U.S. patent application number 13/078654 was filed with the patent office on 2011-09-29 for multiple dose condensation aerosol devices and methods of forming condensation aerosols.
This patent application is currently assigned to ALEXZA PHARMACEUTICALS, INC.. Invention is credited to Steven D. Cross, Matthieu Herbette, Andrew J.G. Kelly, Daniel J. Myers, William W. Shen, Ryan D. Timmons, Curtis Tom, Justin M. Virgili, Martin J. Wensley.
Application Number | 20110233043 13/078654 |
Document ID | / |
Family ID | 35446334 |
Filed Date | 2011-09-29 |
United States Patent
Application |
20110233043 |
Kind Code |
A1 |
Cross; Steven D. ; et
al. |
September 29, 2011 |
MULTIPLE DOSE CONDENSATION AEROSOL DEVICES AND METHODS OF FORMING
CONDENSATION AEROSOLS
Abstract
Devices and methods of entraining a substance within an airflow
are disclosed. Condensation aerosol delivery devices and methods of
consistently producing multiple doses of a substance, such as a
drug, having high purity, high yield, characterized by a particle
size distribution appropriate for pulmonary delivery, and which can
be administered to a user in a single dose are also disclosed.
Inventors: |
Cross; Steven D.; (Alamo,
CA) ; Herbette; Matthieu; (Sunnyvale, CA) ;
Kelly; Andrew J.G.; (Palo Alto, CA) ; Myers; Daniel
J.; (Mountain View, CA) ; Shen; William W.;
(Mountain View, CA) ; Timmons; Ryan D.; (Mountain
View, CA) ; Tom; Curtis; (San Mateo, CA) ;
Virgili; Justin M.; (Palo Alto, CA) ; Wensley; Martin
J.; (San Francisco, CA) |
Assignee: |
ALEXZA PHARMACEUTICALS,
INC.
Mountain View
CA
|
Family ID: |
35446334 |
Appl. No.: |
13/078654 |
Filed: |
April 1, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12474680 |
May 29, 2009 |
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13078654 |
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10861554 |
Jun 3, 2004 |
7540286 |
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12474680 |
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Current U.S.
Class: |
202/185.1 |
Current CPC
Class: |
A61M 16/1075 20130101;
H05B 2203/021 20130101; A61M 11/002 20140204; A61M 15/0045
20130101; A61M 15/0065 20130101; A61M 15/0081 20140204; A61M
15/0021 20140204; A61M 11/042 20140204; A61M 11/041 20130101; A61M
15/0048 20140204; A61M 15/008 20140204; H05B 1/0244 20130101; A61M
16/14 20130101 |
Class at
Publication: |
202/185.1 |
International
Class: |
B01D 5/00 20060101
B01D005/00; B01D 3/00 20060101 B01D003/00 |
Claims
1. A device for producing a condensation aerosol comprising: an
electrically resistive heating element comprising a metal foil
configured to vaporize a substance disposed thereon; and means for
condensing the vaporized substance to produce a condensation
aerosol comprising the substance.
2. The device of claim 1, wherein the metal foil is stainless
steel.
3. The device of claim 1, wherein the thickness of the metal foil
is less than 0.01 inches.
4. The device of claim 1, wherein the surface area of the metal
foil ranges from 0.01 cm.sup.2 to 50 cm.sup.2.
5. The device of claim 1, wherein the metal foil comprises a metal
layer plated on the metal foil.
6. The device of claim 5, wherein the metal layer is chosen from
gold, silver, nickel, and copper.
7. The device of claim 1, wherein the metal foil is arched.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 12/474,680, entitled "Multiple Dose
Condensation Aerosol Devices And Methods Of Forming Condensation
Aerosols", filed on May 29, 2009, which is a divisional of U.S.
patent application Ser. No. 10/861,554, filed Jun. 3, 2004,
entitled "Multiple Dose Condensation Aerosol Devices and Methods of
Forming Condensation Aerosols," now U.S. Pat. No. 7,540,286, the
entire disclosures of which are hereby incorporated by reference.
Any disclaimer that may have occurred during the prosecution of the
above-referenced applications is hereby expressly rescinded, and
reconsideration of all relevant art is respectfully requested.
[0002] This disclosure relates to devices capable of entraining a
substance into an airflow, to articles and methods employing such
devices, and in particular to articles and methods of producing
multiple doses of a condensation aerosol of a drug having high
purity, high yield, characterized by a particle size distribution
suitable for inhalation delivery, and which can be administered to
a user during a single inhalation.
[0003] Pulmonary delivery is known as an effective way to
administer physiologically active compounds to a patient for the
treatment of diseases and disorders. Devices developed for
pulmonary delivery generate an aerosol of a physiologically active
compound that is inhaled by a patient where the compound can be
used to treat conditions in a patient's respiratory tract and/or
enter the patient's systemic circulation. Devices for generating
aerosols of physiologically active compounds include nebulizers,
pressurized metered-dose inhalers, and the dry powder inhalers.
Nebulizers are based on atomization of liquid drug solutions, while
pressurized metered-dose inhalers and dry powder inhalers are based
on suspension and dispersion of dry powder in an airflow and/or
propellant.
[0004] Aerosols for inhalation of physiologically active compounds
can also be formed by vaporizing a substance to produce a
condensation aerosol comprising the active compounds in an airflow.
A condensation aerosol is formed when a gas phase substance formed
from vaporization condenses or reacts to form particulates (also
called particles herein) in the air or a gas. Examples of devices
and methods employing vaporization methods to produce condensation
aerosols are disclosed in U.S. Pat. Nos. 6,682,716; 6,737,042;
6,716,415; 6,716,416; 6,740,307; 6,740,308; 6,737,043; 6,740,309;
and 6,716,417, each of which is incorporated herein by
reference.
[0005] It can be desirable that an inhalation device be capable of
delivering multiple doses of a physiologically active compound and
that each dose comprising the active compound be administered to a
patient during a single inhalation. A dose refers to the amount of
a substance released during one activation of an inhalation device.
A dose can comprise, for example, a therapeutically effective
amount of a physiologically active compound. Furthermore, treatment
regimens can require that each of the multiple doses delivered to a
patient comprise a controlled amount of a physiologically active
compound, and that the active compound administered exhibit high
purity and be free of byproducts, e.g., excipients. Optimal
delivery of a dose to a patient's respiratory tract, and in
particular to a patient's lungs, can also be facilitated by the
aerosol having a mass median aerodynamic diameter of less than
about 4 .mu.m. Furthermore, practical considerations make it
desirable that a substantial amount of each dose contained in the
device, form an aerosol, be emitted from the device, and be inhaled
by the patient.
[0006] When a condensation aerosol is formed in an airflow, a
certain portion of the aerosol can deposit on downstream physical
features such as the side walls of the airway defining the airflow,
the mouthpiece of the device, or other structures and thereby
reduce the amount of active compound emitted by the device and
available for administration. In multiple dose devices, packaging
the multiple doses within a common airway can be attractive for
producing low cost and compact products. However, in multiple dose
devices, where the multiple doses are disposed on surfaces within
an airflow, a certain amount of an aerosol particles formed by
vaporizing an upstream dose, can deposit onto downstream surfaces
comprising unvaporized compound. Not only can the deposition on
unvaporized doses reduce the amount of active compound emitted from
the device, but in addition, the deposition can change the amount
of active compound forming subsequent doses. Thus, particularly
where a device includes a large number of multiple doses, the
latter doses can comprise a variable and uncontrolled amount of an
active compound.
[0007] For many treatment regimens, the ability to deliver a dose
comprising a precise, consistent, and reproducible amount of a
physiologically active compound can impact the therapeutic efficacy
of the treatment regimens, and in some cases, such a capability can
also enable new therapies. Thus, there is a need for inhalation
devices and methods of producing a condensation aerosol that can
repeatedly deliver precise, reproducible and/or controlled amounts
of a physiologically active substance.
[0008] Certain embodiments include devices for entraining a
substance within an airflow comprising an airway with an inlet, and
an outlet; at least one support disposed within the airway; the
substance disposed on the at least one support; and a mechanism
configured to release the substance from the at least one support;
wherein an airflow passing from the inlet to the outlet is directed
to the at least one support such that the substance is entrained in
the airflow when released from the support.
[0009] Certain embodiments include electrically resistive heating
elements comprising a metal foil for vaporizing a substance
disposed thereon to produce a condensation aerosol comprising the
substance.
