U.S. patent application number 10/729604 was filed with the patent office on 2004-04-29 for nasal inhaler.
Invention is credited to Coffee, Ronald Alan, Davies, David Neville, Pirrie, Alastair Bruce.
Application Number | 20040079360 10/729604 |
Document ID | / |
Family ID | 10844449 |
Filed Date | 2004-04-29 |
United States Patent
Application |
20040079360 |
Kind Code |
A1 |
Coffee, Ronald Alan ; et
al. |
April 29, 2004 |
Nasal inhaler
Abstract
An inhaler has a housing containing a chamber (1a) providing a
reservoir (8) for liquid providing an active ingredient to be
supplied to a liquid outlet (10a). First and second electrodes are
spaced apart (11 and 12) with the first electrode being provided at
or adjacent the liquid outlet (10a). A voltage supply (5, 7) is
activated in response to air flowing through an air inlet (30) of
the housing to provide a potential difference between the first and
second electrodes (11 and 12) to create an electric field for
causing comminution of liquid issuing from the liquid supply outlet
(10a) to produce a stream of electrically charged comminuted matter
for supply to the nasal passages of a user via an outlet (4) of the
housing.
Inventors: |
Coffee, Ronald Alan;
(Surrey, GB) ; Pirrie, Alastair Bruce; (Oxford,
GB) ; Davies, David Neville; (Oxford, GB) |
Correspondence
Address: |
FROST BROWN TODD, LLC
2200 PNC CENTER
201 E. FIFTH STREET
CINCINNATI
OH
45202
US
|
Family ID: |
10844449 |
Appl. No.: |
10/729604 |
Filed: |
December 5, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10729604 |
Dec 5, 2003 |
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09868266 |
Aug 9, 2001 |
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6684879 |
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Current U.S.
Class: |
128/200.14 |
Current CPC
Class: |
A61M 15/008 20140204;
B05B 5/053 20130101; A61M 2205/8206 20130101; B05B 12/00 20130101;
A61M 15/0066 20140204; A61M 15/025 20140204; B05B 12/004 20130101;
B05B 5/1691 20130101; B05B 5/0255 20130101 |
Class at
Publication: |
128/200.14 |
International
Class: |
A61M 011/00 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 17, 1998 |
GB |
9827856.7 |
Claims
1. An inhaler, comprising a housing having an outlet and an air
inlet, the housing containing: liquid supply means comprising: a
chamber providing a reservoir for liquid providing an active
ingredient to be supplied to a user and means for supplying liquid
from the reservoir to a liquid outlet; and means for creating an
electric field for causing comminution of liquid issuing from the
liquid supplying means outlet in response to air flowing through
the air inlet so as to produce a stream of electrically charged
comminuted matter for supply to the nasal passages of the housing
outlet.
2. An inhaler according to claim 1, wherein the liquid supplying
means has first and second outlets; and the electric field creating
means comprises a first electrohydrodynamic comminution means for
subjecting liquid issuing from the first outlet to an electrical
potential to cause the liquid to be comminuted to form a
comminution of one polarity; and a second electrohydrodynamic
comminution means for subjecting liquid issuing from the second
outlet to an electrical potential to cause the liquid to be
comminuted to form a comminution of the opposite polarity, means
being provided for providing an air flow to the outlet to modify
any mixing of the two opposite polarity comminutions.
3. An inhaler according to claim 1, wherein the electric field
creating means comprises first and second spaced apart electrodes
with the first electrode being provided at or adjacent the outlet
of the liquid supplying means; and voltage supplying means operable
in response to air flowing through the air inlet to provide a
potential difference between the first and second electrodes.
4. An inhaler according to claim 3, wherein the voltage supplying
means comprises an air flow activated switch for coupling a voltage
generating means across the first and second electrodes.
5. An inhaler according to claim 3, wherein the air flow activated
switch comprises a closure member and spring biassing means
normally biassing the closure member into a position closing off
the supply of air into the housing through the air inlet, the
closure member being movable against the spring biassing to a
position allowing air to flow into the housing through the air
inlet in response to the air flow.
6. An inhaler according to claim 1, 2, 3, 4 or 5, wherein the
housing is arranged to enable a user to create the air flow by
breathing in through the housing outlet.
7. An inhaler according to any one of the preceding claims,
comprising a pump for creating the air flow.
8. An inhaler, comprising a housing having an outlet, the housing
containing: a chamber providing a reservoir for liquid providing an
active ingredient to be supplied to a user; means for supplying
liquid from the reservoir to a liquid outlet; first and second
spaced apart electrodes with the first electrode being provided at
or adjacent the outlet of the liquid supplying means; and
user-operable voltage supplying means for providing a potential
difference between the first and second electrodes to create an
electric field for causing comminution of liquid issuing from the
liquid supplying means outlet to produce a stream of electrically
charged comminuted matter, the first and second electrodes being
spaced from the housing outlet and being arranged so as to provide,
when a potential difference is applied across them by the voltage
supplying means, an electric field which reduces rapidly in the
direction of liquid flow from the liquid supplying means and the
housing having an air flow path to the housing outlet for causing
liquid comminuted by the electric field to be entrained by the air
flow for supply via the housing outlet to the nasal passages of a
user.
9. An inhaler according to any one of claims 3, 5 or 8 or claims 6
and 7 when dependent on claim 3, wherein the first and second
electrodes are spaced apart in a direction perpendicular to the
flow of liquid from the liquid supplying means.
10. An inhaler according to any one of claims 3, 5, 8 or 9 or
claims 6 and 7 when dependent on claim 3, wherein the second
electrode is located downstream of the supply of liquid from the
liquid outlet.
11. An inhaler, comprising a housing having an outlet, the housing
containing: a chamber providing a reservoir for liquid providing an
active ingredient to be supplied to a user; means for supplying
liquid from the reservoir to a liquid outlet; first and second
spaced apart electrodes with the first electrode being provided at
or adjacent the outlet of the liquid supplying means; and
user-operable voltage supplying means for providing a potential
difference between the first and second electrodes to create an
electric field for causing comminution of liquid issuing from the
liquid supplying means outlet to produce a stream of electrically
charged comminuted matter for supply via the housing outlet to the
nasal passages of a user, wherein current-limiting means are
provided for limiting the supply of current by the voltage
supplying means.
12. An inhaler according to any one of claims 3, 5 or 8 or claims 6
and 7 when dependent on claim 3, wherein current-limiting means is
associated with one of the first and second electrodes.
13. An inhaler according to claim 11 or 12, wherein the
current-limiting means comprises a dielectric or semi-insulating
coating or sleeve provided on said one of the first and second
electrodes.
14. An inhaler according to claim 8, 9 or 10, wherein the voltage
supplying means comprises an air flow activated switch for coupling
a voltage generating means across the first and second
electrodes.
15. An inhaler according to claim 14, wherein the air flow
activated switch comprises a closure member and spring biassing
means normally biassing the closure member into a position closing
off the supply of air into the housing through the air inlet, the
closure member being movable against the spring biassing to a
position allowing air to flow into the housing through the air
inlet in response to a user breathing in through the housing outlet
or in response to an air supply to the air inlet.
16. An inhaler according to any one of claims 3, 5, 8 to 15 or 6
and 7 when dependent on claim 3, wherein the voltage supplying
means comprises a further electrode positioned adjacent the second
electrode and resistive means coupling the second electrode to
earth, the voltage supplying means being arranged to cause the
further electrode to generate an ion current for charging the
second electrode to an electrical potential sufficient to provide
the electrical potential for causing comminution of liquid issuing
from the outlet.
17. An inhaler, comprising a housing having an outlet and an air
inlet, the housing containing: a chamber providing a reservoir for
liquid providing an active ingredient to be supplied to a user;
means for supplying liquid from the reservoir to a liquid outlet;
means for creating an electric field for causing comminution of
liquid issuing from the liquid supplying means outlet; and means
for providing a flow of air towards the housing outlet so as to
produce a stream of electrically charged comminuted matter for
supply to the nasal passages of a user via the housing outlet.
18. An inhaler, comprising a housing having an outlet and an air
inlet, the housing containing: a chamber providing a reservoir for
liquid providing an active ingredient to be supplied to a user;
means for supplying liquid from the reservoir to a liquid outlet;
means for creating an electric field for causing comminution of
liquid issuing from the liquid supplying means outlet; and means
for shearing comminuted matter issuing from the liquid outlet to
produce a stream of electrically charged comminuted matter of
smaller size than that produced by the electric field for supply to
the nasal passages of a user via the housing outlet.
19. An inhaler according to claim 18, wherein the shearing means
comprises means for producing air flow in the vicinity of liquid
issuing from the liquid outlet.
20. An inhaler comprising a housing having an outlet and an air
inlet, the housing containing means for supplying liquid to first
and second outlets; a first electrohydrodynamic comminution means
for subjecting liquid issuing from the first outlet to an
electrical potential to cause the liquid to be comminuted to form a
comminution of one polarity; a second electrohydrodynamic
comminution means for subjecting liquid issuing from the second
outlet to an electrical potential to cause the liquid to be
comminuted to form a comminution of the opposite polarity; and
means for providing an air flow to the outlet to modify any mixing
of the two opposite polarity comminutions.
21. An inhaler according to claim 2 or 20, wherein the air flow
providing means is operable to keep the two opposite polarity
comminutions apart.
22. An inhaler according to claim 2, 20 or 21, further comprising
means for controlling at least one of: 1) the relative flow rates
of liquid to the first and second liquid outlets; 2) the relative
electrical potentials to which liquid issuing from the first and
second outlets is subjected; and 3) the air flow provided by the
air flow providing means.
