U.S. patent application number 14/092405 was filed with the patent office on 2014-07-10 for methods and devices for compound delivery.
This patent application is currently assigned to E-NICOTINE TECHNOLOGY, INC.. The applicant listed for this patent is E-NICOTINE TECHNOLOGY, INC.. Invention is credited to Michael Hufford, Peter Lloyd, Martin Wensley, Jeffrey Williams.
Application Number | 20140190496 14/092405 |
Document ID | / |
Family ID | 49979477 |
Filed Date | 2014-07-10 |
United States Patent
Application |
20140190496 |
Kind Code |
A1 |
Wensley; Martin ; et
al. |
July 10, 2014 |
METHODS AND DEVICES FOR COMPOUND DELIVERY
Abstract
Provided herein are methods, devices, systems, and computer
readable medium for delivering one or more compounds to a subject.
Also described herein are methods, devices, systems, and computer
readable medium for transitioning a smoker to an electronic
nicotine delivery device and for smoking or nicotine cessation.
Inventors: |
Wensley; Martin; (Los Gatos,
CA) ; Hufford; Michael; (Chapel Hill, NC) ;
Williams; Jeffrey; (Draper, UT) ; Lloyd; Peter;
(Walnut Creek, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
E-NICOTINE TECHNOLOGY, INC. |
Draper |
UT |
US |
|
|
Assignee: |
E-NICOTINE TECHNOLOGY, INC.
Draper
UT
|
Family ID: |
49979477 |
Appl. No.: |
14/092405 |
Filed: |
November 27, 2013 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
61730738 |
Nov 28, 2012 |
|
|
|
61794601 |
Mar 15, 2013 |
|
|
|
61831992 |
Jun 6, 2013 |
|
|
|
61887045 |
Oct 4, 2013 |
|
|
|
Current U.S.
Class: |
131/273 ;
131/328 |
Current CPC
Class: |
A61M 11/042 20140204;
A61M 2205/3561 20130101; A61M 15/0065 20130101; A61M 2205/3653
20130101; A24F 47/008 20130101; A61M 15/002 20140204; A61M
2205/3553 20130101; A61M 2205/502 20130101; A61M 2205/52 20130101;
Y02A 90/10 20180101; A24B 15/167 20161101; A61M 2205/3592 20130101;
A61M 15/0066 20140204; A61M 15/06 20130101; A61M 2205/3569
20130101; A61M 15/0083 20140204; A61M 11/001 20140204; A61M
2205/3584 20130101; A61M 2205/8206 20130101; A61M 11/002 20140204;
A61M 2016/0015 20130101 |
Class at
Publication: |
131/273 ;
131/328 |
International
Class: |
A24F 47/00 20060101
A24F047/00 |
Claims
1. A condensation aerosol generating device for generating a
condensation aerosol of a liquid formulation, the device
comprising: a. a reservoir comprising a liquid formulation; and b.
a passageway comprising a heater element, wherein the reservoir is
in fluid communication with the heater element, wherein the heater
element is capable of vaporizing the liquid formulation when the
liquid formulation is delivered onto the heater element, and
wherein a flow of air through the passageway condenses the
vaporized liquid formulation into particles having a mass median
aerodynamic diameter (MMAD) of from about 1 .mu.m to about 5
.mu.m.
2. The device of claim 1, wherein the device is configured to
produce an internal air resistance of from about 0.08 to about 0.12
sqrt (cm-H.sub.2O)/LPM.
3. The device of claim 1, wherein the passageway comprises an
upstream opening and a downstream opening, wherein the upstream
opening comprises an inlet for the air and the downstream opening
serves as an outlet for air.
4. The device of claim 3, wherein the heater element is located
within the passageway between the upstream and downstream
openings.
5. The device of claim 3, wherein the reservoir is located within
the passageway between the upstream and downstream openings.
6. The device of claim 3, further comprising an air flow regulator
located in the passageway.
7. The device of claim 6, further comprising a second passageway,
wherein the air flow regulator is capable of directing air through
the second passageway in response to a pressure drop across the air
flow regulator.
8. The device of claim 8, wherein the air flow regulator comprises
one or more gas control valves.
9. The device of claim 1, wherein the heater element comprises a
wire coil.
10. The device of claim 1, further comprising a capillary in fluid
communication with the reservoir.
11. The device of claim 10, wherein the capillary is in fluid
communication with the heater element.
12. The device of claim 10, wherein the capillary comprises a
heatable region.
13. The device of claim 12, further comprising a check valve
located in the capillary between the heatable region and the
reservoir.
14. The device of claim 1, further comprising a controller, wherein
the controller comprises a non-transitory computer readable medium
comprising one or more algorithms, wherein the one or more
algorithms regulate dosing or a delivery schedule of the
condensation aerosol of the liquid formulation.
15. The device of claim 14, further comprising an interface for
communicating with the controller.
16. The device of claim 14, wherein the controller is removably
attached to the passageway and the reservoir.
17. The device of claim 14, wherein the controller is capable of
communicating with one or more electronic devices.
18. The device of claim 1, wherein the liquid formulation comprises
a flavoring.
19. A condensation aerosol generating device for generating a
condensation aerosol of a liquid formulation, the device
comprising: a. a passageway comprising a heater element; and b. a
reservoir comprising the liquid formulation, wherein the reservoir
is in fluid communication with the heater element, wherein the
heater element is capable of vaporizing the liquid formulation when
the liquid formulation is delivered onto the heater element, and
wherein a flow of air through the device delivers the condensation
aerosol of the liquid formulation to the deep lung of a subject
using the device.
20. The device of claim 19, wherein the device permits a flow
resistance of from about 0.08 to about 0.12 sqrt
(cm-H.sub.2O)/LPM.
21. The device of claim 19, wherein the passageway comprises an
upstream opening and a downstream opening, wherein the upstream
opening comprises an inlet for the air and the downstream opening
serves as an outlet for the air, and wherein the heater element is
located in the passageway between the upstream and downstream
openings.
22. The device of claim 19, wherein the reservoir is located within
the passageway between the upstream and downstream openings.
23. The device of claim 19, further comprising an air flow
regulator located in the passageway.
24. The device of claim 23, further comprising a second passageway,
wherein the air flow regulator is capable of directing the air
through the second passageway in response to a pressure drop across
the air flow regulator.
25. The device of claim 24, wherein the air flow regulator
comprises one or more gas control valves.
26. The device of claim 19, wherein the heater element comprises a
wire coil.
27. The device of claim 19, further comprising a capillary in fluid
communication with the reservoir.
28. The device of claim 27, wherein the capillary is in fluid
communication with the heater element.
29. The device of claim 27, wherein the capillary comprises a
heatable region.
30. The device of claim 19, further comprising a controller,
wherein the controller comprises a non-transitory computer readable
medium comprising one or more algorithms wherein the one or more
algorithms regulate dosing or a delivery schedule of the
condensation aerosol of the liquid formulation.
31. The device of claim 30, further comprising an interface for
communicating with the controller.
32. The device of claim 30, wherein the controller is removably
attached to the passageway and the reservoir.
33. The device of claim 30, wherein the controller is capable of
communicating with one or more electronic devices.
34. The device of claim 19, wherein the liquid formulation
comprises a flavoring.
35. A method of administering a condensation aerosol to a deep lung
of a subject, the method comprising: a. generating a condensation
aerosol, wherein the generating comprises vaporizing a liquid
formulation delivered onto a heater element, wherein the heater
element is located in a passageway of a condensation aerosol
generating device, wherein the condensation aerosol has an MMAD of
from about 1 .mu.m to about 5 .mu.m; and b. flowing a gas through
the condensation aerosol generating device to deliver the
condensation aerosol to a deep lung of a subject using the
device.
36. The method of claim 35, wherein the condensation aerosol
generating device is configured to produce an internal air
resistance of from about 0.08 to about 0.12 sqrt
(cm-H.sub.2O)/LPM.
37. The method of claim 35, wherein the passageway comprises an
upstream opening and a downstream opening, wherein the upstream
opening comprises an inlet for the air and the downstream opening
serves as an outlet for air.
38. The method of claim 37, wherein the heater element is located
within the passageway between the upstream and downstream
openings.
39. The method of claim 37, wherein the condensation aerosol
generating device further comprises a reservoir located within the
passageway between the upstream and downstream openings.
40. The method of claim 35, wherein the condensation aerosol
generating device further comprises an air flow regulator located
in the passageway.
41. The method of claim 40, wherein the condensation aerosol
generating device further comprises a second passageway, wherein
the air flow regulator is capable of directing air through the
second passageway in response to a pressure drop across the air
flow regulator.
42. The method of claim 41, wherein the air flow regulator
comprises one or more gas control valves.
43. The method of claim 37, wherein the heater element comprises a
wire coil.
44. The method of claim 37, wherein the condensation aerosol
generating device further comprises a capillary in fluid
communication with the reservoir.
45. The method of claim 44, wherein the capillary is in fluid
communication with the heater element.
46. The method of claim 44, wherein the capillary comprises a
heatable region.
47. The method of claim 46, wherein the condensation aerosol
generating device further comprises a check valve located in the
capillary between the heatable region and the reservoir.
48. The method of claim 35, wherein the condensation aerosol
generating device further comprises a controller, wherein the
controller comprises a non-transitory computer readable medium
comprising one or more algorithms, wherein the one or more
algorithms regulate dosing or a delivery schedule of the
condensation aerosol of the liquid formulation.
49. The method of claim 48, wherein the condensation aerosol
generating device further comprises an interface for communicating
with the controller.
50. The method of claim 48, wherein the controller is removably
attached to the passageway and the reservoir.
51. The method of claim 48, wherein the controller is capable of
communicating with one or more electronic devices.
52. A condensation aerosol generating device for generating a
condensation aerosol of a liquid formulation, the device
comprising: a passageway comprising a heater element, an inlet, and
an outlet, wherein the heater element is located between the inlet
and the outlet of the passageway, wherein the passageway is adapted
to produce a condensation aerosol from a liquid formulation
delivered onto the heater element, and wherein the device is
configured to produce an internal air resistance that is no greater
than that of a cigarette.
53. The device of claim 52, wherein the internal air resistance is
at most 0.20 sqrt (cm-H.sub.2O)/LPM.
54. The device of claim 52, wherein the internal air resistance is
from about 0.08 to about 0.12 sqrt (cm-H.sub.2O)/LPM.
55. The device of claim 52, further comprising a reservoir in fluid
communication with the heater element.
56. The device of claim 52, wherein the device further comprises an
air flow regulator located in the passageway.
57. The device of claim 56, further comprising a second passageway,
wherein the air flow regulator is capable of directing air through
the second passageway in response to a pressure drop across the air
flow regulator.
58. The device of claim 57, wherein the air flow regulator
comprises one or more gas control valves.
59. The device of claim 52, wherein the heater element comprises a
wire coil.
60. The device of claim 52, wherein the device is configured to
detect inhalation from a user.
61. The device of claim 60, wherein the device is further
configured to produce the condensation aerosol within 1000
milliseconds from the detection of inhalation from the user.
62. The device of claim 61, wherein the condensation aerosol is
present in the first third of the volume of air inhaled by the
user.
63. The device of claim 52, wherein the liquid formulation
comprises nicotine.
Description
CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Provisional
Application Nos. 61/730,738, filed on Nov. 28, 2012, 61/794,601,
filed on Mar. 15, 2013, 61/831,992, filed on Jun. 6, 2013, and
61/887,045, filed on Oct. 4, 2013, which applications are
incorporated herein by reference in their entirety.
BACKGROUND
[0002] There is a need for new methods and devices for
administering compounds, such as pharmaceutical agents, to a
subject. In particular, there is a need for methods and devices for
delivery of compounds to a subject where the compounds are
aerosolized to fall within a specified particle size range. In some
cases, particles within a specified size range can be efficiently
delivered to the deep lung. For example, there is an urgent need
for improved methods and devices to deliver nicotine to a subject
in specified doses and in a specified particle range size without
the carcinogens and other chemicals associated with combustible
tobacco products.
[0003] In 2011, an estimated 19% of U.S. adults were current
smokers (43.8 million people), and an estimated 950 children become
addicted to smoking daily. Smokers spend approximately $83 billion
to support their habit, and half of smokers will die from their
habit. Studies indicate that about 85% of smokers want to quit;
however, only about 5% succeed.
[0004] Current nicotine replacement therapies (NRTs) are not
effective for approximately 85% of users. In some cases, existing
NRTs and electronic cigarettes (eCigs) fail to provide sufficient
doses of nicotine. Many smokers using NRTs under-dose, resulting in
break-through cravings, which can lead to smoking lapses and
eventual relapse. Smokers also vary widely in terms of their daily
nicotine intake, ranging from "social smokers" who may only consume
1 or 2 cigarettes in the presence of friends and/or with alcohol,
to heavy smokers who consume 60 or more cigarettes per day. Thus, a
need exists to provide effective, customized doses of nicotine to
individuals attempting to use recreational nicotine products or to
leverage these devices to help quit smoking or nicotine intake all
together.
[0005] Furthermore, to facilitate nicotine delivery and smoking
cessation using an electronic nicotine delivery device, a need
exists to control nicotine particle size generated from an
electronic nicotine delivery device to match the rapid nicotine
pharmacokinetics (PK) from smoking, which can result in deep lung
absorption of nicotine. Deep lung absorption of nicotine can
facilitate rapid delivery of nicotine to the brain, which can
result in a subsequent cessation of nicotine cravings. When smoking
combustible tobacco products, nicotine laden smoke particles are
carried proximally on tar droplets (0.1-1.0 .mu.M in diameter), are
inhaled and travel to the small airways and alveoli in the deep
lung. Nicotine off-gasses from particles and defuses to, and
deposits on, the alveoli wall where it can be rapidly absorbed into
the blood stream. A typical electronic cigarette does not produce
an aerosol of nicotine with a particle size for deep lung delivery.
Aerosol particles with an aerodynamic diameter larger than 5 .mu.m
can be too large to reach the deep lung because the particles can
impact in the mouth and upper airway, resulting in a slow PK.
Conversely, aerosol particles with a median aerodynamic diameter of
less than 1 .mu.m can be small enough to reach the deep lung but
can be too light to gravitationally settle and can be exhaled,
which can result in low dose delivery. Additionally, aerosols with
small aerosol particle size can contain a larger percentage of the
mass in the gas phase, which rapidly diffuses to the mouth and
upper airway. Aerosol particles with an aerodynamic diameter of
about 1 .mu.m to about 5 .mu.m can be small enough to reach the
deep lung but large enough to gravitationally settle in alveoli,
which can result in a rapid PK. A need exists for electronic
nicotine delivery devices that produce such particles. In addition,
a need exists for producing nicotine aerosols that produce such
particles using the liquid drug. Moreover, a need exists for
methods of using such devices to help users achieve a particular
health goal or goals.
[0006] Also, a need exists for considering behavioral factors in
smoking relapse and for integrating smoking cessation programs with
social media to facilitate and maintain behavior change.
[0007] There is also a need for a drug delivery platform that is
capable of dispensing a variety of drugs to a subject in a
specified dose or in a specified particle size range.
SUMMARY
[0008] In one aspect, a condensation aerosol generating device for
generating a condensation aerosol from a liquid formulation is
provided, the device comprising: a) a reservoir comprising a liquid
formulation; and b) a passageway comprising a heater element, an
inlet, and an outlet, wherein the heater element is disposed in the
passageway between the inlet and the outlet, wherein the reservoir
is in fluid communication with the heater element, and wherein the
passageway is configured to produce a condensation aerosol in the
device, wherein the condensation aerosol has a mass median
aerodynamic diameter (MMAD) of from about 1 .mu.m to about 5 .mu.m.
In some cases, the heater element comprises a wick element. In some
cases, the heater element comprises a coil. In some cases, the
heater element comprises a wick element and a coil. In some cases,
the wick element comprises an electrically resistive material. In
some cases, the wick element and coil are formed from the same rod.
In some cases, the rod comprises a pliable material. In some cases,
the coil is wrapped around the wick element. In some cases, the
wick element is capable of being heated. In some cases, the coil
spans a length of from about 0.25 cm to about 0.39 cm (from about
0.1 inch to about 0.15 inches) along the length of the wick
element. In some cases, the heater element comprises a wire
coil.
[0009] In some cases, the device further comprises a positive
displacement pump in fluid communication with the reservoir. In
some cases, the displacement pump is configured to pump the liquid
formulation comprising the liquid formulation to the heater
element. In some cases, the positive displacement pump comprises a
peristaltic pump.
[0010] In some cases, the passageway has an internal diameter of
from 0.20 cm to about 1.3 cm (about 0.08 inches to about 0.5
inches). In some cases, an internal diameter of the passageway
where the heater element is located is from about 0.44 cm to about
0.64 cm (about 0.175 to about 0.25 inches). In some cases, an
internal diameter of the passageway before and after the heater
element is from about 0.07 cm to about 1.3 cm (about 0.03 to about
0.5 inches). In some cases, the length of the passageway is from
about 0.5 cm to about 15.3 cm (from about 0.2 inches to about 6
inches). In some cases, the device further comprises a baffle
disposed in the passageway between the outlet and the heater
element. In some cases, the baffle inhibits flow of particles
having an MMAD of greater than 5 .mu.m.
[0011] In some cases, the device further comprises a second
passageway connected to the passageway. In some cases, the second
passageway connects with the passageway between the outlet and the
heater element. In some cases, the second passageway connects with
the passageway between the air inlet and the heater element. In
some cases, the device further comprises a power source in electric
communication with the heater element. In some cases, the power
source is a battery.
[0012] In some cases, the device further comprises a tube disposed
within the passageway and connected to the reservoir, wherein the
tube is configured to deliver the liquid formulation to the heater
element. In some cases, the tube is a capillary. In some cases, the
tube comprises a valve. In some cases, the tube comprises a second
heater element. In some cases, the tube comprises a heatable
region. In some cases, the device further comprises a valve located
in the tube between the heatable region and the reservoir. In some
cases, the tube comprises an electrically resistive material.
[0013] In some cases, the device further comprises a flow
restrictor disposed in the passageway. In some cases, a flow rate
of a gas through the device is capable of delivering the
condensation aerosol of the liquid formulation to a deep lung of a
user of the device. In some cases, a flow rate of gas through the
device that is capable of delivering the condensation aerosol of
the liquid formulation to a deep lung of a user of the device is
from about 20 liters per minute (LPM) to about 80 LPM. In some
cases, the device permits a flow resistance of from about 0.05 to
about 0.15 sqrt (cm-H2O)/LPM. In some cases, the device permits a
flow resistance of from about 0.08 to about 0.12 sqrt (cm-H2O)/LPM.
In some cases, the condensation aerosol is formed at a flow rate of
about 1 LPM to about 10 LPM past the heater element under a vacuum
of between about 249 Pa to about 3738 Pa (about 1 inch of water to
about 15 inches of water).
[0014] In some cases, the device further comprises a mouthpiece
attached to the outlet. In some cases, the liquid formulation
comprises a flavoring. In some cases, the liquid formulation
comprises a pharmaceutically active agent. In some cases, the
liquid formulation comprises nicotine and a carrier. In some cases,
the carrier comprises propylene glycol or vegetable glycerin. In
some cases, the device further comprises a programmable controller.
In some cases, the programmable controller comprises a
non-transitory computer readable medium, wherein the non-transitory
computer readable medium comprises one or more algorithms for
regulating dosage of the condensation aerosol of the liquid
formulation, frequency of administration of the condensation
aerosol of the liquid formulation, or a delivery schedule of the
condensation aerosol of the liquid formulation. In some cases, the
programmable controller is connected to one or more electronic
devices. In some cases, the one or more electronic devices comprise
a computer, a smartphone, or a mobile phone.
[0015] In some cases, the reservoir is within the passageway. In
some cases, the device further comprises a sensor to detect
inhalation. In some cases, the sensor comprises an optical path. In
some cases, the device further comprises a second heater element.
In some cases, the heater element is a aerosol generating heater
element. In some cases, the heater element is capable of vaporizing
the liquid formulation when the liquid formulation is delivered to
the heater element, wherein the vaporized liquid formulation is
condensed into aerosol particles in the passageway. In some cases,
the device further comprises an air flow regulator. In some cases,
the device further comprises a second passageway, wherein the air
flow regulator is capable of directing air through the second
passageway in response to a pressure drop across the air flow
regulator. In some cases, the air flow regulator comprises one or
more gas control valves.
[0016] In some cases, the device further comprises a controller,
wherein the controller comprises a non-transitory computer readable
medium comprising one or more algorithms, wherein the one or more
algorithms regulate dosing or a delivery schedule of the
condensation aerosol of the liquid formulation. In some cases, the
device further comprises an interface for communicating with the
controller. In some cases, the controller is removably attached to
the passageway and the reservoir. In some cases, the controller is
capable of communicating with one or more electronic devices.