[0010] Certain embodiments include devices for delivering a
condensation aerosol to a subject comprising a dispensing unit and
a separable cartridge. In certain embodiments, the dispensing unit
comprises a first housing comprising a receptacle for a separable
cartridge; a controller for controlling vaporization of the
substance; and a power source. In certain embodiments, the
separable cartridge comprises a second housing; an airway contained
within the housing having an inlet, and an outlet; a mouthpiece
coupled to the outlet; an air bypass hole coupled to the outlet; at
least one electrically resistive heating element disposed within
the airway; a substance disposed on the at least one heating
element; and an actuation mechanism configured to transfer energy
from the power source to the at least one heating element; wherein
an airflow from the inlet to the outlet of the airway causes the
substance to vaporize and condense in the airflow to form a
condensation aerosol.
[0011] Certain embodiments include methods of entraining a
vaporized substance or aerosol particles into an airflow, methods
of producing a condensation aerosol, and methods of administering a
substance to a subject using the devices disclosed herein. For
purposes herein, "entrain" or "entraining" means to direct, lift,
draw in or along, inject, transport, carry, or suspend a vaporized
substance or aerosol particle into an airflow.
[0012] Other embodiments will be apparent to those skilled in the
art from consideration and practice of the invention disclosed
herein. It is intended that the specification and examples be
considered as exemplary only.
[0013] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of certain
embodiments, as claimed.
DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1A is a schematic illustration showing deposition of a
substance on downstream surfaces.
[0015] FIG. 1B is a schematic illustration showing the use of an
airflow through a plurality of holes to entrain a substance into an
airflow and thereby minimize deposition of the substance on
downstream surfaces according to certain embodiments.
[0016] FIGS. 2A-2F are schematic illustrations showing examples of
airflow routing in a device for entraining a condensation aerosol
particle into an airflow according to certain embodiments.
[0017] FIG. 3 is an isometric diagram of a separable cartridge for
an electric multi-dose condensation aerosol delivery device.
[0018] FIG. 4 shows the airflow rate in the airway for different
total airflow rates for a cartridge.
[0019] FIG. 5 is a schematic cross-sectional illustration of a
separable cartridge for an electric multi-dose condensation aerosol
delivery device showing the routing of the airflow according to
certain embodiments.
[0020] FIGS. 6A and 6B show views of a structure separating the
first airway and the second airway according to certain
embodiments.
[0021] FIG. 7 is a isometric view of an electric multi-dose
condensation aerosol delivery device.
[0022] FIG. 8 is a cut-away isometric view of a portion of an
electric multi-dose condensation aerosol delivery device.
[0023] FIG. 9 is an isometric view of a dispensing unit for an
electric multi-dose condensation aerosol delivery device.
[0024] FIG. 10 is a schematic illustration showing a view of an
arched metal foil according to certain embodiments.
[0025] FIGS. 11A-D show an example of the distortion of a flat
metal foil, and an arched metal foil before and during resistive
heating.
[0026] FIG. 12 is a partial cross-sectional view of a separable
cartridge including air routing according to certain
embodiments.
[0027] FIG. 13 is a block diagram of an embodiment the electrical
functions for an electric multi-dose condensation aerosol delivery
device.
[0028] FIG. 14 shows the particle size distribution of a
condensation aerosol comprising a substance emitted from an
electric multi-dose condensation aerosol delivery device according
to certain embodiments.
[0029] FIG. 15 shows the reproducibility of the amount and purity
of doses of fentanyl emitted from a new, an opened, and a
partially-used electric multi-dose condensation aerosol delivery
device according to certain embodiments.
[0030] FIG. 16 shows a temperature profile of a metal foil in an
airflow according to certain embodiments.
[0031] FIGS. 17A and 17B show the temperature uniformity of a metal
foil in an airflow with fentanyl as the substance according to
certain embodiments.
[0032] FIG. 18 shows the amount of substance deposited on
downstream heating elements from vaporized substances from
preceding heating elements for different airflow velocities with
little or no airflow directed upward from underneath the heating
elements.
[0033] FIG. 19 shows the amount of substance deposited on
downstream heating elements from vaporized doses with a percentage
of the total airflow directed upward from underneath the heating
elements, where the airflow distribution was controlled by a layer
of foam between the first and second airways.
[0034] FIGS. 20A and 20B show a relationship between the
temperature of a metal foil and the purity and amount of the dose
emitted from an electric multi-dose condensation aerosol delivery
device according to certain embodiments.
DESCRIPTION OF VARIOUS EMBODIMENTS
[0035] Unless otherwise indicated, all numbers expressing
quantities and conditions, and so forth used in the specification
and claims are to be understood as being modified in all instances
by the term "about."
[0036] In this application, the use of the singular includes the
plural unless specifically stated otherwise. In this application,
the use of "or" means "and/or" unless stated otherwise.
Furthermore, the use of the term "including," as well as other
forms, such as "includes" and "included," is not limiting.
[0037] Condensation aerosols can be formed when a gaseous substance
condenses or reacts to form particulates in air or a gas. A gaseous
substance can be produced when a solid or liquid substance is
thermally sublimed or vaporized. Vaporization refers to a phase
transition in which a substance changes from a solid or liquid
state into a gaseous state. Sublimation refers to a phase
transition in which a substance passes directly from a solid state
to a gaseous state.
[0038] Upon entering an airflow, a gaseous substance can cool and,
at least in part depending on the temperature of the airflow, can
condense to form an aerosol particle. Condensation aerosol
particles not sufficiently entrained within the airflow have a
greater probability of falling out of the airflow to deposit on a
downstream surface.
[0039] Inefficient entrainment of particulates within an airflow
and subsequent deposition of the particulates on downstream
surfaces is shown in FIG. 1A. FIG. 1A shows an airway 10 having an
inlet 11 and an outlet 12. A plurality of supports 13 are located
on one side of airway 10. Plurality of supports 13 include support
14 and downstream supports 17. A substance can be disposed, for
example, on support 14, and an airflow 15 established in airway 10
such that plurality of supports 13 including support 14 are
disposed in airflow 15. When the substance disposed on support 14
is released from support 14 by, for example, vaporization, the
substance can form condensation aerosol particles 16 in airflow 15.
As shown, when the aerosol particles are not fully entrained within
airflow 15, condensation aerosol particles 16 so formed can deposit
on downstream supports 17.
[0040] A schematic illustration of a device for entraining a
particulate, and in particular an aerosol-forming gas phase
substance, within an airflow is shown in FIG. 1B. FIG. 1B shows a
first airway 20 and a second airway 21 separated by a structure 22.
Structure 22 comprises a plurality of holes fluidly connecting
first airway 20 and second airway 21. A plurality of supports 28
including upstream support 24, and downstream supports 27 are
disposed on the surface of structure 22 within first airway 20. As
in FIG. 1A, a substance can be disposed, for example, on upstream
support 24. A first airflow 25 can be established in first airway
20, and a second airflow 26 can be established in second airway 21
such that second airflow 26 passes from second airway 21 to first
airway 20 through the plurality of holes as indicated by the upward
pointing arrows 23. Upon passing through the plurality of hole,
second airflow 26 can provide a flow of air directed toward
plurality of supports 28, including upstream support 24 and
directed toward airflow 25. The flow of air 23 directed toward
airflow 25 can act to lift a substance vaporized from upstream
support 24 to form condensation aerosol particles 19 comprising the
substance, and entrain the condensation particles within first
airflow 25. Entrainment of condensation particles 19 within first
airflow 25 will reduce the likelihood that the condensation
particles 19 will become deposited on the downstream surfaces 27.
As shown in FIG. 1B, by entraining the condensation particles near
the center of first airflow 25, more of the condensation particles
can be emitted as an aerosol from the outlet 29 of the device and
be available, for example, for administration to a subject by
inhalation.
[0041] Another embodiment of a device for entraining a substance,
and in particular, a gas phase substance, within an airflow to form
a condensation aerosol is schematically illustrated in FIG. 2A.
FIG. 2A shows another scheme for routing an airflow through a
plurality of holes and across a surface of a structure. FIG. 2A
shows a device having a first airway 30, a second airway 31, and a
structure 32 separating first airway 30 and second airway 31.
Although structure 32 is shown as comprising two parts, e.g., as
indicated by the thick and thin lines, structure 32 can comprise
one part or multiple parts. Structure 32 includes a plurality of
holes 39 which fluidly connect first airway 30 and second airway
31. First airway 30 and second airway 31 are further defined by
housing 34. Housing 34 includes an air intake 35 to allow airflow
36 to enter second airway 31, and an air outlet 37 to allow airflow
36 to exit the device. As shown in FIG. 2A, first airway 30 and
second airway 31 are further fluidly connected through holes and/or
slots dimensioned to permit a greater, less than, or equal portion
38 of airflow 36 to pass into first airway 30, compared to the
portion of airflow the airflow that passes through plurality of
holes 39. The relative amounts of airflow to each airway can be
altered to suit the desired purpose. In the same manner as
described for FIG. 1B, the airflow through plurality of holes 39 as
indicated by small arrows 33, entrains the vaporized substance and
the condensation particles 41 formed by condensation of the
vaporized substance released from the plurality of supports 40
disposed on structure 32 within airflow 36. Entrainment of
condensation particles 41 within airflow 36 reduces deposition of
the condensation particles 41 on downstream surfaces.