23. An inhaler according to claim 2, 20, 21 or 22, comprising a
respective reservoir for each liquid outlet the reservoirs
containing different liquids.
24. An inhaler according to any one of claims 2, 20, 21, 22 or 23,
wherein the first and second liquid outlets are angled towards one
another.
25. An inhaler according to any one of the preceding claims,
further comprising air flow control valve means for controlling air
flow.
26. An inhaler comprising means for supplying liquid to a liquid
outlet, voltage supply means for subjecting liquid issuing from the
liquid outlet to an electric field for causing comminution of
liquid issuing from the outlet, and means for controlling the size
of the components, for example droplets, of the comminuted
matter.
27. An inhaler comprising means for supplying liquid to a liquid
outlet, voltage supplying means for subjecting liquid issuing from
the liquid outlet to an electric field for causing comminution of
liquid issuing from the outlet, and means for controlling the size
of the comminuted matter such that the comminuted matter has at
least two different controlled sizes.
28. An inhaler comprising means for supplying liquid to a liquid
outlet, voltage supplying means for subjecting liquid issuing from
the liquid outlet to an electric field for causing comminution of
liquid issuing from the outlet to produce a spray of droplets, and
means for controlling the diameter of the droplets so that the
comminuted matter consists of droplets each having one of at least
two different controlled diameters.
29. An inhaler according to claim 21, 22 or 23, wherein the
controlling means comprises means for superimposing on the voltage
supplied by the voltage supplying means an alternating or pulsed
signal.
30. An inhaler according to claim 22 or 23, wherein the controlling
means comprises means for superimposing on the voltage supplied by
the voltage supplying means a signal having two different frequency
components for causing the comminuted matter to contain two
different sizes of components.
31. An inhaler according to claim 29 or 30, wherein the
superimposing means is arranged to superimpose on the voltage
supplied by said voltage supplying means a signal having three or
more different frequency components for causing the comminuted
matter to contain three or more different sizes of components.
32. An inhaler according to claim 30 or 31, wherein said signal is
arranged to consist of said frequency components superimposed
simultaneously on said voltage in phase with one another.
33. A device according to claim 30 or 31, wherein said signal is
arranged such that said different frequency components are
superimposed one after another on said voltage.
34. An inhaler according to any one of claims 25 to 32, wherein the
means for controlling the size of the components of the comminution
comprises means for regulating the liquid flow and/or the liquid
composition.
35. An inhaler according to any one of claims 25 to 34, wherein the
means for controlling the size of the comminution components
comprises a plurality of subsidiary liquid outlets which together
form the liquid outlet and respective different cross-section
supply pipes for supplying liquid to each different one of the
subsidiary liquid outlets.
36. An inhaler according to any one of claims 25 to 35, wherein the
means for controlling the size of the comminution components
comprises a plurality of subsidiary liquid outlets which together
form the liquid outlet each having a respective valve means for
controlling the liquid flow from the outlet.
37. An inhaler according to any one of the preceding claims, having
a respective housing outlet for each nostril of a user or
patient.
38. An inhaler according to any combination of the preceding
claims.
39. An inhaler according to any one of the preceding claims,
wherein the air flow is induced other than by inhalation.
40. An inhaler according to any one of the preceding claims,
comprising a biologically acceptable carrier for the active
ingredients selected from: an oil, an alcohol, a polymer or a
water-based solvent.
41. An inhaler according to any one of the preceding claims,
comprising a supply of liquid carrying as an active ingredient at
least one of the following: a decongestant, a lipid, a vitamin, an
antiseptic, an anti-inflammatory, an antibiotic, an anti-cancer
agent, a vaccine, a protein, an enzyme, a bioadhesive, DNA or DNA
fragments, nicotine and morphine.
42. A liquid formulation for use in an inhaler in accordance with
any one of claims 1 to 38, comprising a biologically acceptable
carrier liquid for an active ingredient and a polymer.
43. A liquid formulation for use in an inhaler in accordance with
any one of claims 1 to 38, comprising a biologically acceptable
carrier liquid for an active ingredient and a medium to high
molecular weight polymer.
44. A liquid formulation for use in an inhaler in accordance with
any one of claims 1 to 38, comprising a biologically acceptable
carrier liquid for an active ingredient and a medium to high
molecular weight polymer such as PVA or PVP.
45. A liquid formulation for use in an inhaler in accordance with
any one of claims 1 to 38, comprising a biologically acceptable
carrier liquid for an active ingredient and an amount of a polymer
selected from amongst the following: 0.2 to 0.7 grammes per 10
centilitres of formulation of PVA; 0.2 grammes per 10 centilitres
of formulation of PVA; from 0.2 to 1.2 grammes per 10 centilitres
of formulation of PVP; or 0.5 grammes per 10 centilitres of
formulation of PVP.
46. A liquid formulation according to claim 42, 43, 44 or 45,
further comprising as an active ingredient at least one of the
following: a decongestant, a lipid, a vitamin, an antiseptic, an
anti-inflammatory, an antibiotic, an anti-cancer agent, a vaccine,
a protein, an enzyme, a bioadhesive, DNA or DNA fragments, nicotine
and morphine.
47. A method of controlling the geometry or shape of comminuted
matter produced by electrohydrodynamic comminution of at least one
liquid, which method comprises controlling the geometry or shape by
controlling or adjusting the amount of at least one medium to high
weight polymer in the or at least one of the liquids.
48. A method of controlling the geometry or shape of comminuted
matter produced by electrohydrodynamic comminution of at least one
liquid, which method comprises controlling the geometry or shape by
controlling or adjusting the amount of PVA or PVP in the or at
least one of the liquids.
49. A method of controlling the geometry or shape of comminuted
matter produced by electrohydrodynamic comminution of at least one
liquid, which method comprises controlling the geometry or shape by
adding sufficient polymer to the liquid to cause at least some of
the comminuted matter to have a granular form with at least some of
the granules having fibrils or tails.
50. A method according to any one of claims 47 to 49, wherein the
liquid comprises water and an alcohol.
51. Use of an oil-based formulation as a carrier for an active
ingredient to be delivered to a user or patient as comminuted
matter formed by electrohydrodynamic comminution of the
formulation.
52. A dispensing device having liquid supply means for supplying
liquid to a liquid outlet means and means for subjecting liquid
issuing from the liquid outlet means to an electric field to cause
electrohydrodynamic comminution of the liquid, wherein the liquid
supply means comprises a supply of liquid in the form of an
oil-based formulation carrying an active ingredient.
53. A nasal inhaler having a housing containing liquid supply means
for supplying liquid to a liquid outlet means and means for
subjecting liquid issuing from the liquid outlet means to an
electric field to cause electrohydrodynamic comminution of the
liquid to provide comminuted matter to an outlet of the housing for
inhalation by a user or patient, wherein the liquid supply means
comprises a supply of liquid in the form of an oil-based
formulation carrying an active ingredient.
54. A delivery device having the features of the inhaler described
in any one of the preceding claims but differing in that the device
is arranged to supply the active ingredient to the mouth, an eye or
a bodily orifice and in that air flow is induced other than by
inhalation or alternatively by oral inhalation when the device is
arranged to supply the active ingredient to or via the mouth.
55. A method of supplying an active ingredient to the nasal
passages of a human or animal which comprises using an inhaler in
accordance with any one of claims 1 to 41.
56. A method of supplying an active ingredient to an eye or bodily
orifice other than the mouth or nose which comprises using a
delivery device in accordance with claim 54.
Description
[0001] This invention relates to an inhaler for enabling delivery
of an active ingredient to the nasal passages.
[0002] Conventionally, nasal inhalers are used for the supply of
decongestants such as oxymetazoline and the like. The nasal
passages are also a good way of supplying drugs and other
medicaments into the bloodstream for treatment of ailments which
are not specific to the nasal passages.
[0003] Conventional hydraulic/pump action nasal inhalers fire or
eject large droplets of liquid into the nose. These droplets are
polydispersed, that is they have a broad spectrum of sizes. The
deposition of such droplets is primarily due to their own inertia
which can lead to a very patchy distribution of the liquid. Indeed
excessive deposition in one region can lead to the droplets
coalescing and flowing out of a nostril or down the back of the
throat which can cause an unpleasant taste or, worse, lead to
detrimental side effects as a result of the drug being delivered to
the digestive or pulmonary system.
[0004] It is an aim of the present invention to provide a device
which enables satisfactory and efficient supply of a substance such
as a medicament or other active ingredient to the nasal mucosa
avoiding deposition in non-target regions such as the lungs or the
stomach.
[0005] A process for producing comminuted matter known as
electrohydrodynamic comminution is described in detail in, for
example, GB-A-1569707. In this process, a dispersed spray or cloud
of comminuted matter such as liquid droplets which are all of
substantially the same size (monodispersed) is produced by
subjecting liquid emerging from an outlet to an electric field.
[0006] The device described in GB-A-1569707 is large, produces
highly charged droplets and is intended primarily for spraying of
crops.
[0007] Inhalers have been proposed that exploit electrohydrodynamic
comminution because they have the advantage, unlike conventional
inhalers, of producing a monodispersed (substantially all the same
size) mist or cloud of droplets so that the droplets may be
targeted more accurately. However, because the conventional wisdom
is that it is difficult, if not impossible, to spray electrically
charged material into a cavity, previous attempts at producing
inhalers using electrohydrodynamic techniques require that the
comminuted matter be electrically discharged before inhalation. For
example, EP-A-0234842 teaches that it is necessary to discharge the
resulting comminution before inhalation to prevent it being
deposited only on the wet conductive surfaces immediately inside
the mouth or throat.