[0017] In another aspect, a condensation aerosol generating device
for generating a condensation aerosol comprising a pharmaceutically
active agent is provided, the device comprising: a) a housing
comprising a heater element for vaporizing a liquid formulation
comprising the pharmaceutically active agent, wherein the heater
element is located between an outlet and an air inlet in the
housing; b) a reservoir comprising the liquid formulation, wherein
the reservoir is in fluid communication with the heater element; c)
a passageway for condensing a vaporized liquid formulation
comprising the pharmaceutically active agent, wherein the
passageway is in fluid communication with the heater element; and
d) a programmable controller. In some cases, the programmable
controller comprises a non-transitory computer readable medium. In
some cases, the non-transitory computer readable medium comprises
one or more algorithms for regulating dosage of the
pharmaceutically active agent, frequency of administration of the
pharmaceutically active agent, or a delivery schedule of the
pharmaceutically active agent. In some cases, the one or more
algorithms regulate dosage of the pharmaceutically active agent,
frequency of administration of the pharmaceutically active agent,
or delivery schedule of the pharmaceutically active agent based on
data provided to the device. In some cases, the device further
comprises an interface for communicating with the programmable
controller. In some cases, the programmable controller comprises a
non-transitory computer readable medium, wherein the non-transitory
computer readable medium comprises sequences of instructions,
which, when executed by the device, cause the device to a) record
data on use of the device; b) generate date on use of the device;
c) retrieve data on use of the device; d) communicate data on use
of the device; or e) input data regarding use of the device into
one or more algorithms. In some cases, the programmable controller
is connected to one or more electronic devices. In some cases, the
connection is local or remote. In some cases, the connection
comprises a wired connection. In some cases, the connection
comprises a wireless connection. In some cases, the one or more
electronic devices comprise a computer, smartphone, or a mobile
phone. In some cases, the device further comprises the ability to
access the Internet.
[0018] In some cases, the heater element comprises a wick element
and a coil. In some cases, the wick element and the coil are formed
from the same rod. In some cases, the coil is wrapped around the
wick element. In some cases, the device further comprises a
positive displacement pump in fluid communication with the
reservoir. In some cases, the device further comprises a baffle
disposed in the passageway between the outlet and the heater
element. In some cases, the device further comprises a second
passageway, wherein the second passageway connects with the
passageway between the outlet and the heater element. In some
cases, the device further comprises a second passageway, wherein
the second passageway connects with the passageway between the
inlet and the heater element.
[0019] In some cases, the device further comprises a tube disposed
within the passageway and connected to the reservoir, wherein the
tube is configured to deliver the liquid formulation comprising the
pharmaceutically active agent to the heater element. In some cases,
the device further comprises a mouthpiece attached to the outlet.
In some cases, the liquid formulation comprises a flavoring. In
some cases, the pharmaceutically active agent is nicotine. In some
cases, the liquid formulation comprises nicotine and a carrier. In
some cases, the device produces condensation aerosol particles
having a mass median aerodynamic diameter (MMAD) of from about 1
.mu.m to about 5 .mu.m. In some cases, a flow rate of gas in the
device is capable of delivering the condensation aerosol of the
liquid formulation comprising the pharmaceutically active agent to
a deep lung of a user, wherein the flow rate is from about 20 LPM
to about 80 LPM at a vacuum of about 249 Pa to about 3738 Pa (about
1 inch of water to about 15 inches of water). In some cases, the
device permits a flow resistance of from about 0.05 to about 0.15
sqrt (cm-H.sub.2O)/LPM.
[0020] In another aspect, a method for generating a condensation
aerosol of a liquid formulation is provided, the method comprising:
a) generating a condensation aerosol, wherein the generating
comprises vaporizing a liquid formulation using a heater element,
wherein the heater element is disposed in a passageway of a
condensation aerosol generating device, wherein the condensation
aerosol has an MMAD of from about 1 .mu.m to about 5 .mu.m; and b)
flowing a gas through the condensation aerosol generating device at
a flow rate effective to allow delivery of the condensation
aerosol. In some cases, the delivery is to the deep lung of a
subject using the device. In some cases, the subject is a human. In
some cases, the flowing comprises flowing a gas at a rate of about
20 LPM to about 80 LPM. In some cases, the condensation aerosol
generating device permits a flow resistance of from about 0.05 to
about 0.15 sqrt (cm-H.sub.2O)/LPM. In some cases, the condensation
aerosol is formed at a flow rate of about 1 LPM to about 10 LPM
past the heater element under a vacuum of between about 1 to about
249 Pa to about 3737 Pa (about 1 to about 15 inches of water). In
some cases, the subject is a human.
[0021] In some cases, the liquid formulation comprises a
pharmaceutically active agent. In some cases, the pharmaceutically
active agent is delivered orally to the subject. In some cases, the
heater element comprises a wick element and a coil. In some cases,
the wick element comprises an electrically resistive material. In
some cases, the wick element and coil are formed from the same rod.
In some cases, the coil is wrapped around the wick element.
[0022] In some cases, the condensation aerosol generating device
comprises a programmable controller. In some cases, the
programmable controller comprises a non-transitory computer
readable medium. In some cases, the non-transitory computer
readable medium comprises one or more algorithms for regulating
dosage of a pharmaceutically active agent, frequency of
administration of a pharmaceutically active agent, or a delivery
schedule of a pharmaceutically active agent. In some cases, the
method further comprises programming the condensation aerosol
generating device to deliver a dose of the pharmaceutically active
agent. In some cases, the method further comprises programming a
delivery schedule for the condensation aerosol generating device.
In some cases, method further comprises programming a dosing
schedule for the condensation aerosol generating device. In some
cases, the passageway comprises an inlet and an outlet. In some
cases, the passageway is disposed between the inlet and the
outlet.
[0023] In some cases, the deep lung comprises alveoli. In some
cases, the liquid formulation comprises a pain medication. In some
cases, the liquid formulation comprises a flavoring. In some cases,
the liquid formulation comprises nicotine. In some cases, the
liquid formulation comprises nicotine and a carrier. In some cases,
the administering produces a nicotine blood concentration in the
subject that is substantially similar to the nicotine blood
concentration of a subject after smoking a cigarette. In some
cases, the nicotine blood concentration is an arterial or venous
nicotine blood concentration. In some cases, the administering
produces a nicotine blood concentration in the subject that is at
least 50% of the nicotine blood concentration of a subject after
smoking a cigarette.
[0024] In some cases, the condensation aerosol generating device
further comprises a baffle located in the passageway, wherein the
baffle inhibits flow of particles having an MMAD of greater than 5
.mu.m. In some cases, the condensation aerosol generating device
further comprises a reservoir comprising the liquid formulation. In
some cases, the reservoir is disposed an inlet and outlet. In some
cases, the condensation aerosol generating device further comprises
a tube located within the passageway and connected to the
reservoir. In some cases, the tube is configured to deliver the
liquid formulation to the heater element. In some cases, the tube
is a capillary. In some cases, the tube is in fluid communication
with the heater element. In some cases, the tube comprises a
heatable region. In some cases, the condensation aerosol generating
device further comprises a valve located in the tube between the
heatable region and the reservoir. In some cases, the condensation
aerosol generating device further comprises a controller, wherein
the controller comprises a non-transitory computer readable medium
comprising one or more algorithms, wherein the one or more
algorithms regulate dosing or a delivery schedule of the
condensation aerosol of the liquid formulation. In some cases, the
condensation aerosol generating device further comprises an
interface for communicating with the controller.
[0025] In some cases, the controller is removably attached to the
passageway and the reservoir. In some cases, the controller is
capable of communicating with one or more electronic devices. In
some cases, the condensation aerosol generating device further
comprises an air flow regulator located in the passageway. In some
cases, the condensation aerosol generating device further comprises
a second passageway, wherein an air flow regulator is capable of
directing air through the second passageway in response to a
pressure drop across the air flow regulator. In some cases, the air
flow regulator comprises one or more gas control valves. In some
cases, the heater element comprises a wire coil.
[0026] In another aspect, a method for treating a condition is
provided, the method comprising: a) producing a condensation
aerosol, wherein the producing comprises vaporizing a liquid
formulation using a heater element, wherein the heater element is
disposed in a passageway of a condensation aerosol generating
device, wherein the condensation aerosol has an MMAD of from about
1 .mu.m to about 5 .mu.m; and b) flowing a gas through the
condensation aerosol generating device at a flow rate effective to
allow delivery of the condensation aerosol comprising the
pharmaceutically active agent to the deep lung of a user of the
device, thereby treating the condition. In some cases, the flowing
comprises flowing a gas at a rate of about 20 LPM to about 80 LPM
at a vacuum of about 249 Pa to about 3738 Pa (about 1 inch of water
to about 15 inches of water). In some cases, the device permits a
flow resistance of from about 0.05 to about 0.15 sqrt
(cm-H.sub.2O)/LPM. In some cases, the condensation aerosol is
formed at a flow rate of about 1 LPM to about 10 LPM past the
heater element under a vacuum of between about 249 Pa to about 3738
Pa (about 1 inch of water to about 15 inches of water).
[0027] In some cases, the condensation aerosol generating device
comprises a programmable controller. In some cases, the method
further comprises programming the condensation aerosol generating
device to deliver a dose of the pharmaceutically active agent. In
some cases, method further comprises programming a delivery
schedule for the condensation aerosol generating device. In some
cases, the method further comprises programming a dosing schedule
for the condensation aerosol generating device.
[0028] In some cases, the subject is a human. In some cases, the
deep lung comprises alveoli.
[0029] In some cases, the condition is pain. In some cases, the
liquid formulation comprises a pain medication. In some cases, the
pharmaceutically active agent is delivered orally to the subject.
In some cases, the condition is addiction to smoking. In some
cases, the condition is nicotine addiction. In some cases, the
treating the condition comprises smoking cessation. In some cases,
the treating the condition comprises transitioning a subject who
smokes from use of cigarettes to use of the condensation aerosol
generating device. In some cases, the liquid formulation comprises
a flavoring. In some cases the liquid formulation comprises
nicotine. In some cases, the liquid formulation comprises nicotine
and a carrier. In some cases, the condition is addiction to smoking
or nicotine addiction, and the delivery produces a nicotine blood
concentration in the subject that is substantially similar to a
nicotine blood concentration of a subject after smoking a
cigarette. In some cases, the nicotine blood concentration is an
arterial or venous nicotine blood concentration. In some cases, the
delivery produces a nicotine blood concentration in the subject
that is at least 50% of the nicotine blood concentration of a
subject after smoking a cigarette.
[0030] In another aspect, a heater element is provided comprising:
a) a coil comprising an electrically resistive material; and b) a
wick element capable of being heated, wherein the coil is wrapped
around the wick element. In some cases, the wick element comprises
an electrically resistive material. In some cases, the wick element
and the coil are independent. In some cases, the wick element and
the coil are formed from the same rod. In some cases, the wick
element and the coil are wire. In some cases, the coil comprises 1
to 9 turns. In some cases, a distance between each turn in a coil
is from about 0.01 to about 0.02 inches. In some cases, the coil
has a length to width aspect ratio of at least 2. In some cases,
the coil comprises an inner diameter of from about 0.027 inches to
about 0.040 inches. In some cases, the coil comprises an outside
diameter of from about 0.047 inches to about 0.080 inches.
[0031] In another aspect, a method is provided comprising producing
a nicotine blood concentration in a subject that is substantially
similar to a nicotine blood concentration of a subject after
smoking a cigarette, the method comprising delivering a
condensation aerosol comprising nicotine to a subject, wherein the
condensation aerosol has a MMAD of from about 1 .mu.m to about 5
.mu.m. In some cases, the nicotine blood concentration is an
arterial or venous nicotine blood concentration. In some cases, the
condensation aerosol is produced from a condensation aerosol
generating device. In some cases, the condensation aerosol
generating device comprises a) a passageway comprising a heater
element, an inlet, and an outlet, wherein the heater element is
disposed in the passageway between the inlet and the outlet; and b)
a reservoir comprising a liquid formulation comprising nicotine,
wherein the reservoir is in fluid communication with the heater
element, wherein the heater element is capable of vaporizing the
liquid formulation comprising the pharmaceutically active agent
when the liquid formulation comprising nicotine is delivered to the
heater element, wherein the vaporized liquid formulation comprising
nicotine is condensed into aerosol particles.
[0032] In another aspect, a condensation aerosol generating device
for generating a condensation aerosol of a liquid formulation is
provided, the device comprising: a) a passageway comprising a
heater element; and b) a reservoir comprising the liquid
formulation, wherein the reservoir is in fluid communication with
the heater element, wherein the heater element is capable of
vaporizing the liquid formulation when the liquid formulation is
delivered to the heater element, and wherein a flow of air through
the device delivers the condensation aerosol of the liquid
formulation to the deep lung of a subject using the device. In some
cases, the device permits a flow resistance of from about 0.08 to
about 0.12 sqrt (cm-H.sub.2O)/LPM. In some cases, the passageway
comprises an upstream opening and a downstream opening, wherein the
upstream opening comprises an inlet for the air and the downstream
opening serves as an outlet for the air, and wherein the heater
element is located in the passageway between the upstream and
downstream openings. In some cases, the reservoir is located within
the passageway between the upstream and downstream openings.
[0033] In some cases, the device further comprises an air flow
regulator located in the passageway. In some cases, the device
further comprises a second passageway, wherein an air flow
regulator is capable of directing the air through the second
passageway in response to a pressure drop across the air flow
regulator. In some cases, the air flow regulator comprises one or
more gas control valves. In some cases, the heater element
comprises a wire coil.
[0034] In some cases, the device further comprises a tube in fluid
communication with the reservoir. In some cases, tube is a
capillary. In some cases, the tube is in fluid communication with
the heater element. In some cases, the tube comprises a heatable
region.
[0035] In some cases, the device further comprises a controller,
wherein the controller comprises a non-transitory computer readable
medium comprising one or more algorithms wherein the one or more
algorithms regulate dosing or a delivery schedule of the
condensation aerosol of the liquid formulation. In some cases, the
device further comprises an interface for communicating with the
controller. In some cases, the controller is removably attached to
the passageway and the reservoir. In some cases the controller is
capable of communicating with one or more electronic devices. In
some cases the liquid formulation comprises a flavoring.
[0036] In another aspect, a condensation aerosol generating device
for producing a condensation aerosol is provided, the device
comprising: a) a passageway comprising an aerosol generating heater
element, an inlet, and an outlet, wherein the aerosol generating
heater element is between the inlet and the outlet in the
passageway, wherein the device is configured to produce a
condensation aerosol from a liquid formulation in the device,
wherein the condensation aerosol has a mass median aerodynamic
diameter (MMAD) of from 1 .mu.M to 5 .mu.M; and b) one or more
additional airflow regulating inlets for air located between the
outlet and the heater element in the passageway, wherein the total
airflow rate out of the outlet is between 20 LPM and 80 LPM at a
vacuum of about 249 Pa to about 3738 Pa (about 1 inch of water to
about 15 inches of water). In some cases, the device further
comprises a reservoir comprising the liquid formulation, wherein
the reservoir is in fluid communication with the aerosol generating
heater element. In some cases, the device further comprises a tube
located within the passageway and connected to the reservoir,
wherein the tube is configured to deliver the liquid formulation to
the aerosol generating heater element. In some cases, the reservoir
is located within the passageway.
[0037] In some cases, the passageway further comprises a positive
displacement pump configured to pump the liquid formulation
comprising through the tube to the heater element. In some cases,
the positive displacement pump comprises a peristaltic pump. In
some cases, the passageway has an internal diameter of from about
0.20 cm to about 1.3 cm (about 0.08 inches to about 0.5 inches). In
some cases, an internal diameter of the passageway where the heater
element is located is from about 0.44 cm to about 0.64 cm (about
0.175 to about 0.25 inches). In some cases, an internal diameter of
the passageway before and after the heater element is from about
0.07 cm to about 1.3 cm (about 0.03 to about 0.5 inches). In some
cases, the length of the passageway is from about 0.5 cm to about
15.3 cm (from about 0.2 inches to about 6 inches).
[0038] In some cases, the passageway comprises a baffle located
between the outlet and the heater element, wherein the baffle is
configured to remove aerosol particles with an MMAD of greater than
5 .mu.m from the aerosol. In some cases, the aerosol generating
heater element comprises a wick element. In some cases, the aerosol
generating heater element comprises a coil. In some cases, the
aerosol generating heater element comprises a coil wrapped around a
wick element, wherein the coil and the wick element are formed from
the same rod. In some cases, the coil spans a length of from about
0.1 to about 0.15 inches along the length of the wick element. In
some cases, the wick element comprises an electrically resistive
material. In some cases, the rod comprises a pliable material.
[0039] In some cases, the device further comprises a sensor to
detect inhalation. In some cases, the sensor comprises an optical
path. In some cases, the device further comprises a power source to
power the heater element. In some cases, the power source is a
battery. In some cases, the tube is a capillary tube. In some
cases, the tube comprises a valve. In some cases, the tube
comprises an electrically resistive material.
[0040] In some cases, the device further comprises a programmable
controller. In some cases, the device is connected to one or more
electronic devices. In some cases, the one or more electronic
devices comprise a computer, smartphone, or mobile phone. In some
cases, the device further comprises a second heater element. In
some cases, the passageway is configured to produce a flow rate of
from about 1 to about 10 LPM at the heater element under a vacuum
of between about 249 Pa to about 3738 Pa (about 1 inch of water to
about 15 inches of water).
[0041] In some cases, the liquid formulation comprises nicotine. In
some cases, the liquid formulation comprises a carrier. In some
cases, the carrier comprises propylene glycol or vegetable
glycerin.
[0042] In another aspect, a condensation aerosol generating device
for producing a condensation aerosol is provided, the device
comprising: a passageway comprising an aerosol generating heater
element, an inlet, and an outlet, wherein the aerosol generating
heater element is between the inlet and the outlet in the
passageway, wherein the passageway is configured to produce a
condensation aerosol from a liquid formulation, wherein the
condensation aerosol has a mass median aerodynamic diameter (MMAD)
of from about 1 .mu.m to about 5 .mu.m, wherein the device is
configured to produce an internal air resistance of from 0.05 to
0.15 sqrt (cm-H.sub.2O)/LPM. In some cases, the device further
comprises a reservoir comprising a liquid formulation, wherein the
reservoir is in fluid communication with the heater element. In
some cases, the device further comprises a tube located within the
passageway and connected to the reservoir, wherein the tube is
configured to deliver the liquid formulation comprising to the
heater element. In some cases, the reservoir is located within the
passageway. In some cases, the passageway further comprises a
positive displacement pump configured to pump the liquid
formulation comprising through the tube to the heater element. In
some cases, the positive displacement pump comprises a peristaltic
pump.
[0043] In some cases, the passageway has an internal diameter of
from about 0.20 cm to about 1.3 cm (about 0.08 inches to about 0.5
inches). In some cases, an internal diameter of the passageway
where the heater element is located is from about 0.44 cm to about
0.64 cm (about 0.175 to about 0.25 inches). In some cases, an
internal diameter of the passageway before and after the heater
element is from about 0.07 cm to about 1.3 cm (about 0.03 to about
0.5 inches). In some cases, the length of the passageway is from
about 0.5 cm to about 15.3 cm (from about 0.2 inches to about 6
inches).
[0044] In some cases, the passageway comprises a baffle located
between the outlet and the heater element, wherein the baffle is
configured to remove aerosol particles with an MMAD of greater than
5 .mu.m from the aerosol. In some cases, the heater element
comprises a wick element. In some cases, the heater element
comprises a coil. In some cases, the heater element comprises a
coil wrapped around a wick element, wherein the coil and the wick
element are formed from the same rod. In some cases, the coil spans
a length of from about 0.25 cm to about 0.39 cm (about 0.1 to about
0.15 inches) along the length of the wick element. In some cases,
the wick element comprises an electrically resistive material. In
some cases, the rod comprises a pliable material.
[0045] In some cases, the device further comprises a sensor to
detect inhalation. In some cases, the sensor comprises an optical
path. In some cases, the device further comprises a power source to
power the heater element. In some cases, the power source is a
battery. In some cases, the tube is a capillary tube. In some
cases, the tube comprises a valve. In some cases, the tube
comprises an electrically resistive material. In some cases, the
device further comprises a second passageway connected to the
passageway. In some cases, the second passageway connects between
the outlet and the heater element in the passageway. In some cases,
the second passageway connects to the passageway between the inlet
and the heater element.
[0046] In some cases, the device further comprises a programmable
controller. In some cases, the device is connected to one or more
electronic devices. In some cases, the one or more electronic
devices comprise a computer, smartphone, or mobile phone. In some
cases, the device further comprises a second heater element. In
some cases, the passageway is configured to produce a flow rate of
from 1 to 10 LPM past the heater element under a vacuum of between
about 249 Pa to about 3738 Pa (about 1 inch of water to about 15
inches of water). In some cases, the liquid formulation comprises
nicotine. In some cases, the liquid formulation comprises a
carrier. In some cases, the carrier comprises propylene glycol or
vegetable glycerin.
[0047] The above elements can be combined in any combination.
