U.S. patent application number 11/159782 was filed with the patent office on 2005-10-27 for pulmonary aerosol delivery device.
Invention is credited to Busick, David R., Dvorsky, James E., Peters, Richard D., Zimlich, William C. JR..
Application Number | 20050236501 11/159782 |
Document ID | / |
Family ID | 26914704 |
Filed Date | 2005-10-27 |
United States Patent
Application |
20050236501 |
Kind Code |
A1 |
Zimlich, William C. JR. ; et
al. |
October 27, 2005 |
Pulmonary aerosol delivery device
Abstract
A device and method for delivering an aerosolized liquid having
therapeutic properties to a user's lungs. The compact and
convenient device includes a housing of such size that it can be
held in a user's one hand with an exit opening in the housing for
directing the aerosol to the user's mouth. The housing encloses a
dispensing system for containing the liquid to be aerosolized and
delivering it to an electrohydrodynamic apparatus and an
electrohydrodynamic apparatus for aerosolizing the liquid and
delivering the aerosol to the exit opening. The electrohydrodynamic
apparatus produces a cloud of aerosolized liquid droplets having a
monodispersed reparable droplet size and near zero velocity. The
aerosolizing apparatus includes a plurality of spray sites each
having a tip end, the spray sites cooperating with a charge source
to result in an aerosolized spray from at least one tip end, a
plurality of discharge electrodes downstream of the tip ends, and a
plurality of reference electrodes downstream of the plurality of
discharge electrodes.
Inventors: |
Zimlich, William C. JR.;
(Dublin, OH) ; Dvorsky, James E.; (Norwich
Township, OH) ; Busick, David R.; (Lewis Center,
OH) ; Peters, Richard D.; (Gahanna, OH) |
Correspondence
Address: |
GIBBONS, DEL DEO, DOLAN, GRIFFINGER & VECCHIONE
1 RIVERFRONT PLAZA
NEWARK
NJ
07102-5497
US
|
Family ID: |
26914704 |
Appl. No.: |
11/159782 |
Filed: |
June 23, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11159782 |
Jun 23, 2005 |
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10951248 |
Sep 27, 2004 |
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10951248 |
Sep 27, 2004 |
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10161545 |
Jun 3, 2002 |
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6796303 |
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10161545 |
Jun 3, 2002 |
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09469042 |
Dec 21, 1999 |
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6397838 |
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09469042 |
Dec 21, 1999 |
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09220249 |
Dec 23, 1998 |
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Current U.S.
Class: |
239/690 ;
239/302; 239/690.1 |
Current CPC
Class: |
B05B 5/1691 20130101;
B05B 5/0255 20130101; A61M 15/0065 20130101; A61M 11/007 20140204;
B05B 5/002 20130101; A61M 15/008 20140204; A61M 15/0081 20140204;
A61M 15/025 20140204; A61M 15/0083 20140204 |
Class at
Publication: |
239/690 ;
239/302; 239/690.1 |
International
Class: |
B05B 005/025; A01G
023/10; A62C 013/62; A62C 013/66; A62C 035/58 |
Claims
What is claimed is:
1. A aerosol delivery device comprising: at least one spray site; a
containment vessel for containing a liquid; a metering system for
delivering a single dose of the liquid from the containment vessel
to the at least one spray site, the metering system comprising a
motor driven piston within the dispensing system; and a charge
source for generating an electric field proximate to the spray
sites to aerosolize the liquid emanating from the at least one
spray site.
2. The device of claim 1 wherein the motor driven piston comprises
a motor mechanically coupled to a screw that is further
mechanically coupled to a plunger.
3. The device of claim 1 wherein the containment vessel has
antimicrobial properties.
4. The device of claim 1 wherein the containment vessel is selected
from the group comprising a holder for a liquid enclosed in single
dose units, a plurality of sealed chambers each holding a single
dose of a liquid, and a vial for enclosing a bulk supply of a
liquid.
5. The device of claim 1 wherein the containment vessel is capable
of maintaining the sterility of a sterile liquid placed
therein.
6. The device of claim 1 further comprising at least one ion
discharge electrode proximate to the at least one spray site for
neutralizing at least a portion of the aerosolized liquid emanating
from the at least one spray site.
7. The device of claim 1 wherein the at least one ion discharge
electrode is electrically coupled to the charge source and the
charge source generates the electric field through the at least one
ion discharge electrode.
8. The device of claim 1 further comprising a valve disposed
between the containment vessel and the spray site.
9. The device of claim 8 further comprising a valve disposed at an
outlet of the containment vessel.
10. A aerosol delivery device comprising: a dispensing system for
containing a liquid; at least one spray site for receiving the
liquid from the dispensing system; a charge source for generating
an electric field proximate to aerosolize the liquid emanating from
the at least one spray site; and a control circuit communicating
with the dispensing system and the charge source.
11. The device of claim 10 further comprising a housing having an
exit opening for directing the aerosolized for inhalation by a
user, the housing enclosing the at least one spray site.
12. The device of claim 1 wherein the at least one ion discharge
electrode is electrically coupled to the charge source and the
charge source generates the electric field through the at least one
ion discharge electrode.
13. The device of claim 10 further comprising at least one ion
discharge electrode for neutralizing at least a portion of the
aerosolized liquid emanating from the at least one spray site.
14. The device of claim 13 wherein the at least one ion discharge
electrode is disposed between the at least one spray site and an
exit opening of the device.
15. The device of claim 14 further comprising a dielectric disposed
in a region between the at least one ion discharge electrode and
the at least one spray site.
16. The device of claim 12 wherein the at least one spray site is
disposed between the ion discharge electrode and an exit opening of
the device.
17. The device of claim 16 further comprising a dielectric disposed
in a region between the at least one ion discharge electrode and
the at least one spray site.
18. The device of claim 12 wherein the plurality of ion discharge
electrodes are spaced substantially equidistant from one
another.
19. The device of claim 12 wherein the control circuit includes an
actuation device for initiating aerosolization of the liquid.
20. The device of claim 19 wherein the actuation device comprises a
sensor for detecting inhalation of a user's breath.
21. The device of claim 20 wherein the sensor cooperates with the
control circuit to initiate the flow of aerosolized liquid.
22. The device of claim 21 wherein the sensor is selected from the
group comprising a flapper switch, a pressure transducer, an air
motion detector, and an air velocity detector.
23. The device of claim 10 further comprising a valve disposed
between the containment vessel and the spray site.
24. A aerosol delivery device comprising: a dispensing system for
containing a liquid; at least one spray site for receiving the
liquid from the dispensing system; a charge source for generating
an electric field proximate to aerosolize the liquid emanating from
the at least one spray site; a control circuit communicating with
the dispensing system and the charge source; and a sensor coupled
to the control circuit, the sensor for detecting inhalation of a
user's breath through said device, wherein the control circuit
includes an actuation device for initiating flow of aerosolized
liquid.
25. The device of claim 24 wherein the sensor is selected from the
group comprising a flapper switch, a pressure transducer, an air
motion detector, and an air velocity detector.
26. The device of claim 24 further comprising at least one ion
discharge electrode for neutralizing at least a portion of the
aerosolized liquid emanating from the at least one spray site.
27. The device of claim 26 wherein the at least one ion discharge
electrode is electrically coupled to the charge source and the
charge source generates the electric field through the at least one
ion discharge electrode.
28. The device of claim 26 wherein the at least one ion discharge
electrode is disposed between the at least one spray site and an
exit opening of the device.
29. The device of claim 26 wherein the at least one spray site is
disposed between the at least one ion discharge electrode and an
exit opening of the device.
30. The device of claim 29 further comprising a dielectric material
disposed within a region between the at least one ion discharge
electrode and the at least one spray site.
31. The device of claim 26 wherein the ion discharge electrodes are
spaced substantially equidistant from one another.
32. The device of claim 23 wherein the dispensing system further
comprises: a containment vessel; and a valve disposed between the
containment vessel and the at least one spray site.
33. An aerosol delivery device comprising: a dispensing system for
containing a liquid to be aerosolized and delivering the liquid to
an apparatus for aerosolizing the liquid; and an apparatus for
aerosolizing the liquid and delivering the aerosolized liquid to
the exit opening of the device, the apparatus comprising: a
plurality of spray sites each having a tip end; and a plurality of
ion discharge electrodes disposed between the tip ends and an exit
opening of the device, the plurality of ion discharge electrodes
being oriented toward the aerosolized spray; and a power supply
system for providing sufficient voltage to the aerosolizing
apparatus to aerosolize the liquid.
34. The apparatus of claim 33 wherein the plurality of ion
discharge electrodes are spaced equidistant from one another.
35. The device of claim 33 wherein the dispensing system further
comprises: a containment vessel; and a valve disposed between the
containment vessel and the spray sites.
36. An aerosol delivery device comprising: a dispensing system for
containing a liquid to be aerosolized and delivering the liquid to
an apparatus for aerosolizing the liquid; and an apparatus for
aerosolizing the liquid and delivering the aerosolized liquid to
the exit opening of the device, the apparatus comprising: a
plurality of spray sites each having a tip end; a plurality of ion
discharge electrodes, the spray sites being disposed between said
ion discharge electrodes and the device exit opening; and a power
supply system for providing sufficient voltage to the aerosolizing
apparatus to aerosolize the liquid.
