U.S. patent application number 10/601127 was filed with the patent office on 2005-01-27 for systems and methods for aerosolizing pharmaceutical formulations.
This patent application is currently assigned to Inhale Therapeutic Systems. Invention is credited to Alston, William W. JR., Bakshi, Aneesh, Clark, Andrew, Nason, Kevin S., Paboojian, Steve, Rasmussen, Dennis R., Schuler, Carlos, Smith, Adrian E., Tuttle, Derrick J., Ward, Brian R.S..
Application Number | 20050016533 10/601127 |
Document ID | / |
Family ID | 26839451 |
Filed Date | 2005-01-27 |
United States Patent
Application |
20050016533 |
Kind Code |
A1 |
Schuler, Carlos ; et
al. |
January 27, 2005 |
Systems and methods for aerosolizing pharmaceutical
formulations
Abstract
Systems and methods are provided for aerosolizing a
pharmaceutical formulation. According to one method, respiratory
gases are prevented from flowing to the lungs when attempting to
inhale. Then, respiratory gases are abruptly permitted to flow to
the lungs. The flow of respiratory gases may then be used to
extract a pharmaceutical formulation from a receptacle and to place
the pharmaceutical formulation within the flow of respiratory gases
to form an aerosol.
Inventors: |
Schuler, Carlos; (Cupertino,
CA) ; Paboojian, Steve; (Menlo Park, CA) ;
Tuttle, Derrick J.; (San Mateo, CA) ; Smith, Adrian
E.; (Belmont, CA) ; Rasmussen, Dennis R.;
(Santa Clara, CA) ; Bakshi, Aneesh; (Belmont,
CA) ; Clark, Andrew; (Half Moon Bay, CA) ;
Ward, Brian R.S.; (Los Altos, CA) ; Alston, William
W. JR.; (San Jose, CA) ; Nason, Kevin S.;
(Mountain View, CA) |
Correspondence
Address: |
NEKTAR THERAPEUTICS
150 INDUSTRIAL ROAD
SAN CARLOS
CA
94070
US
|
Assignee: |
Inhale Therapeutic Systems
San Carlos
CA
|
Family ID: |
26839451 |
Appl. No.: |
10/601127 |
Filed: |
June 19, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10601127 |
Jun 19, 2003 |
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09583312 |
May 30, 2000 |
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6606992 |
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60141793 |
Jun 30, 1999 |
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60198060 |
Apr 18, 2000 |
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Current U.S.
Class: |
128/203.15 ;
128/203.21 |
Current CPC
Class: |
A61M 15/002 20140204;
A61M 15/0096 20140204; A61M 15/0091 20130101; A61M 16/0495
20140204; A61M 2202/064 20130101; A61M 15/0068 20140204; A61M
15/0028 20130101; A61M 15/0051 20140204; A61M 16/208 20130101; A61M
16/0493 20140204; A61M 15/0093 20140204; A61M 15/0083 20140204;
A61M 16/206 20140204; A61M 16/0866 20140204; A61M 15/0036
20140204 |
Class at
Publication: |
128/203.15 ;
128/203.21 |
International
Class: |
A61M 015/00; A61M
016/00 |
Claims
What is claimed is:
1. A method for aerosolizing a pharmaceutical formulation, the
method comprising: preventing respiratory gases from flowing to the
lungs when attempting to inhale, and then abruptly permitting
respiratory gases to flow to the lungs; and using the flow of
respiratory gases to extract a pharmaceutical formulation from a
receptacle and to place the pharmaceutical formulation within the
flow of respiratory gases to form an aerosol.
2. A method as in claim 1, further comprising limiting the flow of
respiratory gases to a rate that is less than a certain rate for a
certain time.
3. A method as in claim 2, wherein the rate is less than about 15
L/min and the time is in the range from about 0.5 seconds to about
5 seconds.
4. A method as in claim 2, wherein the rate is less than about 8
L/min and the time is in the range from about 0.5 seconds to about
5 seconds.
5. A method as in claim 2, wherein the certain rate permits an
inhaled volume that is in the range from about 125 mL to about 1.25
L
6. A method as in claim 1, wherein the flow preventing step further
comprises placing a valve within an airway leading to the lungs and
opening the valve to permit respiratory gases to flow to the
lungs.
7. A method as in claim 6, further comprising opening the valve
when a threshold actuating vacuum caused by the attempted
inhalation is exceeded.
8. A method as in claim 7, wherein the threshold actuating vacuum
is in a range from about 20 cm H.sub.20 to about 60 cm
H.sub.20.
9. A method as in claim 6, wherein the valve comprises an occlusion
member having an opening, and a pull through member that is pulled
through the opening when the threshold actuating vacuum is
produced.
10. A method as in claim 9, wherein the occlusion member comprises
an elastomeric membrane, and wherein the pull through member
comprises a ball.
11. A method as in claim 2, wherein the flow limiting step
comprises providing feedback when an excessive flow rate is
produced to permit a user to adjust their inhalation rate.
12. A method as in claim 2, wherein the flow limiting step
comprises regulating the size of an airway leading to the
lungs.
13. A method as in claim 12, further comprising regulating the size
of the airway with an elastomeric duckbill valve.
14. A method as in claim 12, further comprising regulating the size
of the airway with a spring biased ball that is disposed within a
tapered opening such that the ball in drawn into the opening as the
flow rate increases.
15. A method as in claim 12, further comprising regulating the size
of the airway to permit an increased flow rate after the certain
time has lapsed.
16. A method as in claim 2, further comprising providing another
airway to permit an increase flow of gases to the lungs after the
certain time has lapsed.
17. A method as in claim 1, wherein the pharmaceutical formulation
comprises a powdered medicament, and further comprising using the
flow of respiratory gases to deagglomerate the extracted
powder.
18. A method for administering a pharmaceutical formulation, the
method comprising: providing an inhalation device comprising a
housing having first and second openings to ambient air and a
mouthpiece at one of said openings; preventing respiratory gases
from flowing to the lungs when attempting to inhale through said
mouthpiece; permitting the flow of a first predetermined volume of
respiratory gases to the lungs, said first volume being sufficient
to transport substantially all of a unit dose of a pharmaceutical
formulation contained within the inhalation device out of the
device and into the respiratory tract of a patient; and permitting
a second volume of respiratory gases to flow to the lungs.
19. A method as in claim 18 wherein the flow of respiratory gases
is prevented by providing the device with a valve between said
openings.
20. A method according to claim 19 wherein the flow of respiratory
gases is permitted by opening said valve when a threshold actuating
vacuum by the attempted inhalation is exceeded.
21. A method according to claim 20 wherein said vacuum is within
20-60 cm H.sub.2O.
22. A method as in claim 18 wherein said first predetermined volume
of respiratory gases is in the range from 125 mL to 1.25 L.
23. A method as in claim 18 further comprising regulating the flow
of respiratory gases at a first flow rate until said first
predetermined volume of respiratory gases flows through said
device.
24. A method according to claim 23 wherein the first flow rate is
less than 15 L/min.
25. A method according to claim 23 further comprising regulating
the flow of said second volume of respiratory gases at a second
flow rate.
26. An aerosolization device, comprising: a housing defining an
airway; a coupling mechanism adapted to couple a receptacle
containing a pharmaceutical formulation to the airway; and a valve
to prevent respiratory gases from flowing through the airway until
a threshold actuating vacuum is exceeded at which time the valve
opens to permit respiratory gases to flow through the airway and to
extract the pharmaceutical formulation from the receptacle to form
an aerosol.
27. A device as in claim 26, further comprising a regulation system
to regulate the flow of respiratory gases through the airway to a
certain rate.
28. A device as in claim 27, wherein the regulation system is
configured to limit the flow to a rate that is less than about 15
L/min for a certain time or a certain inhaled volume.
29. A device as in claim 27, wherein the regulation system
comprises a feedback mechanism to provide information on the rate
of flow of the respiratory gases.
30. A device as in claim 29, wherein the feedback mechanism
comprises a whistle in communication with the airway.
31. A device as in claim 27, wherein the regulation system
comprises a restrictive member disposed in the airway, the
restrictive member defining an orifice sized to limit the flow of
respiratory gases through the airway.
32. A device as in claim 27, wherein the regulation system
comprises a restriction mechanism to limit the size of the
airway.
33. A device as in claim 32, wherein the restriction mechanism
comprises an elastomeric duckbill valve that closes as the flow
rate of the respiratory gases increases.
34. A device as in claim 32, wherein the restriction mechanism
comprises a spring biased ball that is drawn into a tapered opening
as the flow rate of the respiratory gases increases.
35. A device as in claim 32, wherein the restriction mechanism is
adjustable to vary the rate of flow of respiratory gases through
the airway.
36. A device as in claim 35, wherein the regulation system further
comprises a control system to adjust the restriction mechanism.
37. A device as in claim 36, wherein the control system is
configured to limit the flow to the certain rate for a certain time
or inhaled volume and then to adjust the restriction mechanism to
permit an increased flow of respiratory gases through the
airway.
38. A device as in claim 28, further comprising a flow integrator
that is configured to open another airway in the housing after a
certain time or inhaled volume.
39. A device as in claim 26, wherein the valve comprises an
occlusion member having an opening, and a pull through member that
is pulled through the opening when the threshold actuating vacuum
is produced.
40. A device as in claim 39, wherein the occlusion member comprises
an elastomeric membrane, and wherein the pull through member
comprises a ball.
41. A device as in claim 26, wherein the threshold actuating vacuum
of the valve is in a range from about 20 cm H.sub.20 to about 60 cm
H.sub.20.
42. A device as in claim 26, further comprising a deagglomeration
mechanism disposed in the airway downstream of the receptacle to
deagglomerate the extracted pharmaceutical formulation.
43. A device as in claim 26, wherein the valve is adapted to be
disposed within the receptacle.
44. An aerosolization system comprising: a receptacle comprising a
chamber having a pharmaceutical formulation and a threshold valve;
a housing defining an airway; and a coupling mechanism to position
the valve across the airway and to place the pharmaceutical
formulation in fluid communication with the airway; wherein the
threshold valve is configured to open when a threshold actuating
vacuum is exceeded to permit respiratory gases to flow through the
airway and extract the pharmaceutical formulation from the chamber
to form an aerosol.
45. A system as in claim 44, wherein the pharmaceutical formulation
comprises a powdered medicament.
46. A system as in claim 44, wherein the pharmaceutical formulation
comprises a liquid medicament.
47. A system as in claim 44, further comprising a regulation system
to regulate the flow of respiratory gases through the airway.
48. A receptacle comprising: a receptacle body defining a cavity
enclosed by a penetrable access lid; and a threshold valve coupled
to the receptacle body.
49. A receptacle as in claim 48; wherein the threshold valve is
configured to open when experiencing a vacuum of at least about 40
cm H.sub.20.
50. An aerosolization device, comprising: a housing having a
mouthpiece; an aerosolization mechanism disposed in the housing,
wherein the aerosolization mechanism is adapted to aerosolize a
powdered medicament when a user inhales from the mouthpiece; and a
positioning system that is adapted to facilitate proper positioning
of a user's mouth over the mouthpiece prior to inhalation.
51. A device as in claim 50, wherein the positioning system
comprises at least one hole in a side of the mouthpiece over which
the user must position the mouth to produce a vacuum sufficient to
cause aerosolization of the powdered medicament.
52. A device as in claim 50, wherein the positioning system
comprises a positioning landmark disposed on the mouthpiece that is
interactable with a physiological feature of the user.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation in part application and
claims the benefit of U.S. Provisional Patent Application Nos.
60/141,793, filed Jun. 30, 1999 and 60/198,060, filed Apr. 18,
2000, the complete disclosures of which are herein incorporated by
reference.
BACKGROUND OF THE INVENTION
[0002] This invention relates generally to the field of drug
delivery, and in particular to the delivery of pharmaceutical
formulations to the lungs. More specifically, the invention relates
to the aerosolization of pharmaceutical formulations using energy
created by patient inhalation.
[0003] Effective drug delivery to a patient is a critical aspect of
any successful drug therapy, and a variety of drug delivery
techniques have been proposed. For example, one convenient method
is the oral delivery of pills, capsules, elixirs and the like.
However, oral delivery can in some cases be undesirable in that
many drugs are degraded in the digestive tract before they can be
absorbed. Another technique is subcutaneous injection. One
disadvantage to this approach is low patient acceptance. Other
alternative routes of administration that have been proposed
include transdermal, intranasal, intrarectal, intravaginal and
pulmonary delivery.
[0004] Of particular interest to the invention are pulmonary
delivery techniques which rely on the inhalation of a
pharmaceutical formulation by the patient so that the active drug
within the dispersion can reach the distal (alveolar) regions of
the lung. A variety of aerosolization systems have been proposed to
disperse pharmaceutical formulations. For example, U.S. Pat. Nos.
5,785,049 and 5,740,794, the disclosures of which are herein
incorporated by reference, describe exemplary powder dispersion
devices which utilize a compressed gas to aerosolize a powder.
Other types of aerosolization systems include MDI's (which
typically have a drug that is stored in a propellant), nebulizers
(which aerosolize liquids using compressed gas, usually air), and
the like.
