention of Designs C and F, particularly
for Design C, compared with Design B, related more to issue with
the manufacturing of the prototypes than with the overall design.
It is believed, however, that if properly manufactured and filled,
Designs C to F would have lower powder retention than Design B.
These "reverse taper" designs (C to F) may also be useful in an
inhaler of a different design.
EXAMPLE 6
[0151] Similar testing to that of Example 5 was performed using the
prototypes for Designs A and B, using 9 different standard and
experimental powder formulations.
[0152] FIG. 13 shows a plot of retention of powder in the cavity
for Design A and Design B. As can be seen, for every formulation
Design B showed less retention of powder.
[0153] For both cavity shapes, the pressure drop across the section
of flow path was 1.5 kPa. The average surface shear stress in the
lower half of the cavity for the original design (calculated in
Example 4) was 2.08 Pa, whilst the same value for the second shape
(from Example 4) was 3.46 kPa. This result supports the hypothesis
that average surface shear stress in the lower half of the cavity
is correlated to emptying efficiency.
EXAMPLE 7
[0154] A slightly different computer model of the flow path for a
device was generated for the purpose of assessing the effect of
flow passage height on the performance of the device. The models
for a 1.5 mm channel height and a 10 mm channel height are shown in
FIGS. 14a, 14b, 15a, and 15b respectively. The width of the channel
was the same for each model, diverging slightly in the downstream
direction and being from 3.1 mm at its narrowest to 5.1 mm at its
widest point. The upstream part 53 of the flow passage 52 was
redesigned to have a flat "floor" 54 (i.e. the wall of the flow
path in which the cavity is formed). The reason for this was that
it was found that, if the inclined floor was retained, in a model
with increased "ceiling" height (i.e. distance 55 from the "floor"
to the opposite wall), then the flow was directed upwards and away
from the flow passage floor. The inclined upstream passage has
relatively little effect when the height of the passage over the
cavity is small (e.g. around 1.5 mm), but a fair assessment of the
effect of increasing flow passage height could only be made if the
passage continued to direct flow across the cavity opening (as
opposed to away from it).
[0155] A number of different channel heights were modeled, each
with a cavity 51 of Design A (see Examples 5 & 6 above).
[0156] CFD calculations were made based on a volume flow rate of 25
l/min passing down the channel in each case. The average surface
shear stress for the lower half of the cavity was calculated for
each case, using the same software as used in Examples 1 and 2,
with the same definitions applying. The results are shown in Table
4 below.
TABLE-US-00004 TABLE 4 Average surface shear stress - Flow passage
height (mm) lower half of cavity (Pa) 1.5 6.6 3 0.99 5 0.05 10
0.03
[0157] As can be seen, the result of increasing the flow passage
height is a dramatic reduction in the average surface shear stress
in the lower half of the cavity. This may be principally due to the
reduced airflow velocity across the cavity.
[0158] To promote manufacturability and accommodate typical
tolerances, the flow passage height is 1.5 mm. However, it is
believed that decreasing the flow passage height would further
increase the emptying efficiency of the device. Flow passage
heights of 1 mm and 0.5 mm are also contemplated.
[0159] Interpolating these results, an average surface shear stress
value over the lower half of the cavity for a flow passage height
of 4 mm would be about 0.5 Pa based on a straight line drawn
between the 3 mm and 5 mm values on a graph.
EXAMPLE 8
[0160] CFD studies with simple cuboid and capsule shaped cavities
were performed and it was found that a cuboid shaped cavity showed
more promising results than a capsule shaped cavity. The rate of
emptying is found to be slightly slower for a capsule shaped
cavity. While the flow in the cuboid shaped cavity is found to be
substantially two-dimensional, the flow in the capsule shaped
cavity is found to be three-dimensional. The three-dimensional flow
in the capsule shaped cavity is found to result in a greater
concentration of particles at and near the centerline downstream of
the cavity. A major difference is in the capacity to promote a
cylindrical flow pattern. It is believed that the capsule-shaped
cavity does not allow the build up of a cylindrical flow
pattern.
[0161] A number of non-limiting embodiments will now be described
with reference to FIGS. 1 to 6.
[0162] A first embodiment is shown schematically in FIG. 4. This is
a multi-dose inhalation device from which a user may inhale doses
of medicament in the form of dry powder. The device 1 includes a
housing 23 and a mouthpiece 3. The mouthpiece 3 may be uncovered by
linear movement of a mouthpiece cover 24. In some embodiments (not
shown), the mouthpiece cover can be pivotally supported by the
housing.