37. The device of claim 36 wherein the dispensing system further
comprises: a containment vessel; and a valve disposed between the
containment vessel and the spray sites.
38. The apparatus of claim 36 further comprising a dielectric
material disposed within a region between the ion discharge
electrodes and the spray sites.
39. An apparatus for aerosolizing a liquid comprising: a tubular
base; a plurality of spray sites each having a base end connected
to the base and a tip end extending axially into a first end of the
base; and a charge source electrically coupled to a plurality of
ion discharge electrodes for generating an electric field to cause
generation of an aerosolized spray from at least one tip end when
liquid is provided to the plurality of spray sites.
40. The apparatus of claim 39 wherein the plurality of discharge
electrodes is oriented toward the aerosolized spray.
41. The apparatus of claim 39 wherein the plurality of discharge
electrodes has a sufficient electric field strength to
substantially neutralize a charge on the droplets generated by the
spray sites.
42. The apparatus of claim 39 wherein at least one of the plurality
of spray sites has a sufficient electric field strength that when a
liquid is caused to flow from said spray site, a net electrical
charge is imparted to the surface of the flowing liquid, the charge
imparted to the liquid surface initially balancing the surface
tension of the liquid to cause the liquid to form a cone adjacent
to the spray site with the cone tip extending away from the spray
site, the charge imparted to the surface eventually overcoming the
surface tension of the liquid in the region of the cone tip to
generate a thin jet of liquid that breaks into an aerosolized
liquid consisting substantially of droplets of respirable size.
43. The apparatus of claim 39 wherein the plurality of discharge
electrodes extend radially inwardly toward an axis defined by the
base end and tip end of one of the plurality of spray sites.
44. The apparatus of claim 39 wherein the plurality of discharge
electrodes are spaced equidistant from one another.
45. The apparatus of claim 39 further comprising a dielectric
material disposed between the discharge electrodes and the spray
sites.
46. The apparatus of claim 39 wherein the plurality of spray sites
are arranged in a generally circular pattern.
47. A aerosol delivery device comprising a dispensing system for
containing a liquid to be aerosolized and delivering the liquid to
an apparatus for aerosolizing the liquid; an apparatus for
aerosolizing the liquid and delivering the aerosolized liquid to
the exit opening of the device, the apparatus comprising: a
plurality of spray sites; and a plurality of ion discharge
electrodes; and a power supply system comprising a battery and a DC
to DC high voltage converter for providing sufficient voltage to
the apparatus to aerosolize the liquid.
48. The device of claim 47 further comprising a housing having an
exit opening for directing the aerosolized for inhalation by a
user, the housing enclosing the spray sites.
49. The device of claim 47 wherein the dispensing system further
comprises: a containment vessel; and a valve disposed between the
containment vessel and the spray sites.
50. The device of claim 47 wherein the device is cordless.
51. The device of claim 47 wherein the plurality of discharge
electrodes are electrically coupled to the power supply for
generating the electric field to aerosolize the liquid emanating
from the spray sites.
52. The device of claim 47 wherein the plurality of discharge
electrodes are electrically coupled to the power supply and have
sufficient electric field strength to substantially neutralize a
charge on the droplets generated by the spray sites.
53. The device of claim 47 wherein the ion discharge electrodes are
disposed between the spray sites and an exit opening of the
device.
54. The device of claim 53 further comprising a dielectric disposed
in a region between the ion discharge electrodes and the spray
sites.
55. The device of claim 47 wherein the spray sites are disposed
between the ion discharge electrodes and an exit opening of the
device.
56. The device of claim 55 further comprising a dielectric disposed
in a region between the ion discharge electrodes and the spray
sites.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of Ser. No. 10/951,248,
filed Sep. 27, 2004 which is a continuation of copending U.S.
application Ser. No. 10/161,545, filed Jun. 03, 2002, now U.S. Pat.
No. 6,796,303, issued Sep. 28, 2004, which is a continuation of
U.S. application Ser. No. 09/469,042, filed Dec. 21, 1999, now U.S.
Pat. No. 6,397,838 B1, issued Jun. 04, 2002, which is a
continuation-in-part of U.S. application Ser. No. 09/220,249, filed
Dec. 23, 1998, now abandoned, each of which is fully incorporated
herein by reference.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
[0002] Not applicable
REFERENCE TO MICROFICHE APPENDIX
[0003] Not applicable
FIELD OF THE INVENTION
[0004] This invention relates to devices and methods for delivering
an aerosolized liquid to a user's lungs, and particularly an
aerosolized liquid having therapeutic properties.
BACKGROUND OF THE INVENTION
[0005] For some therapeutic agents, delivery of the aerosolized
liquid without a propellant is preferred. Such liquids may be
aerosolized, for example, by an electrohydrodynamic apparatus. The
liquid to be aerosolized is made to flow over a region of high
electric field strength, which imparts a net electric charge to the
liquid. This electric charge tends to remain on the surface of the
liquid such that, as the liquid exits the nozzle, the repelling
force of the surface charge balances against the surface tension of
the liquid, forming a cone (a "Taylor cone" as described in, e.g.,
M. Cloupeau and B. Prunet-Foch. "Electrohydrodynamic Spraying
Functioning Modes: A Critical Review," J. Aerosol Sci., Vol. 25,
No. 6, pp. 1021, 1025-1026 (1994)). In the region of the tip of the
cone, which has the greatest charge concentration, the electrical
force exerted on the liquid surface overcomes the surface tension,
generating a thin jet of liquid. The jet breaks into droplets of
more or less uniform size, which collectively form a cloud that may
be inhaled by a user to deliver the aerosol to the user's
lungs.
[0006] Dr. Ronald Coffee of Oxford University, Oxford, England, has
proposed and developed methods of aerosolizing pharmaceutical
formulations and discharging the aerosol particles prior to their
delivery to a user. One such method uses an electrohydrodynamic
apparatus having a single spray site (nozzle) surrounded by four
discharge electrodes and a grounded shield to produce a
monodispersed spectrum of particle sizes.
[0007] Known pulmonary delivery devices that use
electrohydrodynamic spraying are unwieldy and require connection to
either an alternating current power supply or a large direct
current power supply. These conventional devices are suitable for
use in hospital or other clinical applications, such as for
administering a therapeutic agent during a scheduled treatment
appointment, but generally are not suitable for use directly by a
user on a demand or as-needed basis outside a clinical setting.
Conventional devices are particularly unsuited for use during a
user's regular activities at home, at work, while traveling, and
during recreational and leisure activities.
[0008] Known pulmonary delivery devices that use
electrohydrodynamic spraying also lack a sufficient volumetric flow
rate to deliver a desired amount of certain therapeutic liquids
during the inhalation of one to two breaths by a user. Attempts to
increase the flow rate generally have resulted in even more bulky
devices unsuitable for hand-held use. These delivery devices also
arc not generally capable of spraying liquids having a broad range
of conductivities.
SUMMARY OF THE INVENTION
[0009] It is an object of the invention to provide a device and
method that conveniently delivers an aerosolized liquid to a user's
lungs. It is another object of the invention to provide a compact,
portable, hand-held pulmonary delivery device that may be used in a
variety of indoor and outdoor locations. The device would allow
users to administer therapeutic agents on an as-needed basis in
nonclinical settings and provide advantages over conventional
devices used by hospitals and clinicians.
[0010] It is a further object of the invention to provide a compact
and convenient device and method that delivers an increased
volumetric flow rate of liquid so that a desired amount of a
therapeutic liquid dispersed into respirable particles may be
administered during the inhalation of one to two breaths by a
user.
[0011] It is another object of the invention to provide a device
and method capable of electrohydrodynamic spraying of therapeutic
liquids having a broad conductivity range in a compact and
convenient device.
[0012] It is yet another object of the invention to provide an
apparatus for aerosolizing liquid that is useful in the delivery to
a user, in the form of respirable particles, of a desired amount of
a therapeutic liquid within a broad conductivity range.
SUMMARY OF THE INVENTION
[0013] The invention described here provides a compact, convenient
device and method for delivering an aerosolized liquid having
therapeutic properties to a users lungs by electrohydrodynamic
spraying. Preferably, the device is small enough that it can be
comfortably carried by a user, for example, in shirt pocket or
purse, and has a self-contained power supply so that it can be used
anywhere. The device may be disposable or reusable.
[0014] In a preferred embodiment, the pulmonary aerosol delivery
device comprises a housing sized so that it can be held in a user's
hand and having an exit opening for directing the aerosol to the
user's mouth. The housing encloses a dispensing system for
containing the liquid to be aerosolized and delivering it to an
electrohydrodynamic apparatus, an electrohydrodynamic apparatus for
aerosolizing the liquid and delivering the aerosol to the exit
opening; and a power supply system for providing sufficient voltage
to the electrohydrodynamic apparatus to aerosolize the liquid. The
power supply system may comprise a battery and a DC to DC high
voltage converter so the device may be cordless.
[0015] The liquid to be aerosolized may comprise a drug. The
dispensing system of the device may include a containment vessel
for containing the drug, which may be a holder for a drug enclosed
in single dose units, a plurality of sealed chambers each holding a
single dose of a drug, or a vial for enclosing a bulk supply of a
drug. The containment vessel may have antimicrobial properties and
may be capable of maintaining the sterility of a sterile drug
placed therein.