INCORPORATION BY REFERENCE
[0048] All publications, patents, and patent applications mentioned
in this specification are herein incorporated by reference to the
same extent as if each individual publication, patent, or patent
application was specifically and individually indicated to be
incorporated by reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0049] Novel features are set forth with particularity in the
appended claims. A better understanding of the features and
advantages will be obtained by reference to the following detailed
description that sets forth illustrative embodiments, in which the
principles are utilized, and the accompanying drawings of
which:
[0050] FIG. 1 illustrates an embodiment of an electronic nicotine
delivery device.
[0051] FIGS. 2A and 2B illustrate an embodiment of electronic agent
(e.g., nicotine) delivery device.
[0052] FIGS. 3A and 3B illustrate embodiments of a heater
element.
[0053] FIG. 4 illustrates an embodiment of an agent (e.g.,
nicotine) reservoir.
[0054] FIG. 5 illustrates another embodiment of an agent (e.g.,
nicotine) reservoir.
[0055] FIG. 6 illustrates another embodiment of an agent (e.g.,
nicotine) reservoir.
[0056] FIG. 7 illustrates an embodiment of a heater element.
[0057] FIG. 8 illustrates an embodiment of an electronic agent
(e.g., nicotine) delivery device.
[0058] FIG. 9 illustrates another embodiment of a heater
element.
[0059] FIGS. 10A and 10B illustrate additional embodiments of a
heater element.
[0060] FIG. 11 illustrates inertial impaction.
[0061] FIG. 12 illustrates an embodiment of a method of removal of
an agent (e.g., nicotine) mixture from a reservoir and dispensing
the nicotine into desired doses.
[0062] FIG. 13 illustrates another embodiment of a method for
measuring an agent (e.g., nicotine) dose.
[0063] FIG. 14 illustrates another embodiment for measuring an
agent (e.g., nicotine) dose.
[0064] FIG. 15 illustrates another embodiment for measuring an
agent (e.g., nicotine) dose.
[0065] FIGS. 16A and 16B illustrate embodiments for applying an
agent (e.g., nicotine) to a heater element.
[0066] FIGS. 17A and 17B illustrate embodiments of mechanisms for
generating an aerosol.
[0067] FIG. 18 illustrates an embodiment of a mechanism for
dispensing an agent (e.g., nicotine) mixture.
[0068] FIG. 19 illustrates feedback to a nicotine user regarding
nicotine intake and mean craving over time.
[0069] FIG. 20 illustrates customized feedback to a user of an
electronic nicotine delivery device.
[0070] FIG. 21 illustrates an embodiment of a method for flow
control.
[0071] FIG. 22 illustrates an embodiment of a heater element.
[0072] FIG. 23 illustrates another embodiment for measuring an
agent (e.g., nicotine) dose.
[0073] FIG. 24 illustrates another embodiment for measuring an
agent (e.g., nicotine) dose.
[0074] FIGS. 25A and 25B illustrate another embodiment of a method
of removal of an agent (e.g., nicotine) mixture from a
reservoir.
[0075] FIG. 26 illustrates a schematic of a test apparatus used for
testing the effects of altering system parameters of an aerosol
delivery device on particle size distribution.
[0076] FIGS. 27A, 27B, 27C, and 27D illustrate a schematic of a
test bed used for generating an aerosol in the test apparatus of
FIG. 26.
[0077] FIG. 28 shows a comparison of particle sizes of an aerosol
created by an e-cigarette (e-cig) vs. an aerosol created by a
device as provided herein.
[0078] FIG. 29A illustrate a schematic of a test apparatus used for
testing flow control. FIG. 29B illustrates a close-up of the valve
(2904a) that is part of the test apparatus in FIG. 29A.
[0079] FIG. 30A illustrates an alternative valve flap for use in
the valve (2904a) in FIG. 29A. FIG. 30B illustrates a slot for use
in the bypass (2908a) in FIG. 29A.
[0080] FIGS. 31A, 31B, 31C, 31D, and 31E, illustrate embodiments of
airflow configurations and heater element.
[0081] FIGS. 32A, 32B, 32C, 32D, and 32E illustrate embodiments of
flow-through passageways.
[0082] FIG. 33 illustrates an additional embodiment of a
flow-through passageway.
[0083] FIG. 34 illustrates an embodiment of a flow control
valve.
[0084] FIG. 35 illustrates an embodiment of a device comprising a
primary and secondary airway.
[0085] FIG. 36 illustrates another embodiment of a heater
element.
[0086] FIGS. 37A and 37B illustrate embodiments of a heater element
similar to that shown in FIG. 36. FIG. 37A depicts a wire coil
spanning a large percentage of the length of one end of the wire.
FIG. 37B depicts a wire coil spanning a smaller percentage of the
length of one end of the wire than shown in FIG. 37A.
[0087] FIG. 38 is an enlarged representation of the wire coil from
the heater element of FIG. 36.
[0088] FIG. 39 illustrates components of eHealth-enabled electronic
agent (e.g., nicotine) delivery system, in accordance with an
embodiment.
[0089] FIG. 40 illustrates example components of an electronic
agent (e.g., nicotine) delivery system, in accordance with an
embodiment.
[0090] FIG. 41 illustrates example components of an electronic
agent (e.g., nicotine) delivery device for implementing aspects
described herein, in accordance with an embodiment.
[0091] FIG. 42 illustrates an escalating dose protocol utilized
during part 1 of a two part study for assessing the safety,
tolerability, pharmacokinetics, and pharmacodynamics of a
condensation aerosol comprising nicotine and propylene glycol
produced from an electronic agent (e.g., nicotine) delivery device
as provided herein.
[0092] FIG. 43 illustrates a trial design for part 2 of a two part
study for assessing the safety, tolerability, pharmacokinetics, and
pharmacodynamics of a condensation aerosol comprising nicotine and
propylene glycol produced from an electronic agent (e.g., nicotine)
delivery device as provided herein.
[0093] FIGS. 44A, 44B, and 44C illustrate embodiments of a
passageway comprising a baffle for removing particles of a
non-optimal size. FIGS. 44A and 44B illustrate exterior views of a
passageway comprising a baffle. FIG. 44C illustrates an interior
view of a passageway comprising a baffle.
DETAILED DESCRIPTION
I. Overview
[0094] Provided herein are devices, systems, kits, compositions,
computer readable medium, and methods for electronic delivery of an
agent to a subject. For example the devices, systems, computer
readable medium, and methods can be used for electronic nicotine
delivery, which can facilitate recreational nicotine delivery, full
or partial smoking cessation, or facilitate full or partial
cessation of nicotine intake. The subject can be a human. The human
subject can be a smoker or an individual who uses tobacco or
nicotine containing products. Devices described herein can generate
an aerosol comprising an agent (e.g., nicotine), and the agent
(e.g., nicotine) aerosol can have a known and consistent amount of
agent (e g., nicotine). Also, devices and methods for dose
titration are provided.
[0095] The devices, systems, kits, compositions, and computer
readable medium provided herein can be part of an electronic agent
(e.g., nicotine) delivery platform. The electronic platform for
delivering an agent (e.g., nicotine) can be used to deliver the
agent (e.g., nicotine) to a subject in a particular dose, with a
particular mean particle size, pH, and airflow characteristics,
which can affect back of the throat impaction and upper airway
deposition. In one embodiment, the electronic delivery platform
regulates a schedule of delivery of an agent (e.g., nicotine) to a
user over time. Furthermore, provided herein are methods of
tracking usage of an agent (e.g., nicotine) to suggest a dosing
strategy based on the goal or goals of the user. In some cases, a
user is a human. In some cases, a user is a human who smokes or
otherwise uses tobacco or a nicotine containing product.
[0096] Provided herein are devices for generating a condensation
aerosol comprising particles of a size suitable for delivery to the
lungs of a subject. In some cases, a subject is a human. In some
cases, a subject is a human who smokes or otherwise uses tobacco or
nicotine containing products. The particles can be of a size
suitable to delivery to the deep lung (i.e., alveoli) of the
subject. The particles can be any of the sizes provided herein. In
some cases, the particles can comprise a mass median aerodynamic
diameter (MMAD) of from about 1 to about 5 .mu.m. The particles can
have a geometric standard deviation (GSD) of less than 2. The
condensation aerosol can be generated from a formulation comprising
a pharmaceutically active agent. The formulation can be in a liquid
or solid phase prior to vaporization. The agent can be any agent as
provided herein; in some cases, the agent is nicotine, and in some
cases the nicotine is stabilized using one or more carriers (e.g.,
vegetable glycerin and/or propylene glycol). The device can
comprise a heater element as provided herein and a configuration of
flow-through passages or chambers suitable for generating
condensation aerosols comprising particles of a size suitable for
delivery to the deep lungs of a subject. For example, a device can
comprise a primary flow-through chamber in fluid communication with
a secondary flow-through chamber. The primary flow-through chamber
can comprise an upstream and downstream opening, and the upstream
opening can be an inlet for a carrier gas. The device can comprise
an aerosol generation chamber, wherein the aerosol generation
chamber is located (disposed) between the upstream and downstream
openings within the primary flow through chamber. The aerosol
generation chamber can comprise a heater element as provided herein
and a source of a formulation comprising a pharmaceutically active
agent (e.g. nicotine) as provided herein. The aerosol generation
chamber can further comprise a configuration whereby the flow rate
of the carrier gas entering the aerosol generation chamber is
effective to condense a vapor generated from a formulation
comprising a pharmaceutically active agent (e.g. nicotine) as
provided herein within the aerosol generation chamber.
[0097] Devices and methods for aliquoting an agent (e.g., nicotine)
to ensure dose-to-dose uniformity are provided herein. Furthermore,
devices and methods are provided herein for sensing an inhalation
by a user and triggering a device. Devices and methods are also
provided herein for inhalation flow control.
[0098] Devices and methods of use of a closed loop design to
control heating are provided herein. For example, a device provided
herein can incorporate electronics that control for variability in
battery condition and ensure consistent heating by direct
measurement of resistance through the heater element to control for
changes in battery voltage/charge.
[0099] Devices and methods are provided herein for transitioning a
smoker away from cigarettes. For example, devices and methods are
provided for enabling a subject to achieve full smoking or nicotine
cessation. Devices and methods are provided for enabling a subject
to achieve full smoking or nicotine cessation without relapse.
Also, devices and methods are provided for enabling a subject to
achieve full smoking or nicotine cessation with reduced, minimal,
or no withdrawal symptoms. In some cases, a subject is a human. In
some cases, a subject is a human who smokes or otherwise uses
tobacco or a nicotine containing product.
[0100] eHealth tools provided herein can yield customized doses of
an agent (e.g., nicotine) to a subject. In some cases, customized
dosing regimens are provided, which can include instructions to
dose at specific intervals, driven by reminders on the device.
Devices and methods for providing customized feedback and
behavioral support to a subject are also provided. In some cases,
the customized feedback and/or behavioral support comprise simple
instructions. The customized feedback and/or behavioral support can
comprise use of social media to leverage social networks to help
induce and/or maintain behavior change.
[0101] Also provided herein are methods of identifying individual
user goals and matching user goals to an agent (e.g., nicotine)
dose algorithm. Furthermore, provided herein are devices and
methods for giving customized feedback to achieve a nicotine
administration goal. Also, provided herein are devices and methods
for giving customized feedback to achieve an agent administration
goal. In some cases, an individual is a human. In some cases, an
individual is a human who smokes or otherwise uses tobacco or a
nicotine containing product.
II. Devices
[0102] FIG. 1 illustrates an embodiment of an electronic agent
(e.g., nicotine) delivery device for controlling and reducing
aerosol particle size for deep lung delivery and rapid
pharmacokinetics. An agent, e.g., nicotine (102) is held in an
agent (e.g., nicotine) reservoir (104), and can be wicked into a
dosing mechanism (106). Upon inhalation, agent (e.g., nicotine)
droplets are pulled out of the dosing mechanism. Small droplets are
entrapped in airflow in the airway (108). A heater (110) can be in
electrical communication with a battery (112). Larger droplets
inertially impact with a heater (110), deposit, and are vaporized
and reduced in size. Vapor condenses to form an optimum size
aerosol by controlling airflow and vaporization rate.
[0103] Agent Doses
[0104] An electronic agent (e.g., nicotine) delivery device
provided herein can provide doses of agent (e.g., nicotine) in a
consistent and known amount. A dose of an agent (e.g., nicotine)
can about, more than, less than, or at least 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,
25, 26 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,
42, 43, 44, 45, 46, 47, 48, 94, 50, 51, 52, 53, 54, 55, 56, 57, 58,
59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75,
76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92,
93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107,
108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120,
121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133,
134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146,
147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159,
160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172,
173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185,
186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198,
199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211,
212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224,
225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237,
238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250,
260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380,
390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510,
520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640,
650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770,
780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900,
910, 920, 930, 940, 950, 960, 970, 980, 990, 1000 .mu.g of agent
(e.g., nicotine). In some cases, a device can deliver a dose of an
agent of about, more than, less than, or at least 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,
24, 25, 26 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,
41, 42, 43, 44, 45, 46, 47, 48, 94, 50, 51, 52, 53, 54, 55, 56, 57,
58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74,
75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,
92, 93, 94, 95, 96, 97, 98, 99, or 100 mg.
[0105] In one embodiment, a dose of an agent (e.g., nicotine) is
about 1 .mu.g to about 1000 .mu.g, about 1 .mu.g to about 500
.mu.g, about 1 .mu.g to about 1000 .mu.g, about 10 .mu.g to about
500 .mu.g, about 20 .mu.g to about 500 .mu.g, about 25 .mu.g to
about 500 .mu.g, about 30 .mu.g to about 500 .mu.g, about 40 .mu.g
to about 500 .mu.g, about 50 .mu.g to about 500 .mu.g, about 10
.mu.g to about 250 .mu.g, about 20 .mu.g to about 250 .mu.g, about
30 .mu.g to about 250 .mu.g, about 40 .mu.g to about 250 .mu.g,
about 50 .mu.g to about 250 .mu.g, about 1 .mu.g to about 200
.mu.g, about 10 .mu.g to about 200 .mu.g, about 20 .mu.g to about
200 .mu.g, about 30 .mu.g to about 200 .mu.g, about 40 .mu.g to
about 200 .mu.g, about 50 .mu.g to about 200 .mu.g, about 25 .mu.g
to about 50 .mu.g, about 25 .mu.g to about 100 .mu.g, about 25
.mu.g to about 150 .mu.g, about 25 .mu.g to about 200 .mu.g, about
25 .mu.g to about 250 .mu.g, about 25 .mu.g to about 300 .mu.g,
about 25 .mu.g to about 350 .mu.g, about 25 .mu.g to about 400
.mu.g, about 25 .mu.g to about 450 .mu.g, about 25 .mu.g to about
500 .mu.g, about 50 .mu.g to about 750 .mu.g, or about 25 .mu.g to
about 1000 .mu.g of agent (e.g., nicotine). In some cases, a dose
of an agent is about 1 mg to about 100 mg, about 1 mg to about 50
mg, about 10 mg to about 50 mg, about 20 mg to about 50 mg, about
25 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to
about 50 mg, about 50 mg to about 100 mg, about 1 mg to about 25
mg, about 2 mg to about 25 mg, about 3 mg to about 25 mg, about 4
mg to about 25 mg, about 5 mg to about 25 mg, about 1 mg to about
20 mg, about 1 mg to about 20 mg, about 2 mg to about 20 mg, about
3 mg to about 20 mg, about 4 mg to about 20 mg, or about 5 mg to
about 20 mg of agent.
[0106] An emitted dose of an agent (e.g., nicotine) can be about,
more than, less than, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 27,
28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,
45, 46, 47, 48, 94, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,
62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78,
79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95,
96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109,
110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122,
123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135,
136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148,
149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161,
162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174,
175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187,
188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200,
201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213,
214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226,
227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239,
240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 260, 270,
280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400,
410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530,
540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660,
670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790,
800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920,
930, 940, 950, 960, 970, 980, 990, or 1000 .mu.g of agent (e.g.,
nicotine). In some cases, an emitted dose of an agent is about,
more than, less than, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 27,
28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,
45, 46, 47, 48, 94, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,
62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78,
79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95,
96, 97, 98, 99, or 100 mg. In one embodiment, an emitted dose of an
agent (e.g., nicotine) is about 1 .mu.g to about 1000 .mu.g, about
1 .mu.g to about 500 .mu.g, about 1 .mu.g to about 1000 .mu.g,
about 10 .mu.g to about 500 .mu.g, about 20 .mu.g to about 500
.mu.g, about 25 .mu.g to about 500 .mu.g, about 30 .mu.g to about
500 .mu.g, about 40 .mu.g to about 500 .mu.g, about 50 .mu.g to
about 500 .mu.g, about 10 .mu.g to about 250 .mu.g, about 20 .mu.g
to about 250 .mu.g, about 30 .mu.g to about 250 .mu.g, about 40
.mu.g to about 250 .mu.g, about 50 .mu.g to about 250 .mu.g, about
1 .mu.g to about 200 .mu.g, about 10 .mu.g to about 200 .mu.g,
about 20 .mu.g to about 200 .mu.g, about 30 .mu.g to about 200
.mu.g, about 40 .mu.g to about 200 .mu.g, about 50 .mu.g to about
200 .mu.g, about 25 .mu.g to about 50 .mu.g, about 25 .mu.g to
about 100 .mu.g, about 25 .mu.g to about 150 .mu.g, about 25 .mu.g
to about 200 .mu.g, about 25 .mu.g to about 250 .mu.g, about 25
.mu.g to about 300 .mu.g, about 25 .mu.g to about 350 .mu.g, about
25 .mu.g to about 400 .mu.g, about 25 .mu.g to about 450 .mu.g,
about 25 .mu.g to about 500 .mu.g, about 50 .mu.g to about 750
.mu.g, or about 25 .mu.g to about 1000 .mu.g (e.g., nicotine). In
some cases, an emitted dose of an agent is about 1 mg to about 100
mg, about 1 mg to about 50 mg, about 10 mg to about 50 mg, about 20
mg to about 50 mg, about 25 mg to about 50 mg, about 30 mg to about
50 mg, about 40 mg to about 50 mg, about 50 mg to about 100 mg,
about 1 mg to about 25 mg, about 2 mg to about 25 mg, about 3 mg to
about 25 mg, about 4 mg to about 25 mg, about 5 mg to about 25 mg,
about 1 mg to about 20 mg, about 1 mg to about 20 mg, about 2 mg to
about 20 mg, about 3 mg to about 20 mg, about 4 mg to about 20 mg,
or about 5 mg to about 20 mg of agent. In another embodiment, a
device according to any of the embodiments described herein
delivers only a single emitted dose of an agent (e.g.,
nicotine).
[0107] In some cases, the emitted dose can be about, more than,
less than, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 27, 28, 29, 30,
31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,
48, 94, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,
65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81,
82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98,
99, or 100% of the dose (or loaded dose). In some cases, the
emitted dose can be between 1%-10%, 10%-20%, 20%-30%, 30%-40%,
40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, or 90%-100% of the
dose (or loaded dose). In some cases, the emitted dose is more than
20% of the dose (or loaded dose). In some cases, the emitted dose
is less than 20% of the dose (or loaded dose). The dose (or loaded
dose) is the amount of nicotine solution delivered onto the heater
element prior to the creation of the aerosol and can be about 2% of
the target dose (the label claimed dose or goal dose). The emitted
dose can be 92% to 97% of the dose. For example, the amount
actually delivered to the lung if the label claim dose is 100 .mu.g
can be between 90% and 99%.
[0108] Dosing
[0109] Provided herein are methods for administering agent (e.g.,
nicotine) challenge doses to a subject. In some cases, a subject is
a human. In some cases, a subject is a human who smokes or
otherwise uses tobacco or nicotine containing products. Methods are
provided herein for generating condensation aerosols comprising
particles comprising a mass median aerodynamic diameter (MMAD)
effective for delivery to the deep lung of a subject. The methods
can comprise supplying or delivering a liquid formulation
comprising a pharmaceutically active agent (e.g. nicotine) to a
passageway; vaporizing the liquid formulation using a heater
element in the passageway to produce a vaporized liquid
formulation; and flowing a carrier gas through the passageway at a
flow rate effective to allow condensation of the vaporized liquid
formulation into particles comprising a size effective for delivery
to the deep lung. The size of the particles following condensation
can be an MMAD of from about 1 to about 5 .mu.m. The flow rate can
be about 1 to about 10 liters per minute (LPM) (a range from about
1.667.times.10.sup.-5 m.sup.3/s to about 1.667.times.10.sup.-4
m.sup.3/s), e.g., at a vacuum of about 1 to about 15 inches of
water (a range from about 249 Pa to about 3738 Pa). The flow
resistance of the device can be about 0.05 to about 0.15 (cm of
H.sub.2O).sup.1/2/LPM. The liquid formulation can be supplied or
delivered from a reservoir. The reservoir can comprise a tube,
e.g., a capillary tube. The reservoir can be in fluid communication
with the heater element. In some cases, the liquid formulation
comprising a pharmaceutically active agent (e.g., nicotine) is
delivered to the heater element through the use of a positive
displacement pump. The positive displacement pump can be a
reciprocating, metering, rotary-type, hydraulic, peristaltic, gear,
screw, flexible impeller, diaphragm, piston, or progressive cavity
pump, or any other pump utilizing positive displacement as known in
the art. The positive displacement pump can be in fluid
communication with the heater element. The positive displacement
pump can be in fluid communication or fluidically coupled to a
reservoir comprising a pharmaceutically active agent (e.g.,
nicotine). The positive displacement pump can be in fluid
communication with the heater element and a reservoir comprising a
pharmaceutically active agent (e.g., nicotine). The
pharmaceutically active agent (e.g., nicotine) can be a liquid
formulation. The positive displacement pump can be within the
passageway or external to the passageway. The heater element can be
any heater element as provided herein. The carrier gas can be
air.