[0042] Another embodiment of a device for entraining a substance or
condensation particles within an airflow is shown in FIG. 2B. FIG.
2B shows a device similar to that of FIG. 2A wherein a second
airflow 42, which is a portion of airflow 36, enters a third airway
43. Second airflow 42 can then pass through the plurality of holes
39 to provide an airflow directed toward a plurality of supports 40
and the first airway 30. The condensation particles 41 formed by
vaporizing a substance disposed on the supports becomes entrained
in airflow 36, which includes airflows 38 and 42.
[0043] In another embodiment, as shown in FIG. 2C, a portion of
first airflow 36 is directed through a porous element 44. On
passing through porous element 44, this portion of airflow passes
between supports 40 and directs the airflow toward first airway 30.
Porous element 44 can be fabricated from any material and have any
pore size capable of distributing an appropriate portion of the air
entering the device through the plurality of holes forming porous
element 44. For example, in certain embodiments, porous element 44
can be an open cell foam, a mesh, a fibrous material, a glass frit,
a ceramic filter, a microporous element, and the like.
[0044] How effectively a substance is entrained within an airflow
can at least in part depend on the proportion of rate of airflow
across the surface of a support, R.sub.1 to the rate of airflow
through the plurality of openings, R.sub.2. The appropriate
proportion R.sub.1:R.sub.2 for effectively entraining a substance
within an airflow can depend on a number of factors such as the
airflow velocity and the distance of the support from the center of
the airflow. In certain embodiments, R.sub.1:R.sub.2 can range from
80:20 to 20:80 and in other embodiments can range from 60:40 to
40:60. The proportion R.sub.1:R.sub.2 can be established by the
relative areas of the holes through which the first an second
airflows pass. For example, referring to FIG. 2A, a proportion of
60:40 means that the relative area of hole/slot through which
airflow 38 passes is 60 and the relative area of the plurality of
holes 39 is 40.
[0045] Another embodiment of a device for entraining a substance in
an airflow is shown in FIG. 2D. FIG. 2D shows airflow 36 entering
the device. One portion of airflow 36 passes through a plurality of
holes 39 and across a plurality of supports 40. A second portion of
airflow 36 is diverted around the plurality of holes (shown on FIG.
2D as 38). The airflow portion that goes through the plurality of
holes 39 and second airflow portion 38 recombine in first airway 30
and pass through mouthpiece 45 to exit the device.
[0046] In the embodiments shown in FIGS. 1B and 2A-D by introducing
air from below the supports redeposition of the vaporized substance
or aerosol condensation particles is minimized.
[0047] Different arrangements of the supports with respect to the
airflow through the device are shown in FIGS. 2E and 2F. In FIG.
2E, airflow 36 enters first airway 30. Airflow 36 is routed over a
plurality of supports 40 and recombines to pass through mouthpiece
45 to exit the device. In FIG. 2F, airflow 36 entering first airway
30 passes over plurality of supports 40 to pass through mouthpiece
45 to exit the device.
[0048] The concepts underlying the exemplary devices illustrated in
FIGS. 1B, 2 A-2 F can be applied to devices for administering a
condensation aerosol to a subject. A subject includes mammals and
humans. A cartridge for administering multiple doses of a
condensation aerosol to a subject which employs airflow through a
plurality of holes to facilitate entrainment of a substance
released from a support within an airflow is illustrated in FIG. 3.
An exploded assembly view of such a cartridge is shown in FIG. 3 as
part 50. A cross-sectional view of an assembled cartridge is also
illustrated in FIG. 5.
[0049] FIG. 3 shows an isometric assembly view of a cartridge
capable of producing multiple doses of a substance for pulmonary
administration. The cartridge 50 illustrated in FIG. 3 comprises a
first shell 52 and a second shell 54 which can be coupled to form a
housing. When assembled, one end of first shell 52 and second shell
54 form a mouthpiece 56 for insertion in a subject's mouth. An air
bypass hole 58 is located adjacent to mouthpiece 56 in second shell
54 to enable air to enter mouthpiece 56 when the rate of airflow
generated by inhalation exceeds the rate of airflow controlled by
an air inlet valve 62 entering the cartridge. The air inlet valve
62 can assist in minimizing any air flow variation from user to
user. The rate of airflow in the housing can impact particle size
and thus controlling air flow variation allows for more control
over the particle size generated. The air bypass hole 58 allows for
flexibility in that it allows the user to breath at a comfortable
rate without upsetting the amount of air flow that moves through
the housing and across the surface of the supports. For example, a
person typically inhales at a flow rate ranging from 30 L/min to
100 L/min. A device, however, may have a flow rate of 6 L/min,
which refers to the volume of air per time entering the device,
being directed across the surface of the supports and emitted from
the device, the excess airflow from the person will enter bypass
hole 58. Second shell 54 further comprises an air intake 60
(partially hidden). Air intake 60 includes air inlet valve 62 that
fits into receptacle 64 of second shell 54. As discussed above, air
inlet valve 62 controls the airflow rate of the cartridge and can
be any valve that can control the amount of air entering the device
during a single inhalation by a user. Examples of appropriate
valves include flapper valves (a flexible value that bends in
response to a pressure differential), umbrella valves, reed valves,
or flapping valves that bend in response to a pressure
differential, and the like. The purpose of air inlet valve 62 is to
control the amount of air entering the cartridge regardless of the
total airflow rate during and among inhalations. The total airflow
rate includes the airflow rate through air intake 60 and air inlet
valve 62, and the airflow rate through air bypass hole 58.
[0050] FIG. 4 demonstrates that a simple flap valve can be used to
control the airflow rate through the cartridge to about 6 L/min for
total inhalation ranging from 20 L/min to 90 L/min. To generate the
results presented in FIG. 4, a cartridge was fitted with a flap
valve and the airflow rate through the cartridge for various total
airflow rates was measured. Thus, by using air inlet valve 62, the
airflow rate through the cartridge can be relatively independent of
the airflow rate generated by an inhalation. As disclosed herein,
flow control can be used to control the particle size and particle
size distribution of the condensation aerosol emitted from the
device. However, particle size and particle size distribution can
be impacted by a number of additional factors including, for
example, the substance, the vaporization temperature of the
substance, the temperature of the airflow and the cross-sectional
air of the airway. Thus, the airflow rate can be one of several
parameters to be adjusted to produce a desired average particle
size and particle size distribution. In certain embodiments, air
control valve 62 can be designed to control the airflow through the
cartridge between 4 L/min and 8 L/min. In certain embodiments, an
airflow control valve can be activated electronically such that a
signal provide by a transducer located within the airway can
control the position of the valve, or passively, such as, for
example, by a pressure differential between the airway and the
exterior of the device. Additionally, the cross-sectional area of
the airway can be adjusted to produce a desired average particle
size and particle size distribution. In certain embodiments the
cross-section area of the airway ranges from 0.5 cm.sup.2 to 3
cm.sup.2.
[0051] As shown in FIG. 3, second shell 54 further includes a
breath actuation mechanism 67. Breath actuation mechanism 67 is
electrically coupled to a remotely located controller (not shown)
and can send a signal to the controller that interprets the data
and activates the generation of a condensation aerosol when a
certain pre-established airflow velocity is sensed. Breath
actuation mechanism 67 can be, for example, a thermistor, which
senses temperature in response to airflow. First shell 52 and
second shell 54 also include a receptacle 68 for retaining
electrical connector 70. In addition, there can be a counter 66,
which identifies the number of supports that have not been actuated
in that they have not been heated yet to vaporize the substance
contained thereon.
[0052] When cartridge 50 is assembled, a structure 72 separates a
first airway and a second airway. First airway 74 and second airway
76 are formed by structure 72 and the opposing inner walls of first
and second shells 52, 54, respectively, as shown in the
cross-sectional view of the assembled cartridge illustrated in FIG.
5. As shown in FIG. 3, structure 72 is a printed circuit board
enabling electrical connection between connector 70 and a plurality
of electrically resistive heating elements 78. Heating elements 78
are mounted on spacer 80 and soldered to interconnection lands 82
disposed on structure 72. Spacer 80 can be a thermally insulating
material such as, for example, a printed circuit board
material.
[0053] As shown in FIG. 3, structure 72 includes a plurality of
holes 84 extending over most of the surface of structure 72. Each
of the holes 84 extends through the thickness of structure 72.