[0005] Another technique which is of interest to the invention is
the use of inspired gases to disperse the pharmaceutical
formulation. In this way, the patient is able to provide the energy
needed to aerosolize the formulation by the patient's own
inhalation. This insures that aerosol generation and inhalation are
properly synchronized. Utilization of the patient's inspired gases
can be challenging in several respects. For example, for some
pharmaceutical formulations, such as insulin, it may be desirable
to limit the inhalation flow rate within certain limits. For
example, PCT/US99/04654, filed Mar. 11, 1999, provides for the
pulmonary delivery of insulin at rates less than 17 liters per
minute. As another example, copending U.S. patent application Ser.
No. 09/414,384 describes pulmonary delivery techniques where a high
flow resistance is provided for an initial period followed by a
period of lower flow resistance. The complete disclosures of all
the above references are herein incorporated by reference.
[0006] Another challenge in utilizing the patient's inspired gases
is that the inspiration flow rate can drastically vary between
individuals. For instance, as shown in FIG. 1, a random sample of
17 individuals which were measured twice a week for four weeks
produced flow rates ranging from about 5 liters per minute to about
35 liters per minute. Such variability may affect the ability of
the formulation to be dispersed within a gas stream, the ability to
deagglomerate a powdered formulation, and/or the ability of the
aerosolized formulation to adequately reach the deep lung.
[0007] Hence, this invention is related to techniques for
regulating the flow of inspired gases that may be utilized when
dispersing a pharmaceutical formulation. In one aspect, the
invention is related to techniques to enhance the ability of a
formulation to be dispersed within a gas stream produced by patient
inhalation, to enhance the ability to deagglomerate a powdered
formulation, and to enhance the ability of the aerosolized
formulation to adequately reach the deep lung.
SUMMARY OF THE INVENTION
[0008] The invention provides exemplary systems and methods to
provide breath actuated, flow regulated aerosol delivery of
pharmaceuticals. In one aspect, the invention utilizes the flow of
respiratory gases produced by a patient to aerosolize a
pharmaceutical formulation. In another particular aspect of the
invention, the invention is able to extract a powdered
pharmaceutical formulation from a receptacle, deagglomerate the
formulation and deliver the formulation to the lungs using a wide
range of patient inhalation flow rates. According to another aspect
of the invention, devices and methods are provided which provide
efficient delivery of a pharmaceutical aerosol to the deep
lung.
[0009] According to the invention, the flow of respiratory gases
may initially be prevented from flowing to the lungs until a
predetermined vacuum is produced by the user, at which point the
flow of respiratory gases is abruptly initiated. In one particular
embodiment, the abrupt initiation of respiratory gas flow is
utilized to aerosolize a pharmaceutical formulation. According to
this embodiment, respiratory gases are initially prevented from
flowing to the lungs when attempting to inhale through an open
mouthpiece at one end of the device. The respiratory gases are then
abruptly permitted to flow to the lungs after a predetermined
vacuum is produced by the user. The flow of respiratory gases is
utilized to extract a pharmaceutical formulation from a receptacle
and to place the pharmaceutical formulation within the flow of
respiratory gases to form an aerosol.
[0010] By initially preventing respiratory gases from flowing to
the lungs when attempting to inhale, the devices and methods of the
present invention provide a way to ensure that the resulting gas
stream has sufficient energy to extract the pharmaceutical
formulation from the receptacle. In one aspect, the flow of
respiratory gases may initially be prevented from flowing to the
lungs by placing a valve within an airway leading to the lungs and
opening the valve to permit the flow of respiratory gases.
According to the invention, the valve is opened when a threshold
actuating vacuum caused by the attempted inhalation is exceeded. In
this way, when the valve is opened, the resulting gas stream has
sufficient energy to extract and aerosolize the pharmaceutical
formulation.
[0011] In another embodiment, the invention provides an
aerosolization device that comprises a housing defining an airway,
and a coupling mechanism to couple a receptacle containing a
pharmaceutical formulation to the airway. The device further
includes a valve to prevent respiratory gases from flowing through
the airway until a threshold actuating vacuum is exceeded. At such
a time, the valve opens to permit respiratory gases to flow through
the airway and to extract the pharmaceutical formulation from the
receptacle to form an aerosol.
[0012] A variety of threshold valves may be employed to prevent
gases from flowing through the airway as will be discussed in
detail below. For example, the valve may comprise an occlusion
member having an opening, and a pull through member that is pulled
through the opening when the threshold actuating vacuum is
produced. As one specific example, the occlusion member may
comprise an elastically compliant membrane, and the pull through
member may comprise a ball that is pulled through the membrane when
the threshold vacuum has been achieved. In another aspect, the
threshold actuating vacuum of the valve is in the range from about
20 cm H.sub.20 to about 60 cm H.sub.20. In one particular aspect,
the valve is configured to be disposed within the receptacle. In
this way, the valve may conveniently be manufactured along with the
receptacle.
[0013] According to another aspect, the invention provides devices
and methods for regulating the flow of respiratory gases to provide
consistent airflow, independent of the breathing rate of the user.
In another aspect, the system includes a regulation system to
regulate the flow of respiratory gases through the airway after the
valve has been opened. The combination of flow regulation with the
threshold valve according to the present invention results in
devices and methods for aerosol delivery that are effective in
delivering the aerosolized formulation to the deep lung.
[0014] In still another aspect, the devices and methods of the
invention may limit the flow of respiratory gases to a rate that is
less than a certain rate for a certain time. For example, the flow
rate may be limited to a rate that is less than about 15 liters per
minute for a time in the range from about 0.5 second to about 5
seconds, corresponding to a volume in the range from about 125 mL
to about 1.25 L. Regulation of the flow rate is advantageous in
that it may increase systemic bioavailability of the active agent
of certain pharmaceutical formulations via absorption in the deep
lung as described generally in PCT Application No. PCT/U.S.
99/04654, filed Mar. 3, 1999 and in copending U.S. application Ser.
No. 09/414,384, previously incorporated by reference.
[0015] A variety of techniques may be employed to limit or regulate
the flow of respiratory gases. For example, feedback may be
provided to the user when an excessive flow rate is produced to
permit a user to adjust their inhalation rate. Examples of feedback
which may be provided include audio feedback, including a whistle,
visual feedback, such as indicator lights or a level meter, tactile
feedback, such as vibration, and the like. As another alternative,
the flow of respiratory gases may be controlled by regulating the
size of an airway leading to the lungs. For example, an elastically
compliant valve may be used to provide flow resistance based upon
the flow rate through the device and limit the flow to a certain
rate.
[0016] In one aspect, the device further includes a regulation
system to regulate the flow of respiratory gases through the airway
to a certain rate. For example, the regulation system may be
configured to limit the flow to a rate that is less than about 15
liters per minute for a certain time or a certain inspired volume.
A variety of flow regulators may be employed to regulate the flow
of gases to a certain rate as will be discussed in detail below.
For example, the flow regulator may comprise a valve that is
constructed of an elastic element, such as a soft elastomer, that
limits the flow to a certain rate while also preventing flow in the
opposite direction. Such a valve may have an orifice that permits
the flow of air through the valve in response to an applied vacuum,
and one or more collapsible walls surrounding the orifice. In this
way, an increased vacuum pressure level draws the walls toward each
other, thereby reducing or closing the orifice area and providing a
higher resistance or complete resistance to flow. For example such
a valve may be placed in a parallel flow path. Once the flow rate
becomes too great, the valve closes so that all air passing through
the device must pass through the other flow path. By providing this
flow path with a certain size, the flow of gases through the device
may be kept below the threshold rate.
[0017] In another particular aspect, the regulation system may
comprise a feedback mechanism to provide information on the rate of
flow of the respiratory gases. For example, the feedback mechanism
may comprise a whistle that is in communication with the airway and
produces a whistling sound when the maximum flow rate is exceeded.
In another alternative, the regulation system may comprise a
restriction mechanism to limit the size of the airway.
Conveniently, the restriction mechanism may be adjustable to vary
the rate of flow of respiratory gases through the airway. The
restriction mechanism may be adjusted manually or automatically,
such as by the use of an elastically compliant material.
[0018] Optionally, an electronically governed, closed-loop control
system may be provided to adjust the restriction mechanism. In one
aspect, the control system is configured to limit the flow to a
certain rate for a certain time or a certain inspired volume and
then to sense and adjust the restriction mechanism to permit an
increased flow of respiratory gases through the airway. In this
manner, the flow rate of respiratory gases may be regulated to
limit the flow to a certain rate for a certain time to facilitate
proper delivery of the pharmaceutical formulation to the lungs. The
control system may then be employed to adjust the restriction
mechanism so that the user can comfortably fill their lungs with
respiratory gases to deliver the pharmaceutical formulation to the
deep lung. Use of the regulation system and control system
according to the present invention is advantageous in that the
device may be used with numerous users that have different
inhalation flow rates, with the device regulating the flow of
respiratory gases so that the pharmaceutical formulation is
properly delivered to the lungs.
[0019] According to another aspect of the invention, after the flow
rate has been limited for the desired amount of time or inhaled
volume, the size of the airway may be increased to provide for an
increased flow rate. This may be accomplished, for example, by
opening another airway traveling through the device. In this way,
the user may comfortably inhale without substantial resistance in
order to fill the user's lungs with respiratory gases and carry the
pharmaceutical formulation into the deep lung.
[0020] In an alternative aspect, the invention may optionally
utilize a variety of flow integrators to permit an increased flow
rate through the inhalation device after a certain amount of time
to permit the user to comfortably fill their lungs at the end of
the process. Such flow integrators may have one or more moving
members that move based on the volume of flow through the device.
In this way, when the initial (regulated) volume has been inhaled,
the member has moved sufficient to open another gas channel to
permit increased gas flow. Examples of flow integrators that may be
used are discussed in detail below and include movable pistons,
clutch mechanisms, gas filled bellows with a bleed hole, and the
like.
[0021] The pharmaceutical formulation for use with the systems and
methods of the present invention may be a liquid or powder
formulation. In one aspect of the method, the pharmaceutical
formulation comprises a powdered medicament. The flow of
respiratory gases is used to deagglomerate the powder once
extracted from the receptacle. Optionally, various structures may
be placed into the airway to assist in the deagglomeration
process.
[0022] In still yet another embodiment, the invention provides a
receptacle that comprises a receptacle body defining a cavity that
is enclosed by a penetrable access lid. The receptacle further
includes a threshold valve that is coupled to the receptacle body.
In one aspect, the threshold valve is configured to open when
experiencing a vacuum of at least about 40 cm H.sub.2O.
[0023] According to another aspect, the invention may also utilize
a variety of techniques to ensure that the user properly positions
their mouth over the mouthpiece during use of an aerosolization
device. For example, a lip guard may be included on the mouthpiece
to permit the user to place their lips adjacent the lip guard. As
another example, the mouthpiece may include bite or other
landmarks. Alternatively, one or more holes may be provided in the
side of the mouthpiece. These holes must be covered by the lips in
order to create a sufficient vacuum to operate the device. As a
further example, the mouthpiece may have a circular-to-elliptical
profile. The elliptical portion must be covered by the patient's
mouth in order for a vacuum sufficient to actuate the device to be
created.
[0024] These and other aspects of the present invention will be
readily apparent to one of ordinary skill in the art in view of the
drawings and detailed description that follows.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1 is a graph illustrating the average inspiration flow
rate for 17 individuals that were measured twice a week for four
weeks.
[0026] FIG. 2 is a graph illustrating the regulation of a patient's
inspiration flow rate over time according to the invention.
[0027] FIG. 3. is a graph illustrating the regulation of another
patient's inspiration flow rate over time according to the
invention.
[0028] FIG. 4 is a schematic view of one system that may be
utilized to extract a pharmaceutical formulation from a receptacle,
deagglomerate the formulation and to place the formulation within
the flow of respiratory gases to form an aerosol according to the
invention.
[0029] FIG. 5 is a perspective view of an aerosolization device
according to the invention.
[0030] FIG. 6 is a partial cutaway view of the aerosolization
device of FIG. 5 shown in an open or loading position.
[0031] FIG. 7 illustrates the aerosolization device of FIG. 6 in a
closed or operating position according to the invention.
[0032] FIG. 8 illustrates the aerosolization device of FIG. 6 when
inserting a receptacle according to the invention.
[0033] FIG. 9 illustrates the aerosolization device of FIG. 8 when
the receptacle has been inserted, when the device has been moved to
the closed or operating position, and when respiratory gases are
flowed through the device.
[0034] FIG. 10 is a partial cutaway perspective view of a
receptacle and a convergent nozzle through which a pharmaceutical
formulation may be extracted according to the invention.
[0035] FIG. 11 illustrates the receptacle and nozzle of FIG. 10,
with the nozzle being moved further away from a bottom end of the
receptacle to increase the rate of flow of respiratory gases
through the nozzle according to the invention.
[0036] FIG. 12 is a schematic, cross-sectional side view of an
aerosolization system having a spring to regulate the flow of
respiratory gases through the system according to the
invention.
[0037] FIG. 13 is a schematic, cross-sectional view of an
aerosolization system having a flow regulation system to regulate
the flow of respiratory gases through the aerosolization system
according to the invention.
[0038] FIG. 14 illustrates one embodiment of a nozzle that may be
employed to deagglomerate a pharmaceutical formulation according to
the invention.