[0110] Methods for aliquoting an agent (e.g., nicotine) to ensure
dose-to-dose uniformity are provided herein. For example, an
element comprising porous materials can wick out fluid comprising
agent (e.g., nicotine) at a particular rate in order to measure out
a dose to provide dose-to-dose uniformity. A tube, e.g., a
capillary tube can be used to measure out a dose. In one
embodiment, heat is used as a means of ejecting a dose. A material
or geometry of a device can be used to measure out a dose. In one
embodiment, providing dose consistency controls for variability in
environment and device. In another embodiment, inhalation flow
control ensures that variability in inhalations by a user are
controlled and corrected for, which can result in dose-to-dose
consistency and predictable and desirable aerosol particle
sizes.
[0111] In some cases, an agent (e.g., nicotine) is metered out into
a pre-vaporization area in a device (dosing mechanism) through
capillary action. The metering can occur between inhalations of a
user of a device. Upon inhalation by a subject, an agent (e.g.,
nicotine) can be drawn into a vaporization chamber or onto a heater
element. The agent can be a pharmaceutically active agent. The
agent can be in a formulation that is liquid. The liquid
formulation comprising a pharmaceutically active agent (e.g.,
nicotine) can be drawn or metered out into a vaporization chamber
or onto a heater element upon inhalation by a subject. The subject
can be a human. The human subject can be a smoker or user of
tobacco or nicotine containing substances. The agent (e.g.,
nicotine) in the vaporization chamber or heater element can be
vaporized and subsequently condense to form an aerosol. The aerosol
can comprise agent (e.g., nicotine) particles of an optimum size to
achieve certain biological effects (e.g., deep lung delivery
producing rapid pharmacokinetics). Devices described herein can
comprise a mechanism for separating out and reducing large aerosol
particles to a size that can navigate to the deep lung of a
subject. In the deep lung, the particles can settle and be rapidly
absorbed. Also provided herein are methods for controlling aerosol
particle size, pH, and other inhalation characteristics, which can
ensure deep lung delivery and rapid pharmacokinetics. For example,
the aerosol size control can result in rapid, cigarette-like
nicotine absorption, which can help to satisfy nicotine cravings.
In some cases, aerosol particles comprising nicotine produced by a
heater element or device as provided herein can achieve peak plasma
concentrations similar to peak plasma concentrations achieved by
smoking a cigarette. In some cases, aerosol particles comprising
nicotine produced by a heater element or device as provided herein
can achieve peak plasma concentrations in a time frame similar to
the time frame required to achieve peak plasma concentrations
achieved by smoking a cigarette. The condensation aerosol
comprising nicotine produced by any of the devices provided herein
can result in rapid, cigarette-like nicotine absorption resulting
in nicotine plasma concentrations similar or substantially similar
to the nicotine plasma concentration achieved from smoking a
cigarette. In some cases, the plasma concentration can be an
arterial plasma concentration. In some cases, the plasma
concentration can be a venous plasma concentration. Smoking a
single cigarette can produce peak increments of plasma nicotine
concentration of 5-30 ng/ml.
[0112] In some cases, use of a device described herein can produce
an arterial plasma nicotine concentration in the user of the device
of about 1 ng/mL to about 200 ng/mL, about 1 ng/mL to about 150
ng/mL, about 1 ng/mL to about 100 ng/mL, about 1 ng/mL to about 75
ng/mL, about 1 ng/mL to about 50 ng/mL, about 1 ng/mL to about 40
ng/mL, about 1 ng/mL to about 30 ng/mL, about 1 ng/mL to about 20
ng/mL, about 1 ng/mL to about 10 ng/mL, about 10 ng/mL to about 200
ng/mL, about 10 ng/mL to about 150 ng/mL, about about 10 ng/mL to
about 100 ng/mL, about 10 ng/mL to about 75 ng/mL, about 10 ng/mL
to about 50 ng/mL, about 10 ng/mL to about 40 ng/mL, about 10 ng/mL
to about 30 ng/mL, about 10 ng/mL to about 20 ng/mL, about 10 ng/mL
to about 15 ng/mL, about 20 ng/mL to about 200 ng/mL, about 20
ng/mL to about 150 ng/mL, about 20 ng/mL to about 100 ng/mL, about
20 ng/mL to about 75 ng/mL, about 20 ng/mL to about 50 ng/mL, about
20 ng/mL to about 40 ng/mL, about 20 ng/mL to about 30 ng/mL, about
20 ng/mL to about 24 ng/mL, about 30 ng/mL to about 200 ng/mL,
about 30 ng/mL to about 150 ng/mL, about 30 ng/mL to about 100
ng/mL, about 30 ng/mL to about 75 ng/mL, about 30 ng/mL to about 50
ng/mL, about 30 ng/mL to about 40 ng/mL, or about 30 ng/mL to about
35 ng/mL. In some cases, use of a device described herein can
produce an arterial plasma nicotine concentration in a user of the
device of about, more than, less than, or at least 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,
24, 25, 26 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,
41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,
58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74,
75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,
92, 93, 94, 95, 96, 97, 98, 99, 100 ng/mL. The arterial plasma
nicotine concentration can be produced after receiving at least 1,
2, 3, 4, 5, 6, 7, 8, 9, or 10 doses from the condensation aerosol
generating device.
[0113] In some cases, use of a device described herein can produce
a peak plasma nicotine concentration in a user of the device within
about 30 seconds to 30 minutes, 30 seconds to 20 minutes, 30
seconds to 10 minutes, 30 seconds to 5 minutes, 30 seconds to 2
minutes, 1 to about 30 minutes, about 1 minute to about 25 minutes,
about 1 minute to about 20 minutes, about 1 minute to about 15
minutes, about 1 minute to about 10 minutes, about 5 minutes to
about 30 minutes, about 5 minutes to about 25 minutes, about 5
minutes to about 20 minutes, about 5 minutes to about 15 minutes,
about 5 minutes to about 10 minutes, about 10 minutes to about 30
minutes, about 10 minutes to about 25 minutes, about 10 minutes to
about 20 minutes, or about 10 minutes to about 15 minutes of use of
the device. A use of the device can be an inhalation of a dose
delivered by the device.
[0114] The peak increments of plasma nicotine concentration from
smoking a cigarette can be achieved within 10 minutes. The nicotine
arterial plasma concentration can be about, more than, less than,
or at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%,
14%, 15%, 16%, 17%, 18%, 19%, 20%, 30%, 31%, 32%, 33%, 34%, 35%,
36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%,
49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%,
62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%,
75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
of the nicotine plasma concentration achieved by smoking a
cigarette. The nicotine arterial plasma concentration can be
between 1%-10%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%,
60%-70%, 70%-80%, 80%-90%, or 90%-100% of the nicotine plasma
concentration achieved by smoking a cigarette. The nicotine
arterial plasma concentration can be about 1% to about 10%, about
10% to about 20%, about 20% to about 30%, about 30% to about 40%,
about 40% to about 50%, about 50% to about 60%, about 60% to about
70%, about 70% to about 80%, about 80% to about 90%, or about 90%
to about 100% of the nicotine plasma concentration achieved by
smoking a cigarette.
[0115] FIG. 12 illustrates an embodiment of a method of removal of
an agent (e.g., nicotine) mixture from a reservoir and dispensing
the agent (e.g., nicotine) into desired doses. FIG. 12 shows an
agent (e.g., nicotine) reservoir (1202) next to a frit (1204) or
porous material, such as a metal (stainless steel) or a ceramic,
and allowing the agent (e.g., nicotine) to wick into it. Then, upon
inhalation, the air can draw the agent (e.g., nicotine) into the
airway (1208) and onto the heater element (1206). In some cases,
the mixture is a liquid formulation comprising an agent (e.g.,
nicotine).
[0116] FIG. 13 illustrates another embodiment of a method for
measuring a dose. Another method of dosing out the mixture is to
draw the material out using a venturi. The device can comprise a
tube, e.g., a capillary tube (1302), an agent (e.g., nicotine)
reservoir (1304), and a heater element (1306). In some cases, the
mixture is a liquid formulation comprising an agent (e.g.,
nicotine).
[0117] FIG. 14 illustrates another embodiment of a method for
measuring a dose. In this embodiment, an agent (e.g., nicotine)
mixture can be wicked into a space between two parallel plates. The
device can comprise a heater element (1402), plates (1404), tube,
e.g., capillary tube (1406), and an agent (e.g., nicotine)
reservoir (1408). In some cases, the mixture is a liquid
formulation comprising an agent (e.g., nicotine).
[0118] FIG. 15 illustrates another embodiment for measuring a dose.
An agent (e.g., nicotine) mixture can be ejected using a
piezoelectric device (1502) and an attached chamber with an opening
or orifice (1506). When the piezo is activated, either as a single
pulse or as a series of pulses (vibrated) the mixture can be driven
from the opening. By controlling the amplitude of the pulse or the
number of pulses, the amount of material dosed can be controlled.
The device can comprise an agent (e.g., nicotine) reservoir (1508)
and a heater element (1504). In one embodiment, a piezo electric
device is mounted on an end or a side of the reservoir and receipt
of an electrical pulse causes the piezo to deflect and push a small
amount of the agent (e.g., nicotine) formulation out of a tube,
e.g., capillary tube mounted on another end of the reservoir onto a
heater element. In some cases, the agent formulation is liquid.
[0119] All of the forgoing mechanisms to power the dispensing of a
mixture (heat, piezo) can be powered by a user performing a
maneuver such as pushing a button or lever. Mechanical energy from
the user can also allow for alternative methods of applying agent
(e.g., nicotine) to a heater surface. An agent (e.g., nicotine) can
be applied to the heater element (1602), where the reservoir is
moved over the heater surface in a sweeping (see FIG. 16A) or
rolling motion (see FIG. 16B). The heater surface can be etched or
pitted to accept the mixture.
[0120] To have the device generate an agent (e.g., nicotine)
aerosol upon inhalation by a user, a movable member (e.g., vane
(1702a or 1702b)) can be used that moves upon air flow (1704a or
1704b) caused by inhalation (see e.g., FIG. 17A or 17B). This
member can break an optical path (1706a) (e.g., when no inhalation
is occurring), move out of an optical path (1706a) when inhalation
occurs (see e.g., FIG. 17A), or can complete an optical path when
inhalation occurs (by, e.g., reflection; see e.g., FIG. 17B). An
LED (1708a or 1708b) can be used to generate the light. To ensure
that a sensor or detector (1710a or 1710b) does not get confused by
stray light, the LED (1708a or 1708b) can be strobed in a
particular pattern and only when that pattern is detected is an
inhalation present. In some cases, optical light pipes can be used
to route the light to the valve and to route the light back to the
detector.
[0121] To dispense the agent (e.g., nicotine) mixture (1802) out of
some of the fits (1804) or capillaries using the pressure from the
inhalation a valve can be designed to create increased pressure in
the initial part of the inhalation and decrease the resistance for
the duration of the inhalation (see e.g., FIG. 18).
[0122] In one embodiment, an electronic agent (e.g., nicotine)
delivery device is provided that provides a dose of from 25 to 200
.mu.g of freebase agent (e.g., nicotine). The agent (e.g.,
nicotine) can be in a mixture of propylene glycol at a ratio of
agent (e.g., nicotine) to propylene glycol of from about 1:1 to
about 1:20, or about 1:5 to about 1:10. In some cases, a mixture
comprises propylene glycol and about 1.25% to about 20% nicotine.
In some cases, the mixture is liquid formulation comprising an
agent (e.g., nicotine). In some cases, the mixture is liquid
formulation comprising an agent (e.g., nicotine) during use of the
device. An aerosol can have an MMAD of about 1 to about 5 microns
with a geometric standard deviation (GSD) of less than 2.0. Dose to
dose consistency over the lifetime of the product can be no greater
than .+-.30%. The device can have a dose to dose consistency over
the lifetime of the product that can be about, more than, less
than, at least, or at most .+-.1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,
10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 30%, 31%,
32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%,
45%, 46%, 47%, 48%, 49%, or 50%. The device can be activated by an
inhalation. The device can have an interior air resistance (to
inhalation) no greater than that of a cigarette. The device can
have an interior air resistance (to inhalation) no greater than
0.08 (cm H.sub.2O).sup.1/2/LPM. The device can have an interior air
resistance (to inhalation) about, more than, less than, at least,
or at most 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09,
0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20
(cm H.sub.2O).sup.1/2/LPM.
[0123] FIG. 23 illustrates another embodiment of a method for
measuring a dose. Another method of dosing out the mixture is to
draw the material out using a peristaltic pump comprising a
rotatable cam. The device can comprise a tube, e.g., capillary tube
(2302), agent (e.g., nicotine) reservoir (2304), and a rotatable
cam (2306) to pull or draw an agent (e.g., nicotine) mixture from
the nicotine reservoir. In one embodiment, an agent (e.g.,
nicotine) delivery device comprises a disposable component that
comprises the tube, e.g., capillary tube, and agent (e.g, nicotine)
reservoir and a reusable component comprising the rotatable cam,
wherein the tube, e.g., capillary tube and agent (e.g., nicotine)
reservoir are mechanically connected to the rotatable cam by mating
the disposable component to the reusable component. In some cases,
the mixture is a liquid formulation comprising an agent (e.g.,
nicotine).
[0124] FIG. 24 illustrates another embodiment of a method for
measuring a dose. The device can comprise a tube, e.g, capillary
tube (2402), agent (e.g., nicotine) reservoir (2404), and a cam
made of variable durometer material (2406). The cam can comprise an
area of high durometer material surrounded by low durometer
material, wherein the tube, e.g., capillary tube can be sealed
within the high durometer material. In one embodiment, an agent
(e.g., nicotine) mixture can be pushed out of the tube, e.g.,
capillary tube by compression, wherein pressure is exerted on the
low durometer material of the cam to cause compression of the tube,
e.g., capillary tube, within the high durometer material. In one
embodiment, an agent (e.g., nicotine) delivery device comprises a
disposable component that comprises the tube, e.g., capillary tube
and the agent (e.g., nicotine) reservoir and a reusable component
comprising the cam made of variable durometer material, wherein the
tube, e.g., capillary tube and agent (e.g., nicotine) reservoir are
mechanically connected to the cam made of variable durometer
material by mating the disposable component to the reusable
component. In some cases, the mixture is a liquid formulation
comprising an agent (e.g., nicotine).
[0125] FIG. 25 illustrates an embodiment of a method of removal of
an agent (e.g., nicotine) mixture from a reservoir. FIG. 25A shows
a tube, e.g., capillary tube (2502a) adjacent to, but separate
from, an agent (e.g., nicotine) reservoir (2504a) comprising an
agent (e.g., nicotine) mixture (2506a). FIG. 25B shows that the
tube, e.g., capillary tube (2502b) can pierce the agent (e.g.,
nicotine) reservoir (2504b) such that the agent (e.g., nicotine)
mixture (2506b) within the agent (e.g., nicotine) reservoir can
move into the tube, e.g., capillary tube and subsequently onto a
heater element as provided herein. In one embodiment, the agent
(e.g., nicotine) reservoir comprises a septum or seal, wherein the
tube, e.g., capillary tube pierces the septum or seal. In one
embodiment, the agent (e.g., nicotine) reservoir is a collapsible
bag or container. In one embodiment, the collapsible bag or
container is made of plastic, foil, or any other collapsible
material known in the art. In a further embodiment, the tube, e.g.,
capillary tube can directly pierce an agent (e.g., nicotine)
reservoir that is made of a collapsible material. In one
embodiment, the tube, e.g., capillary tube is not inserted into the
agent (e.g., nicotine) reservoir prior to a first use of the
device, wherein upon first use, the tube, e.g., capillary tube, is
inserted into the agent (e.g., nicotine) reservoir such that an
agent (e.g., nicotine) mixture can move from the agent (e.g.,
nicotine) reservoir into the tube, e.g., capillary tube and
subsequently onto a heater element as provided herein. In some
cases, the mixture is a liquid formulation comprising an agent
(e.g., nicotine).
[0126] Carriers/Excipients
[0127] In some cases, an agent (e.g., nicotine) is mixed with one
or more other substances. When mixed with an agent (e.g., nicotine)
as provided herein, the mixture can be liquid at room temperature.
When mixed with an agent (e.g., nicotine) as provided herein, the
mixture can be liquid during use of the device such that the liquid
mixture is delivered to the heater element during use of the
device. The one or more other substances can be pharmaceutically
acceptable excipients or carriers. The suitable pharmaceutically
acceptable excipients or carriers can be volatile or nonvolatile.
The volatile excipients, when heated, can be volatilized,
aerosolized and inhaled with the agent (e.g. nicotine). Classes of
such excipients are known in the art and include, without
limitation, gaseous, supercritical fluid, liquid and solid
solvents. The excipient/carriers can be water; terpenes, such as
menthol; alcohols, such as ethanol, propylene glycol, glycerol and
other similar alcohols; dimethylformamide; dimethylacetamide; wax;
supercritical carbon dioxide; dry ice; and mixtures or combinations
thereof.
[0128] The one or more other substances can be, e.g., propylene
glycol (1,2-dihydroxypropane, 1,2-propanediol, methyl glycol, or
trimethyl glycol). The ratio of agent (e.g., nicotine) to propylene
glycol can be about, more than, less than, or at least 100:1, 95:1,
90:1, 85:1, 80:1, 75:1, 70:1, 65:1, 60:1, 55:1, 50:1, 45:1, 40:1,
35:1, 30:1, 25:1, 20:1, 15:1, 10:1, 5:1, 2:1, 1:1, 1:2, 1:5, 1:10,
1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65,
1:70, 1:75, 1:80, 1:85, 1:90, 1:95, or 1:100. The ratio of agent
(e.g., nicotine) to propylene glycol can be from about 100:1 to
about 1:100, about 75:1 to about 1:100, about 50:1 to about 1:100,
about 25:1 to about 1:100, about 25:1 to about 1:50, about 10:1 to
about 1:100, about 10:1 to about 1:50, about 10:1 to about 1:20,
about 5:1 to about 1:20, or about 1:1 to about 1:20. In one
example, a 100 .mu.g dose of agent (e.g., nicotine) and 1:10 ratio
yields a volume of 1 mm.sup.3 (1 mg). A mixture of agent (e.g.,
nicotine) and another substance, e.g., propylene glycol, can be
held in an agent (e.g., nicotine) reservoir (e.g., as a
liquid).
[0129] In one embodiment, the one or more other substances is
vegetable glycerin. The ratio of an agent (e.g., nicotine) to
vegetable glycerin can be about, more than, less than, or at least
100:1, 95:1, 90:1, 85:1, 80:1, 75:1, 70:1, 65:1, 60:1, 55:1, 50:1,
45:1, 40:1, 35:1, 30:1, 25:1, 20:1, 15:1, 10:1, 5:1, 2:1, 1:1, 1:2,
1:5, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55,
1:60, 1:65, 1:70, 1:75, 1:80, 1:85, 1:90, 1:95, or 1:100. The ratio
of an agent (e.g., nicotine) to vegetable glycerin can be from
about 100:1 to about 1:100, about 75:1 to about 1:100, about 50:1
to about 1:100, about 25:1 to about 1:100, about 25:1 to about
1:50, about 10:1 to about 1:100, about 10:1 to about 1:50, about
10:1 to about 1:20, about 5:1 to about 1:20, or about 1:1 to about
1:20. In one example, a 100 .mu.g dose of agent (e.g., nicotine)
and 1:10 ratio yields a volume of 1 mm.sup.3 (1 mg). A mixture of
agent (e.g., nicotine) and vegetable glycerin can be held in an
agent (e.g., nicotine) reservoir (e.g., as a liquid).
[0130] In another embodiment, the one or more other substances
comprise vegetable glycerin and propylene glycol. The ratio of
vegetable glycerin to propylene glycol can be about, more than,
less than, or at least 100:1, 95:1, 90:1, 85:1, 80:1, 75:1, 70:1,
65:1, 60:1, 55:1, 50:1, 45:1, 40:1, 35:1, 30:1, 25:1, 20:1, 15:1,
10:1, 5:1, 2:1, 1:1, 1:2, 1:5, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35,
1:40, 1:45, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:85, 1:90,
1:95, or 1:100. The ratio of agent (e.g., nicotine) to vegetable
glycerin can be from about 100:1 to about 1:100, about 75:1 to
about 1:100, about 50:1 to about 1:100, about 25:1 to about 1:100,
about 25:1 to about 1:50, about 10:1 to about 1:100, about 10:1 to
about 1:50, about 10:1 to about 1:20, about 5:1 to about 1:20, or
about 1:1 to about 1:20.