[0008] The present inventors have, surprisingly, found that, by a
combination of electrohydrodynamic, discharging or partial
discharging techniques and aerodynamic forces on the resultant
comminution, an inhaler can be provided which generates by
electrohydrodynamic means electrically charged comminuted matter
which can be inhaled so as to deposit evenly onto the conductive
inner surface of the nasal passages from whence an active
ingredient carried by the comminution can be rapidly absorbed into
the bloodstream without being inhaled into the pulmonary
system.
[0009] In one aspect, the present invention provides an inhaler
having electrohydrodynamic comminution means arranged to be
activated by inhalation by a user, which facilitates entrainment of
electrically charged comminuted matter into the air flow and thence
into the nasal passages of the user.
[0010] In one aspect the present invention provides an inhaler
having electrohydrodynamic comminution means with the electrode or
electrodes of the comminution means being shielded from the user so
that the user cannot make direct electrical contact with the
electrodes.
[0011] In one aspect the present invention provides an inhaler
wherein the material to be inhaled is electrohydrodynamically
produced and the electrical charge and/or size of the comminuted
material, generally droplets, are/is controlled so that the
material can be deposited evenly into the nasal passages but supply
to the pulmonary system or the back of the throat is prevented,
thereby enabling the inhaler to be used for the supply to the nasal
passages of medicaments which may produce unpleasant or undesirable
effects if they were supplied to the pulmonary or digestive
system.
[0012] In one aspect the present invention provides an inhaler
having a supply of liquid carrying an active ingredient, means for
supplying the liquid to an outlet and means for subjecting liquid
issuing from the outlet to an electrical field sufficient to cause
comminution of the liquid to produce electrically charged
comminuted matter for inhalation by the user, the liquid or liquids
being selected so as to control the manner in which active
ingredient in the electrically charged comminuted matter is
released when the electrically charged comminuted matter is
deposited in the nasal passages. The liquid may be an oil or
alcohol-based formulation allowing rapid supply of the active
ingredient into the bloodstream via the surfaces of the nasal
passages. As another possibility, the liquid may be such that the
resulting comminuted matter has a gel-like structure enabling
continued release of the active ingredient.
[0013] In one aspect the present invention provides an inhaler
having means for subjecting liquid issuing from an outlet to an
electric field sufficient to cause comminution of the liquid and
means for causing electrically charged comminuted matter to be
deposited onto the surfaces of the nasal passages. The latter means
may comprise means for causing or facilitating an air flow through
the inhaler which entrains the charged comminuted matter. Such an
air flow may be generated by inhalation by a user, by artificial
means such as a pump or a combination of both of these.
[0014] In one aspect, the present invention provides an inhaler
having comminution means arranged to provide an electric field
which has a strength which reduces rapidly in the direction of
liquid flow from liquid supply means enabling liquid comminuted by
the electric field to be easily entrained in an air flow path from
the inhaler into a nostril of a user during use.
[0015] In one aspect, the present invention provides an inhaler
having means for supplying liquid to an outlet and means for
subjecting liquid issuing from the outlet to an electrical field
sufficient to cause comminution of liquid issuing from the outlet,
and means for generating an electrical potential at the one of the
first and second electrodes most remote from the liquid outlet,
said means for generating the electrical potential comprising means
for generating an ion current for indirectly charging said one
electrode.
[0016] In this aspect, the ion current generating means may
comprise a further electrode located adjacent the one electrode and
means for providing a high resistance path to earth from said one
electrode. The high resistance path to earth may be provided by an
actual resistor in series with said one electrode or, for example,
a resistive or semiconductive coating on said one electrode.
Indirect charging of said one electrode reduces the possibility of
deposition of comminuted matter onto said one electrode because any
electrically charged comminuted matter which approaches said one
electrode will be at least partially electrically discharged by the
generated ions. Furthermore, a more even deposition or greater
penetration within the nasal passages should be achieved because of
the at least partial discharge of some of the comminuted matter by
the ion generating means.
[0017] In one aspect, the present invention provides an inhaler
having means for supplying liquid to a comminution site and
electrical current limiting means for limiting the supply of
electrical current to the comminution site. The current-limiting
means may comprise a dielectric or semi-insulating coating or
sleeve or a high resistance coupled in the path from a high
capacitance high voltage source to an electrode. Otherwise, a low
capacitance high voltage source, such as a piezoelectric voltage
source, may be used.
[0018] In one aspect, the present invention provides an inhaler
capable of supplying opposite polarity comminutions to the nasal
passages.
[0019] In one aspect, the present invention provides a dispensing
device, which may be an inhaler, having means for supplying liquid
to an outlet, means for subjecting liquid issuing from the outlet
to an electrical field sufficient to cause comminution of liquid
issuing from the outlet and means for controlling the size of
individual elements of the comminuted matter, for example droplets,
in the resulting comminution.
[0020] Embodiments of the present invention will now be described,
by way of example, with reference to the accompanying drawings, in
which:
[0021] FIG. 1 illustrates schematically use of an inhaler in
accordance with the present invention;
[0022] FIG. 2 shows a diagrammatic, part-cross-sectional view of an
embodiment of an inhaler in accordance with the present
invention;
[0023] FIG. 3 shows a block schematic electrical diagram for the
inhaler shown in FIG. 2;
[0024] FIG. 4 shows a part-cross-sectional view, on an enlarged
scale, of part of the inhaler shown in FIG. 2 to show one example
of an electrohydrodynamic comminution site for the inhaler shown in
FIG. 2;
[0025] FIG. 5 shows a part-cross-sectional view, on an enlarged
scale, of part of the inhaler shown in FIG. 2 to show another
example of an electrohydrodynamic comminution site for the inhaler
shown in FIG. 2;
[0026] FIG. 6 shows a part-cross-sectional view, on an enlarged
scale, of part of a further embodiment of an inhaler in accordance
with the present invention;
[0027] FIG. 7 shows a part-cross-sectional view, on an enlarged
scale, of part of another embodiment of an inhaler in accordance
with the present invention;
[0028] FIG. 8 shows very schematically another example of an
inhaler embodying the present invention using a compressed airflow
for activation;
[0029] FIGS. 9a to 9d show droplet spectrums with FIG. 9a showing a
droplet spectrum for an inhaler embodying the invention and FIGS.
9b to 9d showing droplet spectrums for various forms of
conventional inhaler;
[0030] FIG. 10 shows a diagrammatic part cross-sectional view
similar to FIG. 2 of another embodiment of an inhaler in accordance
with the present invention;
[0031] FIG. 11 shows a diagrammatic part cross-sectional view
similar to FIG. 2 of another embodiment of an inhaler in accordance
with the present invention;
[0032] FIG. 12 shows, on an enlarged scale, part of the inhaler
shown in FIG. 2 to illustrate a modification thereof;
[0033] FIG. 13 shows very schematically a further modification of
an embodiment of an inhaler in accordance with the present
invention;
[0034] FIG. 14 is a diagram for illustrating the operation of an
inhaler having the modification shown in FIG. 13;
[0035] FIG. 15 shows a part cross-sectional enlarged view of part
of another embodiment of an inhaler in accordance with the
invention; and
[0036] FIG. 16 shows a part cross-sectional enlarged view of part
of another embodiment of an inhaler in accordance with the
invention.
[0037] As illustrated schematically in FIG. 1, an inhaler 1
embodying the invention is intended primarily for use as a
pocket-sized, hand-held device which is actuated by a user to
enable delivery of an active ingredient, drug or active ingredient
into the nostril of the user. For example, the inhaler may be
arranged to deliver a decongestant such as oxymetazoline to the
nasal passages or to deliver drugs or other medicaments such as
insulin or triptans (for example Elitriptan) into the bloodstream
via the nasal mucosa. The inhaler may also be used to deliver flu
vaccines such as Flumist (a product being developed by Aviron of
Mountain View, Calif., USA) which is arranged to be effective in
the relatively low temperature environment of the nasal mucosa.
[0038] The inhaler 1 comprises a housing 3. The housing may be made
mainly of electrically insulative material such as a plastics
material although at least a part of the housing that a user will
inevitably touch in use provides an electrically conductive region
that enables, as will be described below with reference to FIGS. 2
and 3, an earth connection via the user. The inhaler has an outlet
4 through which liquid droplets to be inhaled are supplied to the
user. The outlet 4 is sized and shaped so as to fit snugly against
or slightly into the user's nostril so as to make a reasonably
air-tight seal. The outlet may be detachable from the housing to
allow different sized and shaped outlets to be used so as to enable
a snug fit to different sizes of nostrils to enable, for example,
use by both adults and children. Although a snug fit is desirable
from the viewpoint of efficiency, in practice, it may be sufficient
for the inhaler to be placed in close proximity to a nostril.
[0039] The inhaler 1 is rotationally symmetric about its
longitudinal axis so as to be generally cylindrical. Typically, the
housing will be about one inch (25.4 mm) diameter and about 4 to 5
inches (102 to 127 mm) in length.
[0040] FIG. 2 illustrates a part sectional view through one example
of an inhaler embodying the invention, while FIG. 3 shows a block
circuit diagram of components of the inhaler.
[0041] As shown in FIG. 2, the housing 3 of the inhaler 1 has an
internal wall 3a which divides the housing into first and second
chambers 1a and 1b.