[0039] FIG. 15 is a perspective view of one embodiment of an
aerosolization device according to the invention.
[0040] FIG. 16 is a perspective view of another embodiment of an
aerosolization device according to the invention.
[0041] FIG. 16A illustrates a cover of the aerosolization device of
FIG. 16.
[0042] FIG. 17 is a perspective view of still another embodiment of
an aerosolization device according to the invention illustrating
the use of a flow rate feedback device.
[0043] FIG. 18 illustrates still yet another embodiment of an
aerosolization device according to the invention.
[0044] FIG. 19 illustrates one particular embodiment of an
aerosolization device according the invention.
[0045] FIG. 19A illustrates a disk having multiple receptacles that
may be inserted into the aerosolization device of FIG. 19.
[0046] FIG. 19B illustrates a front end of the aerosolization
device of FIG. 19.
[0047] FIG. 20 illustrates another embodiment of an aerosolization
device according the invention.
[0048] FIG. 20A illustrates the aerosolization device of FIG. 20
showing a lid moved to an open position.
[0049] FIG. 21 is a perspective view of yet another embodiment of
an aerosolization device according to the invention.
[0050] FIG. 22 illustrates one particular embodiment of an
aerosolization device according the invention capable of holding
multiple drug packets.
[0051] FIG. 22A illustrates a clip for use with the aerosolization
device of FIG. 22.
[0052] FIG. 23 illustrates yet another alternative embodiment of an
aerosolization device according the invention.
[0053] FIG. 23A illustrates a mouthpiece cover of the
aerosolization device of FIG. 23.
[0054] FIG. 24 illustrates a strip of receptacles that may be
utilized within the aerosolization device of FIG. 23.
[0055] FIG. 25 illustrates still another alternative embodiment of
an aerosolization device according to the invention.
[0056] FIG. 26 illustrates one embodiment of an aerosolization
device according to the invention.
[0057] FIG. 27 is a schematic diagram of a threshold valve
according to the invention.
[0058] FIG. 28 is a ball and membrane threshold valve according to
the invention.
[0059] FIG. 29 is an umbrella type threshold valve according to the
invention.
[0060] FIG. 30 schematically illustrates one embodiment of a
threshold valve according to the invention.
[0061] FIGS. 31A and 31B illustrate a flapper type threshold valve
according to the invention.
[0062] FIG. 32 illustrates a spindle type threshold valve according
to the invention.
[0063] FIG. 33 illustrates another spindle type threshold valve
according to the invention.
[0064] FIGS. 34A and 34B illustrate an umbrella type threshold
valve according to the invention.
[0065] FIG. 35 illustrates a ball and magnet type threshold valve
according to the invention.
[0066] FIGS. 36A and 36B illustrate a bistable dome type threshold
valve according to the invention.
[0067] FIGS. 37A and 37B illustrate a mechanical pressure switch
type threshold valve according to the invention.
[0068] FIG. 38 illustrates a frangible membrane type of threshold
valve according to the invention.
[0069] FIG. 39 illustrates another mechanical pressure switch type
threshold valve according to the invention.
[0070] FIG. 40 illustrates a pull through type threshold valve
according to the invention.
[0071] FIG. 41 is a schematic diagram of a flow regulator according
to the invention.
[0072] FIGS. 42A and 42B illustrate a shuttle type flow regulator
according to the invention.
[0073] FIG. 43 illustrates a ball type flow regulator according to
the invention.
[0074] FIGS. 44A and 44B illustrate a bellows type flow regulator
according to the invention.
[0075] FIG. 45 illustrates a cone type flow regulator according to
the invention.
[0076] FIG. 46 illustrates another embodiment of a flow regulator
according to the invention.
[0077] FIG. 47 illustrates a foam type flow regulator according to
the invention.
[0078] FIG. 48 illustrates an umbrella type flow regulator
according to the invention.
[0079] FIG. 49 illustrates a liquid reservoir flow regulator
according to the invention.
[0080] FIG. 50 illustrates another embodiment of a flow regulator
according to the invention.
[0081] FIG. 51 illustrates a spindle type flow regulator according
to the invention.
[0082] FIG. 52 illustrates an expandable cone type flow regulator
according to the invention.
[0083] FIGS. 53A and 53B illustrate an iris type flow regulator
according to the invention.
[0084] FIG. 54 illustrates a paddle wheel type flow regulator
according to the invention.
[0085] FIGS. 55A and 55B illustrate a flap type flow regulator
according to the invention.
[0086] FIGS. 56A and 56B illustrate an elastomeric duck bill type
flow regulator according to the invention.
[0087] FIGS. 57-59 illustrate alternative elastomeric duck bill
type flow regulators according to the invention.
[0088] FIG. 60 schematically illustrates a flow through type flow
integrator according to the invention.
[0089] FIG. 61 schematically illustrates a flow-by type flow
integrator according to the invention.
[0090] FIGS. 62A and 62B illustrate a flow through shuttle type
flow integrator according to the invention.
[0091] FIG. 63 illustrates an impeller type flow integrator
according to the invention.
[0092] FIG. 64 is an end view of a cam of the flow integrator of
FIG. 63.
[0093] FIG. 65 illustrates a paddle wheel that may be used in the
flow integrator of FIG. 63.
[0094] FIGS. 66A and 66B illustrate a shuttle type flow integrator
according to the invention.
[0095] FIG. 67 illustrates a brake timer flow integrator according
to the invention.
[0096] FIG. 68 illustrates a brake and a wheel of the flow
integrator of FIG. 67.
[0097] FIG. 69 schematically illustrates an aerosolization system
having various components arranged in series according to the
invention.
[0098] FIG. 70 schematically illustrates an aerosolization system
having a parallel flow-by type flow integrator according to the
invention.
[0099] FIG. 71 schematically illustrates an aerosolization system
having a parallel flow through type flow integrator according to
the invention.
[0100] FIG. 72 is a front perspective view of one embodiment of an
aerosolization device according to the invention.
[0101] FIG. 73 illustrates the device of FIG. 72 in a loading
position.
[0102] FIG. 74 is a rear perspective view of the device of FIG.
72.
[0103] FIG. 75 is a cross sectional view of the device of FIG.
73.
[0104] FIG. 76 is a cross sectional view of the device of FIG.
72.
[0105] FIG. 77 is a cross sectional side view of the device of FIG.
72.
[0106] FIG. 78 illustrates the device of FIG. 72 when in the
loading position.
[0107] FIG. 79 is a front perspective view of another embodiment of
an aerosolization device according to the invention.
[0108] FIG. 80 illustrates the device of FIG. 79 in a loading
position.
[0109] FIG. 81 is a cross sectional view of the device of FIG.
79.
[0110] FIG. 82 illustrates the device of FIG. 82 when another flow
path has been opened to permit an increased flow of air through the
device.
[0111] FIG. 83 is a side view of the device of FIG. 81.
[0112] FIG. 84 is a front perspective view of another embodiment of
an aerosolization device according to the invention.
[0113] FIG. 85 illustrates the device of FIG. 84 when in a loading
position.
[0114] FIG. 86 is a cross sectional view of the device of FIG.
84.
[0115] FIG. 87 is a side view of the device of FIG. 86.
[0116] FIG. 88 is a front perspective view of one embodiment of a
mouthpiece according to the invention.
[0117] FIG. 89 is a side view of an alternative mouthpiece
according to the invention.
DEFINITIONS
[0118] "Active agent" as described herein includes an agent, drug,
compound, composition of matter or mixture thereof which provides
some pharmacologic, often beneficial, effect. This includes foods,
food supplements, nutrients, drugs, vaccines, vitamins, and other
beneficial agents. As used herein, the terms further include any
physiologically or pharmacologically active substance that produces
a localized or systemic effect in a patient. The active agent that
can be delivered includes antibiotics, antiviral agents,
anepileptics, analgesics, anti-inflammatory agents and
bronchodilators, and viruses and may be inorganic and organic
compounds, including, without limitation, drugs which act on the
peripheral nerves, adrenergic receptors, cholinergic receptors, the
skeletal muscles, the cardiovascular system, smooth muscles, the
blood circulatory system, synaptic sites, neuroeffector junctional
sites, endocrine and hormone systems, the immunological system, the
reproductive system, the skeletal system, autacoid systems, the
alimentary and excretory systems, the histamine system and the
central nervous system. Suitable agents may be selected from, for
example, polysaccharides, steroids, hypnotics and sedatives,
psychic energizers, tranquilizers, anticonvulsants, muscle
relaxants, antiparkinson agents, analgesics, anti-inflammatories,
muscle contractants, antimicrobials, antimalarials, hormonal agents
including contraceptives, sympathomimetics, polypeptides, and
proteins capable of eliciting physiological effects, diuretics,
lipid regulating agents, antiandrogenic agents, antiparasitics,
neoplastics, antineoplastics, hypoglycemics, nutritional agents and
supplements, growth supplements, fats, antienteritis agents,
electrolytes, vaccines and diagnostic agents.
[0119] Examples of active agents useful in this invention include
but are not limited to insulin, calcitonin, erythropoietin (EPO),
Factor VIII, Factor IX, ceredase, cerezyme, cyclosporine,
granulocyte colony stimulating factor (GCSF), alpha-1 proteinase
inhibitor, elcatonin, granulocyte macrophage colony stimulating
factor (GMCSF), growth hormone, human growth hormone (HGH), growth
hormone releasing hormone (GHRH), heparin, low molecular weight
heparin (LMWH), interferon alpha, interferon beta, interferon
gamma, interleukin-2, luteinizing hormone releasing hormone (LHRH),
somatostatin, somatostatin analogs including octreotide,
vasopressin analog, follicle stimulating hormone (FSH),
insulin-like growth factor, insulintropin, interleukin-1 receptor
antagonist, interleukin-3, interleukin-4, interleukin-6, macrophage
colony stimulating factor (M-CSF), nerve growth factor, parathyroid
hormone (PTH), thymosin alpha 1, IIb/IIIa inhibitor, alpha-1
antitrypsin, respiratory syncytial virus antibody, cystic fibrosis
transmembrane regulator (CFTR) gene, deoxyribonuclease (Dnase),
bactericidal/permeabili- ty increasing protein (BPI), anti-CMV
antibody, interleukin-1 receptor, 13-cis retinoic acid, pentamidine
isethionate, albuterol sulfate, metaproterenol sulfate,
beclomethasone dipropionate, triamcinolone acetamide, budesonide
acetonide, ipratropium bromide, flunisolide, fluticasone, cromolyn
sodium, ergotamine tartrate and the analogues, agonists and
antagonists of the above. Active agents may further comprise
nucleic acids, present as bare nucleic acid molecules, viral
vectors, associated viral particles, nucleic acids associated or
incorporated within lipids or a lipid-containing material, plasmid
DNA or RNA or other nucleic acid construction of a type suitable
for transfection or transformation of cells, particularly cells of
the alveolar regions of the lungs. The active agents may be in
various forms, such as soluble and insoluble charged or uncharged
molecules, components of molecular complexes or pharmacologically
acceptable salts. The active agents may be naturally occurring
molecules or they may be recombinantly produced, or they may be
analogs of the naturally occurring or recombinantly produced active
agents with one or more amino acids added or deleted. Further, the
active agent may comprise live attenuated or killed viruses
suitable for use as vaccines.
[0120] "Mass median diameter" or "MMMD" is a measure of mean
particle size, since the powders of the invention are generally
polydisperse (i.e., consist of a range of particle sizes). MMD
values as reported herein are determined by centrifugal
sedimentation, although any number of commonly employed techniques
can be used for measuring mean particle size.
[0121] "Mass median aerodynamic diameter" or "MMAD" is a measure of
the aerodynamic size of a dispersed particle. The aerodynamic
diameter is used to describe an aerosolized powder in terms of its
settling behavior, and is the diameter of a unit density sphere
having the same settling velocity, generally in air, as the
particle. The aerodynamic diameter encompasses particle shape,
density and physical size of a particle. As used herein, MMAD
refers to the midpoint or median of the aerodynamic particle size
distribution of an aerosolized powder determined by cascade
impaction.
DESCRIPTION OF THE SPECIFIC EMBODIMENTS
[0122] The invention provides systems and methods for the
administration of aerosolized pharmaceutical formulations using the
flow of respiratory gases produced by a patient. The pharmaceutical
formulations that may be aerosolized include powdered medicaments,
liquid solutions or suspensions, and the like, and may include an
active agent. The devices of the present invention may be used for
single or multiple administrations.
[0123] In some embodiments, the flow of respiratory gases produced
by the patient is employed to extract the pharmaceutical
formulation from a receptacle, to deagglomerate the pharmaceutical
formulation and deliver the pharmaceutical formulation to the
patient's lungs. One particular advantage of the invention is the
ability to perform such functions independent of the patient's
natural inhalation flow rate. Hence, in one aspect of the
invention, the inhaled respiratory gases are controlled so that
they remain within an acceptable range of flow rates to adequately
deliver the pharmaceutical formulation to the lungs.