[0131] The ratio of agent (e.g., nicotine) to mixture of vegetable
glycerin and propylene glycol can be about, more than, less than,
or at least 100:1, 95:1, 90:1, 85:1, 80:1, 75:1, 70:1, 65:1, 60:1,
55:1, 50:1, 45:1, 40:1, 35:1, 30:1, 25:1, 20:1, 15:1, 10:1, 5:1,
2:1, 1:1, 1:2, 1:5, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45,
1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:85, 1:90, 1:95, or
1:100. The ratio of agent (e.g., nicotine) to vegetable glycerin
and glycerin can be from about 100:1 to about 1:100, about 75:1 to
about 1:100, about 50:1 to about 1:100, about 25:1 to about 1:100,
about 25:1 to about 1:50, about 10:1 to about 1:100, about 10:1 to
about 1:50, about 10:1 to about 1:20, about 5:1 to about 1:20, or
about 1:1 to about 1:20.
[0132] In another embodiment, the one or more other substances can
be polyethylene glycol (PEG). The PEG can be PEG200, PEG300,
PEG400, PEG600, PEG1000, PEG2000, PEG4000, or PEG6000.
[0133] In one embodiment, the one or more other substances is
glycerol.
[0134] In another embodiment, an electronic agent (e.g., nicotine)
delivery device comprises a mixture of agent (e.g., nicotine) and
polyethylene glycol. A mixture can comprise an agent (e.g.,
nicotine), polyethylene glycol, and vegetable glycerin. A mixture
can comprise an agent (e.g., nicotine), polyethylene glycol,
vegetable glycerin, and propylene glycol. In another embodiment, a
mixture comprises an agent (e.g., nicotine), polyethylene glycol,
and propylene glycol. A mixture can comprise an agent (e.g.,
nicotine), propylene glycol, and vegetable glycerin.
[0135] In one embodiment, the percentage of an agent (e.g.,
nicotine) in a formulation (e.g., solution) comprising an agent
(e.g., nicotine) can be about, more than, less than, or at least
0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25,
3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5,
6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75,
10, 10.25, 10.5, 10.75, 11, 11.25, 11.5, 11.75, 12, 12.25, 12.5,
12.75, 13, 13.25, 13.5, 13.75, 14, 14.25, 14.5, 14.75, 15, 15.25,
15.5, 15.75, 16, 16.25, 16.5, 16.75, 17, 17.25, 17.5, 17.75, 18,
18.25, 18.5, 18.75, 19, 19.25, 19.5, 19.75, 20, 20.5, 21, 21.5, 22,
22.5, 23, 23.5, 24, 24.5, or 25% by volume. The percentage of an
agent (e.g., nicotine) in a formulation (e.g., solution) comprising
an agent (e.g., nicotine) can be from about 0.25 to about 1.25,
about 1.25 to about 2.5, about 2.5 to about 5, about 5 to about
7.5, about 7.5 to about 10, about 10 to about 12.5, about 12.5 to
about 15, about 15 to about 17.5, about 17.5 to about 20, or about
20 to about 25% by volume. The formulation (e.g., solution) can
further comprise one or more substances. The one or more substances
can be propylene glycol and/or vegetable glycerin. The formulation
can be liquid at room temperature or at temperatures at which the
device is generally used by a subject.
[0136] The source of nicotine for use in the devices and methods as
provided herein can be a tobacco or tobacco material. Here, a
tobacco or tobacco material can be defined as any combination of
natural and synthetic material that can be vaporized for pleasure
or medicinal use. The formulation comprising nicotine can comprise
flue-cured tobacco, glycerin, and flavorings. The formulation
comprising nicotine can comprise flue-cured tobacco, propylene
glycol, and flavorings. A liquid formulation comprising nicotine
can be produced by chopping tobacco into fine pieces (less than 3
mm diameter, less than 2 mm), adding the other ingredients (e.g.,
propylene glycol, vegetable glycerin, water, and/or flavorings),
and mixing until even consistency is achieved.
[0137] pH
[0138] An electronic agent (e.g., nicotine) delivery device
described herein can control a pH of an agent (e.g., nicotine)
mixture or aerosol. The pH of the agent (e.g., nicotine) mixture or
aerosol can be about, more than, less than, or at least 1, 1.5, 2,
2.5, 3, 3.5, 4, 4.5, 5, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3,
6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7,
7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9 9, 9.5,
10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, or 14. In some cases, the
pH of an agent (e.g., nicotine) mixture or aerosol can be about 1
to about 14, about 2 to about 13, about 3 to about 12, about 4 to
about 11, about 5 to about 10, about 6 to about 9, about 6 to about
8, about 6 to about 7, about 4 to about 6, about 4 to about 8,
about 5 to about 8, about 5 to about 7, about 7 to about 9, about
5.5 to about 8.5, about 6.5 to about 8.5, about 6.5 to about 7.5,
about 7.5 to about 9, or about 7 to about 8.5. One or more buffers
can be added to a mixture to adjust the pH of the mixture.
[0139] The one or more buffers can be any buffers known in the art.
The one or more buffers can be acidic buffers or alkaline buffers.
The one or more buffers can be a phosphate, bicarbonate or protein
buffer system. Examples of buffers can include, but are not limited
to, TAPS (3-{tris(hydroxymethyl)methyl]amino}propanesulfonic acid),
Bicine (N,N-bis(2-hydroxyethyl)glycine), Tris
(tris(hydroxymethyl)methylamine), Tricine
(N-tris(hydroxymethyl)methylglycine), TAPSO
(3-N-Tris(hydroxymethyl)methylamino]-2-hydroxypropanesulfonic
Acid), HEPES (4-2-hydroxyethyl-1-piperazineethanesulfonic acid),
TES (2-{[tris(hydroxymethyl)methyl]amino}ethanesulfonic acid), MOPS
(3-(N-morpholino)propanesulfonic acid), PIPES
(piperazine-N,N'-bis(2-ethanesulfonic acid)), cacodylate
(dimethylarsinic acid), SSC (saline sodium citrate), MES
(2-(N-morpholino)ethanesulfonic acid), succinic acid
(2(R)-2-(methylamino)succinic acid), sodium acetate/acetic acid,
sodium citrate/citric acid, CHES, sodium borate/boric acid, diethyl
barbituric acid, potassium dihydrogen phosphate, Carmody buffer,
Britton-Robinson buffer, or mixtures thereof.
[0140] Flavorings
[0141] In one embodiment, a mixture comprises one or more
flavorings. The one or more flavorings can be a flavor offered by,
e.g., Flavourart (Italy), Flavor Apprentice, or LorAnn A flavor can
be, e.g., almond, almond amaretto, apple, Bavarian cream, black
cherry, black sesame seed, blueberry, brown sugar, bubblegum,
butterscotch, cappuccino, caramel, caramel cappuccino, cheesecake
(graham crust), cinnamon redhots, cotton candy, circus cotton
candy, clove, coconut, coffee, clear coffee, double chocolate,
energy cow, graham cracker, grape juice, green apple, Hawaiian
punch, honey, Jamaican rum, Kentucky bourbon, kiwi, koolada, lemon,
lemon lime, tobacco, maple syrup, maraschino cherry, marshmellow,
menthol, milk chocolate, mocha, Mountain Dew, peanut butter, pecan,
peppermint, raspberry, banana, ripe banana, root beer, RY4,
spearmint, strawberry, sweet cream, sweet tarts, sweetner, toasted
almond, tobacco, tobacco blend, vanilla bean ice cream, vanilla
cupcake, vanilla swirl, vanillin, waffle, Belgian waffle,
watermelon, whipped cream, white chocolate, wintergreen, amaretto,
banana cream, black walnut, blackberry, butter, butter rum, cherry,
chocolate hazelnut, cinnamon roll, cola, creme de menthe, eggnog,
English toffee, guava, lemonade, licorice, maple, mint chocolate
chip, orange cream, peach, pina colada, pineapple, plum,
pomegranate, pralines and cream, red licorice, salt water taffy,
strawberry banana, strawberry kiwi, tropical punch, tutti frutti,
or vanilla. The number of flavors in a mixture can be about, more
than, less than, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.
[0142] A flavoring can be used to pair nicotine administration with
certain gustatory and/or olfactory sensations. Subsequent
administration of agent (e.g., nicotine) doses can be reduced while
retaining the flavoring to help the user reduce their agent (e.g.,
nicotine) dependency and enable cravings to be fully or partially
sated using the flavoring as a conditioned stimulus.
[0143] Particle Size
[0144] A device provided herein can generate an aerosol that can be
particles of an optimum size for delivery to the deep lung. The
aerosol can be a condensation aerosol. The particle size can be
about, more than, less than, or at least 0.01, 0.015, 0.02, 0.025,
0.03, 0.035, 0.04, 0.045, 0.05, 0.055, 0.06, 0.065, 0.07, 0.075,
0.08, 0.085, 0.09, 0.095, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16,
0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27,
0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38,
0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49,
0.5, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.6,
0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71,
0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82,
0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93,
0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5,
5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12,
12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5,
19, or 20 microns. The particle size can be from about 1 to about
10 microns, about 1 to about 9 microns, about 1 to about 7 microns,
about 1 to 6 microns, about 1 to about 5 microns, about 1 to about
4 microns, about 1 to about 3 microns, or about 1 to about 2
microns. The particle size can be from about 0.5 to about 10
microns, about 0.5 to about 9.5 microns, about 0.5 to about 9
microns, about 0.5 to about 8.5 microns, about 0.5 to about 8
microns, about 0.5 to about 7.5 microns, about 0.5 to about 7
microns, about 0.5 to about 6.5 microns, about 0.5 to about 6
microns, about 0.5 to about 5.5 microns, about 0.5 to about 5
microns, about 0.5 to about 4.5 microns, about 0.5 to about 4.0
microns, about 0.5 to about 3.5 microns, about 0.5 to about 3
microns, about 0.5 to about 2.5 microns, about 0.5 to about 2
microns, about 0.5 to about 1.5 microns, or about 0.5 to about 1
microns. The particle size can be less than 1 micron. The particle
size can be greater than 5 microns. The particle size can be less
than 5 microns. The particle size can be greater than 1 micron. In
one embodiment, the particle size is from about 1 to about 5
microns. In one embodiment, the particle size is from about 1 to
about 3 microns. In one embodiment, the particle size is a mass
median aerodynamic diameter (MMAD).
[0145] A device provided herein can generate an aerosol that can
create particles of an optimum size for delivery to the deep lung.
The geometric standard deviation (GSD) of the particles can be
about, more than, less than, or at least 1, 1.1, 1.2, 1.3, 1.4,
1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8,
2.9, or 3. The GSD can be from about 1 to about 3 or about 1 to
about 2. The GSD can be between about 1 to about 1.5, about 1.5 to
about 2, or about 2 to about 3. In one embodiment, the GSD is less
than 2.
[0146] Agent (e.g., Nicotine) Reservoir
[0147] FIG. 4 illustrates an embodiment of an agent (e.g.,
nicotine) reservoir (404) that can be used in an electronic agent
(e.g., nicotine) delivery device provided herein. A tube, e.g.,
capillary tube (400) with a valve (402) does not need to be
inserted into a separate reservoir, but can be the reservoir (404)
itself by extending away from the ejection end. The diameter of the
tube, e.g., capillary tube, can be increased to store more mixture.
To allow for the mixture to be pulled from the reservoir without
creating a low pressure, which could resist the mixture leaving,
the back end can have a vent (406). To stop an agent (e.g.,
nicotine) from vaporizing or evaporating from the back end a
section of the reservoir could be filled with a soft material such
as a wax or grease plug. This plug (408) can be drawn along the
reservoir as the mixture is used. In one embodiment, the agent
(e.g., nicotine) reservoir is cylindrical. In one embodiment, the
agent (e.g., nicotine) reservoir holds a formulation comprising 200
mg of agent (e.g., nicotine) mixed with 1000 mg of propylene
glycol. In one embodiment, the agent (e.g., nicotine) reservoir
holds a formulation comprising 200 ug of agent (e.g., nicotine)
mixed with 1000 ug of propylene glycol. In some cases, the agent
(e.g., nicotine) formulation is a liquid formulation.
[0148] FIG. 5 illustrates another embodiment of a reservoir. An
agent (e.g., nicotine) reservoir (500) can be a porous, open cell
foam (502) within a cartridge; a tube, e.g., capillary tube (504)
can extend from the reservoir.
[0149] FIG. 6 illustrates another embodiment of an agent (e.g.,
nicotine) reservoir. The mixture can be held in a collapsible bag
(602) which can be held within a secondary container (600). A tube,
e.g., capillary tube (604) can extend from the reservoir.
[0150] In one embodiment, doses of a liquid agent (e.g., liquid
nicotine) are held in a safe dose cartridge container until needed.
A container for an agent (e.g., nicotine) can comprise a sealing
mechanism that can keep the agent (e.g., nicotine) in the container
even if the container is crushed. In one embodiment, the sealing
mechanism comprises septum sealing. Methods are provided herein for
safely puncturing and reclosing access to a drug (e.g., nicotine)
cartridge. In one embodiment, a septum and a puncturing needle is
used to extract an agent (e.g., nicotine) from a cartridge. A
semi-porous material can be used to ensure that the rate of agent
(e.g., nicotine) transfer is safe. For example, materials can
include a frit or other material (e.g., ceramic, foam, or metal)
that has a convoluted or open structure.
[0151] In one embodiment, a device comprises a dose cartridge. In
one embodiment, the dose cartridge is a disposable dose cartridge.
In another embodiment, the dose cartridge houses an agent (e.g.,
nicotine) formulation and an aerosol creation mechanism as
described herein. In another embodiment, the agent (e.g., nicotine)
formulation is housed in a reservoir. In one embodiment, the dose
cartridge comprises a reservoir comprising an agent (e.g.,
nicotine) formulation. In one embodiment, the dose cartridge
comprises a reservoir comprising an agent (e.g., nicotine)
formulation and dispensing tube, e.g., capillary tube, for
dispensing the agent (e.g., nicotine) formulation. In one
embodiment, the dose cartridge comprises a mouthpiece. In another
embodiment, the mouthpiece comprises a cap. The cap can help
prevent contamination. The cap can provide a tamper resistance
feature. The cap can provide a child resistance feature. In one
embodiment, the cap covers both the mouthpiece and any air inlets.
In another embodiment, the cap is reusable. In one embodiment, the
dose cartridge comprises a mouthpiece at one end and a mating
mechanism whereby the dose cartridge can connect to a controller at
another end. In one embodiment, the dose cartridge comprises a
mechanism for breath detection. In one embodiment, the dose
cartridge comprises a flow control valve. In one embodiment, the
dose cartridge comprises a flow control valve that can regulate
inhalation. The mechanism for breath detection or inhalation
sensing can comprise breath sensory components. The breath sensory
components can comprise an optical chase whereby light can be
routed to and from a flow sensor.
[0152] In one embodiment, the dose cartridge comprises a heater
element. In one embodiment, the heater element comprises a metal
foil. The metal foil can be made of stainless steel or any other
electrically resistive material. In one embodiment, the metal foil
is made of stainless steel. In one embodiment, the heater element
comprises a steel or metal foil that can be about 0.013 mm thick in
order to ensure rapid vaporization. In one embodiment, the heater
element comprises a coil of wire or wire coil. The coil of wire or
wire coil can be from about 0.12 to about 0.5 mm in diameter. In
another embodiment, the dose cartridge comprises more than one
heater element. In one embodiment, the dose cartridge comprises two
heater elements. In some cases, the heater element can be rapidly
heated. In one embodiment, a heating element can comprise a heating
rate of about 1600.degree. C. (1873.15.degree. K) per second for a
duration of 250 msec, which can cause a 400.degree. C.
(673.15.degree. K) rise in the temperature of the heater element.
In some cases, a heater element is activated for a duration of
about 10 msec to about 2000 msec, about 10 msec to about 1000 msec,
about 10 msec to about 500 msec, about 10 msec to about 250 msec,
about 10 msec to about 100 msec, about 50 msec to about 1000 msec,
about 50 msec to about 500 msec, about 50 msec to about 250 msec,
about 100 msec to about 1000 msec, about 100 msec to about 500
msec, about 100 msec to about 400 msec, or about 100 msec to about
300 msec. In some cases, a heater element is activated for about
10, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650,
700, 750, 800, 850, 900, 950, or 1000 msec. In some cases, a heater
element is activated for at least 10, 50, 100, 150, 200, 250, 300,
350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or
1000 msec. In some cases, the maximum temperature of the heater
element is about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550,
600.degree. C. (a range from about 373.15.degree. K to about
873.15.degree. K). In some cases, the maximum temperature of the
heater element is at least 100, 150, 200, 250, 300, 350, 400, 450,
500, 550, 600.degree. C. (a range from about 373.15.degree. K to
about 873.15.degree. K).
[0153] In one embodiment, a device provided herein is made up of
multiple components. In one embodiment, the device provided herein
is comprised of two components wherein one component comprises a
controller and the other component comprises a dose cartridge. In a
further embodiment, the controller is reusable and the dose
cartridge is replaceable. In yet another embodiment, the dose
cartridge is mated to the controller. Mating of the dose cartridge
to the controller can be accomplished by inserting the dose
cartridge into an interlocking channel in the controller and
engaging a locking mechanism. The locking mechanism can comprise a
tab or button on the controller which can be depressed. In one
embodiment, the dose cartridge is detachable from the controller.
In one embodiment, detachment of the dose cartridge is accomplished
by releasing the locking mechanism. In one embodiment, releasing
the locking mechanism entails depressing the tab or button on the
controller. Electrical connection between the dose cartridge and
the controller can be accomplished through a set of mating
electrical contacts. In one embodiment, attachment or mating of the
dose cartridge to the controller establishes a breath detection
mechanism. The breath detection mechanism can comprise breath
sensory components. In one embodiment, the breath detection
mechanism comprises detecting an alteration in an optical signal,
wherein attachment or mating of the dose cartridge to the
controller establishes an optical path through which the optical
signal can be sent and received. In one embodiment, a source and
detector of an optical signal is present in the controller, while
the dose cartridge comprises an optical path. The optical path can
comprise reflectors for reflecting an optical signal. The optical
path can comprise a vane, wherein an inhalation can move the vane
in such a way as to cause an alteration in an optical signal. In
one embodiment, the dose cartridge comprises a vane, wherein an
inhalation can move the vane in such a manner as to cause an
alteration in an optical signal. The optical signal can be light of
any wavelength.
[0154] Tube, e.g., Capillary Tube
[0155] FIGS. 2A and 2B illustrate embodiments of components of an
electronic nicotine delivery device. FIG. 2A illustrates an agent
(e.g., nicotine) reservoir (202) and a tube, e.g., capillary tube
(204). FIG. 2B illustrates an expanded view of the device. The
agent (e.g., nicotine) reservoir can comprise an agent (e.g.,
nicotine)/propylene glycol (PG) mixture (206). The tube, e.g.,
capillary tube can comprise a region on the interior which has been
coated with an agent (e.g., nicotine)/PG philic material (208) to
promote wicking out of a reservoir. A region on the interior which
has been coated with an agent (e.g., nicotine)/PG phobic material
(210) (such as polytetrafluoroethylene (PTFE)) can lie at the open
end. This coating can cause the agent (e.g., nicotine)/PG to stop
wicking short of the open end, thereby reducing the surface area of
the mixture exposed to air, and air devoid of agent (e.g.,
nicotine) vapor. The tube, e.g., capillary tube can comprise a
heated section (212) of the tube, e.g., capillary tube which, upon
heating, can cause the mixture in the tube to vaporize and expand,
pushing the mixture from the open end. A ball valve (214) can be
trapped between two indentations in the tube, e.g., capillary tube,
the end indentation being such that the ball, if pushed by fluid,
will form a seal. This configuration can allow the liquid to be
ejected from the end upon heating rather than back into the
reservoir. All four of these elements can form a pump which can
eject a known dose of the mixture from the end of the tube, e.g.,
capillary tube.
[0156] To eject a dose of an agent (e.g., nicotine)/PG mix with a
1:10 ratio, 1 mm.sup.3 of material can be in the tube, e.g.,
capillary tube. For a tube, e.g., capillary tube with an interior
diameter of 0.5 mm, the length can be .about.5 mm.
[0157] Valve
[0158] A valve can be a check valve, and the check valve can be a
ball which can be made of a metal, such as stainless steel or can
be made of a plastic, such as nylon, delrin, or a homopolymer
acetal. The ball can have a diameter less than the interior
diameter of the tube, e.g., capillary tube sufficient to allow an
agent (e.g., nicotine)/PG mix to wick by it.