Structure 72 also includes a set of slots 86 near the end of
structure 72 on which connector 70 is mounted. The number and
dimensions of plurality of holes 84 and set of slots 86 determine
the relative proportion of air which flows through the plurality of
holes 84 and set of slots 86 when a subject inhales on mouthpiece
56. As shown in FIG. 5, when a subject inhales on mouthpiece 56 of
cartridge 50, an airflow 88 is generated such that air enters air
intake 60, the flow of air entering the device is controlled by air
inlet valve 62 to enter second airway 76. A first portion of
airflow passes from second airway 76 through a set of slots 86 into
first airway 74 to be inhaled by a subject. At the same time, a
second portion of airflow passes through plurality of holes 84 and
enters first airway 74 to be inhaled by the subject. The airflows
passing through the plurality of holes 84 and the set of slots 86
combine to pass through mouthpiece 56 to exit the device.
[0054] A top view showing the positioning of plurality of holes 84
and set of slots 86 with respect to plurality of supports 78 is
shown in FIGS. 6A and 6B. FIG. 6A shows structure 72 comprising
connector 70, set of slots 86 and plurality of holes 84. Set of
slots 86 are shown as rectangular slots. However, set of slots 86
can have any number of openings, shapes, and/or dimensions as
appropriate to cause a vaporized substance to become entrained
within the airflow so as to form a condensation aerosol that
exhibits appropriate properties for inhalation administration.
Plurality of holes 84 is shown as comprising a regular array of
round openings. However, plurality of holes 84 can have any number
of openings, shapes, and/or dimensions as appropriate to cause a
vaporized substance and condensation aerosol particles to be
entrained within the airflow to form a condensation aerosol
exhibiting appropriate properties for inhalation administration.
For example, each row of holes 88 can instead be a narrow slot.
Plurality of holes 84 can also be placed in a different arrangement
over the surface of structure 72.
[0055] As shown in FIG. 6B, in certain embodiments, holes 84 can be
positioned beneath gaps 90 between adjacent heating elements 78.
Air flowing from holes 84 through gaps 90 can direct a substance
released from supports 78 into an airflow. In certain embodiments,
at least some of the plurality of holes 84 can be located beneath
at least some of the supports 78.
[0056] A cartridge as described in FIGS. 2-6 can be used in a
condensation aerosol delivery device for the administration of a
physiologically active substance to a subject. A solid view of an
exemplary condensation aerosol delivery device 100 according to the
disclosure is shown in FIG. 7. An isometric view with the top of
the device and the cartridge removed is shown in FIG. 8, and an
exploded isometric view of the condensation aerosol delivery device
100 is shown in FIG. 9. Referring to FIG. 9, the condensation
aerosol delivery device 100 includes cartridge 50 and a dispensing
unit 102. As shown in FIG. 9 cartridge 50 can be a separable unit.
In certain embodiments, cartridge 50 can be an integral component
of dispensing unit 102. Dispensing unit 102 includes a first shell
104 and a second shell 106 which can be assembled to form the
housing of dispensing unit 102. As shown in FIG. 9, dispensing unit
102 further includes a battery power source 108, and a printed
circuit board 110 incorporating a microprocessor controller 112, a
display 114, and a connector 116 for connecting the dispensing unit
with the cartridge and which also connects to controller 112 and
power source 108 comprising three AAA batteries to cartridge
50.
[0057] To deliver a condensation aerosol to a subject, the subject
places mouthpiece 56 of condensation aerosol delivery device 100
into his or her mouth. The subject then inhales on mouthpiece 56 to
generate an airflow as described herein. When a certain minimum
airflow or a rate in change in airflow is sensed, the device is
triggered. A signal from the airflow sensor is sent to the
controller to cause the battery power source to connect to at least
one support. As described herein, the supports can be, for example,
electrically resistive heating elements. Heat produced by the
electrically resistive heating element thermally vaporizes the
substance disposed thereon. The vaporized substance condenses in
the airflow to form condensation particles and hence, a
condensation aerosol. As described herein, the airflow passing from
beneath the heating element causes the substance vaporized from the
heating element or the condensed aerosol particles to become
entrained in the airflow as opposed to depositing on other supports
prior to passing through the cartridge. The aerosol upon passing
through the cartridge is subsequently inhaled by the subject.
Activation of the condensation aerosol delivery device, generation
of the condensation aerosol, and inhalation of the condensation
aerosol can occur in a single breath. The inhaled condensation
aerosol then enters the subject's respiratory tract where the
condensation aerosol comprising the active substance can be
deposited in the respiratory tract, and in particular the pulmonary
alveoli, of the subject.
[0058] A device for generating a condensation aerosol can include
at least one support and in certain embodiments, for example, as
shown in FIGS. 2-5 and 8, can include a plurality of supports. The
supports can provide a surface and/or structure on which a
substance to be released into an airflow can be disposed. In
certain embodiments, the supports can be located at a side of the
airway, for example on the surface of the structure, or can be
located toward, near, or in the center of the airway. The shape and
dimensions of the supports, and the material or materials forming
the supports can be chosen to facilitate release of a substance
disposed on the supports upon the application of energy, to
minimize degradation of the substance during release, to cause
rapid heating of the substance disposed thereon and/or to minimize
the amount of energy used to release the substance.
[0059] Selection of the appropriate material for forming the
support can also, at least in part, be determined by the source of
energy used to release the substance from the support. For example,
the source of energy used to release the substance can be
mechanical, acoustic, radiation such as microwave, radio frequency
or optical, and/or thermal. When the applied energy is absorbed
directly by the substance, the support can be non-thermally
conductive. For example, an optical source can be used to ablate
and/or vaporize a substance disposed on a support. Alternatively,
in certain embodiments, it can be more efficient or practical to
heat a thermally conductive support which transfers thermal energy
to the substance disposed thereon to release the substance from the
support. In such embodiments, the support can be a thermally
conductive material such as a metal, a metal alloy, a metal
composite having more than one layer and/or composition, graphite,
or the like. For example, in certain embodiments the metal can be
stainless steel, copper, nickel, aluminum, gold, or silver, and can
be plated with one or more of the foregoing materials or other
metals. In some embodiments, the thickness of the plating of a
metal layer on the metal can be within the range of between 0.001
.mu.m to 3 .mu.m and in other embodiments. In some embodiments, the
support can be a semi-conducting material.
[0060] In certain embodiments, for example, where the condensation
aerosol delivery device is designed for portable use with a battery
power source, efficient energy use can be desirable. Minimization
of the energy used to release a substance from a support can, at
least in part, depend on the shape and dimensions of the support,
the materials forming the support, and the placement of the support
within the airway. In certain embodiments, the support can comprise
an electrically resistive material such as a foil. In certain
embodiments, the foil can be a stainless steel foil and can include
a layer of one or more materials such as a gold layer to
facilitate, for example, forming an electrical connection, and/or
modifying the electrical properties such as the resistance of a
portion of the foil. The appropriate dimensions for a foil can
depend at least in part, on the desired resistance, the amount of
substance disposed on the support, the amount of energy needed to
vaporize the substance disposed on the support, and/or on
mechanical stability considerations.
[0061] To maximize transfer of thermal energy produced by the
support to the substance disposed thereon, it is desirable that a
thermally conductive support be thermally isolated. Minimizing the
contact area between the support and the connector helps to
thermally isolate the support. As shown, for example, in FIG. 3,
thermal isolation can be accomplished by suspending the support in
the airflow above the surface of the structure by means of a spacer
whereby the ends of the metal foil can be electrically connected to
the power source. As shown in FIGS. 3, 8 and 10, in certain
embodiments, the metal foil can be arched. During heating, thin
foils can have a tendency to distort. This phenomenon is
schematically illustrated in FIG. 11, where a metal foil is shown
suspended between two conductors. FIG. 11A shows a flat metal foil
spanning two conductors. During heating, the flat metal foil can
distort as shown schematically in FIG. 11B. In a multiple dose
condensation aerosol delivery device comprising several metal foil
supports, such mechanical distortion of the foils can interact with
the airflow to increase deposition of the condensation aerosol
particles on downstream surfaces. To facilitate the accuracy and
reproducibility of the amount of substance released upon firing
from each support or heating element and transferred to recipient,
it can be desirable that the airflow characteristics of the device
be consistent for each actuation of the device. While distortion of
a metal foil can be minimized by using thicker foils, efficient
heating of the metal foils with minimum power consumption indicates
the use of thin foils. It has been found that the mechanical
stability of a metal foil can be improved by producing a slight
arch in the foil. An example of an arched foil is shown in FIG.
11C. During heating, the arched metal foil shown in FIG. 11C can
exhibit a slight upward movement as indicated in FIG. 11D, and
following heating returns to approximately the same arched
configuration as prior to heating. The arch can be formed a number
of ways, such as, for example, but not limitation, assembly by
placing the metal foil, or plurality of metal foils over an arched
mandrel and bonding the ends to a platform. The metal foil can be
too thin to take a permanent set, but can be held in slight
compression to maintain the arch. The platform on which the arched
metal foil is mounted can be for example, a spacer such as spacer
80 as shown in FIG. 3, or can be structure 72 separating the first
and second airways in embodiments where a spacer is not employed.