[0124] In another aspect, the invention is configured to regulate
the flow of inspired gases so that the gases have sufficient energy
to extract the pharmaceutical formulation from a receptacle,
deagglomerate the formulation, and deliver it to the patient's
lungs. In some cases, the invention is further configured to
maintain the inhalation flow rate below a maximum level for at
least a certain time or inhaled volume when initially delivering
the drug. In this way, the aerosolized formulation will flow at an
acceptable flow rate to enhance its ability to traverse the
patient's airway and enter into the lungs. After initial delivery
of the pharmaceutical formulation to the lungs, some embodiments of
the invention may be configured to permit the patient to breath at
a normal inspiration flow rate to fill the patient's lungs with
respiratory gases and to further deliver the pharmaceutical
formulation to the deep lung.
[0125] To aerosolize the pharmaceutical formulation, the flow of
respiratory gases preferably contains sufficient energy to extract
the pharmaceutical formulation from the receptacle. To ensure that
the respiratory gases contain sufficient energy, the invention may
be configured to prevent respiratory gases from flowing to the
patient's lungs when the patient attempts to inhale. Abruptly, the
respiratory gases may then be permitted to flow to the patient's
lungs after a threshold vacuum has been reached. By abruptly
permitting the flow of respiratory gases only when sufficient
vacuum has been applied by the user, a relatively high rate of flow
is achieved to provide the gas stream with sufficient energy. One
way to accomplish such a process is by placing a restriction,
valve, or other blocking mechanism in the patient's airway to
prevent respiratory gases from entering the patient's lungs when
the patient attempts to inhale. The restriction or valve may then
be rapidly removed or opened to permit respiratory gases to flow to
the lungs. Hence, a patient may be instructed to inhale until a
threshold actuating vacuum is overcome. The threshold actuating
vacuum may be configured such that it will produce sufficient
energy in the resulting gas stream when the gases are allowed to
flow to the patient's lungs. Preferably, the threshold vacuum is in
the range from about 20 cm H.sub.20 to about 60 cm H.sub.20 so that
the resulting gas stream will have sufficient energy to extract and
deagglomerate the pharmaceutical formulation. Most preferably, the
threshold vacuum is at least 40 cm H.sub.20.
[0126] A variety of threshold valves may also be employed to
prevent respiratory gases from reaching the patient's lungs until a
threshold inhalation vacuum is obtained. For example, the threshold
valve may comprise an elastically compliant valve such as a
flexible membrane that is disposed across the airway and is
configured to flex when the threshold vacuum is met or exceeded.
Alternatively, the threshold valve may comprise a scored membrane
that is configured to tear or burst once the threshold vacuum is
met or exceeded. As another example, the threshold valve may
comprise an elastomer membrane having an opening. A ball is pulled
through the opening once the threshold pressure has been met or
exceeded. Other types of threshold valves include bi-stable
mechanisms, diaphragms, and the like.
[0127] In one particular aspect of the invention, the threshold
valve may be incorporated into a receptacle that also holds the
pharmaceutical formulation. In this way, each time a new receptacle
is inserted into an aerosolization device, the device is provided
with a new threshold valve. This is particularly advantageous when
the threshold valve comprises a membrane that is configured to tear
or burst after the threshold vacuum is met or exceeded.
[0128] Once the respiratory gases are allowed to flow to the lungs,
the flow rate of the respiratory gases (in some cases) may need to
be controlled or regulated so that the gases do not exceed a
maximum flow rate during delivery of the pharmaceutical formulation
to the lungs. Typically, the flow rate of respiratory gases may be
regulated to be less than about 15 liters per minute for a time in
the range from about 0.5 seconds to about 5 seconds, corresponding
to an inhaled volume in the range from about 125 mL to about 1.25
L, to permit the aerosolized formulation to pass through the
patient's airway and enter into the lungs. For example, as
previously illustrated in connection with FIG. 1, some patients
have a natural inhalation rate that exceeds a desired maximum flow
rate.
[0129] For breathers that naturally breath above the maximum
desired flow rate, the invention provides for the slowing of the
flow rate during the time when the aerosolized formulation is being
delivered to the lungs. This is illustrated graphically in FIG. 2.
At time T.sub.1, the patient is inhaling causing respiratory gases
to flow to the patient's lungs. At time T.sub.1, the flow rate is
well above a starting flow rate, Q.sub.START, which is desirable
for initially extracting the pharmaceutical formulation from the
receptacle as previously described. Hence, a threshold valve or
other flow prevention mechanism may not be needed for such
breathers. Shortly after time T.sub.1 is time T.sub.2, where the
flow rate has been regulated to be below a Q.sub.DELIVERY flow
rate. The flow rate is maintained below the Q.sub.DELIVERY rate
from time T.sub.2 to time T.sub.3, where the aerosolized
formulation is being delivered to the patient's lungs. After time
T.sub.3, the regulation of the gas flow is ceased and the patient
is permitted to inhale at their regular flow rate to fill their
lungs with respiratory gases that serve to further deliver the
pharmaceutical formulation to the deep lung.
[0130] FIG. 3 graphically illustrates an example of where the
patient has a natural inhalation flow rate that is below
Q.sub.DELIVERY As shown in FIG. 3, by preventing the flow of
respiratory gases during patient inhalation, and then abruptly
permitting the flow of respiratory gases, the starting flow rate at
time T.sub.1, is at Q.sub.START. In this way, sufficient energy is
provided to extract the formulation from the receptacle. After the
patient continues to inhale, the flow rate rapidly falls below the
Q.sub.DELIVERY flow rate because the patient's natural inhalation
flow rate is less than the Q.sub.DELIVERY flow rate. Hence, after
time T.sub.1, the patient's inhalation flow rate does not need to
be regulated, thereby permitting the patient to inhale at a
comfortable level.
[0131] A variety of schemes and techniques may be provided to
regulate the inhalation flow rate to be below the Q.sub.DELIVERY
flow rate from time T.sub.2 to time T.sub.3. As one example, the
patient may be provided with various types of feedback to permit
the patient to self-regulate their inhalation flow rate. For
instance, an aerosolization device may be provided with a whistle
that creates a whistling sound when the patient's flow rate exceeds
the Q.sub.DELIVERY flow rate. Other types of feedback that may be
utilized include visual feedback, tactile feedback, auditory
feedback, and the like. Optionally, a controller may be provided
with a timing mechanism to indicate to the user when time T.sub.3
has elapsed so that the user may finish their inhalation at a
comfortable level.
[0132] As another example, the patient's inhalation flow rate may
be regulated by restricting or impeding the respiratory gases being
inhaled. For example, the size of the airway may be varied to
control the rate of flow of inspired gases. The manner of
regulation may be either manual, semi-automated, or automated. For
example, the user may manually adjust the size of the airway or
place a restriction in the airway to control the rate of flow.
Alternatively, the size of the airway may be adjusted based on the
patient's own inhalation as described in greater detail
hereinafter. In still another example, an automated system with one
or more flow sensors may be provided to regulate the size of the
airway to regulate the flow of respiratory gases.
[0133] One particular advantage of restricting the flow of
respiratory gases to control the inhalation flow rate is that a
relatively high pressure drop may be created. Because power is
generally proportional to both the pressure drop and flow rate, the
flow rate may be kept low while still providing sufficient energy
to aerosolize the formulation and to deliver the formulation to the
patient's lungs.
[0134] As another alternative, the flow of respiratory gases may be
regulated by placing an orifice or other restriction member into
the patient's airway that is made for use with a specific patient.
In this way, an aerosolization device may be tailored to a specific
patient simply by utilizing an orifice sized according to the
patient's natural inhalation flow rate.
[0135] Devices according to the present invention may comprise
series or parallel flowpaths. In either case, it may be desirable
to maintain a constant, predetermined flow rate across a large
patient population. For series constructs, as depicted in FIG. 4,
it is preferred that the flow resistance/vacuum relationship is
substantially linear. For parallel constructs, as shown in FIG. 70
for example, it is preferable to provide that the flow
resistance/vacuum relationship is highly nonlinear.
[0136] Referring now to FIG. 4, a system 10 utilizing a series
construct for extracting a powdered medicament from a receptacle 12
using a patient's inspired respiratory gases will be described.
System 10 comprises a threshold valve 14 that may be configured to
open when the vacuum within a line 16 downstream of threshold valve
14 experiences a vacuum of within 20-60 cm H.sub.20, preferably
greater than about 40 cm H.sub.20. Also coupled to line 16 is a
regulation system 18 that regulates the flow of respiratory gases
through system 10. As one example, regulation system 18 may include
a restriction mechanism that may be employed to control the
internal size of line 16 and thereby regulate the flow of
respiratory gases through line 16. Conveniently, regulation system
18 may include a control system that adjusts the restriction
mechanism. The control system may be either manually operated or
operated in an automated manner using a controller. For example,
gas flow sensors may be disposed in system 10 and coupled to the
controller to determine the rate of flow of respiratory gases
through the system. Using this information, the controller may be
employed to control the degree of restriction of line 16. Although
regulation system 18 is shown upstream of receptacle 12, it will be
appreciated that regulation system 18 may be provided in other
locations, including downstream of receptacle 22 and upstream of
threshold valve 14.
[0137] Regulation system 18 is coupled to receptacle 12 by a line
20. Exiting receptacle 12 is a line 22 that is in communication
with a deagglomeration mechanism 24. In this way, powder extracted
from receptacle 12 may be deagglomerated before leaving system 10
and passing into the patient's lungs. Exiting deagglomeration
mechanism 24 is a line 26 that may be coupled to a mouthpiece (not
shown) from which the patient inhales. Hence, with system 10, a
patient may receive a dose of an aerosolized medicament by inhaling
from the mouthpiece until the patient produces a vacuum sufficient
to open threshold valve 14. When threshold 14 opens, the powdered
medicament is extracted from receptacle 12 and passes through
deagglomeration mechanism 24. At the same time, regulation system
18 controls the flow of respiratory gases within an acceptable rate
so that the aerosolized medicament may properly pass into the
patient's lungs. After a certain amount of time, the regulation
system 18 may be configured to cease operating so that the patient
may inhale at a comfortable rate to fill the lungs with respiratory
gases and to move the delivered medicament to the deep lung.
[0138] Referring now to FIG. 5, an exemplary embodiment of an
aerosolization device 28 will be described. Device 28 comprises a
generally cylindrical housing 30 having a mouthpiece 32 at one end.
Housing 30 further includes openings 34, 36 and 38 which define a
flow path for respiratory gases as described in greater detail
hereinafter. Conveniently, a divider 40 is provided between
openings 36 and 38 to permit the flow of respiratory gases to pass
temporarily outside of housing 30. Similarly, a divider 42 is
provided to facilitate the introduction of respiratory gases into
housing 30 through opening 34 (see FIG. 6).
[0139] Pivotally coupled to housing 30 is a receptacle carrier 44.
Conveniently, a pin 46 is employed to pivotally couple carrier 44
to housing 30. In this way, carrier 44 may be moved to an open
position as shown in FIG. 6 to permit a receptacle to be loaded
into device 28. Carrier 44 may then be moved to a closed or
operating position as shown in FIG. 7. As best shown in FIGS. 6 and
7, carrier 44 includes an opening 48 that is aligned with opening
34 when carrier 44 is moved to the closed position. Carrier 44
further includes another opening 50 that is positioned below two
penetrating tabs 52 on housing 30.
[0140] As best shown in FIG. 8, once carrier 44 is moved to the
open position, a receptacle 54 may be inserted into device 28.
Receptacle 54 comprises a receptacle body 56 having a chamber 58
(shown in phantom line) which holds the powdered medicament.
Receptacle body 56 is configured so that the portion above chamber
58 is penetrable by tabs 52 as described in greater detail
hereinafter. Disposed in receptacle body 56 is a threshold valve 60
that comprises a membrane that is configured to rupture or tear at
a specified threshold vacuum.
[0141] Receptacle 54 is inserted into device 28 so that threshold
valve 60 is aligned with opening 36. Also, chamber 58 rests within
opening 50. Once receptacle 54 is inserted onto carrier 44, carrier
44 is moved to the closed or operating position as illustrated in
FIG. 9. When in the closed position, threshold valve 60 is aligned
with opening 34. Further, tabs 52 penetrate body 56 over chamber 58
and peel back the lid to provide a pair of openings that provide
access to the powder contained within chamber 58. Once carrier 44
is moved to the closed position, a user may place his mouth over
mouthpiece 32 and attempt to inhale. The flow of respiratory gases
through device 28 is prevented until the user creates sufficient
vacuum to open threshold valve 60. At this point, respiratory gases
are abruptly permitted to flow through opening 34, through opening
36, through chamber 58, through opening 38 and out mouthpiece 32 as
illustrated by the arrows.
[0142] Turning now to FIGS. 10 and 11, an example of one technique
that may be employed to regulate the flow of respiratory gases
through an aerosolization device, such as device 28, will be
described. Shown in FIG. 10 is a receptacle 62 having a chamber 64
that is typically filled with a pharmaceutical formulation (not
shown). In FIG. 10, a penetrating tube 66 has already penetrated
the lid over chamber 64, and a distal end 68 of tube 66 is disposed
within chamber 64. In FIG. 10, distal end 68 of tube 66 is
positioned near the bottom of chamber 64. In this way, the airway
between distal end 68 and the bottom of chamber 64 is reduced in
size to restrict the respiratory gases flowing into chamber 64 and
out penetrating tube 66. As shown in FIG. 11, distal end 68 is
moved vertically upward so that it is further distanced from the
bottom end of chamber 64. In this way, the flow rate of respiratory
gases may be increased.