[0016] The dispensing system delivers a single dose of the drug
from the containment vessel to the electrohydrodynamic apparatus,
which may be accomplished using a metering system. The metering
system may include a chamber for collecting a predetermined volume
of liquid having an inlet communicating with the containment vessel
and an outlet communicating with the electrohydrodynamic apparatus;
a chamber housing above the chamber; a chamber housing spring
adjacent to the chamber; and a button spring above the chamber
housing. The button spring exerts a downward force against the
chamber housing when an actuator button is depressed to force
liquid in the chamber through the outlet and the chamber housing
spring exerts an upward force against the chamber housing when the
actuator button is released. The upward travel of the chamber
housing induces a vacuum in the chamber to draw liquid from the
containment vessel through the inlet. The chamber volume is
controlled by an adjustable stop that limits the upward travel of
the chamber housing. The metering system may further include check
valves at the chamber inlet and outlet to provide unidirectional
liquid flow.
[0017] The device may further include a control circuit
communicating with the dispensing system, the electrohydrodynamic
apparatus and the power supply system. The control circuit may
include an on/off power indicator, a power save feature, or a
lockout to prevent use by an unauthorized user.
[0018] The control circuit may include an actuation device for
initiating the flow of aerosolized liquid. The actuation device may
be a breath sensor for detecting a user's inhalation of one or more
breaths, such as a flapper switch, a pressure transducer, an air
motion detector, or an air velocity detector, which cooperates with
the electrohydrodynamic apparatus to initiate the flow of
aerosolized liquid. The actuation device also may be a manual
actuator on the exterior of the housing.
[0019] The electrohydrodynamic apparatus of the device may be
capable of aerosolizing the liquid at a flow rate of at least about
20 .mu.L/sec. It also may be capable of aerosolizing the liquid
into droplets such that at least about 80% of the droplets have a
diameter of less than or equal to about 5 microns.
[0020] The housing of the device may have antimicrobial properties.
The exit opening of the housing may be movable to assist in
directing the aerosol to the user's mouth.
[0021] In another preferred embodiment, a pulmonary aerosol
delivery device includes a housing sized so it can be held in a
user's hand and having an exit opening for directing the aerosol to
the user's mouth. The housing encloses a containment vessel holding
a liquid to be aerosolized, an electrohydrodynamic apparatus for
aerosolizing the liquid and delivering the aerosol to the exit
opening, a power supply for providing sufficient voltage to the
electrohydrodynamic apparatus to aerosolize the liquid, and a
dispensing system for delivering the liquid to be aerosolized from
the containment vessel to the electrohydrodynamic system.
[0022] The dispensing system may include a metering system for
dispensing a desired amount of the liquid to the
electrohydrodynamic apparatus, which may comprise a
mechanically-actuated piston pump. The metering system and the
control circuit may cooperate to provide a dose counter or a dose
display, which may show the doses administered or the doses
remaining. The control circuit may include a timer that cooperates
to limit the delivery of the liquid by the metering system. The
control circuit also may include a signal that cooperates with the
timer to alert a user that a dose is due by an alarm or a visual
display showing the time when the next dose is due.
[0023] The control circuit includes a memory for storing dose
information to be provided to the metering system or recording the
dose history.
[0024] The electrohydrodynamic apparatus of the device may include
a charge neutralizer for aiding in the delivery of the drug to a
user's lungs. The electrohydrodynamic apparatus also may include a
generally circular base plate having upper and lower surfaces; a
plurality of spray sites arranged in a circular pattern along the
perimeter of the lower surface of the base plate, each of the spray
sites having a base end mounted to the base plate and a tip end
oriented vertically downward; a skirt extending downward from the
base plate; a plurality of discharge electrodes each extending
radially inward from the skirt in the area of the spray site tip
ends; and a plurality of reference electrodes each extending
radially inward from the skirt downstream of and between the
discharge electrodes. A dielectric material may be enclosed within
the skirt or the skirt may be comprised of a dielectric
material.
[0025] The tip end of at least one spray site may be chamfered. The
exterior of at least one of the spray sites also may be coated with
a low surface energy coating. The electrohydrodynamic apparatus
further may include a manifold extending between the dispensing
system and the base ends of the spray sites.
[0026] In another preferred embodiment, the pulmonary aerosol
delivery device includes a housing sized so it can be held in a
user's hand and having an exit opening for directing the aerosol to
the user's mouth. The housing includes a dispensing system for
containing the liquid to be aerosolized and delivering it to an
electrohydrodynamic apparatus; an electrohydrodynamic apparatus for
aerosolizing the liquid and delivering the aerosol to the exit
opening; and a power supply system for providing sufficient voltage
to the electrohydrodynamic apparatus to aerosolize the liquid. The
electrohydrodynamic device includes a spray site having a
sufficient electric field strength that a net electrical charge is
imparted to the surface of a liquid flowing over the spray site,
with the surface charge initially balancing the surface tension of
the liquid to cause the liquid to form a cone and eventually
overcoming the surface tension of the liquid in the region of the
tip of the cone to generate a thin jet of liquid that breaks into
droplets of respirable size.
[0027] In a preferred embodiment, the method of orally
administering an aerosolized liquid therapeutic agent includes the
steps of storing the liquid in a containment vessel; dispensing the
liquid from the containment vessel to an electrohydrodynamic
apparatus; electrically actuating the electrohydrodynamic apparatus
to aerosolize the liquid; metering a desired amount of liquid to be
dispensed from the containment vessel to the electrohydrodynamic
apparatus; and enclosing the containment vessel and
electrohydrodynamic apparatus within a cordless housing of such
size that it can be held in a user's one hand, the housing
including an exit opening for directing the aerosol to the user's
mouth. In the above-described method, the treating step may include
neutralizing the electrical charge imparted to the aerosolized
liquid and the electrical actuation step may be initiated by a
user's inhalation of breath.
[0028] In another preferred embodiment, the method for orally
administering an aerosolized liquid therapeutic agent comprises the
steps of storing the liquid in a containment vessel; metering a
desired amount of liquid to be dispensed from the containment
vessel to the electrohydrodynamic apparatus; dispensing the liquid
from the containment vessel to an electrohydrodynamic apparatus;
electrically actuating the electrohydrodynamic apparatus to
aerosolize the liquid; treating the aerosolized liquid to modify an
electrical charge imparted to the aerosolized liquid by the
electrohydrodynamic apparatus; and enclosing the containment vessel
and electrohydrodynamic apparatus within a cordless housing of such
size that it can be held in a user's one hand, the housing
including an exit opening for directing the aerosol to the user's
mouth. The electrical actuation step may be initiated by a user's
inhalation of breath.
[0029] Another preferred embodiment of the pulmonary aerosol
delivery device comprises a housing of such size that it can be
held in a user's one hand, the housing having an exit opening for
directing the aerosol to the user's mouth and including therein, a
dispensing system for containing the liquid to be aerosolized and
delivering it to an apparatus for aerosolizing the liquid; an
apparatus for aerosolizing the liquid and delivering the aerosol to
the exit opening; and a power supply system for providing
sufficient voltage to the aerosolizing apparatus to aerosolize the
liquid. The apparatus for aerosolizing the liquid comprises a
plurality of spray sites each having a tip end, the spray sites
cooperating with a charge source to result in an
electrohydrodynamic spray from at least one tip end, a plurality of
discharge electrodes downstream of the tip ends, and a plurality of
reference electrodes downstream of the plurality of discharge
electrodes.
[0030] The invention also encompasses an apparatus for aerosolizing
a liquid. In one preferred embodiment, the aerosolizing apparatus
comprises a plurality of spray sites each having a tip end, the
spray sites cooperating with a charge source to result in an
aerosolized spray from at least one tip end, a plurality of
discharge electrodes downstream of the tip ends, and a plurality of
reference electrodes downstream of the plurality of discharge
electrodes. The apparatus also may include a charge source for
charging the spray sites sufficiently to result in an
electrohydrodynamic spray from at least one tip end.
[0031] The plurality of discharge electrodes and the plurality of
reference electrodes may be oriented toward the aerosolized spray
and particularly may be oriented radially toward the aerosolized
spray. Preferably, the plurality of discharge electrodes are spaced
equidistant from one another and the plurality of reference
electrodes are located in the interstices between the discharge
electrodes.
[0032] The aerosolizing apparatus also may include a dielectric
material between the plurality of discharge electrodes and the
plurality of reference electrodes. The reference electrodes may
extend through slots provided in the dielectric material.
[0033] Preferably, at least one of the plurality of spray sites has
a sufficient electric field strength that a net electrical charge
is imparted to the surface of a liquid flowing over the spray site
such that the surface charge initially balances the surface tension
of the liquid to cause the liquid to form a cone and eventually
overcomes the surface tension of the liquid in the region of the
tip of the cone to generate a thin jet of liquid that breaks into
aerosolized droplets of respirable size. At least one of the
plurality of discharge electrodes may have a sufficient electric
field strength to substantially neutralize a charge on the
aerosolized droplets generated by the spray site.
[0034] The tip ends of the plurality of spray sites may be oriented
vertically downward. Preferably, the plurality of spray sites are
arranged in a generally circular pattern and are spaced equidistant
from one another. The tip end of at least one of the plurality of
spray sites may be chamfered. Also, the exterior of at least one of
the plurality of spray sites may be coated with a low surface
energy coating.