In some embodiments of the invention, the height of the arch can
ranges from 0.5 mm to 2 mm.
[0062] Particularly for portable, battery operated condensation
aerosol delivery devices, it can be useful to minimize the amount
of power used to vaporize a substance. Several characteristics of
the metal foil can be chosen to facilitate the efficient thermal
vaporization of a substance from a metal foil, including, but not
limited to, the thickness of the metal foil, the impedance of the
metal foil, and the ratio of the surface area to the thermal mass
of the metal foil. In certain embodiments, the thickness of the
metal foil can be less than 0.01 inches, in certain embodiments,
less than 0.001 inches, and in certain embodiments, less than
0.0005 inches. To minimize power dissipation in the electrical
circuit and thereby maximize power delivered to the heating
element, it can be desirable that the impedance of the metal foil
be closely matched to the impedance of the power source. For
example, in certain embodiments, the difference between the
impedance of the resistive heating element and the impedance of the
power source can be less than 50% of the impedance of the power
source, in certain embodiments, less than 10% of the impedance of
the power source, and in certain embodiments, less than 2% of the
impedance of the power source. To facilitate the efficient transfer
of thermal energy produced by the resistive heating element to the
substance disposed thereon, it can be useful to maximize the ratio
of the surface area of the resistive heating element to the thermal
mass of the resistive heating element. Accordingly, in certain
embodiments the ratio of the surface area of the heating element to
the thermal mass of the resistive heating element can be greater
than 10 cm.sup.2/J/.degree. C., in certain embodiments, greater
than 100 cm.sup.2/J/.degree. C., and in certain embodiments,
greater than 500 cm.sup.2/J/.degree. C.
[0063] Low ratios of the surface area of the heating element to the
thermal mass of the resistive heating element can facilitate the
transfer of heat to the substrate, and lead to rapid thermal
vaporization of the substance. Rapid thermal vaporization of a
substance can minimize thermal degradation of the substance during
vaporization and thereby maximize the purity of the condensation
aerosol formed therefrom. For example, in certain embodiments, the
support, and in particular, a metal foil can be heated to a
temperature of at least 250.degree. C. in less than 500 msec, in
certain embodiments, to a temperature of at least 250.degree. C. in
less than 250 msec, and in certain embodiments, to a temperature of
at least 250.degree. C. in less than 100 msec.
[0064] Efficient transfer of thermal energy produced by the
resistive heating element to the substance disposed thereon can
further be facilitated by the substance being disposed on the
surface as a thin layer. For example, in certain embodiments, the
thickness of the layer of substance can range from 0.01 .mu.m to 50
.mu.m, in certain embodiments, can range from 0.01 .mu.m to 20
.mu.m, and in certain embodiments, can range from 0.01 .mu.m to 10
.mu.m.
[0065] The amount of energy to thermally vaporize a substance can
be minimized by, for example, using an electrically resistive
heating element comprising a thin metal foil, closely matching the
impedance of the electrically resistive heating element to the
impedance of the power source, maximizing the ratio of the surface
area of the resistive heating element to the thermal mass of the
resistive heating element, and using a thin film of substance
disposed on the heating element. By appropriate design and
selection of at least the foregoing parameters, in certain
embodiments, the amount of energy to vaporize a substance from a
support can be less than 250 joules, in certain embodiments, less
than 50 joules, and in certain embodiments, less than 10 joules. In
more specific embodiments, the amount of energy to vaporize one mg
of substance from a support can be less than 250 joules, in certain
embodiments, less than 50 joules, and in certain embodiments, less
than 10 joules.
[0066] The number of supports forming a condensation aerosol
delivery device and/or cartridge is not particularly limited. For
example, in certain embodiments, a cartridge or drug delivery
device can comprise from 1 to 200 supports, in certain embodiments,
from 1 to 50 supports, and in certain embodiments, from 1 to 25
supports, and in certain embodiments, from 1 to 10 supports.
[0067] The cartridge can be separable from the condensation aerosol
delivery device. In such embodiments, a subject can use the
delivery device, for example, to administer more than one
physiologically active substance, or more than one dose of the same
physiologically active substance by replacing one cartridge with
another. Also, when all the doses in a particular cartridge are
exhausted, the user can obtain and insert a new cartridge into the
delivery device.
[0068] While certain embodiments of the present disclosure can
comprise a single support, it is contemplated that embodiments
comprising a plurality of supports can be particularly useful in,
for example, providing a convenient method of delivering multiple
doses of a physiologically active compound or drug over a period of
time. The terms physiologically active compound and drug are used
interchangeably herein. As used herein, a drug refers to a
substance recognized in an official pharmacopoeia or formulary,
and/or a substance intended for use in the diagnosis, cure,
mitigation, treatment or prevention of disease where disease refers
to any disease, disorder, condition, symptom or indication. In such
embodiments, the substance disposed on at least one support can
comprise a therapeutically effective amount of a drug. For example,
a therapeutically effective amount or dose of a drug can be
disposed on a single support, on each of multiple supports, or on
more than one support. In certain embodiments of a condensation
aerosol delivery device, the same amount of physiologically active
compound can be disposed on each support. In certain embodiments,
different amounts of a physiologically active compound can be
disposed on each of the plurality of supports, or a certain amount
of active compound can be disposed on several supports, and a
different amount of active compound on several other supports.
Having different amounts of a drug on different supports can be
useful in effecting treatment regimens where administering a
variable amount of drug during a period of time is useful.
[0069] In certain embodiments, where the active compound disposed
on several supports is an abusable substance, a second compound
comprising an agonist can be disposed on one or more other
supports. "Abusable substance" refers to a substance that can be
improperly used, for example, by administering more than a
prescribed or intended dosage, or by altering the route of
administration from the intended route. For example, an opioid
analgesic can be abused by using the opioid analgesic to elicit a
euphoric effect, rather than therapeutically for the treatment of
pain. Abusable substances include substances regulated by a
regulatory agency focused on preventing drug abuse, such as, for
example, the United States Drug Enforcement Agency (DEA). In
certain embodiments, an abusable substance can be a substance
listed on DEA schedule II, III, IV, or V. The second compound is a
chemical compound that can act to reduce or to counteract the
physiological activity and/or pharmacological effects of another
chemical substance. Having both an abusable substance and a second
compound capable of counteracting the effects of the abusable
substance in the same device will complicate the ability of an
abuser to selectively remove the abusable substance from heating
elements. Proper use of the device would only allow the abusable
substance to be activated in prescribed doses.
[0070] A substance to be released can be disposed on at least one
surface of a support. For example, the substance can be disposed on
the surface facing the center of the first airway and/or toward the
part of the airflow where the velocity is highest. The substance
can be applied to a surface of a support by any appropriate method
and can depend at least in part on the physical properties of the
substance and the final thickness of the layer to be applied. In
certain embodiments, methods of applying a substance to a support
include, but are not limited to, brushing, dip coating, spray
coating, screen printing, roller coating, inkjet printing,
vapor-phase deposition, spin coating, and the like. In certain
embodiments, the substance can be prepared as a solution comprising
at least one solvent and applied to a support. In certain
embodiments, a solvent can comprise a volatile solvent such as
acetone, or isopropanol. In certain embodiments, the substance can
be applied to a support as a melt. In certain embodiments, a
substance can be applied to a film having a release coating and
transferred to a support. For substances that are liquid at room
temperature, thickening agents can be admixed with the substance to
produce a viscous composition comprising the substance that can be
applied to a support by any appropriate method, including those
described herein. In certain embodiments, a layer of substance can
be formed during a single application or can be formed during
repeated applications to increase the final thickness of the layer.
In other embodiments, the substance can be applied on more than one
surface of the support.
[0071] In certain embodiments, more than one active compound can be
disposed on one or more of the plurality of supports. For example,
a first active compound can be disposed on certain supports, and a
second active compound can be disposed on other supports, and in
certain embodiments, a composition comprising a first active
compound and a second active compound can be disposed on one or
more supports.
[0072] A dose can correspond to the amount of active compound
released from a single support, or the amount of active compound
released from more than one support. A dose or dosage as used
herein refers to the amount of substance released during a single
activation of a condensation aerosol delivery device. A dose can
comprise a therapeutically amount of a physiologically active
compound, meaning that the dose provides effective treatment of a
condition and/or disease in a patient. The therapeutically
effective amount of a physiologically active compound can vary from
compound to compound, from subject to subject, and can depend upon
factors such as the condition of the subject.