[0163] Inside the housing 23 is a disc-shaped structure 18
containing a plurality of cavities 5. The cavity disc 18 is
rotatably supported in a cavity disc holder 19. The cavities 5 are
arranged in an annular pattern around the periphery of the disc.
The disc 18 has a large central hole 26 which accommodates other
components of the inhaler device including an air inlet channel
(not shown) and a mechanism (also not shown) for moving the disc
around to expose new cavities for each inhalation. A separate flow
channel (not shown) is provided over each cavity 5, with the top
surface 25 of the disc 18 forming the lower surface of the
channel.
[0164] FIG. 1 schematically shows a cavity 5 and an adjacent flow
path 4 of the first embodiment. The height of the flow path is
shown at 13. The cavity 5 is cuboid shaped and the cavity opening
20 has a rim 6 where the sides of the cavity 5 meet the flow
passage lower wall or "floor" 7. The cavity contains medicament
powder 2. It is advantageous that the cavity is shaped to allow a
cylindrical airflow pattern within the cavity 5. The cylindrical
flow pattern in the cavity is developed around an axis located
transverse to the flow direction and approximately in the middle of
the cavity. The sides of the cavity are perpendicular to the floor
7.
[0165] Now, with reference to FIGS. 1 and 3 the overall function of
the device 1 will be described in more detail. Part of the flow
passage 4 has a flat floor 7 (i.e. the lower wall of the passage
when the device is in its normal orientation). The floor 7 includes
an opening 20 into the powder-containing cavity 5. The passing of
an air stream in the flow direction F along the flow passage and
across the opening 20 generates a cylindrical circulating flow in
the cavity 5 due to the phenomenon of shear driven cavity flow. The
powder particles are agitated in this energetic, somewhat
turbulent, circulating flow, and also impact the sides of the
cavity. The entrainment of particles in the energetic flow and the
impacting of particles against the sides of the cavity 5 may
contribute to deaggregation, bringing the formulation into a
condition ready for inhalation. The powder particles entrained in
the circulating flow may tend to be thrown outwardly (or, more
precisely, will tend to move tangentially to the flow), and thus
may exit the cavity and become entrained in the airflow in the
passage 4.
[0166] The cavity 5 and cavity opening 20 each have a length 10 in
the flow direction F of the flow passage 4 of 5 mm. The cavity
depth 22 is also 5 mm.
[0167] The distance 11 from the top of the cavity 5 (i.e. the plane
of the cavity opening) to the top of the leveled powder particle
bed in an initial condition is 1 mm. This distance is referred to
as the headspace 11 of the cavity. The depth of powder in the
cavity is shown at 9.
[0168] In side section, the cavity is square; the inner corners of
the cavity are essentially sharp, that is to say the lower front
(downstream) edge 16 and the lower rear (upstream) edge 17 are
sharp. In some embodiments (not shown), the edges have a radius of
about 0.5 mm in order to provide some guidance in the rotational
movement of the generated circulating flow.
[0169] FIGS. 3a to 3d show schematically the emptying of the cavity
5. Air moves along the passage 4 under the influence of a pressure
drop created by a patient inhaling (not shown). For the whole
inhaler, this may be between 2 and 6 kPa. The pressure drop over
the section of passage shown in FIG. 3 may be between 0.5 kPa and 5
kPa.
[0170] FIG. 3a shows the initial state of the powder-filled cavity
5. An airflow along the flow passage 4 is initiated in the flow
direction F and emptying of the cavity 5 starts. In FIG. 3b some of
the powder 2 has left the cavity 5, the build up of a circulating
flow in the cavity 5 has begun and it can be seen that the cavity 5
starts to empty at the downstream end. As can be seen in FIG. 3c,
the powder level is gradually eroded downwardly and in an upstream
direction. The time elapsed from the initial state in FIG. 3a to
the final state in FIG. 3d depends partly speed of the flow and the
exact powder composition, but a normal time for this embodiment
would be about 300 ms.
[0171] A second embodiment will now be described with reference to
FIG. 2. The only aspect which is changed from the first embodiment
is the shape of the cavity. Reference numerals in this embodiment
are the same as for the first embodiment for equivalent
features.