[0035] Mother preferred aerosolizing apparatus comprises a tubular
base having a generally circular cross-section, a plurality of
spray sites each having a tip end extending axially into a first
end of the base, the spray sites cooperating with a charge source
to result in an aerosolized spray from at least one tip end, a
plurality of discharge electrodes each connected to the interior of
the base downstream of the spray sites, and a plurality of
reference electrodes each connected to the interior of the base
downstream of the plurality of discharge electrodes. The apparatus
may further include a charge source for charging the spray sites
sufficiently to result in an electrohydrodynamic spray from at
least one tip end.
[0036] Preferably, the plurality of discharge electrodes and the
plurality of reference electrodes arc oriented toward the
aerosolized spray. The plurality of discharge electrodes may be
located in the area of the tip ends of the plurality of spray
sites.
[0037] In the above-described aerosolizing apparatus, at least one
of the plurality of spray sites preferably has a sufficient
electric field strength that a net electrical charge is imparted to
the surface of a liquid flowing over the spray site such that the
surface charge initially balances the surface tension of the liquid
to cause the liquid to form a cone and eventually overcomes the
surface tension of the liquid in the region of the tip of the cone
to generate a thin jet of liquid that breaks into aerosolized
droplets of respirable size. At least one of the plurality of
discharge electrodes may have a sufficient electric field strength
to substantially neutralize a charge on the aerosolized droplets
generated by the spray site.
[0038] The plurality of reference electrodes and the plurality of
discharge electrodes may extend radially inwardly from the interior
of the base. The plurality of discharge electrodes preferably are
spaced equidistant from one another and the plurality of reference
electrodes are located in the interstices between the discharge
electrodes.
[0039] The aerosolizing apparatus also may include a dielectric
material within the base between the discharge electrodes and the
reference electrodes. Preferably, the reference electrodes extend
through slots provided in the dielectric material.
[0040] The tip ends of the plurality of spray sites provided in the
aerosolizing apparatus preferably are oriented vertically downward.
The plurality of spray sites may be arranged in a predetermined
pattern, and particularly in a generally circular pattern.
[0041] In yet another preferred embodiment, the aerosolizing
apparatus comprises a generally circular base plate having upper
and lower surfaces, a plurality of spray sites arranged in a
circular pattern along the perimeter of the lower surface of the
base plate, each of the spray sites having a base end mounted to
the base plate and a tip end, the spray sites cooperating with a
charge source to result in an aerosolized spray from at least one
tip end, a skirt extending downward from the base plate, a
plurality of discharge electrodes each extending from the skirt
downstream of the spray site tip ends; a plurality of reference
electrodes each extending from the skirt downstream of the
discharge electrodes, and a dielectric material between the
plurality of discharge electrodes and the plurality of reference
electrodes. The dielectric material may be a discrete member
provided within the skirt or the skirt may be comprised of a
dielectric material. The aerosolizing apparatus also may include a
charge source for charging the spray sites sufficiently to result
in an electrohydrodynamic spray from at least one tip end.
[0042] The plurality of reference electrodes may be positioned in
interstices between the discharge electrodes. Preferably, the
plurality of discharge electrodes are spaced equidistant from one
another with the plurality of reference electrodes are located in
the interstices between the discharge electrodes. The reference
electrodes may extend through slots provided in the dielectric
material.
[0043] In the above-described aerosolizing apparatus, at least one
of the plurality of spray sites preferably has a sufficient
electric field strength that a net electrical charge is imparted to
the surface of a liquid flowing over the spray site such that the
surface charge initially balances the surface tension of the liquid
to cause the liquid to form a cone and eventually overcomes the
surface tension of the liquid in the region of the tip of the cone
to generate a thin jet of liquid that breaks into droplets of
respirable size. At least one of the plurality of discharge
electrodes may have a sufficient electric field strength to
substantially neutralize a charge on the aerosolized droplets
generated by the spray site.
BRIEF DESCRIPTION OF THE DRAWINGS
[0044] These and further objects of the invention will become
apparent from the following detailed description.
[0045] FIG. 1 is a perspective view of a device of the present
invention with a top portion of the housing removed.
[0046] FIG. 2 is an exploded view of the device of FIG. 1.
[0047] FIG. 3A is a detail view of a preferred nozzle useful in the
device of the present invention.
[0048] FIG. 3B is a bottom view of the nozzle of FIG. 3A.
[0049] FIG. 3C is a cross-sectional view of the nozzle of FIG. 3B
along line A-A.
[0050] FIG. 4 is a state diagram showing the relationships among
the operational states of an embodiment of the device of the
present invention.
[0051] FIG. 5 is a side elevational view of a containment vessel
and metering system useful in the device of the present
invention.
[0052] FIG. 6 is a cross-sectional view of the containment vessel
and metering system of FIG. 5 along line B-B.
[0053] FIG. 7 is a cross-sectional view of the containment vessel
and metering system of FIG. 5 along line C-C.
DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS
[0054] The invention described here provides a compact, convenient
apparatus for delivering an aerosolized liquid having therapeutic
properties to a user's lungs. The hand-held pulmonary drug delivery
device efficiently aerosolizes a therapeutic liquid into droplets
of respirable size and administers a clinically relevant dose of a
variety of therapeutic liquids to a user.
[0055] Liquids amenable to aerosolization by electrohydrodynamic
spraying generally are characterized by particular electrical and
physical properties. Without limiting the scope of the invention,
liquids having the following electrical and physical
characteristics permit optimum performance by the device and method
to generate a clinically relevant dose of respirable particles
within a few seconds. The surface tension of the liquid typically
is in the range of about 15-50 dynes/cm, preferably about 20-35
dynes/cm, and more preferably about 22-33 dynes/cm. Liquid
resistivity typically is greater than about 200 ohm-meters,
preferably greater than about 250 ohm-meters, and more preferably
greater than about 400 ohm-meters. The relative electrical
permittivity typically is less than about 65, preferably less than
about 45. Liquid viscosity typically is less than about 100
centipoise, preferably less than about 50 centipoise. Although the
above combination of characteristics allows optimum performance, it
may be possible to effectively spray liquids with one or more
characteristics outside these typical values using the device and
method of the invention. For example, certain nozzle configurations
may allow effective spraying of less resistive (more conductive)
liquids.
[0056] Therapeutic agents dissolved in ethanol generally are good
candidates for electrohydrodynamic spraying because the ethanol
base has a low surface tension and is nonconductive. Ethanol also
is an antimicrobial agent, which reduces the growth of microbes
within the drug formulation and on the housing surfaces. Other
liquids and solvents for therapeutic agents also may be delivered
using the device and method of the invention. The liquids may
include drugs or solutions or microsuspensions of drugs in
compatible solvents.
[0057] As described above, the electrohydrodynamic apparatus
aerosolizes the liquid by causing the liquid to flow over a region
of high electric field strength, which imparts a net electric
charge to the liquid. In the present invention, the region of high
electric field strength typically is provided by a negatively
charged electrode within the spray nozzle. The negative charge
tends to remain on the surface of the liquid such that, as the
liquid exits the nozzle, the repelling force of the surface charge
balances against the surface tension of the liquid, forming a
Taylor cone. The electrical force exerted on the liquid surface
overcomes the surface tension at the tip of the cone, generating a
thin jet of liquid. This jet breaks into droplets of more or less
uniform size, which collectively form a cloud.
[0058] The device produces aerosolized particles of respirable
size. Preferably, the droplets have a diameter of less than or
equal to about 6 microns, and more preferably, in the range of
about 1-5 microns, for deep lung administration. Because many
formulations are intended for deep-lung deposition, at least about
80% of the particles preferably have a diameter of less than or
equal to about 5 microns for effective deep lung administration of
the therapeutic agent. The aerosolized droplets arc substantially
the same size and have near zero velocity as they exit the
apparatus.
[0059] The range of volumes to be delivered is dependent on the
specific drug formulation. Typical doses of pulmonary therapeutic
agents are in the range of 0.1-100 .mu.L. Ideally, the dose should
be delivered to the patient during a single inspiration, although
delivery during two or more inspirations may be acceptable under
particular conditions. To achieve this, the device generally must
be capable of aerosolizing about 0.1-50 .mu.L, and particularly
about 10-50 .mu.L, of liquid in about 1.5-2.0 seconds. Delivery
efficiency is also a major consideration for the pulmonary delivery
device so liquid deposition on the surfaces of the device itself
should be minimal. Optimally, 70% or more of the aerosolized volume
should be available to the user.
[0060] The hand pulmonary delivery device is cordless, portable,
and small enough to be held and operated with one hand. Preferably,
the device is capable of delivering multiple daily doses over a
period of at least 30 days without requiring a refill or other user
intervention.
[0061] The pulmonary delivery device 10 of the present invention,
shown in FIGS. 1 and 2, includes a housing 12 sized so that it can
be held in a user's hand. The housing 12 has an exit opening 14 for
directing the aerosol to the user's mouth. The housing 12 encloses
a dispensing system 20 for containing the liquid to be aerosolized
and delivering it to an electrohydrodynamic apparatus 30, an
electrohydrodynamic apparatus 30 for aerosolizing the liquid and
delivering the aerosol to the exit opening 14, and a power supply
50 for providing a sufficient voltage to the electrohydrodynamic
apparatus 30 to aerosolize the liquid. The device 10 may include a
control circuit 60 that communicates with the dispensing system 20,
the electrohydrodynamic apparatus 30, and the power supply 50.