[0042] In this example, the first chamber accommodates a voltage
source 5 in the form of a battery. As shown most clearly in FIG. 3,
the positive terminal of the battery 5 is connected via a
user-operable switch SW1 to a reset input of a counter 6 and to a
further switch SW2. Although not shown in FIG. 2, the negative
terminal of the battery 5 is also connected to the electrically
conductive region of the housing mentioned above so, as shown
schematically in FIG. 3, the user H provides a path to earth
(ground). The switch SW1 is a conventional manually operable switch
such as, for example, a toggle or push switch. The switch SW2 is
arranged to be activated by airflow and will be described in
greater detail below. A high voltage generator 7 is coupled to the
battery 5 via the switches SW1 and SW2 and a counter 6 which is
arranged to be reset by closure of the switch SW1 and which outputs
the battery voltage to the high voltage generator positive voltage
input until a predetermined count is reached when the output of the
counter goes low. The high voltage generator may be a conventional
electromagnetic high voltage multiplier of the type supplied by
Brandenburg, Astec Europe, of High Street, Wollaston, Stourbridge,
West Midlands DY8 4PG, UK, or Start Spellman of Unit 1, Broomers
Park, Broomers Hill Lane, Pulborough, West Sussex RH20 2RY, UK. As
an alternative, a piezoelectric high voltage source which has a low
capacitance may be used.
[0043] The first chamber 1a also contains a reservoir 8 for the
liquid to be dispensed by the inhaler. The reservoir may be formed
as a flexible collapsible bag or bellows-type arrangement having a
chemically inert interior surface. Alternatively, a piston-like
arrangement may be used so that as the liquid is used up, the
piston moves with the liquid surface in the chamber so avoiding the
possibility of air coming into contact with the liquid in the
reservoir. A pump 9 is provided to pump liquid from the reservoir 8
to a liquid supply outlet pipe 10. The pipe is made of an
insulating material which does not retain charge for any
significant length of time. A suitable material is, for example,
polyacetyl or Delrin (Trademark).
[0044] The liquid supply pipe 10 has an outlet nozzle 10a. A
conductive core or rod 11 provided within the liquid outlet pipe
terminates adjacent the nozzle outlet 10a and provides a first
electrode. In this example, the first electrode 11 is coupled to
the negative or earth terminal of the battery 5 via line 5'.
[0045] The outer surface of the insulative supply pipe 10 carries a
second electrode 12 (see FIG. 4) extending around the pipe 10. The
second electrode 12 is located so as to be upstream of the tip 11a
of the first electrode in the direction of the liquid flow through
the liquid supply pipe 10. The first electrode 11 may, as shown, be
pointed.
[0046] In this example, the second electrode 12 comprises a coated
electrode having a central conductive core 12a which is coupled to
a high voltage output 7a of the high voltage generator 7 and is
encased in a dielectric or semi-insulating coating or sleeve 12b.
Such a coated electrode is described in, for example, EP-A-0186983.
The coating or sleeve may have a resistivity within the range
5.times.10.sup.11 to 5.times.10.sup.13 .OMEGA.cm and a thickness of
approximately 2 mm. Suitable coatings are certain grades of
sodaglass and phenolformaldehyde/paper composites. Kite brand tubes
supplied by Tufnol Limited of Birmingham, England or Paxoline may
be used. The core may be formed of, for example, beads of carbon
tightly packed within the coating 12b. The coating should have a
time constant or relaxation time over which it leaks or conducts
charge of, typically, approximately 10.sup.-5 seconds. The second
electrode 12 may, however, be uncoated.
[0047] As can be seen from FIG. 2, the first and second electrodes
11 and 12 are located well within the electrically insulative
housing 4 so that the portion 4a of the housing defining the
chamber 1b shields the user from the electrodes so that direct
contact by the user with the electrodes is avoided. The outlet 4 is
sized so as to prevent a user inserting a finger into the chamber
1b. Also, although an electrical shorting is extremely unlikely,
this would occur between the first and second electrodes and so
would not subject the user to an electrical shock.
[0048] The pump 9 is an electrically operated pump and may be, for
example, a piezoelectric pump or any other suitable form of
electrically or mechanically operated pump. The pump 9 is coupled
to the positive terminal of the battery 5 via the switches SW1 and
SW2, and the counter 6. A delay circuit 120, for example a
conventional capacitor-resistor (CR) network, may be provided
between the counter 6 output and the pump so that supply of the
voltage necessary to activate the pump 9 is delayed until an
electric field sufficient to cause electrohydrodynamic comminution
of liquid supplied to the nozzle 10a has been established between
the first and second electrodes.
[0049] The output of the counter 6 is also supplied, as shown in
FIG. 3, to an indicator light or buzzer 13.
[0050] As shown in FIG. 2, the air flow activated switch SW2
comprises a first electrical contact 20 mounted on a spring
biassing arm 21 secured to the inner wall of the housing chamber
1a. The switch SW2 has an outer insulative body 22 which is caused
by the spring biassing member 21 to block an air inlet 30 provided
in the housing 3. An air path from the air inlet 30 to an aperture
32 in the partition member 3a is defined by an insulative tubular
body 33. An inner wall of the insulative tubular body 33 carries a
further electrical contact 34 coupled via conductor 35 to the
positive power supply terminal of the high voltage generator 7.
[0051] The air path tube 33 may be modified so as to provide air
paths 33' coupling to two or more apertures 32 provided in the
partition member 3a and evenly distributed about the longitudinal
axis L as shown in dashed lines in FIG. 2.
[0052] To use the inhaler 1, a person first inserts the outlet 4
into or places the outlet snugly against a nostril and then
manually actuates the switch SW1 which couples the reset terminal
of the counter 6 to the positive supply of the battery 5 and so
resets the count of the counter. The user then inhales through
their nose as they would if using a conventional inhaler. The air
flow resulting from the user inhaling thus causes the contact 20 of
the switch SW2 to be moved towards the contact 34 against the
biassing force of the spring member 21. Once the contacts 20 and 34
of the switch SW2 make contact, power is supplied to the high
voltage generator 7 which supplies the required high voltage,
typically 3 to 12 kV (kilovolts) to the second electrode 12 so as
to establish the necessary electric field between the first and
second electrodes 11 and 12 to provide the electrohydrodynamic
comminution site. Once this electric field has been established,
the delay circuit 120 provides the necessary electrical power to
the pump 9 which then pumps liquid from the reservoir to the outlet
nozzle 10a.
[0053] Liquid issuing from the outlet nozzle 10a is
electrohydrodynamically comminuted. The separation of the first and
second electrodes 11 and 12 in the radial direction (that is
perpendicular to the longitudinal axis L) can be relatively small
(typically about 1 cm) because the coating on the second electrode
enables the two electrodes to be close together whilst suppressing
any electrical breakdown of the air in between. This relatively
small separation results in a very high strength electric field
which drops off or reduces rapidly in the longitudinal direction L.
This facilitates entrainment of the resulting charged comminuted
matter in the air flow through the tube 33 to the output 4 so
reducing the possibility of the electrically charged matter
depositing on the inner wall of the chamber 1b.
[0054] Comminuted matter then issues from the nozzle 4 and is
deposited uniformly onto the conductive surface inside the nasal
passages.
[0055] When a predetermined time since activation of the switch SW1
has passed, that is when the predetermined count is reached, the
output from the counter 6 goes low switching off the high voltage
generator 7, the pump and the light or buzzer 13. After use, the
user then can disable the device by pressing the switch SW1 again
to disconnect the voltage source 5.
[0056] The counter 6 thus enables the user to be advised when the
required dose of medicament has been delivered.
[0057] The coating or sleeving of the electrode 12 provides a
current limiting effect to prevent excessive or dangerous currents
from passing between it and the first electrode 11.
[0058] FIG. 5 shows a modification in which the insulative liquid
supply pipe and conductive core 10 and 11 of FIG. 2 are replaced by
a hollow electrically conductive capillary tube pipe 14 which
provides both the first electrode and the outlet 14a. In this case,
the second electrode 12 is a discrete uncoated electrode provided
on the inner wall of the first chamber so as to be disposed
downstream of the end of the first electrode 14 in the direction of
liquid flow through the conductive pipe 14. As shown in FIG. 5, the
inhaler has an air supply pipe outlet 33" (which may be an
extension of the pipe 33' shown in dashed lines in FIG. 2) which
causes, in use, an air curtain to be provided in front of the
electrode to inhibit deposition of droplets on the electrode 12.
This modification may also be made in the arrangement shown in FIG.
2. Although shown as a discrete uncoated electrode, the second
electrode 12 may in this case comprise an annular slot electrode or
a number of individual electrodes distributed around the inner
periphery of the wall of the second chamber 1b. Also, the electrode
12 may be coated as described with reference to FIG. 4 and may be
positioned slightly upstream or adjacent the first electrode. In
this case, when an electrical field sufficient to cause
electrohydrodynamic comminution is established between the first
and second electrodes 14a and 12, multiple jets or cones will
generally be formed at the end of the conductive pipe 14.
[0059] In use, satellite droplets are sometimes produced during the
electrohydrodynamic comminution. These satellite droplets will not
generally present a problem and will normally deposit onto the
interior surface of the inhaler or the second or counter electrode.
However, if the inhalers described above are used frequently over
an extended period of time, the build-up of droplets and/or residue
resulting from subsequent evaporation of the droplets may adversely
affect the operation of the counter electrode 12 so reducing the
overall efficiency of the device. One way to avoid this problem is
to design the inhaler body so that, for example, the portion 4a of
the housing defining the chamber 1b can be removed (for example the
housing portion 4a may be connected by screw-thread connected to
the housing portion 4b) to enable a user to wipe the counter
electrode to remove deposited droplets or other matter. An
alternative, automatic means of maintaining the operational
function of electrode 12 is described below.