[0143] A variety of techniques may be employed to adjust the
distance between distal end 68 and the bottom of chamber 64. For
example, one technique is to employ the use of a suction force
created by patient inhalation. More specifically, as the patient
begins to inhale, the vacuum source created within tube 68 by the
inhalation will tend to move the bottom end of chamber 64 toward
distal end 68. Various mechanisms may then be employed to control
the distance between distal end 68 and the bottom end of chamber
64. For example, a variety of biasing mechanisms may be included to
control the relative movement between receptacle 62 and penetrating
tube 66. Automated mechanisms, such as solenoids, pistons, and the
like may also be employed. Further, various manual techniques may
also be used, including utilization of the user's hands or
fingers.
[0144] One feature of penetrating tube 66 is that it forms a
convergent nozzle that serves as a deagglomerator for the power
contained within chamber 64. More specifically, as the patient
inhales to extract the powder from chamber 64, the convergent flow
path created by penetrating tube 66 tends to deagglomerate the
powder to facilitate its aerosolization and deposition within the
lung.
[0145] Referring now to FIG. 12, an embodiment of an aerosolization
device 70 will be described to illustrate one technique for
regulating the flow of respiratory gases through the device. For
convenience of illustration, only a portion of device 70 is
illustrated, it being appreciated that other components may be
utilized to complete the device. Aerosolization device 70 comprises
a housing 72 and a receptacle carrier 74. Receptacle carrier 74 may
be configured to be movable relative to housing 72 for convenient
loading and unloading of a receptacle 76. Receptacle 76 includes a
chamber 78 and a threshold valve 80 that may be constructed to be
similar to other embodiments described herein. Receptacle carrier
74 includes an opening 82 that is aligned with valve 80 to permit
respiratory gases to flow through valve 80 once opened. Coupled to
housing 72 is a penetrating tube 84 that penetrates receptacle 76
to provide access to chamber 78 in a manner similar to that
described with the previous embodiments. In this manner, when a
patient inhales from device 70, threshold valve 80 opens when the
threshold vacuum is overcome. Respiratory gases then flow through
chamber 78 and out penetrating tube 84 as illustrated by the
arrows.
[0146] Device 70 further includes a spring 86 disposed between
housing 72 and receptacle carrier 74. Once valve 80 is opened, the
vacuum within penetrating tube 84 causes the bottom end of chamber
78 to be drawn toward penetrating tube 84. The spring constant of
spring 86 may be selected to control the distance between the
bottom end of chamber 78 and penetrating tube 84 to regulate the
gas flow through the device. In some cases, it may be desirable to
select the spring constant of spring 86 based on the average
inhalation flow rate produced by the patient. In this way, device
70 may be tailored to a particular patient. Device 70 further
includes a pin 88 that maintains the spacing between the bottom of
chamber 78 and penetrating tube 84 to a certain distance. In this
way, chamber 78 will not completely be drawn against penetrating
tube 84.
[0147] Referring now to FIG. 13, an aerosolization device 90 will
be described. Device 90 may be constructed from elements similar to
that previously described in connection with aerosolization device
70. Hence, for convenience of discussion, similar elements used for
aerosolization device 90 will be referred to with the same
reference numerals used to describe device 70 and will not be
described further. Aerosolization device 90 differs from
aerosolization device 70 in that it employs an electronic
controller 92 to control the distance between penetrating tube 84
and the bottom end of chamber 78. Controller 92 is electronically
coupled to a solenoid 94 that may be extended or retracted to
control the spacing between penetrating tube 84 and chamber 78.
Optionally, a flow control sensor 96 may be disposed anywhere
within the airway of device 90 to sense the rate of flow through
the device. When controller 92 receives a signal from sensor 96, it
may send a signal to solenoid 94 to adjust the spacing to thereby
regulate the flow rate. One advantage of using controller 92 is
that it may also include a timing circuit so that solenoid 94 may
be fully extended after a certain amount of time. In this way, once
the aerosolized formulation has reached the patient's lungs,
solenoid 94 may be fully extended to permit the user to comfortably
inhale without substantial resistance to fill their lungs with
respiratory gases.
[0148] Referring now to FIG. 14, another embodiment of a nozzle 98
that may be placed downstream of a receptacle will be described.
Nozzle 98 comprises a tubular structure 100 having a bent section
102 and a contracted section 104. As the pharmaceutical formulation
is extracted from the receptacle, it passes through tubular
structure 100 as indicated by the arrows. The change in the
direction caused by bent section 102 causes the agglomerated powder
to engage the walls of structure 100 to assist in its
deagglomeration. When reaching contracted section 104, the powder
is further agitated and the flow is increased to further
deagglomerate the powder. Although shown with one bent section
followed by a contracted section, it will be appreciated that
various other tubular structures may be provided with various
arrangements of direction changes and/or constrictions to
facilitate deagglomeration of the powder.
[0149] Referring now to FIGS. 15-26, various embodiments of
aerosolization devices will be described. Although not shown, the
aerosolization devices of FIGS. 15-26 will typically include a
penetrating tube with one or more penetrating structures to pierce
the lid of a receptacle similar to the embodiments previously
described. These devices may also include threshold valves and
regulation systems for regulating the flow of respiratory gases to
the patient's lungs in a manner similar to that described with
previous embodiments. Further, it will be appreciated that the
components of the various devices of FIGS. 15-26 may be shared,
substituted and/or interchanged with each other.
[0150] First referring to FIG. 15, one embodiment of an
aerosolization device 106 will be described. Device 106 comprises a
housing 108 having a lid 110. Lid 110 is movable to an open
position to receive a sheet 112 of receptacles 114. Lid 110
includes various buttons 116 that may be pressed to puncture an
associated receptacle 114 prior to inhalation. Conveniently, lid
110 includes a window 118 to indicate that sheet 112 is loaded and
may also show a date and type of medication printed on sheet 112.
Housing 108 further includes a mouthpiece 120 and a slidable cover
122 that may be slid over mouthpiece 120 when not in use.
[0151] When a patient is ready to receive a treatment, the patient
slides cover 122 to expose mouthpiece 120. One of buttons 116 is
then pressed and the user inhales while their mouth is over
mouthpiece 120. Once all of buttons 116 have been pressed, sheet
112 may be replaced with a new sheet of receptacles.
[0152] FIG. 16 illustrates an aerosolization device 124 that
comprises a cover 126 (see also FIG. 16A) and a drawer 128 that is
slidable within cover 126 as indicated by the arrow. Drawer 128 is
configured to hold a receptacle 130. As shown in FIG. 16A, when
drawer 128 is closed, receptacle 130 is held within cover 126.
Conveniently, the chamber of receptacle 130 may be configured to be
pierced when drawer 128 is closed. Various press buttons 132 may be
provided to allow drawer 128 to be retracted following use. Cover
126 further includes a mouthpiece 134 and a window to indicate that
receptacle 130 is loaded, along with showing a date and type of
medication. Optionally, a counter 138 may be provided to show the
cumulative number of uses for the device.
[0153] FIG. 17 illustrates an aerosolization device 140 comprising
a housing 142 having a mouthpiece 144 and a lid 146. Lid 146 is
movable between an open position and a closed position as
illustrated in phantom line. When lid 146 is opened, a receptacle
148 may be placed within housing 142. When lid 146 is closed,
receptacle 148 is pierced and device 140 is ready for operation.
Conveniently, lid 146 may include a raised window 150 containing a
ball 152. The region behind window 150 may be placed in
communication with the airflow path, thereby causing ball 152 to
move within the region depending on the rate of flow of respiratory
gases through device 140. Conveniently, plus and minus signs may be
used to provide the patient with visual feedback on the rate of
flow through the device. In this way, the patient may adjust their
inhalation rate based on the visual feedback. Optionally, device
140 may include a storage compartment 154 for holding extra
receptacles 148.
[0154] FIG. 18 illustrates a device 156 comprising a housing 158
having a mouthpiece 160 and a lid 162. A hinge 164 is employed to
pivotally couple lid 162 to housing 158. Lid 162 is movable between
an open position and a closed position. When in the open position,
a receptacle 166 may be loaded into housing 158. Lid 162 is then
closed, with receptacle 166 being visible through a window 168. Lid
162 includes a press button 170 which is pushed to pierce
receptacle 166 prior to use.
[0155] FIG. 19 illustrates an aerosolization device 172 comprising
a housing 174 and a door 176 that is coupled to housing 174 by a
hinge 178. Insertable into device 172 is a disk 180 having multiple
receptacles 182 as illustrated in FIG. 19A. Conveniently, each of
the receptacles may be numbered as illustrated in FIG. 19A. Door
176 includes a dial 184 that is rotatable to rotate disk 180 within
device 172. Door 176 also includes a window 186 to view the
receptacle that has been pierced by rotating dial 184. When ready
to receive a treatment, the user places their mouth over a nose 187
of device 172 and begins to inhale. The patient's inhalation opens
a lid 188 to permit the aerosolized formulation to enter into the
patient's lungs. To receive another treatment, the user simply
dials dial 184 to the next receptacle which is pierced, making
device 172 ready for operation.
[0156] Referring now to FIGS. 20 and 20A, an alternative
aerosolization device 190 will be described. Device 190 comprises a
housing 192 and a lid 194 that is coupled to housing 192 by a hinge
196. Device 190 further includes a mouthpiece 198 through which the
patient inhales. As shown in FIG. 20A, device 190 is in an open
position where a receptacle 200 is placed in a loaded position. Lid
194 may then be closed to the position illustrated in FIG. 20. Lid
194 includes a press button 202 that is pressed to pierce
receptacle 200 so that the pharmaceutical formulation may be
extracted. Lid 194 also includes a timer 204 that is manually set
by having the user pull timer 204 toward button 202 prior to
operation. The user then begins to inhale from mouthpiece 198 to
aerosolize the pharmaceutical formulation. Preferably, the user
inhales until timer 204 expires. As shown in FIG. 20A, lid 194 may
include multiple storage locations for storing additional
receptacles 200.
[0157] FIG. 21 illustrates an aerosolization device 206 comprising
a housing 208 having a slot 210 for receiving a receptacle 212.
Device 206 further includes a cocking device 214 that is cocked to
cause receptacle 212 to be pierced. Device 206 further includes a
trap door 216 and an extendable mouthpiece 218 (shown in phantom
line). When cocking device 214 is cocked to pierce receptacle 212,
trap door 216 is also opened and mouthpiece 218 is extended.
[0158] Referring now to FIG. 22, another aerosolization device 220
will be described. Device 220 comprises a housing 222 and a clip
224 that may be coupled to housing 222. As best shown in FIG. 22A,
clip 224 includes a storage region 226 and a waste region 228.
Storage region 226 includes multiple receptacles 230 that may be
loaded into housing 222 as described hereinafter. Once a receptacle
has been used, it is ejected into waste region 228. Conveniently, a
removable seal 232 may be disposed over storage region 226. Use of
clip 224 is advantageous in that replacement clips, having a fresh
supply of receptacles, may easily be coupled to housing 222, making
device 220 a multi-use device.
[0159] As best shown in FIG. 22, housing device 220 further
includes a rotatable dial 234 that is rotated to advance one of the
receptacles 230 from storage region 226 and into housing 222. When
placed within housing 222, receptacle 230 is pierced. Further,
housing 222 includes a counter 236 to display how many receptacles
remain unpierced. A tethered mouthpiece cover 238 is coupled to
housing 222 and is removed prior to inhalation.
[0160] Hence, to use device 220, the user simply rotates dial 234
to advance and pierce the next receptacle. Cover 238 is removed and
the patient inhales to aerosolize the pharmaceutical formulation
and deposit the formulation within the patient's lungs. When ready
for a next dosage, dial 234 is again dialed causing the used
receptacle to be ejected into waste region 228 and advancing
another receptacle. When all receptacles have been used, clip 224
is removed and placed with a replacement clip.
[0161] FIG. 23 illustrates an aerosolization device 240 comprising
a housing 242 and a lid 244 pivotally coupled to housing 242. A
removable mouthpiece cover 246 is also provided (see also FIG.
23A). Cover 246 is removed prior to inhalation by the patient.
Device 240 is configured to hold a strip 248 of receptacles 250 (as
shown in FIG. 24). Once strip 248 is within housing 242, a slide
252 may be moved to indicate the desired receptacle that is to be
pierced. Slide 252 may then be depressed to pierce the selected
receptacle. Optionally, slide 252 may be coupled to plumbing within
device 240 so that the plumbing is moved to the appropriate
receptacle along with slide 252. Device 240 may also include a
whistle 254 that produces an audible signal when the user inhales
in excess of a maximum inhalation flow rate. The user may simply
inhale at a slower flow rate until whistle 254 ceases producing a
whistling sound.
[0162] FIG. 25 illustrates an aerosolization device 256 comprising
a housing 258 and a mouthpiece cover 260 that is tethered to
housing 258. Cover 260 is removed prior to use. Housing 258 further
includes a slot 262 that extends through housing 258. In this way,
a continuous strip 264 of receptacles 266 may be fed through slot
262. Alternatively, strip 264 may be separated into segments so
that an individual receptacle may be fed into slot 262. Housing 258
includes a button 268 that may be depressed to pierce the loaded
receptacle.