[0172] In the second embodiment, the parallel front and rear walls
of the cavity 5 are oriented at an acute angle .alpha. in relation
to the vertical direction (normal to the cavity opening). The
cavity opening 20 is still aligned with flow passage floor 7 in the
flow passage 4 adjacent the cavity 5. The inclination of the walls
in relation to the flow passage 4 may make it more difficult for
the particles entrained in the circulating flow in the cavity to
escape into the flow passage 4. Hence, in the second embodiment the
degree of deaggregation may be increased, since the time for which
the medicament powder 2 is entrained in the energetic circulating
flow and subject to wall contact/impact is increased. On the other
hand, emptying time may be longer for the second embodiment. In
FIG. 2 the cavity is shown angled in the direction of flow (arrow
F), but in a modification the cavity could be angled in the
opposite direction of the cavity shown in FIG. 2, that is to say
with the angle .alpha. in FIG. 2 having a negative value.
[0173] It has been found that powder can be retained by the cavity
in the lower upstream and downstream corners/edges. To counteract
this, in the second embodiment the lower front (downstream) edge 17
of the cavity 5 has a radius of about 0.5 mm, whilst the lower rear
(upstream) edge 16 has a radius of approximately 1 mm.
[0174] A third embodiment will now be described with reference to
FIG. 6, which shows a part side section through a multi-dose dry
powder inhaler 30. A housing member 31, together with other
components (not shown) of an inhaler housing, contain the various
components of the inhaler.
[0175] A cavity disc 32 has a number of powder-containing cavities
33. In use, as with the first embodiment, the disc 32 is rotated in
order to bring the individual cavities into registry with a
mouthpiece (not shown) located at the edge of the device. Amongst
the components not shown in FIG. 6 is the mechanism for supporting
and advancing the cavity disc.
[0176] Associated with each cavity 33 is a lid member 35 which, in
an initial state, seals the cavity via a sealing membrane 36. An
air inlet 34 is provided in the casing 31 through which air is
drawn when a patient inhales through the mouthpiece. Air flows
through the device along a path shown by arrows B in FIG. 6. An air
stream entering the device triggers the lifting of the lid member
35 associated with whichever cavity is in registry with the
mouthpiece at that time. The triggering and lid lifting mechanisms
are not shown in FIG. 6.
[0177] The lid member 35 on the left hand side of FIG. 6 is shown
in the open position. It may be seen that the lid member 35
provides the upper wall, or ceiling, of a flow passage 37 which
passes across the top of the now open cavity 33. The lower wall, or
floor, of the flow passage is provided by an upper surface of the
cavity disc 32. The side walls of the flow passage 37 are provided
by the closed lid members 35 on each side of the open member 35. A
closed lid member 35 is shown for example on the right side of FIG.
6, but it will be appreciated that there can be a number of these
members 35 all around the circumference of the disc 32. In some
embodiments, the side walls of the flow passages 37 may be provided
by separate wall members (not shown) extending between the lid
members 35.
[0178] As can be seen from the above description, a cavity 33 is
opened essentially at the same time that a flow of air passes
through the flow passage 37 across the opening of the cavity. A
circulating airflow, represented highly schematically at 39, is
induced in the cavity by the phenomenon of shear driven cavity
flow. Powder 38 in the cavity is entrained in the circulating flow
39 during which time it is deaggregated, and then the deaggregated
powder subsequently entrained in the flow through the flow passage
37 and then through the mouthpiece to the patient.
[0179] Each cavity is 4.5 mm long in the flow direction, 5 mm deep
and (in plan view) is tapered in the flow direction, with an
average width of 2.3 mm. It is filled with powder to a depth of 2.5
mm, leaving a 2.5 mm headspace. A large radius (2 mm) is provided
on the upstream lower edge of the cavity to assist the development
of a cylindrical circulating flow. A smaller 1 mm radius is
provided on the downstream lower edge.
[0180] The device is intended to be used with the cavity openings
facing upwards. However, since a cavity is only opened when there
is already an airflow in the device and, it is believed that a
circulating, shear driven flow is induced in the cavity before the
powder has a chance to fall out of the cavity under gravity. It has
been found that the performance of the device is largely
independent of orientation.
[0181] In some embodiments, the cavities have the shape of Design B
(see Example 4).
[0182] A fourth embodiment (not shown in the figures) includes a
single inhalation device containing one cavity with medicament
powder in a simple cylindrical plastic case with an inlet and a
mouthpiece. The cavity has the same geometry as one of the cavities
of the third embodiment, and the flow passage above the cavity has
the same dimensions. The flow passage communicates with the air
inlet and the mouthpiece. In place of a lid member, the cavity is
sealed with a foil strip which extends outside the housing of the
inhaler and may be removed by pulling.
* * * * *