[0060] FIG. 6 shows a part-cross-sectional view of mainly the lower
chamber 16 of another inhaler embodying the invention. The internal
construction of the upper chamber 1a is essentially the same as
that described above with reference to FIG. 2.
[0061] In FIG. 6, the counter electrode 12' is mounted to the inner
wall 1b' of the lower chamber 1b. The counter electrode 12' may be
annular or may be formed by a discrete single point electrode or a
number of separate electrically connected electrodes spaced apart
around the wall 1b'.
[0062] The counter electrode 12' is, in this example, an uncoated
electrically conductive electrode which is coupled via wire 50' and
a resistor R to the conductor 5' which is coupled to the negative
or earth terminal of the voltage source 5.
[0063] A further electrode 120 is mounted in a conventional manner
(not shown) in the lower housing 1b so as to be considerably closer
to the counter or second electrode 12 than to the first electrode
11. Typically, for the dimensions given above for the inhaler, the
electrode 120 may be 2 mm from the counter electrode 12' and 5 mm
from the first electrode 11. The counter electrode 120 is coupled
via the conductor 7a to the high voltage output of the high voltage
generator 7 (not shown in FIG. 6).
[0064] When an inhaler having the structure shown in FIG. 6 is
used, the high voltage applied to the electrode 120 causes ions to
be generated by corona discharge from the electrode 120. These ions
migrate to the closest conductive body--in this case the counter
electrode 12'--so providing an ion current to earth via the counter
electrode 12' and the resistor R which may, typically, have a value
of 600 megaohms. This enables the counter electrode 12' to be
indirectly charged to the required electrical potential. Any
charged comminuted matter issuing from the nozzle 10a which is
inadvertently attracted toward the counter electrode 12' will be at
least partially electrically discharged by the ion current
generated by the ion generating electrode 120 so reducing the
likelihood of the charged matter depositing onto the counter
electrode 12' and obviating the need for a user to wipe the counter
electrode periodically.
[0065] FIG. 7 illustrates a modification of the arrangement shown
in FIG. 6 in which the resistance provided by the coating of the
counter electrode 12" is sufficient to enable the required
electrical potential to be achieved at the counter electrode 12"
without the need for the resistor R. In other respects, the
arrangement shown in FIG. 7 operates in the same manner as the
arrangement shown in FIG. 6.
[0066] Although FIGS. 6 and 7 show only one ion generating
electrode 120, a plurality of ion generating electrodes 120 may be
provided around the liquid supply pipe. As another possibility, the
ion generating electrode may be provided by a knife edge or wire
surrounding the liquid supply pipe.
[0067] It has been found that the arrangements shown in FIGS. 6 and
7 enable a more even distribution of comminuted matter to a greater
depth within the nasal passages; thus improving the uniformity of
droplet distribution still further. This is believed to arise
because electrically charged comminuted matter which comes into the
vicinity of the ion injecting electrode 120 will have been at least
partially electrically discharged so that some of the comminuted
matter which is inhaled will be less highly charged and will
therefore have a tendency to be deposited further into the nasal
passages.
[0068] The air flow path in FIGS. 6 and 7 may be modified as
described above with reference to FIG. 5 to provide the second
electrode with a protective air curtain.
[0069] In the arrangements described above, the airflow switch SW2
is activated by the user inhaling. It is, however, possible that
the user may be so frail that they are not capable of inhaling
sufficiently strongly to activate the switch SW2. In such a case,
the inhaler may be provided, as shown in FIG. 8, with an adaptor
100 which couples around the area of the switch SW2 and can be
connected via a pipe 101 to a manually actuable device 102 such as
a bladder or bellows which can be squeezed by the patient or
another person such as a doctor, nurse or carer to force a flow of
air to open the air inlet 30 and close the switch SW2 or to a
pressurised air or gas bottle or a compressor which may be
electrically operated to supply air at the desired flow rate down
the pipe to the air inlet 30.
[0070] FIGS. 9a to 9d show experimental droplet spectra produced
using a Malvern Mastersizer X manufactured by Malvern Instruments
of Malvern, UK. FIG. 9a shows a typical droplet spectrum produced
using a device of the type shown in FIG. 1. As can be seen from
FIG. 9a, the medium particle or droplet diameter is around 10 .mu.m
which is at the lower end of desirable droplet diameters for nasal
delivery. FIGS. 9b to 9d show the equivalent droplet spectra
produced by three commercially available nasal inhalers with FIG.
9b showing the droplet spectra produced by an "Otravine"
(Registered Trade Mark) nasal inhaler which comprises a squeezable
plastic bottle supplying xylometazoline hydrochloride as a nasal
decongestant and is supplied by Novartis Consumer Health of Horsham
RH12 4AB, UK, FIG. 9c showing the droplet spectra for a "Flixonase"
nasal inhaler and which uses a metering valve and a pressurised
reservoir and which supplies fluticasone propionate and is supplied
by Allen & Hanburys of Stockley Park, Middlesex UB11 1BT, UK
and FIG. 9d showing the droplet spectrum output by a "Beconase"
pump action nasal inhaler which comprises beclomethasone
dipropionate and is also supplied by Allen & Hanburys. As can
be seen from a comparison of FIGS. 9b to 9d with FIG. 9a, the three
conventional inhalers produce a larger range of particle or droplet
diameters and control over the droplet sizes is poor in comparison
to that achievable with the electrohydrodynamic device shown in
FIG. 9a. It should also be noted that the conventional inhalers do
not charge the droplets and rely on turbulence and inertia alone to
deposit the droplets. Furthermore, the performance of conventional
propellant inhalers is very dependent on the air flow in the nasal
passages that can be generated by the user.
[0071] The operation of the inhaler 1 shown in FIG. 1 has been
tested on models of the nose and it has been found that the
resulting charge sprays deposit evenly over the conductive surface
representing the interior of the nose. The liquid used in these
experiments had an electrical resistivity of 4500 .OMEGA.cm, a
surface tension of 30 mN/m (milli Newtons per metre) and a
viscosity of 2.4 cP (centipoise) and a voltage in the range of 8 to
12 kV was applied between the first and second electrodes.
[0072] The embodiments described above are intended primarily for
comminuting liquids of relatively high resistivity such as oils and
alcohol. FIG. 10 shows a modified version of the inhaler shown in
FIG. 2 that is suitable for comminuting very electrically
conductive liquids such as water and salt solutions.
[0073] In the inhaler 300 shown in FIG. 10, the air path tube 33
shown in FIG. 2 is replaced by an air path tube 330 in the form of
a hollow body defining an air channel 330 a which extends through
an aperture 32 in the wall 3a to terminate in a ring-like nozzle
outlet 331 surrounding the outlet nozzle 10a. In all other
respects, the inhaler 300 shown in FIG. 10 is the same as that
shown in FIG. 2.
[0074] The inhaler 300 operates in the same way as the inhaler 3
shown in FIG. 2 apart from one significant aspect. Thus, when a
user takes a sharp intake of breath through a nostril using the
inhaler 300, a fast moving stream of air is supplied via the nozzle
331 to the area in which comminution occurs. The air flow from the
nozzle 331 acts to shear droplets that are electrohydrodynamically
formed from liquid issuing from the outlet nozzle 10a so resulting
in droplets that are smaller than they would be without the air
flow. This enables the inhaler to be used for conductive liquids
such as water and salt solutions which are otherwise difficult to
comminute electrohydrodynamically.
[0075] Experiments have been carried out using tap water as the
liquid to be comminuted with a liquid supply pipe having an outlet
nozzle 10a with an internal diameter of 0.2 mm and with 2.5
kilovolts applied between the first and second electrodes 11 and
12. The diameter of the tube is selected in accordance with the
average expected nasal inhalation rate of a user to provide an air
flow rate from the nozzle 331 sufficient to cause shearing, in this
example 10 m/second. Where the air flows at approximately 20 to 30
litres/minute through a tube which is coaxial with and surrounding
the outlet nozzle, then generally the tube outlet should have an
area of a few square millimetres so as to be comparable with the
air flow impedance provided by the nasal passages.
[0076] Droplets having a diameter of approximately 20 micrometers
were detected. The droplet charge to mass ratio was determined to
be approximately 10.sup.-4 coulombs/kilogram. The droplets were
thus significantly smaller than they would have been without the
air flow.
[0077] The air flow rate of approximately 10 m/second mentioned
above is sufficient to cause shearing and is roughly equivalent to
the air flow generated by a relatively healthy person taking a
sharp intake of breath.
[0078] It will be appreciated that the modification described with
reference to FIG. 10 may be used in combination with any
appropriate ones of the modifications described with reference to
any one of FIGS. 4 to 8 above so that, for example, the counter
electrode 12 may be positioned downstream of the first electrode 11
as shown in FIG. 5. It will also be appreciated that one, two or
more air flow nozzles may be provided in the vicinity of the
comminution area or site. All that matters is that a sufficient air
flow is achieved at the comminution area or site to cause shearing
without causing undue turbulence. In this regard, it will be noted
that as shown in FIG. 10, the outlet nozzle 331 is directed so as
to provide an air flow extending obliquely of the direction in
which liquid issues from the outlet nozzle 10a.
[0079] Apart from the reasons given in the introduction of this
application, a person skilled in the art may have thought that it
would be undesirable for the user of an inhaler to inhale charged
droplets because the supply of charge to the user would, if the
user was not earthed during use of the inhaler, result in a voltage
rise of the user which could result in the user experiencing an
unpleasant electrical shock when he subsequently was connected to
earth.