[0163] When the patient begins to inhale, their flow rate is
monitored by a gas gauge 270. In this way, the user is provided
with visual feedback to assist them in inhaling at the proper flow
rate. Optionally, housing 258 may include a clip 272 to permit
device 258 to be carried on the pocket like a pen.
[0164] FIG. 26 illustrates an aerosolization device 274 comprising
a housing 276 having a mouthpiece 278 and a rotatable body 280 that
is rotatable relative to housing 276. Device 274 is configured to
receive a receptacle pack 282 at a back end of device 274.
Receptacle pack 282 includes multiple receptacles 284 that may be
pierced when ready for use. Although receptacle pack 282 is shown
as being cylindrical in geometry, it will be appreciated that other
geometries may be employed, including square shaped tubes.
[0165] Once receptacle pack 282 is inserted into device 274,
rotatable body 280 is rotated to advance one of the receptacles to
an engaging position where the receptacle is pierced. Conveniently,
housing 276 includes a counter 286 to display the remaining number
of receptacles. If the patient inhales at an excessive flow rate,
housing 276 is configured to vibrate to provide the user with
feedback so that they may adjust their inhalation flow rate.
[0166] A wide variety of threshold valves may be used to prevent
the flow of gases to the patient's lungs until the patient has
produced a sufficient vacuum needed to extract the powder from the
receptacle. Such valves may be configured to prevent any flow of
gases until the vacuum produced by the patient meets or exceeds the
threshold actuating pressure of the valve. After the valve opens,
minimal flow resistance is provided by the valve. Once the flow
stops, the valve may be configured to reset to its former starting
position.
[0167] Shown in FIG. 27 is a schematic diagram of a valve system
300 having a threshold valve 302 that may be configured to crack at
a pressure in the range from about 20 cm H.sub.2O to about 60 cm
H.sub.2O, and more preferably at least about 50 cm H.sub.2O, to
allow gas flow through the aerosolization device in the direction
indicated by the arrows. In this way, a relatively high flow rate
may be achieved for a short duration at the beginning of inhalation
to allow the powder to be dispersed from the receptacle.
[0168] Optionally, system 300 may include a check valve 304 to
prevent the user from blowing through the device. Such a check
valve may be incorporated anywhere in the aerosolization device,
and for convenience may be integrated with the threshold valve.
System 300 may be configured to have little resistance to the flow
of gases once valve 302 is opened. In some cases, system 300 may be
configured to have a reset feature to reset valve 302, if needed.
In some cases, system 300 may be configured to have an adjustment
mechanism to permit the adjustment of the threshold actuating
pressure, lowering of any reset vacuum level, and/or raising of
back flow resistance pressure.
[0169] One type of threshold valve that may be used is a silicone
rubber valve that is tailored to provide flow onset at the desired
threshold pressure and to provide reverse flow inhibition. Such a
valve is also self resetting, requiring no mechanical resistance.
Examples of such valves are described in, for example, U.S. Pat.
Nos. 4,991,745, 5,033,655, 5,213,236, 5,339,995, 5,377,877,
5,409,144, and 5,439,143, the complete disclosures of which are
herein incorporated by reference.
[0170] Examples of various types of threshold valves that may be
incorporated into an aerosolization device are illustrated in FIGS.
28-40. Shown in FIG. 28 is a pull through threshold valve 306 that
is constructed of a housing 308 having an inlet 310 and an outlet
312. A membrane 314, such as an elastomeric membrane, is disposed
across the interior of housing 308 and has a central opening 316. A
ball 318 is sealed within housing 308 and is configured to be
pulled through opening 316 when a sufficient vacuum is created by
the user as shown in phantom line. Once ball 318 passes through
membrane 314, gas flow is permitted through housing 308 by passing
through passages 320. Conveniently, a reset rod 322 may be used to
push ball 318 back to the other side of membrane 314 in order to
reset the valve for another use.
[0171] FIG. 29 illustrates an umbrella pull through valve 324.
Valve 324 comprises a housing 326 having a support member 328 for
supporting an umbrella member 330. Housing 326 also includes tabs
332 which prevent axial movement of umbrella member 330 until the
user creates a sufficient vacuum. At such a time, umbrella member
330 flexes to pass tabs 332 as shown in phantom line. Gases are
then permitted to flow through openings 334 in support 328. A reset
rod 336 may be used to push umbrella member 330 back past tabs 332
prior to another use.
[0172] FIG. 30 illustrates a threshold valve 338 comprising a
tubular housing 340 across which a valve member 342 is pivotally
disposed. A biasing member 344 biases valve member 342 against a
tab 346. In this way, gases are permitted to flow through housing
340 once a sufficient vacuum is created to overcome the biasing
force and thereby permit valve member 342 to open as shown in
phantom line.
[0173] FIG. 31A illustrates a flapper valve 348 that may be used in
a tubular housing. Valve 348 comprises two valve members 350 that
are pivotally coupled to a shaft 352. A spring (not shown) biases
members 350 in the position shown in FIG. 31A. When a sufficient
vacuum force is provided, the spring force is overcome and members
350 move to the open position shown in FIG. 31B to permit to flow
of gases.
[0174] FIG. 32 illustrates a spindle type valve 354 that comprises
a tubular housing 356 having a spindle 358 that is held between
tabs 360 and 361. Pass through channel 362 are arranged such that
gases are permitted to flow through channels 362 and around spindle
358 when the vacuum created by the user moves the spindle to tabs
361.
[0175] The frictional force between spindle 358 and housing 356 may
be varied depending on the desired threshold force required to open
the valve.
[0176] FIG. 33 illustrates another spindle type valve 364
comprising a tubular housing 366 having a stop 368. A spindle 370
is disposed within housing 366 so as to be adjacent stop 366,
thereby preventing the flow of gases through housing 366. When a
sufficient vacuum has been produced by the patient, spindle 370
slides within housing 366 and away from stop 366. In this way,
gases are permitted to flow through housing 366.
[0177] FIG. 34A illustrates a threshold valve 372 that comprises a
tubular housing 374 having a support 376 that holds an evertible
umbrella member 378 having a ball 380. Ball 380 serves to secure
member 378 to support 376 when a vacuum is applied by the user. As
shown in FIG. 34B, member 378 is configured to evert when a
sufficient vacuum is produced by the user. When in the everted
position, gases flow through openings 382 in support 376 as shown.
Member 378 may be reset to the position shown in FIG. 34A prior to
another use.
[0178] The threshold valve may be a valve designed to alternate
between open and closed positions based upon a predetermined
magnetic field strength. For example, FIG. 35 illustrates a
threshold valve 384 comprising a housing 386 that holds a steel
ball 388. Also disposed within housing 386 is a magnet 390 and an
elastomeric gasket 392 having a central opening 394 that is smaller
in diameter than ball 388. In this way, magnet 390 holds ball 388
across opening 394 to prevent the flow of gases through housing
386. When the user provides a sufficient vacuum, ball 388 is moved
against a stop 396 as shown in phantom line. Gases are then free to
flow through opening 394 and around ball 388. The magnetic field is
designed to be strong enough such that the ball is reset to
obstruct airflow when the user stops the inhalation.
[0179] FIG. 36A illustrates a threshold valve 398 comprising a
tubular housing 400 having a restriction 402 with a central orifice
404. A bistable dome 406 is coupled to a support 407 and is
disposed across the interior of housing 400 to cover orifice 404
when in the position shown in FIG. 36A. When a user provides a
sufficient vacuum, dome 406 performs a bistable function to move to
the position shown in FIG. 36B. In this way, gases may flow through
orifice 404 and then through openings 408 in support 407 as shown
by the arrows.
[0180] FIG. 37A illustrates a threshold valve 410 that comprises a
tubular housing 412 having a flexible bladder 414 that is sealed to
housing 412. When the pressure is below a threshold pressure,
bladder 414 maintains the shape shown in FIG. 37A. In this way, a
ball 416 is prevented from passing through bladder 414, thereby
preventing the flow of gases through housing 412. Channels 418 are
in communication with the interior of bladder 414 so that when the
patient produces a vacuum that is greater in magnitude than the
threshold pressure, bladder 414 moves to the position shown in FIG.
37B to permit gases to flow through housing 412.
[0181] FIG. 38 illustrates a threshold valve 420 comprising a
tubular housing 422 having a frangible diaphragm 424. Diaphragm 424
is configured to rupture when a threshold vacuum has been applied
by the user as shown in phantom line.
[0182] FIG. 39 illustrates a threshold valve 426 comprising a
tubular housing 428 and a valve member 430 pivotally coupled to
housing 428. Valve member 430 prevents the flow of gases through
housing 428 when in a closed position as shown in FIG. 39. A stop
432 prevents valve member 430 from opening until a threshold vacuum
is produced by the user. Stop 432 is coupled to a membrane 434 that
is held within a chamber 436. Chamber 436 is in communication with
the interior of housing 428 by a passage 438. In this way, when a
sufficient vacuum has been produced; stop 432 is lifted up to
permit valve member 430 to open. Conveniently, a vent 440 may be
provided to permit air to flow into chamber 436 when membrane 434
moves upward. Also, a spring 442 may be provided to move valve
member 430 to the open position when stop 432 is raised.
[0183] FIG. 40 illustrates a pull through type threshold valve 444
that comprises a housing 446 and a valve member 448 that is
disposed within housing 446. A stop 450 holds valve member 448 in
place until a threshold pressure is produced by the patient. At
such a time, valve member 448 collapses as shown in phantom line to
permit valve member 448 to pass beyond stop 450.
[0184] A variety of flow regulators may be used to limit the flow
of gases through the aerosolization device and into the user's
lungs after the powder has been extracted from the receptacle and
aerosolized. Such flow regulators are provided to limit the flow
rate through the device for a specified time to insure that the
flow rate is slow enough for the aerosol to travel through the
airways and past the anatomical dead volume.
[0185] FIG. 41 schematically illustrates one embodiment of a flow
regulator 460. Regulator 460 may be configured to limit the flow of
gases to be less than about 15 L/min, and more preferably less than
about 10 L/min. Regulator 460 may be configured such that the
resistance to the flow is small at low vacuum and increases with
the vacuum generated by the user. Conveniently, regulator 460 may
be placed in a flow path that is parallel to the receptacle
containing the powder. In such a case, the flow regulator may
provide a system resistance to flow R that varies from about 0.1
(cm H.sub.20).sup.1/2/standard liters per minute (SLM) up to the
resistance of the receptacle flow path. Alternatively, the flow
controller may be placed in series with the receptacle. In such a
case, the system resistance R may vary from the resistance of the
receptacle flow path up to a resistance greater than 1.0 (cm
H.sub.20).sup.1/2/SLM.
[0186] Shown in FIGS. 42-59 are various types of flow regulators
that may be used in aerosolization devices to regulate gas flow
after the receptacle has been opened. For example, FIG. 42A
illustrates a flow regulator 462 comprising an L shaped housing 464
having a flow channel 466. A shuttle 468 having skirt seals 470 is
slidable within housing 464. A return spring 472 biases shuttle 468
in the position shown in FIG. 42A. As the flow rate through housing
464 increases, shuttle 468 moves within housing 464 to compress
spring 472 and close off flow channel 466. In this way, the flow
rate is limited to a certain rate. If the flow rate is too
excessive, channel 466 closes as shuttle 468 engages stops 474 as
shown in FIG. 42B. When the flow stops, spring 472 moves shuttle
468 to the starting position.
[0187] FIG. 43 illustrates a flow regulator 476 that also includes
a threshold valve that is similar in construction to that
previously described in connection with FIG. 28. Regulator 476
comprises a housing 478 having a tapered flow channel 480 and a
membrane 482 that serves as a threshold valve in a manner similar
to that previously described. In FIG. 43, a ball 484 has passed
through membrane 482 and is forced against a spring 486 by the
vacuum produced by the user. As the vacuum increases, spring 486
compresses as ball 484 moves further into channel 480 as shown in
phantom line. As a result, the flow path is restricted, thereby
limiting the flow of gases. The spring constant of spring 486 may
be adjusted to provide the desired flow control features.
[0188] FIGS. 44A and 44B illustrate a flow regulator 488 comprising
a tubular housing 490 into which a bellows 492 is disposed. Bellows
492 may be constructed of an elastomer that is configured to
compress when the flow through housing 490 increases as shown in
FIG. 44A. As bellows 492 compresses, a flow path 494 through the
bellows decreases to limit the flow rate.
[0189] FIG. 45 illustrates a flow regulator 496 comprising a
tubular housing 498 into which a cone member 500 having orifices
501 is slidably disposed. A restriction member 502 having a flow
channel 504 is also held within housing 498. A spring 506 is
disposed between cone member 500 and restriction member 502. As the
flow rate through orifices and flow channel 504 increases, spring
506 compresses and cone member 500 moves further into flow channel
504, thereby limiting the flow of gases through housing 498.
[0190] FIG. 46 illustrates a flow regulator 508 that comprises a
tubular housing 510 having a closed end 512 and flow channels 514
that permit gases to flow into housing 510 from another housing 516
having flow channels 518. A spring 520 biases housing 510 to the
left as shown in FIG. 46. As the flow rate increases, spring 520
extends and moves housing 510 to the right of FIG. 46. In so doing,
flow channels 514 are restricted by housing 516 to limit the gas
flow.