[0159] Heater Element
[0160] A heater element can be any heater element as provided
herein. The heater element can be used to generate a condensation
aerosol from a liquid formulation comprising a pharmaceutically
active agent as provided herein. The condensation aerosol can
comprise particles of a size suitable for delivery to the lungs of
a subject as provided herein. In some cases, the heater element
comprises a coil. The coil can be a wire coil. The coil can further
comprise a wick element capable of being heated. The heater element
can vaporize the liquid formulation when the liquid formulation is
delivered to the heater element. In some cases, the liquid
formulation comprising a pharmaceutically active agent (e.g.,
nicotine) is delivered to the heater element through the use of a
positive displacement pump. The positive displacement pump can be a
reciprocating, metering, rotary-type, hydraulic, peristaltic, gear,
screw, flexible impeller, diaphragm, piston, or progressive cavity
pump, or any other pump utilizing positive displacement as known in
the art. The positive displacement pump can be in fluid
communication with the heater element. The positive displacement
pump can be in fluid communication or fluidically coupled to a
reservoir comprising a pharmaceutically active agent (e.g.,
nicotine). The positive displacement pump can be in fluid
communication with the heater element and a reservoir comprising a
pharmaceutically active agent (e.g., nicotine). The
pharmaceutically active agent (e.g., nicotine) can be a liquid
formulation. The positive displacement pump can be within the
passageway or external to the passageway. The heater element can
comprise a rod comprising electrically resistive material. The rod
can be a wire. The rod can be a pliable rod. The rod can comprise a
coil, wherein a segment of the rod can pass through the interior of
the coil. The coil can be a wire coil. The heater element can
comprise a wick element capable of being heated. The wick element
capable of being heated can pass through and exit the center of the
coil. In some cases the heater element comprises a heatable wick
element. The rod can comprise the heatable wick element. In some
cases, the rod comprises a coil and a heatable wick element,
wherein the heatable wick element is a segment of the rod that
passes through the interior or center of the coil.
[0161] FIGS. 3A and 3B illustrate configurations of a heater
element. The tube, e.g., capillary tube can be made of stainless
steel, or a similar matter, which has an electrical resistance
substantially greater than other metals (aluminum, brass, iron).
The tube, e.g., capillary tube can be made of a thin wall material
(FIG. 3A), or a section of the wall can be narrowed (FIG. 3B) to
result in that section having an electrical resistance such that
when an electrical current is passed across the section heating
happens. Alternately the tube, e.g., capillary tube can be wrapped
with a heater wire. This configuration can allow for the tube,
e.g., capillary tube to be made of a non-electrically conductive
material such as Kapton (polyimide), which can withstand heat.
Electrical heating can be powered directly from a battery or can be
powered from a charged capacitor.
[0162] A heater element can be used to vaporize an agent (e.g.,
nicotine)/PG mixture to form an aerosol with a particle size
(MMAD=Mass Median Aerodynamic Diameter) of about 1 to about 5
.mu.m. Aerosols with this particle size can deposit in the deep
lung and result in rapid PK.
[0163] FIG. 7 illustrates a configuration of a heater element (704)
in an airway (706). The heater element can be made of a thin
stainless steel foil. The foil can be of a thickness of about
0.0005 to about 0.005 inches (a range from about 0.01 mm to about
0.13 mm) thick, or from about 0.0005 to about 0.001 inches (a range
from about 0.01 mm to about 0.025 mm) so that less electrical
current is needed to vaporize the mixture. The foil can be of a
thickness of about, less than, more than, at least or at most
0.0005, 0.0006, 0.0007, 0.0008, 0.0009, 0.001, 0.002, 0.003, 0.003,
0.004, or 0.005 inches (a range from about 0.01 mm to about 0.13
mm). The heater element (704) can be positioned at the exit of the
tube, e.g., capillary tube (710) so that the mixture can deposit
(708) on the heater element (704). The heater element (704) can be
positioned in an airway (706) so that a user upon inhalation can
cause the aerosol to pass through the mouthpiece (702) and be drawn
into the lungs. The agent (e.g., nicotine) reservoir (712) can be
in the airway. FIG. 8 illustrates that in some cases, an agent
(e.g., nicotine) reservoir (802) can be placed outside of an airway
(804), while the heater element (806) can be in the airway (804). A
tube, e.g., capillary tube (808) can enter the airway (804).
[0164] FIGS. 31A-D illustrates another configuration of a heater
element (3106a-d) in an airway (3112a-d). FIG. 31A depicts a device
(ENT-100-A), comprising a primary carrier gas inlet (3112a),
positive and negative brass contacts (3110a), a heater element
(3106a) comprising a coil located distally from the inlet to the
primary airway (3112a) and two bypass inlets (3104a) located
(disposed) downstream of the heater element but prior to the outlet
(3102a). FIG. 31B depicts a device designated ENT-100-B, which is
the same as ENT-100-A except that the heater element has been moved
to be proximal to the inlet of the primary airway (3112b). FIG. 31C
depicts a device designated ENT-100-C, which is similar to the
ENT-100-A device except that the wire coil heater element has been
moved to an intermediate position relative to the location of the
coil in ENT-100-A and ENT-100-B. Any of the devices depicted in
FIG. 31A-C can comprise the wire coil heater element designated "A
Coil" (3114e) or "B Coil" (3116e) as illustrated in FIG. 31E. The
coil in both types of heater elements comprise inner diameter of
0.26 inches (about 6.6 mm). The "A Coil" comprises a stretch of
coil followed by a straight lead on either end of the coil which
connects to the brass contacts. The "B Coil" comprises a stretch of
coil, wherein the coil itself connects to the brass contacts. FIG.
31D depicts a device designated ENT-100-D with a primary passageway
(3112d) for air to flow through, brass contacts (+/-) embedded
within the wall of the primary passageway, and a heater element
(3106d) comprising a wire wherein one end of the wire wraps around
another segment of the wire, wherein a wire coil is formed with an
end of the wire passes through the center of the wire coil. An
example of this type of heater element is shown in FIGS. 36-38. In
some cases, a liquid formulation comprising a pharmaceutically
active agent (e.g., nicotine) is delivered to the heater element of
FIGS. 31A-D from a reservoir comprising the liquid formulation
comprising a pharmaceutically active agent (e.g., nicotine) through
the use of a tube, e.g., capillary tube as provided herein, wherein
the tube, e.g., capillary tube is coupled or capable of being
coupled to the reservoir. In some cases, a liquid formulation
comprising a pharmaceutically active agent (e.g., nicotine) is
delivered to the heater element of FIGS. 31A-D from a reservoir
comprising the liquid formulation comprising a pharmaceutically
active agent (e.g., nicotine) through the use of a positive
displacement pump as provided herein, wherein the positive
displacement pump is fluidically coupled to the reservoir.
[0165] FIG. 9 illustrates another embodiment for a heater element.
To aid in reducing an agent (e.g., nicotine) from evaporating from
the end of a tube, e.g., capillary tube (902) (attached to an agent
(e.g., nicotine) reservoir (904)), the heater element (906) can be
positioned to cover the end of the tube, e.g., capillary tube when
cold. Upon heating the heater would move away from the end (908)
due to thermal expansion, opening up the end and allowing the
mixture to leave. The position of deposited material (910) is
shown.
[0166] FIGS. 10A and 10B illustrate additional configurations of a
heater element. FIG. 10A illustrates that a heater element (1006a)
can be positioned at the end of the tube, e.g., capillary tube
(1004a), where the tube, e.g., capillary tube can be attached to an
agent (e.g., nicotine) reservoir (1002a). FIG. 10B illustrates an
agent (e.g., nicotine) reservoir (1002b) and a tube, e.g.,
capillary tube (1004b), where the geometry of the tube, e.g.,
capillary tube is modified at the end (1006b) by narrowing or
flattening to aid in vaporization.
[0167] FIG. 22 illustrates another embodiment of a heater element.
The heater element (2200) can be a rod comprising a coil (2202)
that can be made of stainless steel, or a similar matter, which has
an electrical resistance substantially greater than other metals
(aluminum, brass, iron). In some cases, the rod is a wire, wherein
the coil is a wire coil. The rod can comprise an electrically
resistive material. The electrically resistive material can have an
electrical resistance such that when an electrical current is
passed across the rod heating happens. The rod is connected to
brass contacts (2204) through segments of the rod that do not form
the coil. In some cases, the segments of the rod that connect to
the brass contacts comprise leads. The brass contacts can serve to
pass electrical current across the rod, including the coil. The
electrical current can serve to heat the coil and vaporize material
(i.e. an agent (e.g., nicotine) mixture) that contacts or is
delivered to the coil. The coil can be an open coil that can allow
for air to flow between the coils and carry away the vaporized
material. In FIG. 22, the brass contacts (2204) are located
(disposed) on either side of an airflow channel and the rod,
including the coil, span the channel. In some cases, the coil can
be oriented parallel to the flow of a carrier gas (e.g, air). In
some cases, the coil can be oriented perpendicular to the flow of a
carrier gas (e.g., air). In FIG. 22, a tube, e.g., capillary tube
(2206) attached to a reservoir (2208) comprising an agent (e.g.,
nicotine) mixture is located at one end of the coil and an agent
(e.g., nicotine) mixture is dispensed from the end of the tube,
e.g., capillary tube onto the coil. The agent (e.g., nicotine)
mixture, once dispensed, can wick along the coil to cover the
entire or part of the coil. The coil can be heated which can
vaporize the agent (e.g., nicotine) mixture.
[0168] FIGS. 36-38 illustrate yet another embodiment of a heater
element. In this embodiment, a first (3602a; +) and a second
(3602b; -) brass contact or terminal are located adjacent to each
other. The brass contacts can be embedded within or placed proximal
to a wall of a housing or channel of a device for generating an
aerosol as provided herein. The heater element can be a rod
comprising electrically resistive material, wherein a first end or
lead (3604a) is connected to one brass contact (3602a; +), while a
second end or lead (3604b) is connected to another, separate brass
contact (3602b; -). As illustrated in FIG. 36, a portion or segment
of the rod between the leads is configured into a coil (3606). In
addition, a separate portion or segment (3608) of the rod passes
through the interior of the coil (3606). Supplying current to the
rod through the brass contacts (3602a,b) can serve to heat both the
coil (3606) as well as the segment (3608) of the rod that passes
through the interior of the coil (3606). In some cases, the segment
of the rod that runs through the center of the coil is capable of
holding a liquid formulation comprising an agent (i.e. nicotine) as
provided herein. The liquid formulation can wick or be delivered by
any of dosing mechanisms provided herein onto the segment of the
rod that runs through the center of the coil from a source of the
liquid formulation (e.g., a reservoir). In some cases, supplying
current to the rod through the brass contacts (3602a,b) serves to
heat both the coil (3606) as well as the segment (3608) of the rod
that passes through the interior of the coil (3606), wherein a
liquid formulations that wicks or is delivered by any of dosing
mechanisms provided herein onto the segment of the rod running
through the coil is vaporized. In FIG. 36, the coil is oriented
perpendicular to the flow of a carrier gas (e.g. air flow) (3610).
In some cases, the coil is oriented parallel to the flow of a
carrier gas (e.g. air flow) in a device for generating a
condensation aerosol as described herein. FIGS. 37A and 37B depict
alternate embodiments to the heater element illustrated in FIG. 36,
wherein the number of coils shown in the heater element of FIG. 37A
is reduced in the heater element of FIG. 37B. As shown in FIG. 37,
alternating the number of coils (3702b, 3702b) in the coil serves
to increase the length of the non-coil segments (3704a, 3704b) of
the rod and decrease the length of the rod covered by the coil.
FIG. 38 illustrates components of the rod and coil in the heater
element illustrated in FIG. 36, including the diameter of the rod
(3802), total length of the coil (3804) (e.g., 0.1 to 0.15 inches
(a range from about 2.54 mm to about 3.81 mm)), inner diameter of
the coil (3808) (e.g., 0.027-0.040 inches (about 0 6 mm to about
1.02 mm)), outer diameter of the coil (3806) (e.g., 0.047-0.06
inches (a range from about 1.19 mm to about 1.53 mm)), and pitch of
the coil (3810).
[0169] An electronic agent (e.g., nicotine) delivery device
provided herein can comprise a heater element comprising a coil,
wherein the coil comprises electrically resistive material. The
coil can be a wire coil. The electrically resistive material can
include but is not limited to: semiconductors such as doped
ceramics, electrically conductive ceramics such as molybdenum
disilicide, carbon, graphite, metals, metal alloys and composite
materials made of a ceramic material and a metallic material. Such
composite materials may comprise doped or undoped ceramics.
Examples of suitable doped ceramics include doped silicon carbides.
Examples of suitable metals include titanium, zirconium, tantalum
and metals from the platinum group. Examples of suitable metal
alloys include stainless steel-, Constantan-, nickel-, cobalt-,
chromium-, aluminium-titanium- zirconium-, hafnium-, niobium-,
molybdenum-, tantalum-, tungsten-, tin-, gallium-, manganese- and
iron-containing alloys, and super-alloys based on nickel, iron,
cobalt, stainless steel, Timetal.RTM. and iron-manganese-aluminium
based alloys. Timetal.RTM. is a registered trade mark of Titanium
Metals Corporation, 1999 Broadway Suite 4300, Denver Colo. In
composite materials, the electrically resistive material can
optionally be embedded in, encapsulated or coated with an
insulating material or vice-versa, depending on the kinetics of
energy transfer and the external physicochemical properties
required. In one embodiment, the coil comprises stainless
steel.
[0170] A heater element comprising a rod as provided herein can
comprise a coil and a wick element around which the coil can be
wrapped. The wick element can be capable of being heated. The wick
element can be connected to the rod. The wick element can be
independent of the rod. In some cases, the wick element is capable
of being heated, and wherein the wick element is connected to the
rod. The rod can be a wire. The coil can be a wire coil. The rod
can comprise a coil along the entire length of the wick element.
The wick element can be capable of wicking or holding a liquid
formulation comprising an agent as provided herein. The wick
element can be a capillary (a self wicking tube). The liquid
formulation comprising an agent as provided herein can be in fluid
communication with a source of the liquid formulation. The source
of the liquid formulation can be any source as provided herein,
including but not limited to, a reservoir. The liquid formulation
comprising an agent as provided herein can be delivered to the wick
element by any means known in the art. The delivery can be through
capillary action or through the use of a pump. In some cases, the
rod comprises a capillary wherein the capillary is in fluid
communication with a reservoir, wherein the reservoir comprises a
liquid formulation comprising a pharmaceutically active agent (e.g.
nicotine), and wherein the capillary is capable of holding the
liquid formulation comprising a pharmaceutically active agent (e.g.
nicotine). The wick element can be made of any material known in
the art capable of wicking or holding a liquid formulation
comprising an agent as provided herein. In some cases, the coil
connects to a source of electricity. The coil can connect to the
source of electricity through one or more leads protruding from
both ends of the coil. The source of electricity can be a battery
or a charged capacitor. The battery can be rechargeable.
[0171] In some cases, the coil can wrap around or span exactly,
about, more than, less than, at least, or at most 1%, 2%, 3%, 4%,
5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%,
19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%,
32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%,
45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%,
58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%,
71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%,
84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,
97%, 98%, 99%, 100% of the length of the wick element. In some
cases, the coil can wrap around or span between 1-10%, 10-20%,
20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%,
10-20% of the length of the wick element. In some cases, the coil
can wrap around or span of about 1 to about 10%, about 10 to about
20%, about 20 to about 30%, about 30 to about 40%, about 40 to
about 50%, about 50 to about 60%, about 60 to about 70%, about 70
to about 80%, about 80 to about 90%, or about 90 to about 100% of
the length of the wick element.
[0172] The total length of the coil can be exactly, about, more
than, less than, at least, or at most 0.01, 0.0125, 0.015, 0.0175,
0.02, 0.0225, 0.025, 0.0275, 03, 0.0325, 0.035, 0.0375, 0.04,
0.0425, 0.045, 0.0475, 0.05, 0.0525, 0.055, 0.0575, 0.06, 0.0625,
0.065, 0.0675, 0.07, 0.0725, 0.075, 0.0775, 0.08, 0.0825, 0.085,
0.0875, 0.09, 0.0925, 0.095, 0.0975, 0.1, 0.11, 0.115, 0.12, 0.125,
0.13, 0.135, 0.14, 0.145, 0.15, 0.155, 0.16, 0.165, 0.17, 0.175,
0.18, 0.185, 0.19, 0.195 or 0.2 inches (a range from about 0.25 mm
to about 5.08 mm). The total length of the coil can be between
0.01-0.015, 0.015-0.02, 0.02-0.025, 0.025-030, 0.03-0.035,
0.035-0.04, 0.04-0.045, 0.045-0.05, 0.05-0.055, 0.055-0.06,
0.06-0.065, 0.065-0.07, 0.07-0.075, 0.075-0.08, 0.08-0.085,
0.085-0.09, 0.09-0.095, 0.095-0.1, 0.1-0.12, 0.12-0.13, 0.13-0.14,
0.14-0.15, 0.15-0.16, 0.16-0.17, 0.17-0.18, 0.18-0.19, or 0.19-0.2
inches (a range from about 0.25 mm to about 5.08 mm). The total
length of the coil can be about 0.01 to about 0.015, about 0.015 to
about 0.02, about 0.02 to about 0.025, about 0.025 to about 03,
about 0.03 to about 0.035, about 0.035 to about 0.04, about 0.04 to
about 0.045, about 0.045 to about 0.05, about 0.05 to about 0.055,
about 0.055 to about 0.06, about 0.06 to about 0.065, about 0.065
to about 0.07, about 0.07 to about 0.075, about 0.075 to about
0.08, about 0.08 to about 0.085, about 0.085 to about 0.09, about
0.09 to about 0.095, about 0.095 to about 0.1, about 0.1 to about
0.12, about 0.12 to about 0.13, about 0.13 to about 0.14, about
0.14 to about 0.15, about 0.15 to about 0.16, about 0.16 to about
0.17, about 0.17 to about 0.18, about 0.18 to about 0.19, or about
0.19 to about 0.2 inches (a range from about 0.25 mm to about 5.08
mm).
[0173] A heater element comprising a rod as provided herein can
comprise one or more segments comprising a coil and one or more
segments not comprising a coil (i.e. non-coil segment). The rod can
be a wire. The coil can be a wire coil. One or more non-coil
segments of the rod can be capable of wicking or holding a liquid
formulation comprising an agent as provided herein. The non-coil
segment can act as a capillary or wick. In some cases, one or more
non-coil segments of the rod comprise a wick element. One or more
wick elements can be capable of being heated, thereby forming one
or more heated wick elements. The liquid formulation comprising an
agent as provided herein can be in fluid communication with a
source of the liquid formulation. The source of the liquid
formulation can be any source as provided herein, including, but
not limited to, a reservoir. The liquid formulation comprising an
agent as provided herein can be delivered to a non-coil segment of
the rod by any means known in the art. The delivery can be through
capillary action or through the use of a pump. In some cases, the
non-coil segment is in fluid communication with a reservoir,
wherein the reservoir comprises a liquid formulation comprising a
pharmaceutically active agent (e.g. nicotine), and wherein the
non-coil segment is capable of holding the liquid formulation
comprising a pharmaceutically active agent (e.g., nicotine).
[0174] The non-coil segments can serve as electrical leads for
connecting the rod to a source of electricity. The rod can comprise
a coil along the entire length of the rod. In some cases, the coil
connects to the source of electricity. The source of electricity
can be a battery or a charged capacitor. The battery can be
rechargeable.
[0175] In some cases, a distance between the first and second leads
of the rod when the first lead is connected to either the first or
second terminal of the power source while the second lead is
connected to the other of the first or second terminal of the power
source is about, more than, less than, or at least 0.01, 0.015,
0.02, 0.025, 0.03, 0.035, 0.04, 0.045, 0.05, 0.055, 0.06, 0.065,
0.07, 0.075, 0.08, 0.085, 0.09, 0.095, 0.1, 0.11, 0.12, 0.13, 0.14,
0.15, 0.16, 0.17, 0.18, 0.19, or 0.2 inches (a range from about
0.254 mm to about 5.08 mm) A distance between the first and second
leads of the rod when the first lead is connected to either the
first or second terminal of the power source while the second lead
is connected to the other of the first or second terminal of the
power source is from about 0.01 to about 0.1 inches, about 0.02 to
about 0.09 inches, or about 0.025 to about 0.8 inches (a range from
about 0.254 mm to about 20.32 mm).
[0176] In some cases, the coil can wrap around a non-coil segment
of the rod, wherein the non-coil segment passes through the coil.
In these cases, the coil can wrap around or span exactly, about,
more than, less than, at least, or at most 1%, 2%, 3%, 4%, 5%, 6%,
7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%,
21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%,
34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%,
47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%,
60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%,
73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%,
86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,
99%, 100% of the length a non-coil segment of the rod. In these
cases, the coil can wrap around or span between 1-10%, 10-20%,
20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%,
10-20% of the length a non-coil segment of the rod. In these cases,
the coil can wrap around or span of about 1 to about 10%, about 10
to about 20%, about 20 to about 30%, about 30 to about 40%, about
40 to about 50%, about 50 to about 60%, about 60 to about 70%,
about 70 to about 80%, about 80 to about 90%, or about 90 to about
100% of the length of a non-coil segment of the rod.