[0080] The present inventors have, however, found that the rise in
the voltage of an unearthed user during a single use of an inhaler
embodying the invention is not sufficiently large to result in an
unpleasant electrical discharge. Also, the amount of charge
transferred to the user may, if desired, be controlled to a
minimum. This may be achieved by, for example, formulating the
liquid carrying the medicament being inhaled with a higher
concentration of the active ingredient or medicament in the liquid
than is normal with aqueous solutions. Thus a smaller amount of
liquid need be inhaled to deliver the required dose. This reduces
the overall space charge and facilitates entrainment of the
comminuted matter in the air flow through the inhaler. Typically,
the concentration may be increased by five fold (say from 10% to
50% by volume of the active ingredient).
[0081] If prolonged or continuous treatment is required, then the
inhalers described above may be modified to periodically reverse
the polarity of the voltage supplied by the high voltage generator
so that the user receives droplets of one polarity charge followed
by droplets of the opposite polarity charge, thereby inhibiting any
significant rise in the voltage of the user. One simple way in
which this may be achieved is to use as the high voltage source a
piezoelectric generator which is manually activated by the user
using a cam and lever arrangement because this automatically
provides a polarity reversal with the voltage generated when the
crystal is squeezed being of opposite polarity to the voltage
generated when the crystal is released.
[0082] In each of the examples described above, the high voltage is
applied to the second or counter electrode. However, the second
electrode could be omitted and the first electrode charged directly
to the required high voltage, especially if a low power, low
capacitance, high voltage generator, such as a piezoelectric
generator, is used.
[0083] FIG. 11 shows a diagrammatic part-cross-sectional view
similar to FIG. 2 of another embodiment of an inhaler in accordance
with the present invention where the first electrode is directly
charged.
[0084] The inhaler 301 shown in FIG. 11 has two liquid supply pipes
10 each having an outlet nozzle 10a. The pipe 10 is coupled to a
corresponding pump 9 so as to receive liquid from a corresponding
reservoir 8. Although not shown explicitly in FIG. 11, each pump 9
is coupled between the delay circuit 120 and the negative terminal
of the voltage source 5. Each of the liquid supply pipes 10 has
supported within it a first electrode 11 in the form of a
conductive core. The first electrode 11 of one liquid supply pipe
10 is coupled to the high voltage output of the high voltage
generator 7 (not shown in FIG. 6). A further high voltage generator
7' providing a high voltage of the opposite polarity, negative in
this case, has its high voltage output coupled to the first
electrode 11 of the other liquid supply pipe 10. In this case,
either the liquid should be sufficiently highly resistive to
inhibit the direct charging of the first electrodes 11 causing a
voltage rise at the pump or the pump should be electrically
isolated from the liquid.
[0085] The air flow path shown in FIG. 11 is also different from
that shown in FIG. 2. Thus, in the inhaler 301 shown in FIG. 11,
the insulative tubular body 33 of FIG. 2 is replaced by an
insulative tubular body 333 which passes through the aperture 32 in
the wall 3a so as to terminate at an air outlet nozzle 334 which,
as shown in FIG. 11, is coaxial with and symmetrically disposed
between the two liquid outlet nozzles 10a. The inhaler 301 shown in
FIG. 11 operates in a similar manner to the inhaler shown in FIG. 2
with the exception that two opposite polarity sprays or
comminutions are produced. The air flow from the air outlet nozzle
334 is sufficient to keep the two opposite polarity comminutions
apart so that two opposite polarity comminutions are supplied to
the nozzle passages. This has the advantage of enabling charged,
comminuted matter to be supplied to the nasal passages without
altering the overall charge of the body of the user. Typically, the
longitudinal axes of the two liquid supply pipes may be 12 to 15 mm
apart.
[0086] It should be appreciated that the modifications described
with reference to FIG. 11 may be used in combination with the
modifications described with reference to any one of FIGS. 4 to 8
above.
[0087] In each of the embodiments described above the air flow rate
is controlled either by how hard the user sniffs or by, in the case
of FIG. 8, the operation of the pump 102. Further control of the
air flow rate in any of the above described embodiments may be
provided by means of a valve in the air flow path. As an example,
FIG. 12 shows part of the inhaler shown in FIG. 2 with a flap valve
or choke 301 pivotally mounted in the air flow path 33. The flap
valve may be operable by means of any conventional mechanism, for
example, the flap valve may be manually rotatable by a user
rotating a knob mounted to the outside of the housing or pivoting
movement of the flap valve may be controlled mechanically using a
camming arrangement or electromechanically using a camming
arrangement and a solenoid, for example, or may be arranged to be
present by a doctor, for example. Other conventional forms of
valves may also be used.
[0088] As described above, the air flow from the outlet nozzle 334
serves to keep the opposite polarity sprays or comminutions apart.
The amount by which the opposite polarity comminutions are kept
apart, and so a degree of mixing can be controlled by controlling
the air flow rate through the pipe 334 by, for example, providing a
throttle or like valve in the air flow pipe 334. This air flow
valve may be preset by the doctor or at factory level (for example
in dependence upon the active ingredient to be delivered by the
inhaler), or may be settable by the user. The zone of deposition of
the comminuted matter in the nasal passages can be controlled by
controlling the overall charge of the comminuted matter supplied to
the nostrils of the user so enabling the area to which the active
ingredient is to be delivered to be targeted by adjusting the air
flow rate with an air flow control valve.
[0089] It will be appreciated that different users or different
patients may have different nasal inhalation rates which, with
conventional propellant nasal inhalers, would cause the inhaled
material to be deposited more deeply into the nasal passages than
if the inhaler was being used by a person with a lower nasal
inhalation rate. However, the nasal inhaler shown in FIG. 11 has
the advantage that a person with a rapid nasal inhalation rate will
cause a more rapid flow of air from the air outlet nozzle 334 than
will a person with a low nasal inhalation rate so that the person
with the high nasal inhalation rate will receive more highly
charged, less mixed, comminuted matter than the person with the low
nasal inhalation rate. As more highly charged matter tends to
penetrate less deeply into the nasal passages, the inhaler shown in
FIG. 11 provides a self-adjusting effect because the tendency of a
greater inhalation rate to cause material to be deposited more
deeply into the nasal passages is counteracted by the greater
charge tending to cause the material to be deposited less deeply
into the nasal passages.
[0090] In the arrangement shown in FIG. 11, the liquid outlets 10a
are parallel to one another. However, the liquid outlets may be
angled towards one another, for example at 45.degree. to the
longitudinal axis L of the inhaler, which may increase the degree
of mixing.
[0091] The overall charge on the comminuted matter delivered by the
inhaler and thus the depth to which that matter penetrates into the
nasal passages may also be controlled by, in addition to or instead
of controlling the air flow rate, controlling the relative voltages
applied to the two first electrodes by adjusting the voltages
supplied by the high voltage generators 7 and 7' and/or by
adjusting the relative flow rates of liquid to the outlet nozzles
10a. These adjustments may be adjustments that can be made at
factory level so that a single inhaler construction can be adapted
within the factory for delivery of different doses (for example for
children and adults) of the same active ingredient or to enable the
same inhaler to be used to deliver different active ingredients
which require different dosages. As another possibility, the
voltages supplied by the generators and/or the flow rates may be
adjustable by a doctor or nurse under clinical conditions or a
pharmacist or the patient or user himself where it is acceptable
for the user to control the dose supplied.
[0092] As described above, it is assumed that the same liquid is
supplied to the two liquid supply pipes 10. If this is the case and
relative flow rate adjustment is not required, then a single
reservoir 8 and a single pump 9 may be provided. Also, instead of
providing separate negative and positive polarity high voltage
generators, a single generator providing a high voltage of one
polarity to one of the first electrodes 11 may be provided and the
other electrode may be connected to earth (ground) so that, in
practice, it is charged by induction from the directly charged
first electrode. This has the advantage of requiring only a single
high voltage generator so reducing the overall costs and reducing
the space required within the inhaler to accommodate the high
voltage generator.
[0093] Where, as shown in FIG. 11, respective reservoirs and pumps
8 and 9 are provided, then the two liquid supply pipes 10 may be
supplied with different liquids that, when the opposite polarity
comminutions are generated, interact with one another. For example,
the two liquids may contain or comprise respective reactive
components that, when the two opposite polarity comminutions are
produced, intermingle and react with one another so as to produce
the required active ingredient. This enables, for example, short
shelf life active ingredients to be formed only as and when needed.
As another possibility, the two liquid supply paths may provide
separate active ingredients for which reaction is not desirable but
which lose their relative efficacy if they are in the presence of
one another for any length of time. As another possibility, one of
the liquids may contain a blowing agent which, when comminuted
matter contained in the blowing agent reacts with the opposite
polarity comminuted matter, causes expansion of the droplets or
particles of the other comminuted matter to form low density
particles, for example spheres, which can penetrate deeper into the
nasal passages. As another possibility, where the liquid issuing
from one of the outlets produces comminuted matter in liquid or
gel-like form, then, when the two opposite polarity comminutions
mix, the liquid or gel-like comminuted matter may cover or coat
particles of the other comminuted matter to form, for example,
microcapsules or coated short fibres or fibrils enabling slow
release of active ingredient from the cores of the coated
particles. The coating material may contain a bioadhesive to
prevent mucocillary clearance and to facilitate long term or
sustained release of the active ingredient when used in conjunction
with controlled release products.
[0094] Another advantage of having two liquid outlets is that the
overall rate at which the active ingredient is delivered to the
nasal passages should be higher than if only a single liquid outlet
nozzle is used. It will be appreciated that more than one pair of
liquid outlets may be used and that it is not necessary for there
to be equal numbers of positive and negative charged first
electrodes especially where, if the arrangement allows complete
mixing of the comminutions, a residual charge should be
ensured.