[0062] Dispensing System. The dispensing system 20 holds the supply
of the liquid to be aerosolized and delivers a single dose of the
liquid to the electrohydrodynamic apparatus 30. The dispensing
system 20 generally delivers the liquid to a single position in the
nozzle 32 of the electrohydrodynamic apparatus 30. If the nozzle 32
has multiple spray sites 34 (shown in FIG. 3A), the nozzle 32
typically performs the function of distributing the liquid to the
various spray sites 34, although it also would be possible for the
dispensing system 20 to perform this function.
[0063] The dispensing system 20 includes a containment vessel 22
for containing and maintaining the integrity of the therapeutic
liquid. The containment vessel 22 may take the form of a holder for
a drug enclosed in single dose units, a plurality of sealed
chambers each holding a single dose of the drug, or a vial for
enclosing a bulk supply of the drug to be aerosolized. Bulk dosing
generally is preferred for economic reasons except for liquids that
lack stability in air, such as protein-based therapeutic
agents.
[0064] The vessel 22 preferably is physically and chemically
compatible with the therapeutic liquid including both solutions and
microsuspensions and is liquid- and air-tight. Vessel 22 may be
treated to give it antimicrobial properties to preserve the purity
of the liquid contained in the vessel 22. The material of the
vessel and any antimicrobial coating applied thereto are
biocompatible.
[0065] The vessel 22 may be capable of maintaining the sterility of
a sterile liquid placed therein. Preferably, vessel 22 is
aseptically filled and hermetically sealed to maintain sterility of
the therapeutic liquid during its shelf life. This maybe
accomplished, for example, using a "form, fill, seal" process or a
"blow, fill, seal" process. The vessel 22 remains sealed until it
is connected to the dispensing system 20 prior to the first use.
After the first use, seals or check valves between the vessel 22
and the dispensing system 20 and unidirectional flow of the liquid
maintain the integrity of the liquid in the vessel 22. In a
preferred embodiment, vessel 22 is an easily collapsible thin
pouch. The shape, collapsibility and outlet orifice of the pouch
allow maximum withdrawal of a drug.
[0066] When bulk dosing is used, the dispensing system 20 includes
a dose metering system 24 for withdrawing a predetermined, precise
dose of the liquid from the containment vessel 22 and delivering
this dose at a controlled flow rate to the nozzle 32 of the
electrohydrodynamic apparatus 30. Preferably, the dose metering
system 24 is capable of consistently metering the desired dose to
within at least about .+-.10%, and more preferably .+-.5%, of the
set dose volume.
[0067] The dose metering system 24 may comprise a piezoelectric
pump (including, but not limited to, the pump described in
copending U.S. patent application Ser. No. 220,310 titled
"Piezoelectric Micropump," filed Dec. 23, 1998), a manually or
mechanically operated piston pump, or a pressurized gas. For
example, a small motor may be coupled to gears to rotate a screw
that in turn depresses the plunger of a vial such as those
customarily used for insulin.
[0068] FIGS. 5-7 show a dispensing system 100 including a
containment vessel 96 coupled with a manually actuated piston pump
metering system 98. The pump 98 is actuated by depressing a button
102 that protrudes through the housing. Depressing the button 102
compresses button spring 106 against chamber housing 108, forcing
the housing 108 downward. As the chamber housing 108 moves
downward, liquid is forced from the chamber 112 below the housing
108 through capillary tube 114 and outlet check valve 116. The
button 102 is held until chamber housing 108 is fully lowered.
[0069] When chamber housing 108 is fully lowered and the button 102
is released, the now compressed chamber housing spring 118, located
below chamber housing 108, forces the chamber housing 108 upward.
The vacuum formed in the chamber 112 as the housing 108 rises draws
liquid into the chamber 112 from the containment vessel 96 through
needle 120 and chamber check valve 122. Chamber housing 108
continues to rise until it reaches dose adjuster stop 124. The
position of the dose adjuster 130 relative to the piston housing
126 limits the travel of the chamber housing 108, which controls
the chamber volume (dose). The stop 124 may include a threaded or
other suitable adjustment 128. Flow rate may be controlled by the
spring rates of springs 106, 118. The piston 110 and check valves
116, 122 provide unidirectional liquid flow.
[0070] Returning to FIGS. 1 and 2, the pump or other metering
system 24 may be formed from injection molded plastic or other
suitable material. Preferably, this material will have
antimicrobial properties or be coated with an antimicrobial
coating. The material and antimicrobial coating of the metering
system 24 are biocompatible. Passages within the metering system 24
that may contact liquid are compatible with the liquid,
biocompatible, and of a design and size compatible with solutions
and microsuspensions. The metering system 24 is actuated by the
control circuit 60 as described below.
[0071] The material of the metering system 24 is compatible with
sterilization techniques. Preferably, the metering system 24 will
be packaged in a sterile condition to provide a sterile shelf life.
As described above, after the first use, seals such as check valves
116, 122 and unidirectional liquid flow maintain the integrity of
the liquid in the passages of the metering system 24.
[0072] The metering system 24 and control circuit 60 may cooperate
to provide a dose counting function. The device 10 may include a
dose display showing the doses administered and the doses
remaining. The dispensing system 20 (and particularly the metering
system 24) may cooperate with the control circuit 60 to limit the
delivery of the liquid to predetermined times or intervals.
[0073] Electrohydrodynamic Apparatus. The electrohydrodynamic
apparatus 30 functions by electrically charging the liquid to be
aerosolized until the repulsive force of the charge overcomes the
force of surface tension, causing the bulk liquid to be broken into
minute droplets. The electrohydrodynamic apparatus 30' provides a
sufficient volumetric flow rate of liquid so that a desired amount
of a therapeutic liquid may be delivered during a user's inhalation
of a single breath. This flow rate has not been achieved before in
a hand-held inhaler 10. Preferred nozzles achieve aerosolization of
particles in the respirable range at high flow using multiple spray
sites in a compact configuration suitable for use in a hand-held
device, with minimal wetting losses and arcing.
[0074] In electrohydrodynamically-generated aerosols, it generally
is known that
D.sub.p.sup.OCQ.sup.1/3
[0075] where D.sub.p is the particle diameter and Q is flow rate.
While spray tip geometry, its association with other electrodes,
and the formulation characteristics affect the effective flow rate,
stable Taylor cones and a high fraction of respirable particles can
be maintained only if the flow rate per spray site is about 1
.mu.L/sec or less. The number and configuration of spray sites
therefore determines the maximum flow rate, i.e., the maximum
amount of therapeutic liquid that may be delivered during a user's
inhalation of a single breath.
[0076] A direct correlation between the mass median diameter (MMD)
of the aerosol and the flow rate also has been observed. In
general, if 80% or more of the particles are to have a diameter of
5 microns or less (as measured using either a Malvern Instruments
Mastersizer.RTM. S or Model 2600 particle size spectrum analyzer),
the flow rate per site likely will be less than or equal to about 1
.mu.L/sec, more likely less than or equal to about 0.5 .mu.L/sec.
It is expected that delivery to a user's lungs of particles having
this size distribution maybe achieved at higher flow rates per site
due to evaporation of the particles during delivery, particularly
when the liquid includes a volatile solvent such as ethanol.
[0077] The device 10 is capable of spraying a wide range of
formulations including liquid pharmaceutical solutions and
suspensions. Small adjustments in the number of spray sites,
volumetric flow rate, or the magnitude of the operating voltages
may be required to tailor the device 10 to a specific formulation,
but the basic design of the device 10 is expected to remain
constant.
[0078] As shown in FIGS. 3A, 3B, and 3C, the electrohydrodynamic
apparatus 30' includes a nozzle 32', at least one electrical
reference electrode 36, and at least one neutralizing or discharge
electrode 38. The nozzle 32' may include a base plate 40 and a
skirt 42 extending downwardly from the base 40. Preferably, the
nozzle 32' is located along the axis of a generally cylindrical
nozzle housing.
[0079] A dielectric material 44 may be recessed within the skirt
42, as shown in FIG. 3A. Alternatively, the skirt 42 may be
comprised of a dielectric material and the dielectric member 44
deleted. A flow director 37 may be provided as shown in FIG. 3C to
aid in moving air past the nozzle 32 to sweep away the aerosol as
described more fully in U.S. application Ser. No. 130,873, filed
Apr. 23, 1999, which is filly incorporated herein by reference. The
flow director 37 may be a discrete element or integral with the
skirt 42.
[0080] The nozzle 32' includes a plurality of spray sites 34
oriented to deliver the spray toward a user's mouth, and
particularly downstream toward the exit opening 14 of the housing
12 of a pulmonary aerosol delivery device 10. Preferably, the spray
sites 34 are oriented vertically downward when the device is in
use.
[0081] Any spray site 34 that supports formation of a Taylor cone
may be used, such as capillary tubes, ball tips and conical tips.
The spray sites 34 may be formed integrally with the nozzle 32',
e.g., by machining or pressing. The nozzle 32' typically performs
the function of distributing the liquid from the dispensing system
20 to the individual spray sites 34.