[0177] The total length of the coil can be exactly, about, more
than, less than, at least, or at most 0.01, 0.0125, 0.015, 0.0175,
0.02, 0.0225, 0.025, 0.0275, 03, 0.0325, 0.035, 0.0375, 0.04,
0.0425, 0.045, 0.0475, 0.05, 0.0525, 0.055, 0.0575, 0.06, 0.0625,
0.065, 0.0675, 0.07, 0.0725, 0.075, 0.0775, 0.08, 0.0825, 0.085,
0.0875, 0.09, 0.0925, 0.095, 0.0975, 0.1, 0.11, 0.115, 0.12, 0.125,
0.13, 0.135, 0.14, 0.145, 0.15, 0.155, 0.16, 0.165, 0.17, 0.175,
0.18, 0.185, 0.19, 0.195 or 0.2 inches (a range from about 0.254 mm
to about 5.08 mm). The total length of the coil can be between
0.01-0.015, 0.015-0.02, 0.02-0.025, 0.025-030, 0.03-0.035,
0.035-0.04, 0.04-0.045, 0.045-0.05, 0.05-0.055, 0.055-0.06,
0.06-0.065, 0.065-0.07, 0.07-0.075, 0.075-0.08, 0.08-0.085,
0.085-0.09, 0.09-0.095, 0.095-0.1, 0.1-0.12, 0.12-0.13, 0.13-0.14,
0.14-0.15, 0.15-0.16, 0.16-0.17, 0.17-0.18, 0.18-0.19, or 0.19-0.2
inches (a range from about 0.254 mm to about 5.08 mm). The total
length of the coil can be about 0.01 to about 0.015, about 0.015 to
about 0.02, about 0.02 to about 0.025, about 0.025 to about 03,
about 0.03 to about 0.035, about 0.035 to about 0.04, about 0.04 to
about 0.045, about 0.045 to about 0.05, about 0.05 to about 0.055,
about 0.055 to about 0.06, about 0.06 to about 0.065, about 0.065
to about 0.07, about 0.07 to about 0.075, about 0.075 to about
0.08, about 0.08 to about 0.085, about 0.085 to about 0.09, about
0.09 to about 0.095, about 0.095 to about 0.1, about 0.1 to about
0.12, about 0.12 to about 0.13, about 0.13 to about 0.14, about
0.14 to about 0.15, about 0.15 to about 0.16, about 0.16 to about
0.17, about 0.17 to about 0.18, about 0.18 to about 0.19, or about
0.19 to about 0.2 inches (a range from about 0.254 mm to about 5.08
mm).
[0178] A heater element comprising a rod as provided herein can
comprise one or more coils. The rod can be a wire. The coil can be
a wire coil. The coil can have exactly, about, more than, less
than, at least or at most 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5,
6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 10, 10.5, 11, 11.5, 12, 12.5, 13,
13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5,
20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26,
26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 31.5, 32, 32.5,
33, 33.5, 34, 34.5, 35, 35.5, 36, 36.5, 37, 37.5, 38, 38.5, 39,
39.5, 40, 41, 42, 43, 44, 45, 46, 47, 4, 49, 50, 51, 52, 53, 54,
55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71,
72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,
89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115,
120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180,
185, 190, 195, or 200 coils. The coil can comprise 1-2, 2-4, 4-6,
6-8, 8-10, 10-12, 12-14, 14-16, 16-18, or 18-20 coils. The coil can
comprise 2-20, 4-20, 6-20, 8-20, 10-20, 12-20, 14-20, or 16-20
coils. The coil can comprise between 1-5, 5-10, 10-15, or 15-20
coils. The coil can comprise between 1-10, 1-20, 1-30, 1-40, 1-60,
1-70, 1-80, 1-90, 1-100 coils. The coil can comprise from about 1
to about 5, about 5 to about 10, about 10 to about 15, or about 15
to about 20 coils. The coil can comprise from about 1 to about 10,
about 1 to about 20, about 1 to about 30, about 1 to about 40,
about 1 to about 60, about 1 to about 70, about 1 to about 80,
about 1 to about 90, or about 1 to about 100 coils. In one
embodiment, the coil comprises from about 5 to about 10 coils. In
one embodiment, the coil comprises from about 1 to about 10 coils.
The distance between successive coils or the pitch of the coils can
be exactly, about, more than, less than, at least or at most 0.01,
0.0125, 0.015, 1.17, 0.0175, 0.02, 0.0225, 0.025, 0.0275, 03,
0.0325, 0.035, 0.0375, 0.04, 0.0425, 0.045, 0.0475, 0.05, 0.0525,
0.055, 0.0575, 0.06, 0.0625, 0.065, 0.0675, 0.07, 0.0725, 0.075,
0.0775, 0.08, 0.0825, 0.085, 0.0875, 0.09, 0.0925, 0.095, 0.0975,
0.1, 0.11, 0.115, 0.12, 0.125, 0.13, 0.135, 0.14, 0.145, 0.15,
0.155, 0.16, 0.165, 0.17, 0.175, 0.18, 0.185, 0.19, 0.195 or 0.2
inches (a range from about 0.254 mm to about 5.08 mm). The distance
between successive coils or the pitch of the coils can be between
0.01-0.015, 0.015-0.3, 0.01-0.02, 0.015-0.02, 0.020-0.025,
0.025-03, 0.03-0.035, 0.035-0.04, 0.04-0.045, 0.045-0.05,
0.05-0.055, 0.055-0.06, 0.06-0.065, 0.065-0.07, 0.07-0.075,
0.075-0.08, 0.08-0.085, 0.085-0.09, 0.09-0.095, 0.095-0.1,
0.1-0.12, 0.12-0.13, 0.13-0.14, 0.14-0.15, 0.15-0.16, 0.16-0.17,
0.17-0.18, 0.18-0.19, or 0.19-0.2 inches (a range from about 0.254
mm to about 5.08 mm). The distance between successive coils or the
pitch of the coils can be about 0.01 to about 0.015, about 0.01 to
about 0.02, about 0.015 to about 0.3, about 0.015 to about 0.02,
about 0.02 to about 0.025, about 0.025 to about 03, about 0.03 to
about 0.035, about 0.035 to about 0.04, about 0.04 to about 0.045,
about 0.045 to about 0.05, about 0.05 to about 0.055, about 0.055
to about 0.06, about 0.06 to about 0.065, about 0.065 to about
0.07, about 0.07 to about 0.075, about 0.075 to about 0.08, about
0.08 to about 0.085, about 0.085 to about 0.09, about 0.09 to about
0.095, about 0.095 to about 0.1, about 0.1 to about 0.12, about
0.12 to about 0.13, about 0.13 to about 0.14, about 0.14 to about
0.15, about 0.15 to about 0.16, about 0.16 to about 0.17, about
0.17 to about 0.18, about 0.18 to about 0.19, or about 0.19 to
about 0.2 inches (a range from about 0.254 mm to about 5.08 mm)
1001791A rod in a heater element comprising a rod as provided
herein can have a diameter of exactly, about, more than, less than,
at least or at most 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.011,
0.012, 0.013, 0.014, 0.015, 0.016, 0.017, 0.018, 0.019, or 0.02
inches (a range from about 0.127 mm to about 0.51 mm). The rod can
have a diameter between 0.005 and 0.01, 0.01 and 0.015, or 0.015
and 0.02 inches (a range from about 0.127 mm to about 0.51 mm). In
one embodiment, the rod has a diameter between 0.005 and 0.02
inches (a range from about 0.127 mm to about 0.51 mm). In one
embodiment, the rod has a diameter between 0.008 and 0.0012 inches
(a range from about 0.2032 mm to about 0.03 mm). The rod can have a
diameter of about 0.005 to about 0.01, about 0.01 to about 0.015,
or about 0.015 to about 0.02 inches (a range from about 0.127 mm to
about 0.508 mm). In one embodiment, the rod has a diameter of about
0.005 to about 0.02 inches (a range from about 0.127 mm to about
0.508 mm). In one embodiment, the rod has a diameter of about 0.008
to about 0.0012 inches (a range from about 0.2031 mm to about 0.03
mm). The rod can be a wire.
[0179] A heater element comprising a coil as provided herein can
have a coil with an inner or internal diameter of exactly, about,
more than, less than, at least or at most 0.01, 0.012, 0.0125,
0.015, 0.0175, 0.02, 0.022, 0.0225, 0.025, 0.0275, 03, 0.032,
0.0325, 0.035, 0.0375, 0.04, 0.042 0.0425, 0.045, 0.0475, 0.05,
0.0520.0525, 0.055, 0.0575, 0.06, 0.062, 0.0625, 0.065, 0.0675,
0.07, 0.072, 0.0725, 0.075, 0.0775, 0.08, 0.0825, 0.085, 0.0875,
0.09, 0.0925, 0.095, 0.0975, 0.1, 0.11, 0.115, 0.12, 0.125, 0.13,
0.135, 0.14, 0.145, 0.15, 0.155, 0.16, 0.165, 0.17, 0.175, 0.18,
0.185, 0.19, 0.195, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27,
0.28, 0.29, 0.3, 0.35, 0.4, 0.45, or 0.5 inches (a range from about
0.254 mm to about 12.7 mm). The inner or internal diameter of the
coil can be between 0.01-0.015, 0.015-0.02, 0.02-0.025, 0.0250-03,
0.03-0.035, 0.035-0.04, 0.04-0.045, 0.045-0.05, 0.05-0.055,
0.055-0.06, 0.06-0.065, 0.065-0.07, 0.07-0.075, 0.075-0.08,
0.08-0.085, 0.085-0.09, 0.09-0.095, 0.095-0.1, 0.1-0.12, 0.12-0.13,
0.13-0.14, 0.14-0.15, 0.15-0.16, 0.16-0.17, 0.17-0.18, 0.18-0.19,
0.19-0.2, 0.2-0.21, 0.21-0.22, 0.22-0.23, 0.23-0.24, 0.24-0.25,
0.25-0.26, 0.26-0.27, 0.27-0.28, 0.28-0.29, 0.29-0.3, 0.3-0.35,
0.35-0.4, 0.4-0.45, or 0.45-0.5 inches (a range from about 0.254 mm
to about 12.7 mm). The inner or internal diameter of the coil can
be about 0.01 to about 0.015, about 0.015 to about 0.02, about 0.02
to about 0.025, about 0.025 to about 0.3, about 0.03 to about
0.035, about 0.035 to about 0.04, about 0.04 to about 0.045, about
0.045 to about 0.05, about 0.05 to about 0.055, about 0.055 to
about 0.06, about 0.06 to about 0.065, about 0.065 to about 0.07,
about 0.07 to about 0.075, about 0.075 to about 0.08, about 0.08 to
about 0.085, about 0.085 to about 0.09, about 0.09 to about 0.095,
about 0.095 to about 0.1, about 0.1 to about 0.15, about 0.15 to
about 0.2, about 0.2 to about 0.25, about 0.25 to about 0.3, about
0.3 to about 0.35, about 0.35 to about 0.4, about 0.4 to about
0.45, or about 0.45 to about 0.5 inches (a range from about 0.254
mm to about 12.7 mm). The inner or internal diameter of the coil
can be between 0.02 and 0.04, 0.04 and 0.06, or 0.02 and 0.06
inches (a range from about 0.508 mm to about 1.524 mm). In one
embodiment, the inner or internal diameter of the coil is between
0.03 and 0.04 inches (a range from about 0.3 mm to about 1.02 mm).
The inner or internal diameter of the coil can be about 0.02 to
about 0.04, about 0.04 to about 0.06, or about 0.02 to about 0.06
inches (a range from about 0.508 mm to about 1.524 mm). In one
embodiment, the inner or internal diameter of the coil is about
0.03 to about 0.04 inches (a range from about 0.3 mm to about 1.02
mm). In one embodiment, the inner or internal diameter of the coil
is about 0.02 to about 0.04 inches (a range from about 0.508 mm to
about 1.02 mm). In one embodiment, the inner or internal diameter
of the coil is between 0.02 to about 0.04 inches (a range from
about 0.508 mm to about 1.02 mm). The coil can be a wire coil.
[0180] A heater element comprising a coil as provided herein can
have a coil with an outer or external diameter of exactly, about,
more than, less than, at least or at most 0.01, 0.0125, 0.015,
0.0175, 0.02, 0.0225, 0.025, 0.0275, 0.03, 0.0325, 0.035, 0.0375,
0.04, 0.0425, 0.045, 0.0475, 0.05, 0.0525, 0.055, 0.0575, 0.06,
0.0625, 0.065, 0.0675, 0.07, 0.0725, 0.075, 0.0775, 0.08, 0.0825,
0.085, 0.0875, 0.09, 0.0925, 0.095, 0.0975, 0.1, 0.11, 0.115, 0.12,
0.125, 0.13, 0.135, 0.14, 0.145, 0.15, 0.155, 0.16, 0.165, 0.17,
0.175, 0.18, 0.185, 0.19, 0.195, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25,
0.26, 0.27, 0.28, 0.29, 0.3, 0.35, 0.4, 0.45, or 0.5 inches (a
range from about 0.254 mm to about 12.7 mm). The outer or external
diameter of the coil can be between 0.01-0.015, 0.015-0.02,
0.02-0.025, 0.025-0.03, 0.03-0.035, 0.035-0.04, 0.04-0.045,
0.045-0.05, 0.05-0.055, 0.055-0.06, 0.06-0.065, 0.065-0.07,
0.07-0.075, 0.075-0.08, 0.08-0.085, 0.085-0.09, 0.09-0.095,
0.095-0.1, 0.1-0.12, 0.12-0.13, 0.13-0.14, 0.14-0.15, 0.15-0.16,
0.16-0.17, 0.17-0.18, 0.18-0.19, 0.19-0.2, 0.2-0.21, 0.21-0.22,
0.22-0.23, 0.23-0.24, 0.24-0.25, 0.25-0.26, 0.26-0.27, 0.27-0.28,
0.28-0.29, 0.29-0.3, 0.3-0.35, 0.35-0.4, 0.4-0.45, or 0.45-0.5
inches (a range from about 0.254 mm to about 12.7 mm). The outer or
external diameter of the coil can be about 0.01 to about 0.015,
about 0.015 to about 0.02, about 0.02 to about 0.025, about 0.025
to about 0.3, about 0.03 to about 0.035, about 0.035 to about 0.04,
about 0.04 to about 0.045, about 0.045 to about 0.05, about 0.05 to
about 0.055, about 0.055 to about 0.06, about 0.06 to about 0.065,
about 0.065 to about 0.07, about 0.07 to about 0.075, about 0.075
to about 0.08, about 0.08 to about 0.085, about 0.085 to about
0.09, about 0.09 to about 0.095, about 0.095 to about 0.1, about
0.1 to about 0.15, about 0.15 to about 0.2, about 0.2 to about
0.25, about 0.25 to about 0.3, about 0.3 to about 0.35, about 0.35
to about 0.4, about 0.4 to about 0.45, or about 0.45 to about 0.5
inches (a range from about 0.254 mm to about 12.7 mm). The outer or
external diameter of the coil can be between 0.02 and 0.04, 0.04
and 0.06, or 0.02 and 0.06 inches (a range from about 0.02 mm and
1.02 mm to about 0.02 mm and 1.524 mm). In one embodiment, the
outer or external diameter of the coil is between 0.03 and 0.04
inches (a range from about 0.0.762 mm to about 1.02 mm). The outer
or external diameter of the coil can be about 0.02 to about 0.04,
about 0.04 to about 0.06, about 0.02 to about 0.06 inches, about
0.02 to about 0.08 inches, about 0.02 to about 0.1 inches (a range
from about 0.508 mm to about 2.54 mm). In one embodiment, the outer
or external diameter of the coil is about 0.03 to about 0.04 inches
(a range from about 0.762 mm to about 1.02 mm). In one embodiment,
the outer or external diameter of the coil is about 0.02 to about
0.04 inches (a range from about 0.508 mm to about 1.02 mm). In one
embodiment, the outer or external diameter of the coil is between
0.02 to about 0.04 inches (a range from about 0.508 mm to about
1.02 mm). The coil can be a wire coil.
[0181] A heater element comprising a coil as provided herein can
have a coil with a length to width aspect ratio exactly, about,
more than, less than, at least or at most 0.1, 0.2, 0.3, 0.4, 0.5,
0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9,
2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3,
3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7,
4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1,
6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5,
7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9,
9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.5, 11, 11.5,
12, 12.5, 13, 13.5, 14, 14.5, or 15. The length to width aspect
ratio of the coil can be between 0.1-0.15, 0.15-0.2, 0.2-0.25,
0.25-0.3, 0.3-0.35, 0.35-0.4, 0.4-0.45, 0.45-0.5, 0.5-0.55,
0.55-0.6, 0.6-0.65, 0.65-0.7, 0.7-0.75, 0.75-0.8, 0.8-0.85,
0.85-0.9, 0.9-0.95, 0.95-1, 1-1.5, 1.5-2, 2-2.5, 2.5-3, 3-3.5,
3.5-4, 4-4.5, 4.5-5, 5-5.5, 5.5-6, 6-6.5, 6.5-7, 7-7.5, 7.5-8,
8-8.5, 8.5-9, 9-9.5, 9.5-10, 10-10.5, 10.5-11, 11-11.5, 11.5-12,
12.5-13, 13-13.5, 13.5-14, 14-14.5, or 14.5-15. The length to width
aspect ratio of the coil can be about 0.1 to about 0.15, about 0.15
to about 0.2, about 0.2 to about 0.25, about 0.25 to about 0.3,
about 0.3 to about 0.35, about 0.35 to about 0.4, about 0.4 to
about 0.45, about 0.45 to about 0.5, about 0.5 to about 0.55, about
0.55 to about 0.6, about 0.6 to about 0.65, about 0.65 to about
0.7, about 0.7 to about 0.75, about 0.75 to about 0.8, about 0.8 to
about 0.85, about 0.85 to about 0.9, about 0.9 to about 0.95, about
0.95 to about 1, about 1 to about 1.5, about 1.5 to about 2, about
2 to about 2.5, about 2.5 to about 3, about 3 to about 3.5, about
3.5 to about 4, about 4 to about 4.5, about 4.5 to about 5, about 5
to about 5.5, about 5.5 to about 6, about 6 to about 6.5, about 6.5
to about 7, about 7 to about 7.5, about 7.5 to about 8, about 8 to
about 8.5, about 8.5 to about 9, about 9 to about 9.5, about 9.5 to
about 10, about 10 to about 10.5, about 10.5 to about 11, about 11
to about 11.5, about 11.5 to about 12, about 12.5 to about 13,
about 13 to about 13.5, about 13.5 to about 14, 14 to about 14.5,
or about 14.5 to about 15. The width of the coil in the length to
width aspect ratio can be the inner or internal diameter, or the
outer or external diameter. The coil can be a wire coil.
[0182] A heater element comprising a rod as provided herein,
wherein the rod can have a coil wherein a ratio of the diameter of
the rod to the diameter of the coil can be exactly, about, more
than, less than, at least or at most 0.1, 0.2, 0.3, 0.4, 0.5, 0.6,
0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2,
2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4,
3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,
4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2,
6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6,
7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9,
9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.5, 11, 11.5,
12, 12.5, 13, 13.5, 14, 14.5, or 15. The ratio of the diameter of
the rod to the diameter of the coil can be between 0.1-0.15,
0.15-0.2, 0.2-0.25, 0.25-0.3, 0.3-0.35, 0.35-0.4, 0.4-0.45,
0.45-0.5, 0.5-0.55, 0.55-0.6, 0.6-0.65, 0.65-0.7, 0.7-0.75,
0.75-0.8, 0.8-0.85, 0.85-0.9, 0.9-0.95, 0.95-1, 1-1.5, 1.5-2,
2-2.5, 2.5-3, 3-3.5, 3.5-4, 4-4.5, 4.5-5, 5-5.5, 5.5-6, 6-6.5,
6.5-7, 7-7.5, 7.5-8, 8-8.5, 8.5-9, 9-9.5, 9.5-10, 10-10.5, 10.5-11,
11-11.5, 11.5-12, 12.5-13, 13-13.5, 13.5-14, 14-14.5, or 14.5-15.