[0073] In certain embodiments, a substance disposed on at least one
support can comprise a therapeutically effective amount of at least
one physiologically active compound or drug. A therapeutically
effective amount refers to an amount sufficient to effect treatment
when administered to a patient or user in need of treatment.
Treating or treatment of any disease, condition, or disorder refers
to arresting or ameliorating a disease, condition or disorder,
reducing the risk of acquiring a disease, condition or disorder,
reducing the development of a disease, condition or disorder or at
least one of the clinical symptoms of the disease, condition or
disorder, or reducing the risk of developing a disease, condition
or disorder or at least one of the clinical symptoms of a disease
or disorder. Treating or treatment also refers to inhibiting the
disease, condition or disorder, either physically, e.g.
stabilization of a discernible symptom, physiologically, e.g.,
stabilization of a physical parameter, or both, and inhibiting at
least one physical parameter that may not be discernible to the
patient. Further, treating or treatment refers to delaying the
onset of the disease, condition or disorder or at least symptoms
thereof in a patient which may be exposed to or predisposed to a
disease, condition or disorder even though that patient does not
yet experience or display symptoms of the disease, condition or
disorder. In certain embodiments, the amount of substance disposed
on a support can be less than 100 micrograms, in certain
embodiments, less than 250 micrograms, in certain embodiments, less
than 500 micrograms, and in certain embodiments, less than 1,000
micrograms.
[0074] When delivering a pharmaceutical compound to a subject, the
amount of substance that is vaporized off the surface is important.
Consistency of delivery of the compound is also critical. In
certain embodiments, at least 80% of the amount of material
disposed on each support passes through the outlet of the device
for deliver to the subject, in other embodiments, at least 90%
passes through the outlet, and in other embodiments, at least 98%
passes through the outlet.
[0075] In certain embodiments, a substance can comprise a
pharmaceutical compound. In certain embodiments, the substance can
comprise a therapeutic compound or a non-therapeutic compound. A
non-therapeutic compound refers to a compound that can be used for
recreational, experimental, or pre-clinical purposes. Classes of
drugs that can be used include, but are not limited to,
anesthetics, anticonvulsants, antidepressants, antidiabetic agents,
antidotes, antiemetics, antihistamines, anti-infective agents,
antineoplastics, antiparkinsonian drugs, antirheumatic agents,
antipsychotics, anxiolytics, appetite stimulants and suppressants,
blood modifiers, cardiovascular agents, central nervous system
stimulants, drugs for Alzheimer's disease management, drugs for
cystic fibrosis management, diagnostics, dietary supplements, drugs
for erectile dysfunction, gastrointestinal agents, hormones, drugs
for the treatment of alcoholism, drugs for the treatment of
addiction, immunosuppressives, mast cell stabilizers, migraine
preparations, motion sickness products, drugs for multiple
sclerosis management, muscle relaxants, nonsteroidal
anti-inflammatories, opioids, other analgesics and stimulants,
ophthalmic preparations, osteoporosis preparations, prostaglandins,
respiratory agents, sedatives and hypnotics, skin and mucous
membrane agents, smoking cessation aids, Tourette's syndrome
agents, urinary tract agents, and vertigo agents.
[0076] Examples of pharmaceutical compounds include fluticasone
propionate, clonidine, triazolam, albuterol, ciclesonide, fentanyl,
terbutaline, flumazenil, triamcinolone acetonide, flunisolide,
ropinirole, alprazolam, buprenorphine, hyoscyamine, atropine,
pramipexole, bumetanide, flunitrazepam, oxymorphone, colchicine,
apomorphine HCl, granisetron, pergolide, nicotine, loperamide,
azatadine, naratriptan, clemastine, benztropine, ibutilide,
butorphanol, fluphenazine, estradiol-17-heptanoate, zolmitriptan,
metaproterenol, scopolamine, diazepam, tolterodine, estazolam,
haloperidol, carbinoxamine, estradiol, hydromorphone, bromazepam,
perphenazine, midazolam, methadone, frovatriptan, eletriptan,
testosterone, melatonin, galanthamine, cyproheptadine,
bropheniramine, and chlorpheniramine. In certain embodiments, the
compound is chosen from alprazolam, buprenorphine, clonindine,
fentanyl, midazolam, pramipexole, ropinirole, and triazolam. In
certain embodiments, the compound is chosen from a compound for the
treatment of pain. In certain embodiments, the compound for the
treatment of pain is fentanyl.
[0077] In certain embodiments, a drug can further comprise
substances to enhance, modulate and/or control release, aerosol
formation, intrapulmonary delivery, therapeutic efficacy,
therapeutic potency, stability, and the like. For example, to
enhance therapeutic efficacy a drug can be co-administered with one
or more active agents to increase the absorption and/or diffusion
of the first drug through the pulmonary alveoli, or to inhibit
degradation of the drug in the systemic circulation. In certain
embodiments, a drug can be co-administered with active agents
having pharmacological effects that enhance the therapeutic
efficacy of the drug. In certain embodiments, a drug can comprise
compounds that can be used in the treatment of one or more
diseases, conditions, or disorders. In certain embodiments, a drug
can comprise more than one compound for treating one disease,
condition, or disorder, or for treating more than one disease,
condition, or disorder.
[0078] In certain embodiments, the substance can comprise one or
more pharmaceutically acceptable carriers, adjuvants, and/or
excipients. Pharmaceutically acceptable refers to approved or
approvable by a regulatory agency of the Federal or a state
government or listed in the U.S. Pharmacopoeia or other generally
recognized pharmacopoeia for use in animals, and more particularly
in humans.
[0079] In general, substances useful in embodiments of the
disclosure can exhibit a heat of vaporization less than about 150
kJoules/mol.
[0080] Not only can the amount of compound forming a dose be
impacted by deposition of aerosol particles on the device and other
supports in the device, but the amount of compound forming a dose
can be reduced by degradation of the active agent during release
from the support. While it will be recognized that the extent and
dynamics of thermal degradation can at least in part depend on a
particular compound, in certain embodiments, thermal degradation
can be minimized by rapidly heating the substance to a temperature
sufficient to vaporize and/or sublime the active substance. In
certain embodiments, the support or heating element can be heated
to a temperature of at least 250.degree. C. in less than 500 msec,
in certain embodiments, to a temperature of at least 250.degree. C.
in less than 250 msec, and in certain embodiments, to a temperature
of at least 250.degree. C. in less than 100 msec.
[0081] In certain embodiments, rapid vaporization of a layer of
substance can occur with minimal thermal decomposition of the
substance, to produce a condensation aerosol exhibiting high purity
of the substance. For example, in certain embodiments, less than
10% of the substance is decomposed during thermal vaporization
resulting in a condensation aerosol with at least 90% purity and in
certain embodiments, less than 5% of the substance is decomposed
during thermal vaporization resulting in a condensation aerosol
with at least 95% purity, and in other embodiments, less than 2% of
the substance is decomposed during thermal vaporization resulting
in a condensation aerosol with at least 98% purity.
[0082] For administration of a compound, the size of the
particulates of the compound comprising the aerosol can be within a
range appropriate for intrapulmonary delivery. Without being
limited by theory, an aerosol having a mass median aerodynamic
diameter ("MMAD") ranging from 1 .mu.m to 3 .mu.m, and ranging from
0.01 .mu.m to 0.10 .mu.m are recognized as optimal for
intrapulmonary delivery of pharmaceutical compounds. Aerosols
characterized by a MMAD ranging from 1 .mu.m to 3 .mu.m can deposit
on alveoli walls through gravitational settling and can be absorbed
into the systemic circulation, while aerosols characterized by a
MMAD ranging from about 0.01 .mu.m to 0.10 .mu.m can also be
deposited on the alveoli walls through diffusion. Aerosols
characterized by a MMAD ranging from 0.15 .mu.m to 1 .mu.m are
generally exhaled. Thus, in certain embodiments, aerosols produced
using devices and methods of producing an aerosol can having a MMAD
ranging from 0.01 .mu.m to 5 .mu.m, in certain embodiments, a MMAD
ranging from 0.05 .mu.m to 3 .mu.m, in certain embodiments, a MMAD
ranging from 1 .mu.m to 3 .mu.m and in certain embodiments, a MMAD
ranging from 0.01 .mu.m to 0.1 .mu.m. In certain embodiments,
aerosols suitable for intrapulmonary delivery of pharmaceutical
compounds can further be characterized by the geometric standard
deviation of the log-normal particle size distribution. In certain
embodiments, aerosols produced using the devices and methods of
producing an aerosol comprise a geometric standard deviation of the
log-normal particle size distribution of less than 3, in certain
embodiments, less than 2.5, and in certain embodiments, less than
2.