[0191] FIG. 47 illustrates a flow regulator 520 that comprises a
tubular housing 522 having a compartment 524 that is filled with an
open cell foam 526. The open cell foam material restricts and
regulates the flow of gases through housing 522, by using the
applied vacuum to compress the foam and constrict the porous flow
channels.
[0192] FIG. 48 illustrates a flow regulator 528 that comprises a
tubular housing 530 having a support 532 with a plurality of
orifices 534. An umbrella member 536 is held by support 532 and
limits gas flow through housing 530. Conveniently, umbrella member
536 may be evertible in a manner similar to that described in
connection with FIGS. 43A and 43B to also function as a threshold
valve.
[0193] FIG. 49 illustrates a flow regular 538 that comprises a
housing 540 having an inlet tube 542 and an outlet tube 544.
Disposed within housing 540 is a liquid 546. As gases flow through
housing 540, the gases bubble through liquid 546 which regulates
the flow of the gases through housing 540.
[0194] FIG. 50 illustrates a flow regulator 548 that comprises a
tubular housing 550 having a necked region 552. A shuttle 554 is
held within housing 550 and is forced into necked region 552 as the
vacuum force increases. The force required to move the shuttle 554
is controlled by a spring 556. In this way, as the vacuum force
increases, the flow path is restricted to limit the flow rate
through housing 550.
[0195] FIG. 51 illustrates a flow regulator 556 that comprises a
tubular housing 558 having a spindle 560 that is slidable within
housing 558. A spring 562 biases spindle 560 to the right as shown
in FIG. 51 so that a flow path 564 of spindle 560 is aligned with
flow paths 566 in housing 558. Hence, in the position shown in FIG.
51, gases may flow through housing 558 by passing through flow
paths 564 and a flow path 568 in spindle 560. However, as the
vacuum force increases, spindle 560 moves to the left to restrict
flow paths 566, thereby limiting the flow of gases through housing
558.
[0196] FIG. 52 illustrates a flow regulator 570 comprising a
tubular housing 572 having an expandable cone 574. Cone 574
includes an orifice 576 and is configured so that gas flow may pass
through orifice 576 as well as around cone 574 when the flow rate
is low as shown in FIG. 52. When the flow rate is increased, cone
574 expands to provide a seal against housing 572 so that gas flow
is only permitted through orifice 576.
[0197] FIGS. 53A and 53B illustrate a flow regulator 580 that
comprises in iris valve 582. One end 584 may be fixed and another
end 586 may be rotated to move iris valve 582 to the position shown
in FIG. 53B. In this way, the flow rate through valve 582 may be
regulated.
[0198] FIG. 54 illustrates a flow regulator 588 that comprises a
housing 590 having a paddle wheel 592 that is rotatable in only one
direction as shown by the arrows. Paddle wheel 592 is pivotally
connected to housing 590 by a frictional connection that may be
adjusted to regulate the amount of gas flow through housing 590. By
being rotatable in only one direction, paddle wheel 592 also serves
as a check valve.
[0199] FIGS. 55A and 55B illustrate a flow regulator 594 comprising
a tubular housing 596 having pivotal flaps 598. Flaps 598 are
configured to close when experiencing a high gas flow as
illustrated in FIG. 55B to reduce the flow rate through housing
596.
[0200] Another type of flow regulator comprises a valve that is
constructed of a flexible material, such as a soft elastomer, e.g.,
a silicone rubber, that limits the flow to a certain rate while
also preventing flow in the opposite direction. Such a valve is
also self-resetting, requiring no mechanical assistance. Such
valves have an orifice that permits the flow of air through the
valve in response to an applied vacuum, and one or more collapsible
walls surrounding the orifice such that an increased vacuum
pressure level results in reduction of orifice area and correspond
higher resistance to flow. One feature of such valves is that they
may be relatively inexpensive to construct. One particular example
of such a valve is described in U.S. Pat. No. 5,655,520, the
complete disclosure of which is herein incorporated by
reference.
[0201] FIGS. 56A and 56B illustrate one embodiment of such a flow
regulator 600. Flow regulator comprises an elastomeric body 602
having a duckbill valve 604 that includes an orifice 606. In FIG.
56A, the flow rate is low and orifice 606 is fully opened. When the
flow rate increases, valve 604 begins to close as shown in FIG. 56B
to limit the flow.
[0202] Other examples of such flow regulators are shown in FIGS.
57-59. In FIG. 57, a flow regulator 608 has a duckbill valve 610
with a top orifice 612. FIG. 58 illustrates a flow regulator 614
having a duckbill valve 616 with an orifice 618 extending from the
top and down the side. FIG. 59 illustrates a flow regulator 620
having a duckbill valve 622 with a separate top orifice 624 and a
side orifice 626.
[0203] After the flow rate through the aerosolization device has
been regulated for a certain time period, the device may be
configured to permit an increased flow rate. In this way, the user
may fill his or her lungs with a sufficient volume of air needed to
carry the aerosol to the deep lung. For example, following
regulation of the flow rate, the device may be configured to permit
the user to comfortably fill his or her lungs as the user continues
to inhale through the device. Typically, the user may be permitted
to fill their lungs at a comfortable rate once an initial volume of
about 500 mL has been inhaled at the regulated flow rate. This
assumes that after about 500 mL of inhaled air, the drug has
traveled past the anatomical dead space.
[0204] To provide such a feature, various timers or flow
integrators may optionally be incorporated into the aerosolization
devices of the invention. Such flow integrators have one or more
moving members that move based on the volume of flow through the
device. In this way, when the initial (regulated) volume has been
inhaled, the member has moved sufficient to open another gas
channel to permit increased gas flow. For example, the flow
integrator may be an airfoil flap made of a film such as a polymer
film having a thickness between 0.005 and 0.020 inches and
preferably having a viscoelastic or other time-dependent behavior.
Airflow over the airfoil flap induces aerodynamic lift. The air
foil flap can be configured to allow access to a parallel flow path
after a predetermined volume of air flows over the flap.
[0205] FIG. 60 schematically illustrates a flow through type flow
integrator 630 that is configured to move based on the flow
velocity, assuming a low pressure drop. Integrator 630 moves based
on the pressure differential between the ambient and the inlet,
which can vary significantly even though the flow rate remains
constant when using a flow regulator as described above. One
advantage of integrator 630 is that it provides an accurate volume
measurement.
[0206] FIG. 61 schematically illustrates a flow-by type integrator
632 that is parallel to the main flow path. Optionally, integrator
632 may trigger a switch at the end of travel to open a parallel
flow path with low flow resistance.
[0207] FIGS. 62A and 62B illustrate a flow through shuttle type
flow integrator 634 that comprises a tubular housing 636 and a
shuttle 638 that is slidable within housing 636. Conveniently,
skirt seals 640 provide a seal between housing 636 and shuttle 638
while still permitting shuttle 638 to slide. Stops 642 and 644 are
also provided to limit travel of shuttle 638. In FIG. 62A, shuttle
638 is in the closed position where the main flow through the
aerosolization device passes through an opening 646 in shuttle 638,
and a parallel flow through a channel 648 is prevented by shuttle
638. Shuttle 638 moves through housing 636 in response to the
velocity of the gas flowing through housing 636. The drag force,
and therefore the speed at which shuttle 638 moves, is proportional
to the flow velocity. As shown in FIG. 62B, shuttle 638 moves past
channel 648 after a certain amount of time to permit increased flow
through housing 636.
[0208] FIG. 63 illustrates a flow integrator 650 that comprises a
tubular housing 652 through which the main gas flow through the
aerosolization device passes. Disposed within housing 652 is an
impeller 654 that is coupled to a gear reduction 656. In turn, gear
reduction 656 is coupled to a cam 658 that has a hole 660 as also
shown in FIG. 64. Cam 658 is rotatable through a tubular housing
662 that provides a parallel flow path through the aerosolization
device. In operation, the user inhales to provide gas flow through
housing 652 which turns impeller 654. In turn, cam 658 is rotated
through gear reduction 656. When cam 658 reaches a specific angle,
hole 660 is aligned with housing 662 to open a parallel flow path
for the chase air.
[0209] As an alternative to the impeller 654, a paddle wheel 664
may be used as illustrated in FIG. 65. In such an embodiment,
paddle wheel 664 may be coupled to gear reduction 656 in a manner
similar to that previously described.
[0210] FIGS. 66A and 66B illustrate a flow integrator 666 that
comprises a tubular housing 668 having a parallel flow path 670.
Coupled to housing 668 is a main flow path 672. An opening 674
places housing 668 and flow path 672 in fluid communication.
Disposed within housing 668 is a shuttle 676 having skirt seals 678
to provide a seal between shuttle 676 and housing 668. A spring 680
is disposed between housing 668 and shuttle 676, and an umbrella
valve 682 with a bleed hole 684 extends through housing 668.
[0211] As shown in FIG. 66B, shuttle 676 prevents parallel gas flow
through flow path 670 when the user first begins to inhale. Shuttle
676 moves under force of spring 680, damped by bleed hole 684 (or
alternatively by controlled leakage around shuttle 676). Shuttle
676 moves faster when the pressure differential between the inlet
side (having bleed hole 684) and the outlet side (having opening
674) is increased due to the vacuum created by the user. When
shuttle 676 reaches the end of its travel, parallel flow path 670
is opened for the chase air. A reset rod 686 may then be used to
reset shuttle 676 to the position shown in FIG. 66B.
[0212] FIG. 67 illustrates a flow integrator 690 comprising a
tubular housing 692 that serves as a main flow path. A brake system
694 having a pivotal brake arm 696 extends into housing 692.
Coupled to brake arm 696 is a brake pad 698 as also shown in FIG.
68. Integrator 690 further comprises a wheel 700 that moves through
a tubular housing 702 that serves as a parallel flow path for the
chase air. Wheel 700 has a hole 703 that aligns with housing 702
when wheel 700 is at a specified angle. Brake arm 696 is spring
loaded against wheel 700 with a spring 701. Also coupled to wheel
700 is a trigger 704 that fits within a groove 706 of brake arm
696.
[0213] To operate integrator 690, the user winds a spring (not
shown) which rotates wheel 700 at a constant rate when released.
When the user creates a main flow through housing 692, brake arm
696 pivots to release trigger 704 and brake pad 698. Wheel 700 then
rotates at a constant rate until hole 703 becomes aligned with
housing 702, thereby opening a parallel flow path for the chase
air.
[0214] The threshold valves, flow regulators and, optionally, flow
integrators of the invention may be arranged in a variety of
configurations within an aerosolization device. For example, FIG.
69 illustrates an aerosolization system 710 where the various
components are arranged in series. System 710 comprises, in series,
an inlet 711, a threshold valve 712, a flow regulator 714, a flow
integrator 716 of the flow through type, a receptacle 718 for
holding a powdered medicament, and an outlet 720. The total
resistance of receptacle 718 may be configured to be less than or
equal to the resistance of the rest of the system until flow
integrator 716 opens. Conveniently, the order of threshold valve
712, flow regulator 714 and flow integrator 716 (if a flow through
type integrator) may be interchanged. Alternatively, flow
integrator 716 may be a flow-by type integrator that may be
parallel to receptacle 718. Receptacle 718 may be last in the
series to prevent the drug from depositing on the other components.
Conveniently, threshold valve 712, flow regulator 714 and flow
integrator 716 may be integrated into one mechanism.
[0215] FIG. 70 illustrates an aerosolization system 722 that
comprises an inlet 724, a threshold valve 726, a flow regulator
728, a receptacle 730, a flow integrator 732 of the flow-by type,
and an outlet 734. Integrator 732 is arranged parallel to threshold
valve 726 and regulator 728. With system 722, the maximum system
resistance may be less than or equal to the resistance of
receptacle 730. In this way, some users may achieve flow rates
above 10 L/min. Integrator 732 operates from the pressure
differential between ambient and outlet 734. Conveniently,
threshold valve 726 and flow regulator 728 may be integrated.
[0216] FIG. 71 illustrates an aerosolization system 736 that
comprises an inlet 738, a threshold valve 740, a flow integrator
742 of the flow through type, a flow regulator 744, a receptacle
746 and an outlet 748. With system 736, the order of threshold
valve 740 and flow integrator 742 may be changed. Further, the
maximum system resistance may be less than or equal to the
resistance of receptacle 746. Use of the flow through type of
integrator provides a more accurate volume measurement since it
operates as a result of the flow rate through it. System 736 also
allows for integration of threshold valve 740 and flow regulator
744, or flow integrator 742 and flow regulator 744. In one aspect,
system 736 may be configured so that flow integrator 742 does not
restrict the flow spike which occurs after threshold valve 740
opens so that the high flow rate passes entirely through receptacle
746 to disperse the powder.
[0217] FIGS. 72-78 illustrate one particular embodiment of an
aerosolization device 750 that incorporates a threshold valve, a
flow regulator and a flow integrator. Device 750 comprises a
housing 752, a door 754 that is pivotally coupled to housing 752 by
a shaft 756 and a pivotable mouthpiece 758. As best shown in FIG.