[0095] Another advantage of providing plural nozzles to achieve
opposite polarity comminutions is that the comminution sprays will
be more strongly attracted to one another than to the walls of the
housing and so the possibility of deposition of comminuted matter
onto the walls of the housing should be reduced.
[0096] Also, the arrangement shown in FIG. 11 should enable larger
size droplets or particles of comminuted matter to be produced
carrying a given charge.
[0097] It will be appreciated that, although the counter electrodes
12 are not necessary in the arrangement shown in FIG. 11, the
arrangement shown in FIG. 11 could be adapted to provide counter
electrodes in a similar manner to that described above with
reference to FIG. 2 with the respective counter electrodes being
coupled to the respective negative and high voltage generators 7
and 7' and the first electrodes 10 being coupled to the negative
terminal of the voltage source or to the high voltage generator of
opposite polarity It should also be appreciated that the counter
electrodes need not be coated with a dielectric although this is
often preferable. This arrangement may facilitate use of the
inhaler shown in FIG. 11 with more conductive liquids.
[0098] In the arrangement shown in FIG. 11, the air supply outlet
334 is disposed centrally of the two liquid outlets. Although this
is preferable where it is desired to keep the two opposite polarity
comminutions apart, where at least some mixing is desired, then the
air outlet may surround the liquid outlets and, for example, air
inlet apertures may be provided in the housing wall 4a. Providing
the air outlets around the liquid outlets should, in addition to
facilitating desired mixing, provide an air curtain to inhibit or
at least reduce further the possibility of deposition on the walls
of the housing.
[0099] As discussed in WO98/03267, in electrohydrodynamic
comminution, the intense electric field to which liquids issuing
from the nozzle outlet 10a is subject establishes a standing wave
along the surface of the liquid producing at least one cusp or cone
(depending upon the size of the outlet 10a) which emits a jet or
jets of charged liquid. Small perturbations inevitably occur in the
liquid jet resulting in a growth wave which causes the jet to
become unstable and the net electrical charge in the liquid
provides a repulsive force which counteracts the surface tension
forces in the liquid to cause comminution. The growth wave will
have a natural frequency and it has been found that the point at
which initiation of the growth wave occurs in the jet can be
controlled by superimposing upon the applied high voltage an AC
signal different from the natural frequency of the growth wave
enabling the size of the resulting droplets to be controlled.
[0100] The present inventors have found that, instead of a
monodispersed comminution, a comminution having droplets of two or
more well-defined controlled diameters can be produced by
superimposing on the high voltage signal an oscillating signal
comprising one or more superimposed frequencies close to natural
frequency of the growth wave for the liquid being comminuted.
[0101] As shown schematically in FIG. 13, a pulse or signal
generator 70 is coupled to the high voltage supply line 7a of the
high voltage generator by means of a high voltage capacitor C.
However, it might be possible to use the natural frequency of the
high voltage generator 7 and to retain some AC ripple on the H.V.
output line 7a.
[0102] Any suitable form of pulse or signal generator which may be
powered by the voltage source 5 (see FIG. 2 for example) of the
inhaler may be used. For example, the pulse/signal generator 70 may
comprise a number of voltage controlled oscillators each of which
receives a respective different drive voltage derived in known
manner using voltage dividing or multiplying techniques from the
voltage source. As another possibility, a numerically controlled
oscillator may be used. For example, the pulse/signal generator may
comprise a digital memory storing at sequential addresses numerical
values which are read out in sequence from the memory and supplied
to a digital-to-analogue converter to reconstitute the desired wave
shape. In such a case, a signal representing the superimposition of
two or more frequencies may be directly generated from the numbers
stored in the memory. Reference may be made to standard electronics
textbooks such as `The Art of Electronics` by Paul Horowitz and
Winfield Hill for details of oscillators which may be used to
provide the pulse/signal generator 70.
[0103] FIG. 14 illustrates how a superimposed varying amplitude
voltage can affect droplet formation with large and small amplitude
impulses or "kicks" (illustrated schematically by line 71 ) applied
to the H.V. output line giving rise to two different size droplets
d and D.
[0104] When the inhaler shown in FIG. 2 is modified in this manner,
in use, liquid issuing from the outlet nozzle 10a is
electrohydrodynamically comminuted and is deposited on the
conductive surface inside the nostril as the user inhales as
described above. However, the smaller droplets which carry less
charge and have lower inertia will travel further into the nasal
passages than the larger droplets so enabling a more uniform
deposition along the length of the nasal passages of the medicament
being delivered.
[0105] It will be appreciated that superimposing three or more
frequencies will allow three or more different size droplets to be
produced in a controlled manner.
[0106] Instead of superimposing the different frequencies,
different frequency signals may be supplied in sequence to the high
voltage line 7a so that the size of the droplets produced changes
in a controlled manner with time depending upon the particular
drive frequency applied at the time the droplets are generated.
[0107] The arrangement discussed above with reference to FIGS. 13
and 14 assumes that the drive signals are sine waves. However, this
need not necessarily be the case and, for example, short duration
spikes having a pulse width of 1 microsecond or less may be used.
Typically the drive signals provided by the pulse generator 70 will
have an amplitude of about 2% of the high voltage, for example
10-100 volts and a frequency in the range of 50 kHz to 10-50 MHz,
depending upon the desired size of the droplets.
[0108] Another possible form of oscillation device is a
piezoelectric resonator with two or more resonators arranged to
resonate at different frequencies being provided to achieve the
required drive frequencies.
[0109] FIGS. 15 and 16 show schematically parts of further modified
versions of the inhaler shown in FIG. 2.
[0110] In the arrangement shown in FIG. 15, the pump 9 is arranged
to supply liquid to three liquid supply pipes 101, 102 and 103 each
having a corresponding outlet 101a, 102a and 103a and each
containing a conductive core or rod 111, 112 and 113. The
conductive core or rod in each case is coupled to the earth
terminal of the voltage generator 5 via line 5a while a second
electrode 121, 122 and 123 carried by the insulative supply pipe
101, 102 and 103 is coupled to the high voltage output line 7a from
the high voltage generator. Each of the supply pipes 101 to 103 has
a flow regulating valve V1, V2 and V3. Each flow regulating valve
V1, V2 and V3 controls the rate of flow of liquid through its
associated liquid supply pipe so that the rate of flow of liquid
from each of the outlets 101a, 102a and 103a is different. Any
suitable form of valve, for example a simple mechanical throttle
valve or an electromechanical solenoid valve, may be used. Because
the flow rates to the respective outlets 101a, 102a and 103a are
different, the size of the droplets produced during
electrohydrodynamic comminution from the respective outlets will be
different. Accordingly, the embodiment shown in FIG. 15 enables
three different sizes of droplets to be produced by providing
respective different flow rates for the three liquid supply
pipes.
[0111] It will be appreciated that two, three or more liquid supply
pipes having different liquid flow rates may be used and that the
liquid flow rates may be prefixed or may be adjustable by the user.
The embodiment shown in FIG. 15 enables simultaneous production of
different size droplets. Sequential production of different size
droplets may be achieved by having a single liquid supply pipe and
adjusting the flow rate with time by controlling the degree to
which the liquid supply valve is open.
[0112] FIG. 16 illustrates another modification. In this case, the
pump 9 is provided with two or more liquid supply pipes 104 and 105
each having a central conductor or rod 114 and 115 providing a
first electrode. In this case the second electrode 124 is mounted
to the housing 4 wall. In this case, the liquid supply pipes 104
and 105 are of different cross-sections and therefore provide
different liquid flow rates.
[0113] As another alternative, different pumps providing different
flow rates may be used for the different liquid supply pipes.
[0114] The generation of comminutions at the different outlets in
FIGS. 15 and 16 may be synchronised by superimposing upon the high
voltage signal on line 7a a drive signal comparable to the natural
frequency of the growth rate using the pulse generator 70.
[0115] In each of the embodiments described above, an air flow is
generated within the lower portion 4a of the housing. In order to
avoid air movements disrupting the Taylor cone required at the
liquid outlets for electrohydrodynamic comminution, an annular
shield may be provided around the liquid pipes in the immediate
vicinity of the liquid outlets 10a.
[0116] In each of the embodiments described above, the inhaler is
designed to enable multiple doses to be supplied from a single
reservoir or reservoirs 8. The inhaler 1 may, however, be a single
dose inhaler with a reservoir containing only sufficient liquid
formulation to provide a single dose. Where this is the case, then
the counter 6 and LED 13 described above with reference to FIG. 3
may be omitted. In the case of a single dose inhaler, the liquid
supply components may be provided as a replaceable plug-in
cartridge that can be replaced by the user. Where this is the case,
then for ease of manufacture and because these components are
relatively cheap, the liquid cartridge will generally include the
first electrodes 11, and the electrodes 12 if present and if not
carried by the housing portion 4a. As another possibility, the
inhaler may be provided with a carousel or magazine of capsules
which carousel or magazine is capable of indexed movement so that,
after each use of the inhaler, a fresh capsule is moved into place
for the next use. Such a magazine may be in the form of a strip
carrying the capsules which is, for example, wound from one spool
to another as the capsules are used up.
[0117] In the embodiments described above, the inhaler has a single
outlet for a single nostril. The inhaler may be provided with twin
outlets, one for each nostril.
[0118] Although particular forms of electrohydrodynamic comminution
means have been described in the examples given above, it will be
appreciated that other forms of electrohydrodynamic comminution
means can be used. Also, other forms of electrically operable pump
may be used.