[0082] The preferred number and arrangement of spray sites 34
provided within the nozzle 32' may depend on the particular
therapeutic agent or class of agents. Therapeutic agents that
require high flow rates (i.e., up to about 50 .mu.L in about 2
seconds) require multiple spray sites 34. When multiple spray sites
34 are used, the sites 34 should be positioned to reduce
interaction among the spray sites 34 and between the spray sites 34
and the housing 12. For spray sites 34 oriented to spray vertically
downward, circular arrangements of spray sites 34 are
preferred.
[0083] In a preferred 17-spray site nozzle 32', the spray sites 34
may be parallel capillary tubes 46 extending from base 40. The
tubes 46 are integral with a sprayer assembly having a single inlet
port (not shown in the drawings). Thus, the 17-spray site nozzle
32' has built-in manifolding to distribute the liquid to the tubes
46, providing a nearly "instant" on and off feature when the
metering system 24 is actuated and deactuated. The tube length may
vary but preferably is at least about 0.003 inch.
[0084] The tubes 46 preferably arc arranged in a circular pattern
and spaced an equal distance from one another. The diameter of the
circle is selected to be large enough to minimize the tendency to
form a single large Taylor cone among the spray sites 34. For
example, the circle may have a diameter of approximately 0.4-0.6
inches in a nozzle 32' intended for use in a hand-held device 10.
The tubes 46 preferably are positioned close to the edge of the
base 40. This reduces both interactions among the tube tips 48 and
electrostatic shielding of the tips 48 by the portion of the base
plate 40 that extends radially beyond the circle of the tips 48,
which allows spraying of liquids with greater conductivities at a
smaller potential than if the tips 48 were shielded. The preferred
arrangement and position of spray sites 34 may vary for nozzles 32'
with different types or numbers of spray sites 34.
[0085] Droplets having a neutral charge are preferred for pulmonary
delivery. The electrohydrodynamic apparatus 30 therefore includes a
charge neutralizer, in the form of a neutralizing or discharge
electrode 38. The discharge electrode 38 provides a stream of ions
having an opposite polarity from those in the aerosolized droplet
cloud 59. The charged droplets engage the oppositely charged ions
to form droplets having a neutral, or at least Less polar, charge.
Preferably, at least one of the plurality of discharge electrodes
has a sufficient electric field strength to substantially
neutralize a charge on the aerosolized droplets generated by a
spray site. A dielectric material may be placed between the spray
sites 34 and the discharge electrode 38 to modify the electric
field and/or reduce the current draw of the electrohydrodynamic
apparatus 30.
[0086] Discharge electrodes 38 aimed toward the sprayer axis may be
positioned around the nozzle 32' downstream of the tip ends,
preferably with the discharge electrodes 38 oriented radially
inwardly and spaced equidistant from one another in the area of the
tube tips 48. The number and position of neutralizing electrodes 38
may vary with the number and configuration of spray sites 34. Eight
discharge electrodes 38 in the position illustrated have produced
satisfactory results in the 17-spray site nozzle 32'.
[0087] A plurality of reference electrodes 36 is arranged
downstream of the discharge electrodes 38, best shown in FIG. 3C,
with the reference electrodes 36 aimed toward the axis. In a
preferred nozzle 32', the reference electrodes 36 are oriented
radially inwardly. The reference electrodes 36 may extend through
slots in the dielectric material 44 below the discharge electrodes
38. Preferably, the number of reference electrodes 36 is equal to
that of the discharge electrodes 38 such that the reference
electrodes 36 may be positioned between and downstream of the
discharge electrodes 38, best shown in FIG. 3B.
[0088] The reference electrodes 36 are maintained at a potential
between that of the spray tip ends 48 and the discharge potential,
which may but need not be true ground. It may be possible to obtain
satisfactory results using reference electrodes that define a
continuous ring rather than a plurality of individual reference
electrodes 36. However, use of a plurality of reference electrodes
36 rather than a continuous ring and the interstitial positioning
of the reference electrodes 36, provides superior resistance to
wetting. The interstitial reference electrodes 36 also reduce
arcing by virtually eliminating a liquid conductive path between
the nozzle tips 48 and the reference electrodes 36. A current
limiting resistor may be used to further control arcing.
[0089] The spray sites cooperate with a charge source sufficient to
result in an electrohydrodynamic spray from at least one tip end.
Preferably, each spray site 34 in the 17-spray site nozzle 32'
produces a Taylor cone and forms an aerosol jet. The spray angle is
not strictly downward but includes a radial component as a result
of electrostatic interaction among the tube tips 48 which causes
the sprays to repel one another. The radial component of the spray
angle is not great enough to result in unacceptable losses from
wetting of the housing 12. Wetting may be reduced by the use of a
dielectric or some other material to modify the electric field. As
described above, the skirt 42 may also be designed to control
airflow streaming past the nozzle to control deposition of aerosol
droplets and to stabilize the Taylor cone. Preferably, the edges of
the tubes 46 are chamfered to improve Taylor cone formation.
[0090] A 17-spray site nozzle 32' with the above-described
discharge configuration is capable of aerosolizing particles in the
respirable range at a flow rate of up to about 20 .mu.L/sec as
measured with either a Malvern Instruments Mastersizer.RTM. S or
Model 2600 particle size spectrum analyzer. The nozzle 32' is
capable of spraying an aerosol of respirable particle size with a
tight distribution at lower flow rates (7-10 .mu.L/sec). At higher
flow rates, a distinct knee may be observed at the high end of the
distribution.
[0091] The 17-spray site nozzle 32 was tested in a delivery system
consisting of a mouthpiece and a source of continuous controlled
air flow. A 1% Triamcinolone formulation (in 80% ethanol/20%
polyethylene glycol 300) was aerosolized at a flow rate of 15
.mu.L/sec, with as particle size distribution of 4.9 microns MMD as
measured by a Malvern Instruments Mastersizer.RTM. S particle size
spectrum analyzer. At 10 .mu.L/s, the distribution was
monodispersed with a MMD of 3.7 microns. At 7 .mu.L/s, the MMD was
less than 3 microns, with 80% or more of the particles having a
diameter less than 5 microns. Similar results were obtained with a
1% Albuterol free base formulation (in 80% ethanol/20% polyethylene
glycol 300). Measurements with an Anderson cascade impactor
confirmed all of the results achieved with the Mastersizer.RTM.
analyzer.
[0092] Wicking losses, which may occur even when the electric field
is off, must be controlled to allow both sustained operation of the
device and delivery of the expected dose of the therapeutic liquid
to a user. If uncontrolled, wicking may result in submersion of the
nozzle and cessation of spray activity. Wicking losses are thought
to result from the low surface tensions of the liquid formulations
(as low as about 15 dynes/cm). To control wicking, the outer
diameter of the spray sites 34 or other surfaces of interest may be
coated with a low surface energy coating. Applying the critical
surface energy concept pioneered by Zisman, a coating having a
solid surface energy well below 15 dynes/cm should be selected.
Fluorocarbon coatings having surface energies lower than that of
Teflon (about 18 dynes/cm) are believed to be suitable for such
use. When the tubes 46 of the 17-spray site nozzle 32' are coated
with a low surface energy coating, the nozzle 32' is capable of
spraying over 3,500 microliters of liquid with minimal accumulation
at the base 40 of the tubes 46.
[0093] The conducting (electrode) components 34, 36, 38,40 of the
nozzle 32' may be fabricated from 303 or 316 stainless steel. Other
suitable conductors also may be used as long as the material is
compatible with the liquid to be sprayed, is resistant to
corrosion, and does not deteriorate during the expected life of the
device. The nonconducting components may be formed from machined
Delrin, Lexan, or other suitable material.
[0094] Power Supply System. Electrospray nozzles 32 rely on high
voltage to charge the formulation as it exits the spray site 34.
The power supply system 50 is capable of providing a voltage
capable of actuating the electrohydrodynamic apparatus 30 to
produce an aerosol having desired characteristics with a minimum of
arcing. Voltages in the range of about 2,600-6,000 V or more at
very low amperages (less than about 100 microamperes, and
preferably less than about 50 microamperes) generally appear to
yield satisfactory results, although voltages outside this range
may be suitable depending on the size of the device 10 and the type
of electrohydrodynamic spray nozzle 32' used. The minimum voltage
generally increases, for example, as the number of spray sites 34
increases. A nozzle 32 with the simplest geometry (i.e., four
electrodes 38 and a single spray site 34) generally requires a
minimum voltage of about 2,600 V. Typical voltages for nozzles 32'
used in the present device 10 are in the range of about 4,000-5,000
V. Voltages above about 6,000 V generally are difficult to achieve
in a hand-held device using conventional power supplies, but higher
voltages (in the range of about 2,600-20,000 V) may be usable with
power supply improvements.
[0095] The power supply 50 includes a high voltage DC to DC
converter, preferably a transformer based switching converter. The
DC to DC converter is connected to a battery 54, which may be
included in the power supply 50. Alternatively, the battery 54 may
be incorporated into the containment vessel 22 so that the supply
of therapeutic liquid and the battery 54 may be replaced
simultaneously.