[0083] In certain embodiments, a cartridge can include a part
disposed in the mouthpiece to control the airflow exiting the
device. A partial section view of the cartridge cross-section of
FIG. 5 is shown in FIG. 12. FIG. 12 shows the front section of
cartridge 50, further including an air routing part 200 disposed
within the mouthpiece 56. The airflow 88 entering air intake 60,
and air inlet valve 62 passes through the internal airways to
entrain a condensation aerosol particles, and passes through the
orifice defined by air routing part 200 to be emitted from the
device. Bypass airflow 202 enters bypass opening 58 and is diverted
around the outside of air routing part 200. The front 204 of air
routing part 200 extends to near the tip 206 of mouthpiece 56. The
use of air routing part 200 can be useful in maintaining smooth
airflow through the device and facilitating control of the
condensation aerosol particle size.
[0084] An embodiment of a condensation aerosol delivery device is
the portable electric multi-dose drug delivery systems discussed
herein, and illustrated in FIGS. 7 to 9. The electric multi-dose
drug delivery system is designed to produce and deliver a
therapeutic condensation aerosol into the respiratory tract, and in
particular to the pulmonary pathway, of a subject. As discussed
herein, the condensation aerosol delivery device includes two
subsystems, referred to as the cartridge and the dispensing unit.
Both the cartridge and the dispensing unit incorporate several
electronic features which facilitate the portability, safety,
versatility, and convenience of the delivery device. As disclosed
herein, the cartridge includes the therapeutic drug in individual
doses, and electronics to sense airflow generated by the subject's
inhalation. The dispensing unit includes a battery power source,
and a microcontroller that controls the drug vaporization process,
and can include a number of communication functions. Such
communication functions include, but are not limited to, cartridge
identification, dose identification, abuse prevention functions,
use monitoring, and dose control.
[0085] A functional block diagram of the electronics for an
exemplary embodiment of an electric multi-dose condensation aerosol
delivery device 100 is shown in FIG. 13. FIG. 13 shows a cartridge
130 comprising an EEPROM 132, a breath sensor 134, and twenty-five
drug coated metal foils 136. EEPROM 132 can include, for example,
an identifying serial number for the cartridge, a manufacturing
date, and/or additional identification and control information, and
monitors the number of doses remaining in the cartridge. EEPROM 132
is electrically connected to microcontroller 152 contained in the
dispensing unit 150. Microcontroller 152 can read or write to
EEPROM 132 to update and record the data stored therein. EEPROM 132
need not require power to maintain the data. Breath actuation
sensor 134 includes circuitry for detection of airflow, and is
electrically connected to microcontroller 152. The circuitry can
comprise two temperature sensing devices such as thermistors, one
of which is heated. Air flowing across the heated sensor 134 is
transduced as a change in voltage, which is monitored by
microcontroller 152. When a certain minimum velocity of airflow 138
is sensed, microcontroller 152 connects power source 154 to at
least one of resistive metal foils 136 to effect vaporization of
the drug disposed thereon. Plurality of drug coated foils 136 are
electrically connected to a switch matrix 156 which is controlled
by microcontroller 152. As disclosed herein, plurality of drug
coated foils 136 can be selectively heated by passing a current
through the foils to vaporize the drug coating to form a
condensation aerosol in airflow 138.
[0086] As shown in FIG. 13, dispensing unit 150 includes
microcontroller 152, power source 154, switch matrix 156, a
hardware safety lock-out mechanism 158, a user-activated switch
160, and a liquid crystal display user interface 162.
Microcontroller 152 incorporates embedded software and controls
operation of the condensation aerosol delivery device. When not
operating, microcontroller 152 is maintained in a sleep mode to
conserve power consumption. Upon momentary depression of user
activation switch 160, microcontroller 152 becomes operational. In
certain embodiments, microcontroller 152 can also be activated by
inserting a cartridge into the delivery device. Microcontroller 152
can then check for the presence of cartridge 130, and if present,
microcontroller 152 reads EEPROM 132 to determine whether the
serial number of cartridge 130 matches the serial number stored in
the controller, and calculates the number of unused doses contained
on drug coated foils 136 remaining in cartridge 130. A purpose of
matching the cartridge and dispensing unit serial number can be to
personalize individual cartridges 130 and dispensing unit 150 to an
individual patient. Personalization can be programmed using the
embedded software by a health care provider to facilitate and
personalize a patient's treatment regimen, and to reduce the
potential for abuse by preventing a particular cartridge from being
used in a dispensing unit having a different serial number. Upon
verification of the parameters, microcontroller 152 updates display
162 with, for example, the number of doses remaining in cartridge
130, and waits for an activation signal from breath sensor 134.
When a patient establishes a sufficient airflow in cartridge 130 by
inhaling on the cartridge mouthpiece, microcontroller 152 connects
power source 154, through switch matrix 156, to one or more of drug
coated foils 136 to release the drug to form a condensation aerosol
comprising the drug in airflow 138 of cartridge 130 that is inhaled
by the patient. Microcontroller 152 is electrically connected to
switch matrix 156, and can connect one or more of drug-coated foils
136 to power source 154 at a given time. In certain embodiments,
microcontroller 152 can connect one or more drug coated foils 136
to power source 154 sequentially, randomly, or in a predetermined
order. Following actuation to deliver a dose to the patient,
microcontroller 152 can enter a lockout period in which a
subsequent dose cannot be released until the lockout period
expires. Microcontroller 152 can enter a sleep mode to conserve
power until manually activated by depressing user activation switch
160, inserting a cartridge in the device, and/or removing a
cartridge.
[0087] Display 162 is an electronic display which can inform a user
of the current state of the device, e.g., whether the device is in
the sleep or activated mode, and the number of unused doses
remaining in the cartridge. User activated switch 160 is a
momentary push button switch that when depressed activates the
system from the sleep mode. Power source 154 comprises three
alkaline primary cells that are used to power the system including
providing the power necessary to vaporize the drug disposed on
metal foils 136. Switch matrix 156 can be an array of MOSFET
switches under control of the microcontroller that couple power
from power source 154 to the appropriate drug coated foils 136.
Hardware safety lockout 158 is a redundant, software-independent
system that can prevent more than one dose from being delivered at
a time and/or prevent a second dose from being delivered before the
end of the lockout period. Hardware safety lockout 158 provides a
redundant safety mechanism in the event of software
malfunction.
[0088] In certain embodiments, the device is such that the total
airflow passing through the outlet ranges from 10 liters/min to 100
liters/min. In other embodiments, the total airflow passing though
the outlet ranges from 20 liters/min to 90 liters/min.
[0089] In certain embodiments of the device, the airflow rate
through the inlet is less than 100 L/min. In other embodiments, the
airflow rate through the inlet is less than 50 liters/min. In yet
other embodiments, the airflow rate through the inlet is less than
25 liters/min; and in still other embodiments, the airflow rate
through the inlet is less than 10 liters/min.
[0090] It should also be evident from the various embodiments
disclosed herein that many parameters can be selected and/or
adjusted to provide a condensation aerosol delivery device, and in
particular an electric condensation aerosol delivery device capable
of delivering multiple doses of a physiologically active substance
to a patient with each dose being delivered during a single
inhalation. It will be appreciated that at least some of the
parameters are interactive, and that the multiple parameters can be
adjusted by routine optimization procedures to generate a
condensation aerosol comprising a dose of a particular
physiologically active substance. As discussed herein, such
parameters include, but are not limited to the properties of a
particular substance, e.g., heat of vaporization, the quantity of
substance comprising a dose, the thickness of the layer disposed on
the support, the thickness of the heating element, the ratio of the
surface area of the heating element to the thermal mass of the
resistive heating element, and the airflow.
EXAMPLES
[0091] Embodiments of the present disclosure can be further defined
by reference to the following examples, which describe in detail
certain embodiments of the present disclosure. It will be apparent
to those skilled in the art that many modifications, both to
materials and methods, may be practiced without departing from the
scope of the present disclosure.
Example 1
Electric Multi-Dose Condensation Aerosol Delivery Device
[0092] Electric multiple dose condensation aerosol delivery devices
as shown in FIGS. 2-5 were fabricated. The two halves forming the
housing of the cartridge were molded from either
acrylonitrile-butadiene-styrene or polycarbonate. The structure
separating the first and second airways was fabricated from
0.032-inch thick FR4 printed circuit board material. When
assembled, the circuit board and the walls of the cartridge define
a 3.5 inch long first airway having a cross-sectional area of 1.5
cm.sup.2, and a 3.0 inch long second airway having a
cross-sectional area of 1.5 cm.sup.2. The total resistance through
the cartridge was 0.07 sqrt(cm-H.sub.2O)/L/min at a total airflow
rate of 20 L/min and 0.09 sqrt(cm-H.sub.2O)/L/min at 90 L/min. The
flow valve was designed to control the flow between 4 L/min and 8
L/min for a total flow rate ranging from 20 L/min to 90 L/min (see
FIG. 4). Circuit boards used to separate the first and second
airways were fabricated having different arrangements and
dimensions of holes. In a certain exemplary embodiment, the
plurality of holes beneath the metal foils comprised an array of
100 round holes situated beneath the gaps between adjacent metal
foils. Sixty percent of the airflow entering the air control valve
passed through a series of slots and across the heating elements in
the first airway. Forty percent of the airflow passed through the
plurality of holes in the circuit board and was directed toward the
heating elements and the center of the first airway.