[0119] Electrically or electromechanically operated valves may be
provided at appropriate points in the liquid flow path from the
reservoir to the outlet 10a so as to inhibit leakage and maintain
microbial integrity.
[0120] Although the above arrangements are described with reference
to the supply of an active ingredient to a human being (solely by
the user or with the assistance of a doctor, nurse or carer), it
will, of course, be appreciated that the device may be adapted for
use with other mammals with the air flow activation being
controlled as described with reference to FIG. 8 by a veterinarian
or other person.
[0121] The active ingredient to be supplied by the inhaler may be
any agent or substance to provide a desired effect in the user. For
example, the active ingredient may be a medicament for use in the
treatment by way of therapy, surgery or diagnosis of an animal body
such as a human being or otherwise to improve quality of life. For
example, the medicament may be nicotine, morphine, a vitamin, an
antiseptic, an anti-inflammatory, antibiotic, anti-cancer agent or
other pharmaceutical product, a vaccine, a protein, an enzyme, DNA
or DNA fragments and so on because electrohydrodynamic comminution
enables delivery of large molecules without denaturing them.
[0122] The liquid formulation within which the active ingredient is
supplied may be a solution, emulsion, suspension or microsuspension
or any other suitable liquid form. Because viscous liquids
(including oils) such as glycerine and linoleic acid can be
comminuted using electrohydrodynamic comminution, the carrier
liquid can be optimised for the active ingredient so that, for
example, where the active ingredient is a lipophilic compound as
may be the case for a drug or medicament, then the use of
electrohydrodynamic comminution should simplify the preparation of
the formulation for that active ingredient. Also, the use of oils
and emollients has the advantages that oil-based medicaments
permeate cell membranes better allowing more rapid absorption of
the medicament when inhaled into the nasal passages. Also, oils and
oil-based formulations should cause less irritation to the nasal
passages than alcohol formulations or aqueous salts. Also oils and
other low conductivity liquids produce droplets with a low charge
to mass ratio so that the charge spray expands at a lower rate,
reducing the likelihood of internal deposition within the device.
Furthermore, such low conductivity liquids are also less likely,
because they are more highly resistive, to initiate short
circuits.
[0123] As is known in the art, it is extremely difficult to
comminute highly electrically conductive liquids satisfactorily
using electrohydrodynamic comminution without the use of
surfactants which may irritate the nasal passages and so are
undesirable for nasal inhalation. The use of relatively highly
conductive liquid formulations may, however, be unavoidable. For
example, it may be that the amount or type of active ingredient
required renders the liquid formulation highly conductive and/or
the carrier liquid required, for example water or a water/ethanol
mixture containing ionic components, renders the liquid highly
conductive. The present inventors have, surprisingly, found that it
is possible to obtain satisfactory electrohydrodynamic comminution
of such relatively highly conductive liquids without the use of
surfactants by incorporating an additional component into the
liquid formulation in the form of a medium to high molecular weight
polymer. This polymer may be a synthetic or naturally occurring
polymer and the molecular weight may, typically, be in the range
40,000 to 400,000.
[0124] Experiments have been carried out using a liquid formulation
consisting of 70% ethanol and 30% 0.5 mol water NaCl solution (salt
water) to mimic a liquid formulation carrying an active
ingredient.
[0125] A first set of experiments was carried out using PVA
(polyvinyl alcohol) as the polymer. For this polymer, a molecular
weight of 125,000 was chosen for the experiment. Details of these
experiments are set out in table 1 below. The maximum stable flow
rate was 3 microlitres/second (ml/s) per nozzle.
1TABLE 1 Resistivity/ Viscosity/ Example Formulation .OMEGA.m cP 1
0.1 g PVA in 5.54 10 10 ml liquid formulation 2 0.2 g PVA in 4.20
24 10 ml liquid formulation 3 0.3 g PVA in 4.80 72 10 ml liquid
formulation 4 0.4 g PVA in 5.21 110 10 ml liquid formulation 5 0.5
g PVA in 5.10 200 10 ml liquid formulation 6 0.6 g PVA in 5.21 360
10 ml liquid formulation 7 0.7 g PVA in 5.25 700 10 ml liquid
formulation
[0126] In each of examples 1 to 7 satisfactory electrohydrodynamic
comminution was achieved. Microscope photographs of the resultant
comminutions were taken and it was found that, surprisingly, the
geometry or structure of the comminuted matter varied with the
amount of polymer added to the formulation. Thus, when the amount
of polymer was 0.1 g in 10 ml, the resulting comminuted matter was
granular in appearance consisting of spheroidal or near-spheroidal
particles. When the amount of PVA was increased to 0.2 g, then the
comminuted matter was still granular but some of the granules had
tails or were attached to fibrils. As the amount of PVA was
increased, that is going from example 2 to example 7, the amount of
fibril or tail formation increased so that at example 7 the
majority of the comminuted matter was formed of small fibres or
fibrils.
[0127] Similar experiments were also carried out using PVP
(polyvinyl pyrrolidone). Table 2 shows the results of experiments
carried out using a PVP molecular weight of 360,000 and a maximum
flow rate of 1.5 microlitres/second per nozzle.
2TABLE 2 Viscosity/ Example Resistivity/.OMEGA.m cP Product 8 0.2 g
PVP in 4.74 10 10 ml liquid formulation 9 0.4 g PVP in 4.76 60 10
ml liquid formulation 10 0.6 g PVP in 5.36 180 10 ml liquid
formulation 11 0.8 g PVP in 5.20 260 10 ml liquid formulation 12
1.0 g PVP in 5.32 480 10 ml liquid formulation 13 1.2 g PVP in 5.82
740 10 ml liquid formulation
[0128] Again, in each of examples 8 to 12, satisfactory
electrohydrodynamic comminution was achieved. Again, microscope
photographs were taken and again the geometry or structure of the
comminuted matter was found to change with the amount of polymer
added to the liquid formulation. Thus, where the amount of polymer
was 0.2 g in 10 ml (millilitres), the comminuted matter was
generally granular with few fibrils or tails, with 0.4 g PVP in 10
ml of the liquid formulation more fibrils or tails were seen, while
with 0.6 g PVP in 10 ml of the formulation significant numbers of
tails and fibrils were seen with few granular components.
Thereafter, the number of fibrils and short fibres seen increased.
As a result of further experiments carried out, a formulation with
0.5 g of PVP in 10 ml of the liquid formulation was found to
produce granular material with a good proportion of tails or
fibrils.
[0129] It can thus be seen that, surprisingly, controlling the
amount of medium to high weight polymer added to the liquid
formulation enables the geometry or shape of the comminuted
material to be controlled so that the comminuted material can be
varied from granular particles to short fibres and fibrils with, in
between, the comminuted material consisting of granular matter some
of which has short tails or attached fibrils. The ability to
control the shape or geometry of the comminuted matter is
advantageous because this means that the shape of the comminuted
matter can be tailored to the desired usage. Generally, the fibrils
or tails were found to be semi-solid and capable of adhering better
to surfaces such as the surfaces of the nasal passages and/or to
themselves, so reducing the possibility of mucocillary clearance.
Also, being able to control the size of the comminuted matter from
very small granular particles having dimensions less than 1
micrometre to short fibres or fibrils enables the rate at which
active ingredient is taken up by the mucous membranes to be
controlled with very small particles enabling fast uptake and
larger particles enabling slower, more sustained release of the
active ingredient. Thus, by tailoring the geometry of the
comminuted matter, the rate of delivery of the active ingredient
can be controlled.
[0130] The use of electrohydrodynamic comminution as described
above to enable delivery of active ingredients by inhalation
through the nasal passages enables the control of the rate and
location of uptake of the active ingredient so that, for example,
the active ingredient can be delivered rapidly to the brain with
low or little systemic uptake which is particularly important where
the drug to be delivered may have deleterious systemic side
effects.
[0131] The above example describes inhalers for supplying an active
ingredient via the nasal passages. However, where the modification
shown in FIG. 8 is provided so that inhalation by the user is not
required, supply of an active ingredient to other body areas,
cavities or organs, or onto or into a wound is possible. Such a
device may be used for supply of active ingredients to the eye
because the electrodes are not exposed so inhibiting the
possibility of electrical shock. Where the device is adapted for
supply of an active ingredient to the surface of the eye, then the
outlet of the housing may, for example, be shaped so as to conform
to the eye socket. A device having the structure of an inhaler
described above with the adaptation shown in FIG. 8 may be used to
supply pre- or post-operative active ingredients, for example, to
reduce, especially in the case of the eye, the likelihood of scar
tissue forming after surgery; to supply antibiotics,
antibacterials, anaesthetics and the like to the surface of the eye
or into a bodily orifice; to supply comminuted matter onto an
exposed interior surface of the body during surgery for example to
supply an adhesive to repair an incision in an arterial wall; or to
apply wound dressing or medicaments onto internal or external
bodily wounds.
[0132] The final form of the comminuted matter will depend upon the
liquid being comminuted. Thus, for example, if the liquid is such
that it starts to solidify or gel after comminution then solid or
gel-like droplets will be formed. If the liquid starts to solidify
or gel just before comminution then generally small fibres or
fibrils will be formed. Where the device is not being used for
inhalation, then the term comminution is also intended to cover the
case where the supplied liquid solidifies or gels before the
applied electric field can break the liquid apart and so forms a
single fibre although, strictly, in this circumstance the liquid is
not comminuted because it does not necessarily break up.
[0133] Other modifications will be apparent to the person skilled
in the art.
* * * * *