73, door 754 may be opened to permit a receptacle 760 (shown
already opened) to be inserted into device 750. Device 750 further
includes a an extraction tube 762 that is in commination with
mouthpiece 758 to permit the drug that is extracted from receptacle
760 to pass into mouthpiece 758. A deagglomerator 764 is provided
in mouthpiece 758 to deagglomerate any agglomerated powder the is
extracted from receptacle 760. Conveniently, deagglomerator 764
also serves as a shaft about which mouthpiece 758 pivots. Coupled
to extraction tube 762 is a cutter 766 that pierces receptacle 760
when door 754 is closed so that the drug may be extracted.
[0218] Incorporated into door 754 is a threshold valve 768 that
comprises a membrane 770 having an opening 772. A valve member 774
having a ball 776 that is movable through opening 772 once a
threshold vacuum that is produced by the user is met or exceeded.
In operation, a user inhales from mouthpiece 758 which creates a
vacuum in tube 762 and in a passage 778 that is in communication
with a right hand side of membrane 770. Once the threshold vacuum
pressure is met or exceeded, ball 776 is pulled through opening 772
to permit outside air to enter into a region 780 of door 754
through a vent (not shown). In this way, air flows through
receptacle 760 to extract the powdered drug where it is delivered
to mouthpiece 758. Conveniently, device 750 further includes a cam
782 that moves ball 780 back through opening 772 when door 754 is
opened and closed to reset the valve.
[0219] Device 750 further includes a flow regulator 784 to limit
the air flow through tube 762 to a certain rate. Regulator 784
comprises a tapered opening 786 into which ball 780 is drawn as the
vacuum created by the user increases. A spring 785 controls the
amount of vacuum require to close opening with ball 776. Hence, if
the flow rate becomes too great, a parallel flow path 788 that
leads back into tube 762 is closed off by ball 780. In this way,
the only air passing through tube 762 must pass through receptacle
760 as previously described. This flow path has sufficient
resistance such that the flow is limited to the desired rate. If
the user does not create a vacuum sufficient to close flow path
788, the air flow is permitted through two parallel flow paths.
[0220] Device 750 further includes a flow integrator 790 to permit
an increased flow rate once a certain amount of time has passed so
that the user may comfortably fill their lungs after the flow has
been regulated for a specified time. Flow integrator 790 comprises
a clutch diaphragm 792 upon which a spool 794 rests. Spool 794 is
biased to rotate by a torsional spring 796. In this way, when
diaphragm 792 is disengaged from spool 794, spool 794 rotates until
an opening (not shown) in spool 794 becomes aligned with an opening
798 (see FIG. 76) in tube 762. At this point, ambient air is able
to flow through a parallel flow path and into tube 762 to permit
the user to comfortably fill their lungs with air.
[0221] Diaphragm 792 is configured to lower to release spool 794
due to the vacuum created in flow path 788 as the user inhales from
mouthpiece 758 as previously described. The rate of spool rotation
(and hence the time required to open the parallel flow path) is
determined by a damping reservoir 800 which contains a damping
grease. A fixed member 802 fits within reservoir 800 to regulate
the rate of spool rotation as member 802 frictionally engages the
damping grease. Although not shown, device 750 may include a reset
lever to reset spool 794 after use.
[0222] FIGS. 79-83 illustrate another embodiment of an
aerosolization device 850 that comprises a lower housing 852, an
upper housing 854 and a rotatable mouthpiece 856. As best shown in
FIG. 80, lower housing 852 may be separated from upper housing 854
to permit a drug containing receptacle 858 to be inserted into
device 850. A lower housing catch 855 is provided to limit the
travel of housing 852 relative to upper housing 854. Coupled to
mouthpiece 856 is a tube 860 having a cutting mechanism 862 to open
receptacle 858 when receptacle 858 is inserted and lower housing
852 is placed adjacent upper housing 854.
[0223] Disposed across lower housing 852 is a membrane 862 having
an opening 864. Extending through opening 864 is a latch 866 having
a ball 868. Positioned below latch 866 is a hole 890 in lower
housing 852. Such a configuration provides a threshold valve for
device 850. In this way, when a user inhales from mouthpiece 856, a
vacuum is created in tube 860 and in the space above membrane 862.
When the user creates a sufficient vacuum, ball 868 is pulled
through opening 864 in membrane 862 to permit outside air to flow
through hole 890, through opening 864, through receptacle 858 and
up through tube 860 where the aerosolized drug exits through
mouthpiece 856.
[0224] Once the drug has been aerosolized, the flow of air through
device 850 is regulated to be less than a certain rate in part
through use of an elastomeric duckbill valve 892. More
specifically, air is permitted to flow through two flow paths, i.e.
through valve 892 and through receptacle 858 provided the flow rate
is below the specified amount. As the air flow rate increases,
valve 892 begins to close to prevent air from flowing through this
flow path. The only available air path is then through receptacle
858 which provides sufficient resistance to limit the flow to a
certain rate.
[0225] Coupled to a cam 893 of latch 866 is a bypass spreader 894
that is engaged with a stop 896. Spreader 894 is coupled to a
spring 897 and is also slidable within a bypass duckbill valve 898.
As the user continues to inhale through mouthpiece 856, cam 893 of
latch 866 moves spreader 894 away from stop 896. This causes spring
897 to expand as shown in FIG. 82 to compress a bellows 900 and to
spread valve 898 which is normally closed. In this way, after a
certain period of time, valve 898 is opened to provide another flow
path so that more ambient air may flow through device 850 through
hole 890. In this manner, the user is permitted to comfortably fill
their lungs after the initial drug delivery. The rate of
compression of bellows 900 is controlled by filling bellows 900
with a known volume of air and by providing a small orifice in
bellows 900. In this way, the rate of compression is controlled by
the time required to force the air out through the orifice once
spreader 894 is released from stop 896.
[0226] FIGS. 84-87 illustrate another embodiment of an
aerosolization device 910 that comprises a lower housing 912, a
middle housing 914, an upper housing 916 and a mouthpiece 918.
Lower housing 912 is movable relative to middle housing 914 to
permit a drug containing receptacle 920 to be inserted as
illustrated in FIG. 85. Coupled to mouthpiece 918 is a tube 922
that is configured to pierce receptacle 920 to provide access to
the drug.
[0227] Middle housing 914 includes a membrane 924 having an opening
926. A valve member 928 having a ball 930 is positioned within
lower housing 912 and functions as a threshold valve to ensure that
a sufficient vacuum is created by the user when initially inhaling
the drug. In operation, the user inhales from mouthpiece 918 to
create a vacuum within tube 922 and in the space above membrane
924. When a sufficient vacuum has been produced, ball 930 is pulled
through opening 926 to permit ambient air to flow into lower
housing 912 through a hole 932, through opening 926, through
receptacle 920, through tube 922 and out mouthpiece 918. In so
doing, the drug is extracted from receptacle 920 and is supplied to
the user.
[0228] Device 910 is further configured to regulate the flow rate
of air through device 910 after ball 930 is pulled through membrane
924. This is accomplished in part by the use of an elastomeric
duckbill valve 934 in upper housing 916. As the user continues to
inhale, ambient air entering through hole 932 also passes through
opening 926 and then through valve 934. The air then travels
through an opening 936, an opening 938 and out mouthpiece 918.
However, if the flow rate becomes too great, valve 934 closes to
prevent air flow through this flow path. As a result, air may only
flow through receptacle 920 and tube 922 which, because of their
limited size, regulates the flow rate to within a specified rate to
permit the aerosolized drug to reach the user's lungs.
[0229] After a specified amount of time, device 910 is configured
to permit an increased flow of air through device 910 so that the
user may comfortably fill their lungs with air. This is
accomplished by use of a piston 940 that is coupled to upper
housing 916 by a pair of rolling seals 942 and 944. Piston 940
further includes a hole 946 that moves between seals 942 and 944
after a certain amount of time. When reaching this position, the
ambient air flowing through opening 932 also through hole 946,
through hole 936 and out mouthpiece 918. In this way, an additional
flow path is provided to permit the user to comfortably fill their
lungs after initial delivery of the drug.
[0230] Piston 940 moves due to a pressure differential between a
region 950 above piston 940 and a region 952 below piston 940. This
pressure differential is produced by a vacuum that is created in
region 950 when the user begins to inhale due to a bleed hole 954
that is in communication with region 950. The size of bleed hole
954 is configured to control the resulting vacuum within region
950, and therefore the rate of upward movement of piston 940.
[0231] A variety of techniques may be used to ensure that the user
properly positions their mouth over the mouthpiece during use of
the aerosolization devices of the invention. For example, a lip
guard may be included on the mouthpiece to permit the user to place
their lips adjacent the lip guard. As another example, the
mouthpiece may include bite or other landmarks. Alternatively, one
or more holes may be provided in the side of the mouthpiece. These
holes must be covered by the lips in order to create a sufficient
vacuum to operate the device. As a further example, the mouthpiece
may have a circular-to-elliptical profile. The elliptical portion
must be covered by the patient's mouth in order for a sufficient
vacuum to be created. Optionally, a tongue depressor may also be
used to depress the user's tongue when inhaling from the
mouthpiece.
[0232] Referring now to FIG. 88, one embodiment of a mouthpiece
1000 will be described. Mouthpiece 1000 comprises a tubular member
1002 having a distal end 1004 that is configured to be coupled to
an aerosolization device and an open proximal end 1006. Distal end
1004 has a circular cross sectional profile, while proximal end
1006 has a curved or elliptical cross sectional profile. In this
way, the user must place their mouth over mouthpiece 1000 until
their lips reach the circular portion in order to create the vacuum
needed to operate the aerosolization device. Another mouth position
device on mouthpiece 1000 is a pair of holes 1008 that must be
covered by the user's lips in order to produce the required vacuum.
As another alternative, mouthpiece 1000 may include bite landmarks
1010 for the user's front teeth. Similar bite marks may be provided
for the user's bottom teeth.
[0233] FIG. 89 illustrates another embodiment of a mouthpiece 1012
comprising a tubular member 1014 having a distal end 1016 that is
slidable over a tubular extension 1018 that in turn is coupled to
an aerosolization device. In this way, the user may adjust the
distance between a proximal end 1020 of tubular member 1014
relative to the aerosolization device. According to one embodiment,
the device is primed for actuation when tubular extension 1018 is
in the patient's mouth and the patient applies a force against
extension 1018 pushing extension 1018 forward in a direction
towards the device, thus priming the device for actuation. Also,
tubular member 1014 includes a tongue depressor 1022 that depresses
the user's tongue during inhalation to facilitate passage of the
aerosolized powder past the user's tongue and into the lungs.
[0234] The devices and methods of the present invention may be used
with both liquid or powdered pharmaceutical formulations. The
amount of active agent in the formulation will be that amount
necessary to deliver a therapeutically effective amount of the
active agent to achieve the desired result. In practice, this will
vary widely depending upon the particular agent, the severity of
the condition, and the desired therapeutic effect. According to a
preferred embodiment for administering powdered formulations,
pulmonary delivery is generally practical for active agents that
must be delivered in doses of from 0.001 mg/day to 100 mg/day,
preferably 0.01 mg/day to 50 mg/day.
[0235] Powdered formulations suitable for use in the present
invention include dry powders and particles suspended or dissolved
within a propellant. The powdered formulations have a particle size
selected to permit penetration into the alveoli of the lungs, that
is, preferably less than 10 .mu.m mass median diameter (MMD),
preferably less than 7.5 .mu.m, and most preferably less than 5
.mu.m, and usually being in the range of 0.1 .mu.m to 5 .mu.m in
diameter. The emitted dose (ED) of these powders is >30%,
usually >40%, preferably >50% and often >60% and the
aerosol particle size distribution is about 1.0-5.0 .mu.m mass
median aerodynamic diameter (MMAD), usually 1.5-4.5 .mu.m MMAD and
preferably 1.5-4.0 .mu.m MMAD. These dry powders have a moisture
content below about 10% by weight, usually below about 5% by
weight, and preferably below about 3% by weight. Such powders are
described in WO 95/24183, WO 96/32149, and WO 99/16419 which are
incorporated by reference herein.
[0236] The receptacles of the invention may conveniently be
configured to have a penetrable access lid that is penetrated by
one or more pointed structures when the aerosolization device is
operated. Examples of such receptacles are described in U.S. Pat.
Nos. 5,740,754 and 5,785,049, the complete disclosures of which are
herein incorporated by reference.
[0237] The invention may utilize various deagglomeration mechanisms
to deagglomerate the pharmaceutical formulation once it is
extracted from the receptacle. For example, the flow path for the
gases may experience one or more changes in direction to cause the
pharmaceutical formulation to,engage the walls of the flow path to
deagglomerate the formulation. The flow path may also include
various contractions or restrictions that may cause the
pharmaceutical formulation to engage the walls of the flow path to
deagglomerate the formulation. As another example, the flow path
may include one or more obtrusions or obstacles that serve to
engage the pharmaceutical formulation as it passes through the flow
path. According to a preferred embodiment, the diameter of the
deagglomeration mechanism is greater than that of the flow
path.
[0238] The invention has now been described in detail for purposes
of clarity of understanding. However, it will be appreciated that
certain changes and modifications may be practiced within the scope
of the appended claims.
* * * * *