[0096] Lithium batteries are preferred because of their energy
density to volume ratio, their long shelf life and their voltage
stability over their operating life. Other batteries such as
alkaline batteries and rechargeable nickel metal hydride batteries
(e.g., NiCad batteries) also may be used. The high voltage power
supply 50 preferably has dual outputs with one output at positive
DC voltage and the second output at negative DC voltage. The supply
50 also has a reference output, nominally at ground potential, that
is common to both the positive and negative outputs. The
anticipated output voltage range is .+-.5000 VDC, measured with
respect to the reference output. Each of the dual outputs
preferably has the same tolerance and operates to within about 2%
of the nominal output voltage. The maximum allowable ripple for
each of the dual outputs preferably is about 1%, measured with
respect to the reference output.
[0097] The power supply 50 preferably can accept an input voltage
over the range of about 6-9 VDC and generate a maximum output
current for each of the dual outputs of about 100 microamperes. The
supply 50 should be able to supply this maximum output current on
both outputs simultaneously and continuously. The power supply 50
should not be damaged in any way if the outputs (one or both) are
shorted to ground or shorted together for a duration of less than
one minute and should resume normal operation if the short on the
output is removed.
[0098] Practical limitations are imposed on the physical size of
both the high voltage power converter and the battery 54 in a
cordless hand-held unit 10. While commercially available DC-to-DC
converters readily can accept input voltages of 12 or 24 VDC and
generate outputs of 10 kV and higher, these converters are large
and would be nearly impossible to package into a hand-held
pulmonary delivery device. The voltage output of smaller converters
often is limited to 3-6 kV. The battery size limits the energy
available to the high voltage converter. To maintain the desired
operating life of at least thirty days with multiple doses per day,
operation of the nozzle 32' requires no more than about 1.0 watts
and preferably no more than about 0.5 watts.
[0099] For the device 10 of the present invention, the target upper
limit on the magnitude of the operating voltages for the nozzle 32'
is 5 kV. Because the package size preferably is as small as is
reasonably possible, the maximum physical envelope of the high
voltage power converter preferably is about
2.0".times.0.7".times.0.6"(50.8 mm.times.17.8 mm.times.15.24 mm)
and the maximum weight of the high voltage power converter
preferably is about 30 grams (1 ounce).
[0100] The power supply 50 preferably is fully encapsulated using
glass-filled epoxy or an equivalent conformal coating having the
dielectric strength to allow tight packaging of the high voltage
conversion circuitry into a small volume. Any wires emanating from
the power supply modules 50 will have sufficient insulation to meet
the requirements of EN6060 I and UL2601 standards.
[0101] Control Circuit. The device 10 includes a control circuit 60
communicating with the dispensing system 20, the
electrohydrodynamic apparatus 30, and the power supply system 50.
The power supply system 50 may be integrated into the control
circuit 60. Preferably, a single integrated circuit 60 such as a
programmable logic device (PLD) controls all the functions of the
device 10, which may include metering control, actuating devices,
high voltage control, power save feature, status indicators, user
inputs, dose counting and breath sensing. It is expected that the
integrated circuit 60 can control all desired functions without
software, but the device 10 also may perform effectively with a
control circuit 60 including software.
[0102] The control circuit 60 includes an actuation device for
initiating the flow of aerosolized liquid. The actuation device may
include a sensor (not shown in the drawings) for detecting a user's
inhalation of breath that cooperates with the electrohydrodynamic
apparatus 30 to initiate the aerosol flow. For example, the breath
sensor may be a flapper switch, a pressure transducer, or a
piezoelectric or other air motion or air velocity detector.
Alternatively, the actuation device may comprise a manual actuator
64 on the exterior of the housing 12.
[0103] In the manually-actuated device 10 (i.e., a device without a
breath sensor), the control circuit 60 includes an On/Off button 62
and a Dosing button 64 or equivalent devices on the exterior of the
housing 12. These actuators 62, 64 preferably are actuated easily
by users with limited abilities.
[0104] The On/Off button 62 initially causes the control circuit 60
to actuate the high voltage supply 50, a shut-down timer and a
self-priming feature. Actuation of the On/Off button 62 may be
indicated by illumination of a power status indicator. The Dosing
button 64 actuates the metering 24 or dispensing 22 control. Manual
operation of the device 10 therefore requires two inputs from the
user (or person assisting the user). The On/Off and Dosing buttons
62, 64 must be pressed in sequence for the dose to be delivered. If
the buttons 62, 64 are pressed in the wrong order the device 10
will turn on but no drug will be delivered. Multiple actuations of
either button 62, 64 within a specified interval are treated as a
single actuation.
[0105] The operation of the device 10 may be accomplished by a
series of timers and clocks that are inputs for a state machine.
The device 10 steps from "state" to "state" as a result of clocked
inputs, with the outputs determined by the operational "state" then
in effect. The state machine may be implemented in a PLD control
circuit 60 such that control signals to the various subsystems
originate from the PLD 60.
[0106] In one potential control paradigm for a manually-actuated
device 10, the state machine consists of five states as shown in
FIG. 4. The Off or Power Save state 66 is the baseline state for
the control system 60 when the device 10 is not functioning. In
this state 66, the high voltage supply 50 is turned off and the
current thaw from the battery 54 is minimal.
[0107] The Warm-Up state 68 is entered when the user presses the
On/Off button 62 and the drug vessel 22 is not empty. A status LED,
visible on the exterior of the housing 12, illuminates green. The
high voltage supply 50 and the shut down timer are turned on in
this state 68. Self-priming, which causes the liquid to fill the
residual nozzle volume and be delivered to the spray sites 34 so
aerosolization can begin immediately upon actuation of the Dosing
button 64 or a breath sensor, also is turned on in the Warm-Up
state 68. The shut down timer ensures that if the Dosing button 64
is not pressed within a specified time after entering the Warm-Up
state 68, for example, about 12 seconds, the device 10 will return
to the Off state 66. A purge cycle may be carried out before the
device 10 returns to the Off state 66 to expel from the device 10
the unused liquid supplied to the electrohydrodynamic apparatus 30
during self-priming.
[0108] Actuation of the Dosing button 64 while the device 10 is in
the Warm-Up state 68 (e.g., within about twelve seconds of pressing
the On/Off button 62), causes the control system 60 to enter the
Breathe state 70. Actuation of the Dosing button 64 is associated
with a flashing green breath prompt indicator followed by the solid
green indicator display during the breath hold period. The device
10 will not respond to actuation of the Dosing button 64 until the
previous dosing cycle is completed. The allowed interval between
doses may be preset to allow or prohibit administration of
sequential doses.
[0109] In the Breathe state 70, the metering control system 24 is
activated for approximately two seconds to deliver drug to the
nozzle 32. This causes the nozzle 32 to begin aerosolizing the drug
immediately. After about four seconds, the control system 60 exits
this state 70 and enters the Hold state 72. Once in the Hold state
72, the device 10 will wait about four additional seconds to allow
any remaining material on the nozzle 32 to be aerosolized before
entering the Finish state 74. (If a breath sensor is present, the
device enters the Finish state 74 if there is no signal from this
sensor after being in the Breathe state 72 for about one
second.)
[0110] Once the control system 60 enters the Finish state 74, the
high voltage supply 50 is turned off. If the device 10 includes a
purge cycle for emptying unused or residual liquid from the
electrohydrodynamic apparatus 30, this cycle may be actuated in the
Finish state 74. The control system 60 stays in the Finish state 74
until the run-time counter reaches about twenty seconds. Once the
run-time counter times out, all status indicators are turned off
and the control system 60 returns to the Off state 66.
[0111] As described above, the control circuit 60 may communicate
with and control the metering system 24 by PLD output in response
to actuation of the Dosing button 64. The control circuit 60 may
have a memory for storing dose information, which may then be
provided to the metering system 24. Drug dosing within the
hand-held device 10 can be implemented with a variety of mechanisms
such as those described above.
[0112] For a motor-driven metering system, the PLD activates the
motor for about the first two seconds of the Breathe state in the
dosing cycle. Dose volume is determined by the gearing of the motor
and the voltage that is applied to the motor. Both are held
constant in the current design and yield, for example, a 20 .mu.l
dose. For a piezoelectric micropump, the PLD output forms a pulse
train that is applied to the piezoelectric valves that make up the
pump. The timing within the pulse train provides the proper valve
actuation for pumping.
[0113] The high voltage power supply 50 maybe actuated by a simple
on/off function controlled by the PLD 60. The magnitude of the high
voltage output is determined by the design of the power supply 50
and cannot be altered by the user or clinician. In a preferred
embodiment, the high voltage supply 50 becomes active upon
actuation of the On/Off button 62. During a normal operating cycle
in which the Dosing button 64 is depressed and drug is delivered,
the high voltage supply 50 is active for about twenty seconds. If
the Dosing button 64 is not depressed, the high voltage power
supply 50 is deactivated after about twelve seconds.
[0114] The control circuit 60 preferably will include indicators to
display the device status, which may, for example, comprise LED
indicators. A preferred combination and arrangement of LEDs is
described. Other combinations and arrangements of indicators
(including indicators made from components other than LEDs) also
may be used to accomplish the same objectives.
[0115] A preferred embodiment includes a two-LED combination (not
shown in the drawings) in which one LED is a power status indicator
and the other is a breath prompt signal. The power status LED
preferably indicates a single color, preferably green. This
indicator follows the same operating cycle as the high voltage
power supply 50: the indicator is illuminated when the On/Off
button 62 is actuated and remains illuminated while the high
voltage power supply 50 is active, illumination of the power status
LED indicates that the device 10 is ready for normal operation.