[0093] The device incorporated 25 supports. The supports were
fabricated from 0.0005 inch thick stainless steel foils having a
surface area of 0.2 cm.sup.2 and mounted in an arched configuration
to minimize distortion during heating. Fifty .mu.g of fentanyl was
deposited on the surface of each foil by spray coating from a
solution comprising either isopropyl alcohol, acetone, or
acetonitrile. The 50 .mu.g layer of fentanyl was 3 .mu.m thick. The
resistance of the metal foils on which the fentanyl was deposited
was 0.4.OMEGA., the ratio of the surface area of the metal foil to
the thermal mass of the heating foil was 47 cm.sup.2/J/C. Either
three AAA batteries or a Hewlett Packard 6002A DC power supply were
used, depending on the experiment conducted, to provided 1.7 joules
of energy to the heating element to vaporize the 50 .mu.g of
fentanyl.
Example 2
Aerosol Particle Size Measurement
[0094] The size of aerosol particles can impact the therapeutic
efficacy of a pharmaceutical administered by inhalation. For
example, aerosols having a particle size ranging from 0.01 .mu.m to
3 .mu.m are considered optimal for pulmonary delivery. In addition
to the dynamics of aerosols during inhalation, it can be important
that a condensation aerosol delivery device generate a consistent
and reproducible particle size distribution. Aerosol particle size
can be characterized by the mass median aerodynamic diameter (MMAD)
of the aerosol. MMAD refers to the median of the distribution of
particle sizes forming the aerosol.
[0095] Aerosol particle size distributions for condensation
aerosols formed using the condensation aerosol delivery device
described in Example 1 are presented in FIG. 14. Each foil of a
25-foil cartridge contained 50 .mu.g of fentanyl as a 3 .mu.m thick
layer. A single foil was heated to a peak temperature of
400.degree. C. within 350 msec in a 6 L/min airflow. The particle
size distribution of the aerosol emitted from the device was
measured by the Anderson Impaction method using an eight stage
Cascade Impactor Series 20-800 Mark II (Anderson, Copley
Scientific, Nottingham, UK). The particle size distribution for two
replicates from each of front foils (1-5), middle foils (10-15) and
back foils (20-25) (closest to the mouthpiece) are presented in
FIG. 14. The particle size distribution of the aerosol from each
foil is consistent, exhibiting a range of particle size from about
5.8 .mu.m to about 0 .mu.m with a MMAD of 1.8 .mu.m, and a
geometric standard deviation (GSD) of 1.7 .mu.m.
Example 3
Effect of Airflow on Particle Size
[0096] The airflow in a condensation aerosol delivery device as
described in Example 1 was adjusted and the particle size of five
emitted doses measured using the Anderson impaction method. The
airflow volume was increased from 4 L/min to 8 L/min to increasing
the airflow velocity from 1 msec to 2 msec. In tests 1, 2, and 4, a
bypass air routing part was inserted into the mouthpiece section of
the cartridge (to get the total airflow up to 28.3 L/min for the
Andersen impactor to function properly) such that the bypass air
and the airflow containing the condensation aerosol joined just
prior to entering the impactor. In test 3, however, bypass air was
introduced into the outgoing airflow immediately after passing over
the heating elements. The results are presented in Table 1.
TABLE-US-00001 TABLE 1 Effect of Airflow Rate on Aerosol Particle
Size Test 1 Test 2 Test 3 Test 4 Airflow Rate (L/min) 4 6 6 8
Airflow Velocity (m/sec) 1 1.5 1.5 2 Percent Recovery 83 90 86 90
Emitted Dose (.mu.g) 208 225 216 224 MMAD (.mu.m) 2.53 1.88 1.37
1.25 GSD 1.99 2.09 2.36 2.10 FPF (1-3.5 .mu.m) (%) 56 61 60 58
Fraction 0-2 .mu.m (%) 37 53 69 76 Fraction <5 .mu.m (%) 91 98
100 100
Example 4
Stability of Fentanyl in Multi-Dose Device
[0097] The stability of fentanyl in multi-dose condensation aerosol
delivery devices was determined by measuring the amount and purity
of fentanyl in an emitted dose for a newly manufactured cartridge
(diagonal lines), an unused cartridge that was stored at room
temperature for 7 days (cross-hatch), and a cartridge that was used
to emit 10 doses and then stored at room temperature for 7 days
(solid). The results are presented in FIG. 15.
Example 5
Temperature Profile of Heating Element
[0098] Three AAA batteries provided 1.7 joules of energy to a
0.0005 inch thick stainless steel foil on which 50 .mu.g of
fentanyl was deposited. The airflow velocity was 1 msec
corresponding to an airflow rate of 4 L/min. As shown in FIG. 16,
the temperature of the foil increased to a temperature of about
200.degree. C. within 50 msec, a maximum temperature of 400.degree.
C. within 284 msec, and returned to room temperature within 1.5 sec
after reaching maximum temperature.
Example 6
Temperature Uniformity Measurements
[0099] The temperature uniformity of a foil having a thin layer of
50 .mu.g of fentanyl was measured during heating. The results are
shown in FIGS. 17A and 17B.
Example 8
Effect of Second Airflow on Aerosol Particle Deposition
[0100] The effects of the airflow in a cartridge on the deposition
of the aerosol particles on downstream surfaces is demonstrated in
FIGS. 18 and 19. The results presented in FIG. 18 were obtained
using a cartridge as described in Example 1 with the exception that
there was no circuit board separating the first and second airways
and flow was controlled by flow meters instead of a flow valve. The
heating elements were supported at the edges only and there was no
flow control between the first and second airways; the amount of
air entering the first and second airways was controlled by flow
meters at the inlet to each airway. For the 1 m/s and 2 m/s
examples in FIG. 18 the first and second airways were separated by
a piece of tape to test aerosol particle deposition when all the
airflow passed over the top of the heating elements. In the 90/101
m/s example, in contrast, the tape was removed and the flow meters
were set such that 90% of the inlet airflow entered through the
first airway and 10% entered through the second airway. The air
that entered through the second airway had to flow through the gaps
between the heating elements to reach the airway outlet. Finally,
in the 1 m/s, tape under 16-25 case a piece of tape was placed
below heating elements 16-25 and again the flow meters were set
such that 90% of the inlet airflow entered through the first airway
and 10% entered through the second airway. The tape was intended to
increase the amount of air flowing up past heating elements 1-15.
In each experiment heating elements 3, 9, 16, and 22 contained a 3
.mu.m thick layer of 50 .mu.g of fentanyl from which fentanyl was
vaporized, with the downstream elements fired before the upstream
elements so that any deposited aerosol particles would not be
revaporized. As shown in FIG. 18, for each of these conditions up
to about 5 .mu.g of fentanyl was deposited on each downstream
heating element.
[0101] FIG. 19 shows the results from three tests conducted using
the same airway as described above for the results in FIG. 18. In
these tests, however, the first and second airways were separated
by a thin piece of foam placed directly below the heating elements
and the flow meters were set such that 50% of the inlet airflow
entered through the first airway and 50% entered through the second
airway. The foam created a pressure drop between the first and
second airway, evenly distributing the flow from the second airway
past each heating element and into the center of the first airway.
In these experiments 50 .mu.g of fentanyl were vaporized from each
of the 25 heating elements (in contrast to the experiments from
FIG. 18 where fentanyl was only vaporized from 4 heating elements)
from downstream heating element 25 to upstream heating element 1,
and essentially no fentanyl was deposited on the downstream heating
elements.
Example 9
Purity and Yield of Emitted Dose
[0102] The purity and yield of emitted doses for devices as
described in Example 1, except that the surface area of each
support was 0.25 cm.sup.2, are presented in FIGS. 20A and 20B. FIG.
20A shows that the purity of a 2.4 .mu.m thick, 60 .mu.g dose of
fentanyl emitted from the device is greater than 98% when the peak
temperature of the heating element is at least 375.degree. C. As
shown in FIG. 20B, at least 96% of the 2.4 .mu.m thick, 60 .mu.g
dose of fentanyl disposed on a heating element was emitted from the
device when heated to a temperature of at least 375.degree. C. For
FIGS. 20A and 20B, the condensation aerosols comprising fentanyl
were characterized by a MMAD of 2.0 .mu.m and a GSD of 1.8
.mu.m.
* * * * *