[0116] The breath prompt LED preferably indicates each of three
operational states for the device 10: Breath; Hold Breath, and Unit
Empty. This may be accomplished, for example, using an LED that is
capable of flashing green, solid green, and solid yellow
indications. The flashing green is displayed when the device 10
enters in the Breathe state 70 and continues for about four
seconds. The flashing green alerts the user that the drug is being
delivered and that the user should breathe in deeply while the
flashing green is displayed.
[0117] The solid green indication appears after the flashing green
indication is complete and lasts about four seconds. The solid
green alerts users to hold their breath for a short time after
inhaling of the aerosolized liquid to promote retention of the
aerosol in the lungs for a long enough time for effective liquid
absorption.
[0118] The solid yellow indicator is illuminated any time the
device 10 is activated (e.g., by pressing the Dosing button 64)
after the last dose is delivered. The solid yellow indicates to the
user that the vessel 22 is empty and maintenance is required.
Preferably, dose status is controlled by a signal from a dose
counter. Dose counting may be implemented using the PLD 60 or other
means such as a mass or volume sensor in the vessel 22. When the
PLD 60 is used, the dose count is incremented upon completion of a
dosing cycle. When the dose count reaches a preset limit, the
device 10 indicates an empty vessel 22 by displaying the solid
yellow LED display and will no longer function. After the device is
serviced, the dose counter may be reset and normal operation cycles
may be resumed.
[0119] The control circuit 60 may have a memory for recording dose
information and/or dose history. The control circuit 60 may
communicate with metering system 24, for example, by sending dose
information stored in its memory to the metering system 24. The
metering system 24 in turn may send dose history information to the
control circuit 60 for storage in its memory.
[0120] The device 10 preferably includes a breath sensor to
determine if proper inhalation was occurring during spraying. The
PLD 60 may monitor the status of the breath sensor. If no breath is
sensed one second after the Dosing button 62 is actuated, the PLD
60 will signal the high voltage power supply 50 and the metering
system 24 to shut down and drug delivery will cease.
[0121] In a particularly preferred embodiment, the device 10 is
actuated by a user's breath rather than a Dosing button 64 to
optimize intake of the aerosol by a user. In this preferred
operational mod; the device 10 primes itself upon actuation of the
On/Off button 62 by moving liquid to the spray site tips 48 so that
drug delivery can begin immediately upon actuation of the Dosing
button 64. The flow of the aerosol is actuated by a user's
inhalation of breath, eliminating the need for the user to
coordinate his or her breathing with actuation of the device 10. To
accomplish this, the actuation device comprises a breath sensor
that cooperates with the electrohydrodynamic apparatus 30 to
initiate the aerosol flow. The sensor also may detect a multiple
breaths by a user and cooperate with the control circuit 60 to
display this on a multiple breath indicator. If desired, a manual
actuator such as Dosing button 64 may be provided in addition to
the breath sensor.
[0122] A lockout (not shown in the drawings) cooperating with a
keypad, smart ring, magnetic ring, or the like may be incorporated
into the control circuit 60 to prevent use by an unauthorized user.
The device 10 also may include a position sensor that prevents
operation of the device 10 unless the electrohydrodynamic apparatus
30 is in a predetermined (e.g., vertical) orientation.
[0123] The control circuit 60 may include a timer that cooperates
with the dispensing system 20 to limit the delivery of the liquid
to predetermined times or time intervals. The timer also may
provide a signal to alert the user, by a display or alarm, that a
dose is due.
[0124] Housing. The housing 12 preferably is constructed from a
durable, easily cleanable, nonconductive, biocompatible,
inexpensive material compatible with the liquid to be aerosolized,
such as polyethylene or polypropylene, although other suitable
materials also may be used. The material may be treated so that it
has antimicrobial properties or provided with a biocompatible
antimicrobial coating to assist in controlling the growth of
microorganisms in and on the housing.
[0125] Typically, the housing 12 has a generally cylindrical or
oblong shape that allows the electrohydrodynamic apparatus 30 to be
in a substantially vertical position during use, but other housing
shapes also may be used. The housing 12 preferably is streamlined
so it may be stored conveniently in a shirt pocket, purse, or other
small space.
[0126] The housing 12 defines an exit opening 14, generally
positioned on a lower side wall. The exit opening 14 may include a
mouthpiece 16 or collar extending from the housing 12 to assist in
directing the aerosolized liquid to the user's mouth. The
mouthpiece 16 may be formed integrally with the housing 12 or
provided as a separate piece that slides or pivots into position
when needed.
[0127] The housing 12 is molded or otherwise shaped so a user
easily may grasp the housing 12 and position it so that the exit
opening 14 is directed toward the user's mouth. Preferably, the
housing 12 has rounded edges so a user may grasp it comfortably.
Ridges may be provided on the housing 12 to guide the placement of
a user's fingers.
[0128] The device 10, including the housing 12 and the mouthpiece
16, must transport the maximum amount of aerosol droplets to the
user. Losses of aerosol droplets within the housing 12 will result
in delivery of a lower than expected dose of the therapeutic agent
to the user. The electrohydrodynamic apparatus 30 should be
positioned within the housing 12 to reduce wetting losses. With the
17-spray site nozzle 32', positions away from the back wall of the
elbow between the housing 12 and the mouthpiece 16 are preferred.
The 17-spray site nozzle 32' achieved transport efficiencies in the
range of about 76-93 percent with an average transport efficiency
of about 83 percent.
[0129] In addition to wicking losses, substantial losses may result
from droplet deposition on the mouthpiece walls. In the present
arrangement, the nozzle 32' sprays vertically downwards and the
spray must be turned through an angle between 45 and 90 degrees in
the mouthpiece 16 to reach the user. Droplet deposition on
mouthpiece walls as the spray turns through this angle tends to
result from the complex flow pattern in the bend that carries
droplets towards the walls (with large droplets impacting the wall
because of their inertia and small droplets diffusing to the wall
by fluid turbulence) and turbulence produced in the flow,
especially near the spray sites 34, which increases droplet
diffusion to the wall.
[0130] Losses from droplet deposition on the mouthpiece walls may
be controlled by careful design of the mouthpiece shape and airflow
dynamics through the mouthpiece 16. The interior of the housing 12
should be shaped to allow natural convection currents to aid in
moving the aerosol cloud out of the housing 12. An air inlet (not
shown in the drawings) may be provided in the housing 12 in the
area of the spray sites 34 to promote discharge of the aerosolized
particles. The inlet to the mouthpiece 16 should be sized to assist
in moving the spray around the bend and toward the exit opening
14.
[0131] Substantial losses from droplet deposition on or near the
electrodes also may occur. These losses may be controlled by nozzle
placement and geometry. The nozzles described above result in an
acceptable level of losses at or near the electrodes.
[0132] The pulmonary delivery device 10 of the present invention
may be either disposable or reusable. A disposable unit 10 may have
a battery 54 and containment vessel 22 filled with the applicable
therapeutic agent sealed within housing 12. The disposable unit 10
could provide, for example a 30-day supply of a therapeutic agent,
depending on such factors as the volume of therapeutic agent and
its stability. The disposable unit 10 may include a dose counter
with an indicator to signal that all doses have been expended.
[0133] A reusable unit 10 may be provided with an initial supply of
a therapeutic agent within the containment vessel 22 and a battery
54. The housing 12 may comprise at least two interlocking mating
segments so that it may be disassembled to refill the containment
vessel 22 or replace the battery 54. The battery 54 may be
incorporated into the vessel 22 for more convenient refills.
[0134] The reusable unit 10 also may include enhancements such as
electronic features. These features may include, for example, dose
reminder, dose counter and dose indicator. The unit 10 also may
include a lockout cooperating with a timer to prevent overdoses or
a lockout to prevent use by an unauthorized person.
[0135] Methods of Aerosol Administration. The invention also
includes a method for oral administration of an aerosolized liquid
therapeutic agent, which includes the steps of storing the liquid
in a containment vessel 22, dispensing the liquid from the
containment vessel 22 to an electrohydrodynamic apparatus 30, and
electrically actuating the electrohydrodynamic apparatus 30 to
aerosolize the liquid. The electrical actuation step may be
initiated by a user inhalation of breath.
[0136] The method also may include the steps of metering a desired
amount of liquid to be dispensed from the containment vessel 22 to
the electrohydrodynamic apparatus 30 and enclosing the containment
vessel 22 and electrohydrodynamic apparatus 30 within a cordless
housing 12 that can be held in a user's hand, the housing 12
including an exit opening 14 for directing the aerosol to the
user's mouth. The method of the present invention f may include the
step of neutralizing the electrical charge imparted to the
aerosolized liquid by the electrohydrodynamic apparatus 30.
[0137] The preferred embodiment of this invention can be achieved
by many techniques and methods known to persons who are skilled in
this field. To those skilled and knowledgeable in the arts to which
the present invention pertains, many widely differing embodiments
will be suggested by the foregoing without departing from the
intent and scope of the present invention. The descriptions and
disclosures herein are intended solely for purposes of illustration
and should not be construed as limiting the scope of the present
invention which is described by the following claims.
* * * * *