The ratio of the diameter of the rod to the diameter of the coil
can be about 0.1 to about 0.15, about 0.15 to about 0.2, about 0.2
to about 0.25, about 0.2 to about 0.4, about 0.25 to about 0.3,
about 0.3 to about 0.35, about 0.35 to about 0.4, about 0.4 to
about 0.45, about 0.45 to about 0.5, about 0.5 to about 0.55, about
0.55 to about 0.6, about 0.6 to about 0.65, about 0.65 to about
0.7, about 0.7 to about 0.75, about 0.75 to about 0.8, about 0.8 to
about 0.85, about 0.85 to about 0.9, about 0.9 to about 0.95, about
0.95 to about 1, about 1 to about 1.5, about 1.5 to about 2, about
2 to about 2.5, about 2.5 to about 3, about 3 to about 3.5, about
3.5 to about 4, about 4 to about 4.5, about 4.5 to about 5, about 5
to about 5.5, about 5.5 to about 6, about 6 to about 6.5, about 6.5
to about 7, about 7 to about 7.5, about 7.5 to about 8, about 8 to
about 8.5, about 8.5 to about 9, about 9 to about 9.5, about 9.5 to
about 10, about 10 to about 10.5, about 10.5 to about 11, about 11
to about 11.5, about 11.5 to about 12, about 12.5 to about 13,
about 13 to about 13.5, about 13.5 to about 14, 14 to about 14.5,
or about 14.5 to about 15. The width of the coil in the ratio of
the diameter of the rod to a diameter of the coil can be the inner
or internal diameter, or the outer or external diameter. The rod
can be a wire. The coil can be a wire coil.
[0183] A heater element comprising a rod is provided herein,
wherein the rod can have a coil wherein the volume of the rod can
be less than the volume of the coil. The volume of the rod can be
exactly, about, more than, less than, at least or at most 1%, 2%,
3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%,
18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%,
31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%,
44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%,
57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%,
70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%,
83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%,
96%, 97%, 98%, 99%, 100% of the volume of the coil. The volume of
the rod can be between 1-10%, 10-20%, 20-30%, 30-40%, 40-50%,
50-60%, 60-70%, 70-80%, 80-90%, or 90-100% of the volume of the
coil. The volume of the rod can be about 1 to about 10%, about 10
to about 20%, about 20 to about 30%, about 30 to about 40%, about
40 to about 50%, about 50 to about 60%, about 60 to about 70%,
about 70 to about 80%, about 80 to about 90%, or about 90 to about
100% of the volume of the coil. The rod can be a wire. The coil can
be a wire coil. In some cases, the volume of the coil be about,
more than, less than, at least, or no greater than 1.1, 1.2, 1.3,
1.4, 1.5, 1.6, 1.7, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8,
2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.5,
5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 times the volume of
the rod.
[0184] A heater element comprising a rod is provided herein,
wherein the rod can have a coil, wherein the surface area of the
rod can be less than, greater than or equal to the surface area of
the outer or external surface of the coil. The surface area of the
rod can be exactly, about, more than, less than, at least or at
most 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%,
15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%,
28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%,
41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%,
54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%,
67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%,
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,
93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% greater than or less than
the outer surface area of the coil. The surface area of the rod can
be between 1-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%,
70-80%, 80-90%, or 90-100% greater than or less than the outer
surface area of the coil. The surface area of the rod can be about
1 to about 10%, about 10 to about 20%, about 20 to about 30%, about
30 to about 40%, about 40 to about 50%, about 50 to about 60%,
about 60 to about 70%, about 70 to about 80%, about 80 to about
90%, or about 90 to about 100% greater than or less than the outer
surface area of the coil. The rod can be a wire. The coil can be a
wire coil. In some cases, a surface area of a rod can be 1.1, 1.2,
1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6,
2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4,
4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4,
5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8,
6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2,
8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6,
9.7, 9.8, 9.9, or 10 times greater than a surface area of a
coil.
[0185] A heater element as provided herein can comprise an
electrical resistance that can be exactly, about, more than, less
than, at least or at most 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8,
0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2,
2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6,
3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5,
5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4,
6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8,
7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2,
9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10 Ohms. The electrical
resistance can be between 0.1-0.15, 0.15-0.2, 0.2-0.25, 0.25-0.3,
0.3-0.35, 0.35-0.4, 0.4-0.45, 0.45-0.5, 0.5-0.55, 0.55-0.6,
0.6-0.65, 0.65-0.7, 0.7-0.75, 0.75-0.8, 0.8-0.85, 0.85-0.9,
0.9-0.95, 0.95-1, 1-1.5, 1.5-2, 2-2.5, 2.5-3, 3-3.5, 3.5-4, 4-4.5,
4.5-5, 5-5.5, 5.5-6, 6-6.5, 6.5-7, 7-7.5, 7.5-8, 8-8.5, 8.5-9,
9-9.5, or 9.5-10 Ohms. The electrical resistance can be about 0.1
to about 0.15, about 0.15 to about 0.2, about 0.2 to about 0.25,
about 0.25 to about 0.3, about 0.3 to about 0.35, about 0.35 to
about 0.4, about 0.4 to about 0.45, about 0.45 to about 0.50, about
0.5 to about 0.55, about 0.55 to about 0.6, about 0.6 to about
0.65, about 0.65 to about 0.7, about 0.7 to about 0.75, about 0.75
to about 0.8, about 0.8 to about 0.85, about 0.85 to about 0.9,
about 0.9 to about 0.95, about 0.95 to about 1, about 1 to about
1.5, about 1.5 to about 2, about 2 to about 2.5, about 2.5 to about
3, about 3 to about 3.5, about 3.5 to about 4, about 4 to about
4.5, about 4.5 to about 5, about 5 to about 5.5, about 5.5 to about
6, about 6 to about 6.5, about 6.5 to about 7, about 7 to about
7.5, about 7.5 to about 8, about 8 to about 8.5, about 8.5 to about
9, about 9 to about 9.5, or about 9.5 to about 10 Ohms. The
electrical resistance can be the electrical resistance at room
temperature.
[0186] A heater element as provided herein can vaporize a liquid
formulation comprising a pharmaceutically active agent (e.g.,
nicotine) as provided herein, wherein substantially all of the
liquid formulation in contact with or delivered to the heater
element is vaporized. The vaporization of the liquid formulation
that contacts or is delivered to a heater element as provided
herein can be exactly, about, more than, less than, at most, or at
least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%,
15%, 16%, 17%, 18%, 19%, 20%, 30%, 31%, 32%, 33%, 34%, 35%, 36%,
37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%,
50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%,
63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%,
76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%,
89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. The
vaporization of the liquid formulation that contacts or is
delivered to a heater element as provided herein can be between
1%-10%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%,
70%-80%, 80%-90%, or 90%-100%. The vaporization of the liquid
formulation that contacts or is delivered to a heater element as
provided herein can be about 1% to about 10%, about 10% to about
20%, about 20% to about 30%, about 30% to about 40%, about 40% to
about 50%, about 50% to about 60%, about 60% to about 70%, about
70% to about 80%, about 80% to about 90%, or about 90% to about
100%. The vaporization of the liquid formulation that contacts or
is delivered to a heater element as provided herein can be greater
than 95%, 99%, or 99.5%.
[0187] The amount of residue or build-up of non-vaporized liquid
formulation comprising a pharmaceutically active agent (e.g.,
nicotine) that contacts or is delivered to a heater element as
provided herein can be reduced by exactly, about, more than, less
than, at most, or at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%,
11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 30%, 31%, 32%,
33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%,
46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%,
59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%,
72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%,
85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%, 99%, or 100%. The amount of residue or build-up of
non-vaporized liquid formulation comprising a pharmaceutically
active agent that contacts or is delivered to a heater element as
provided herein can be between 1%-10%, 10%-20%, 20%-30%, 30%-40%,
40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, or 90%-100%. The
amount of residue or build-up of non-vaporized liquid formulation
comprising a pharmaceutically active agent that contacts or is
delivered to a heater element as provided herein can be reduced by
about 1% to about 10%, about 10% to about 20%, about 20% to about
30%, about 30% to about 40%, about 40% to about 50%, about 50% to
about 60%, about 60% to about 70%, about 70% to about 80%, about
80% to about 90%, or about 90% to about 100%. The amount of residue
or build-up of non-vaporized liquid formulation comprising a
pharmaceutically active agent that contacts or is delivered to a
heater element as provided herein can be reduced by greater than
95%, 99%, or 99.5%.
[0188] Methods of renewal of a heater element are provided herein.
Heating elements can be renewed with changes in an agent (e.g.,
nicotine) dose cartridge to ensure dose consistency by removal of
any build up of combusted material on the heater element.
[0189] In some cases, the heater element comprises a coil and a
wick element, wherein the coil wraps around the wick element, and
wherein the liquid formulation wicks onto the heated wick element,
wherein the liquid formulation is vaporized through heating of the
coil and wick element.
[0190] The heater element can be in fluid communication with a
source of liquid formulation comprising an agent (e.g., nicotine)
as provided herein. In some cases, the heater element further
comprises a source of a liquid formulation comprising an agent
(e.g., nicotine), wherein the source is in fluid communication with
the wick element capable of being heated, wherein the liquid
formulation comprising an agent (e.g., nicotine) wicks onto the
wick element capable of being heated, whereby the liquid
formulation is aerosolized by heating of the coil and wick element
capable of being heated upon activation of a power source, wherein
the power source is electrically coupled to the heater element. In
some cases, the heater element further comprises a source of a
liquid formulation comprising an agent, wherein the source is in
fluid communication with the heatable wick element, wherein the
liquid formulation comprising an agent wicks onto the heatable wick
element, wherein the heatable wick element is heated after the
formulation has wicked onto the heatable wick element, whereby the
liquid formulation is aerosolized by heating of the coil and
heatable wick element upon activation of the power source.
[0191] The heater element comprising a coil with a center exit wick
element capable of being heated as described herein can vaporize
substantially all of the liquid formulation comprising the
pharmaceutically active agent (e.g., nicotine) that wicks onto the
center wick element. The heater element comprising a coil with a
center exit wick element capable of being heated can have a reduced
or substantially no splatter. In some cases, the heater element
comprises a coil with a center exit wick element capable of being
heated, wherein a liquid formulation comprising a pharmaceutically
active agent (e.g., nicotine) is held or wicks onto the center exit
wick element capable of being heated, and wherein both the wick
element capable of being heated and coil are heated, thereby
vaporizing the liquid formulation, wherein substantially all of the
liquid formulation is vaporized. The heater element comprising a
coil with a center exit wick element capable of being heated can
vaporize greater than 95% of the liquid formulation wicked onto the
wick element. The amount of residue or build-up of non-vaporized
liquid formulation comprising a pharmaceutically active agent
(e.g., nicotine) can be substantially reduced. Following
vaporization of a liquid formulation as provided herein by a heater
element comprising a coil and a center exit wick element capable of
being heated less than 5% residue of non-vaporized liquid
formulation can remain on the heater element.
[0192] In some cases, a heater element is connected to a timing
device.
[0193] Removal of Particles
[0194] In some cases, an issue with vaporization within the
capillary can arise. First, liquid droplets can be ejected by vapor
pushing the material out. Second, because the high vapor
concentration can be high within the capillary end, rapid
condensation and aggregation leading to larger than optimum
particle size can result. To reduce the particle size of the
aerosol the large particles can be removed and revaporized. Removal
can be accomplished thru inertial impaction (FIG. 11). FIG. 11
shows an agent (e.g., nicotine) reservoir (1104), tube, e.g.,
capillary tube (1106), heater element 1 (1108), and a heater
element 2 (1110). One consideration is whether a restriction in a
nozzle (1102) can cause an unacceptable increase in the air flow
resistance. The following formula can be used to calculate the
diameter of an orifice (D.sub.J) (1112).
d 50 C c = [ 9 .pi. ND J 3 ( Stk 50 ) 4 P p Q ] 1 / 2
##EQU00001##
[0195] Where d.sub.50=is the average aerosol practice size.
[0196] Where:
[0197] N=viscosity (of air)=1.81.times.10.sup.-5 P.sub.a sec
[0198] D.sub.J=The nozzle diameter in meters
[0199] Stk.sub.50=Stokes number for a round nozzle=0.24
(dimensionless)
[0200] P.sub.p=Density of particle, for liquids assumed to be 1000
kg/meter.sup.3
[0201] Q=Flow rate in liters/mixture (assume 15 L/min (about
2.5.times.10.sup.-4 m.sup.3/s))
[0202] Additionally to correct for slip factor the following
equation can be used:
d.sub.50=d.sub.50 {square root over (C.sub.c)}-0.078 in microns
[0203] Using the above, a table of nozzle sizes vs. particle sizes
that will impact can be generated as shown in Table 1:
TABLE-US-00001 TABLE 1 Nozzle Size (mm) Particle Size (.mu.m) 7
6.41 6 5.07 5 3.84 4 2.72
[0204] If a particle size of approximately 5 .mu.m is desired, a
nozzle with a diameter of about 6 mm can be used, which can be
acceptable for a pressure drop at 15 L/min (about
2.5.times.10.sup.-4 m.sup.3/s) flow rate of inhalation.
[0205] In some cases, a device for generating a condensation
aerosol from a liquid formulation comprising a pharmaceutically
active agent (e.g., nicotine) as provided herein comprises a means
for removing aerosol particles of a size not optimal for deep lung
delivery and subsequent rapid PK. The non-optimal particles can
have an MMAD of greater than 5 .mu.m. The means for removing the
non-optimal particles can be a solid structure within a passageway
in which a condensation aerosol generated as provided herein flows.
In some cases, the structure is a planar surface attached to one or
more walls of the passageway, wherein the planar structure
comprises one or more holes wherein particles of specific sizes
(e.g. less than 5 .mu.m) pass through. In some cases, the structure
comprises a planar surface attached to the passageway such that the
planar surface has a diameter or width that occupies a portion of
the diameter or width of the passageway such that only particles of
an optimal size flow or are diverted around the planar surface
while non-optimally sized particles impact the surface and are
incapable of flowing around the surface. In some cases, the
optimally sized particles have an MMAD of less than or equal to 5
.mu.m. In some cases, the optimally sized particles have an MMAD of
about 1 to about 5 .mu.m. In some cases, the optimally sized
particles have an MMAD of greater than 5 .mu.m. The structure can
be a baffle or baffle plate. FIGS. 44 A-C illustrate an embodiment
of a passageway comprising a baffle for removing condensation
aerosol particles whose size is not optimal for deep lung delivery
and subsequent rapid PK. FIGS. 44A and B illustrate exterior views
of the passageway comprising the baffle, while FIG. 44C provides an
interior view of a cone shaped baffle (4402) and its orientation
within a passageway through which a condensation aerosol flows
(4410). In FIG. 44C, a condensation aerosol comprising a
pharmaceutically active agent (e.g., nicotine) generated by any
means as provided herein enters a portion of a passageway
comprising the baffle (4402) through an aerosol inlet (4404). The
aerosol inlet can be a portion of a passageway downstream of a
heater element that narrows following the area of the passageway
that comprises the heater element. The aerosol inlet (4404) serves
to funnel the aerosol through a narrowed passageway prior to the
aerosol encountering the planar surface of the cone-shaped baffle
(4402). Prior to the baffle (4402), the passageway widens, wherein
the diameter of the planar surface of the baffle occupies a
substantial portion of the diameter of the widened passageway. Upon
entry into the widened passageway, the aerosol flows toward the
baffle (4402), wherein large particles (>5 .mu.m) flow into the
planar surface of the baffle, while small particles (.ltoreq.5
.mu.m), flow around the edges of the baffle (4402). As the small
particles flow around the baffle (4402), they flow into a wider
passageway towards the outlet (4406) of the passageway. The widened
passageway downstream of the baffle (4402) entrains the small
particles into additional carrier gas (4408) that enters through
secondary carrier gas (4408) inlets. In some cases, a flow of
carrier gas through the passageway is about 1 to about 10 LPM (a
range from about 1.667.times.10.sup.-5 m.sup.3/s to about
1.667.times.10.sup.-4 m.sup.3/s) (e.g., at a vacuum of about 1 to
about 15 inches of water (a range from about 249 Pa to about 3738
Pa)), while the carrier gas (4408) entering through the secondary
carrier gas (4408) inlets entrains the small particles in an air
flow of about 20 to about 80 LPM (a range from about
3.times.10.sup.-4 m.sup.3/s to about 1.3.times.10.sup.-3
m.sup.3/s). In some cases, the passageway depicted in FIG. 44C is
connected to and downstream of the passageways depicted in any one
of FIGS. 31A-D, wherein the passageway depicted in FIG. 44C is
connected at the aerosol inlet (4404). In some cases, the aerosol
inlet of the passageway depicted in FIG. 44C is a downstream
extension of the passageways depicted in any one of FIGS.
31A-D.
[0206] The inner diameter of the passageway at the aerosol inlet of
FIG. 44C and downstream of the narrow channel can be can be
exactly, about, more than, less than, at least or at most 0.2,
0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.35,
0.4, 0.45, or 0.5 inches (a range from about 0.508 mm to about 12.7
mm). The inner diameter of the passageway at the aerosol inlet of
FIG. 44C and downstream of the narrow channel can be between
0.2-0.21, 0.21-0.22, 0.22-0.23, 0.23-0.24, 0.24-0.25, 0.25-0.26,
0.26-0.27, 0.27-0.28, 0.28-0.29, 0.29-0.3, 0.3-0.35, 0.35-0.4,
0.4-0.45, or 0.45-0.5 inches (a range from about 0.508 mm to about
12.7 mm). The inner diameter of the passageway at the aerosol inlet
of FIG. 44C and downstream of the narrow channel can be about 0.2
to about 0.25, about 0.25 to about 0.3, about 0.3 to about 0.35,
about 0.35 to about 0.4, about 0.4 to about 0.45, or about 0.45 to
about 0.5 inches (a range from about 0.508 mm to about 12.7 mm).
The inner diameter of the outlet (4406) can be exactly, about, more
than, less than, at least or at most 0.2, 0.21, 0.22, 0.23, 0.24,
0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.35, 0.4, 0.45, or 0.5 inches
(a range from about 0.508 mm to about 12.7 mm). The inner diameter
of the outlet (4406) can be between 0.2-0.21, 0.21-0.22, 0.22-0.23,
0.23-0.24, 0.24-0.25, 0.25-0.26, 0.26-0.27, 0.27-0.28, 0.28-0.29,
0.29-0.3, 0.3-0.35, 0.35-0.4, 0.4-0.45, or 0.45-0.5 inches (a range
from about 0.508 mm to about 12.7 mm). The inner diameter of the
outlet (4406) can be about 0.2 to about 0.25, about 0.25 to about
0.3, about 0.3 to about 0.35, about 0.35 to about 0.4, about 0.4 to
about 0.45, or about 0.45 to about 0.5 inches (a range from about
0.508 mm to about 12.7 mm). The inner diameter of the narrow
channel can be exactly, about, more than, less than, at least or at
most 0.01, 0.0125, 0.015, 0.0175, 0.02, 0.0225, 0.025, 0.0275,
0.03, 0.0325, 0.035, 0.0375, 0.04, 0.0425, 0.045, 0.0475, 0.05,
0.0525, 0.055, 0.0575, 0.06, 0.0625, 0.065, 0.0675, 0.07, 0.0725,
0.075, 0.0775, 0.08, 0.0825, 0.085, 0.0875, 0.09, 0.0925, 0.095,
0.0975, 0.1, 0.11, 0.115, 0.12, 0.125, 0.13, 0.135, 0.14, 0.145, or
0.15 inches (a range from about 0.254 mm to about 3.81 mm). The
inner diameter of the narrow channel can be between 0.01-0.015,
0.015-0.02, 0.02-0.025, 0.025-0.03, 0.03-0.035, 0.035-0.04,
0.04-0.045, 0.045-0.05, 0.05-0.055, 0.055-0.06, 0.06-0.065,
0.065-0.07, 0.07-0.075, 0.075-0.08, 0.08-0.085, 0.085-0.09,
0.09-0.095, 0.095-0.1, 0.1-0.12, 0.12-0.13, 0.13-0.14, or 0.14-0.15
inches (a range from about 0.254 mm to about 3.81 mm). The inner
diameter of the narrow channel can be about 0.01 to about 0.015,
about 0.015 to about 0.02, about 0.02 to about 0.025, about 0.025
to about 03, about 0.03 to about 0.035, about 0.035 to about 0.04,
about 0.04 to about 0.045, about 0.045 to about 0.05, about 0.05 to
about 0.055, about 0.055 to about 0.06, about 0.06 to about 0.065,
about 0.065 to about 0.07, about 0.07 to about 0.075, about 0.075
to about 0.08, about 0.08 to about 0.085, about 0.085 to about
0.09, about 0.09 to about 0.095, about 0.095 to about 0.1, or about
0.1 to about 0.15 inches (a range from about 0.254 mm to about 3.81
mm).
[0207] Flow Regulation
[0208] A device provided herein can be configured to limit a flow
of a carrier gas through the passageway or aerosol generation
area/chamber to permit condensation of the vaporized liquid
formulation. The carrier gas can be air. The flow of a carrier gas
through the aerosol generation chamber or passageway comprising or
in fluid communication with the heater element can be limited to
about 1 to about 10 liters per minute (LPM) (a range from about
1.667.times.10.sup.-5 m.sup.3/s to about 1.667.times.10.sup.-4
m.sup.3/s). The device can be configured to comprise a flow
resistance (to inhalation) of about 0.05 to about 0.15 sqrt
(cm-H.sub.2O)/LPM. The device can be configured to comprise an
inhalation resistance comprising a vacuum pressure of about 1 to
about 10 inches of H.sub.2O (a range from about 249 Pa to about
2488 Pa).
[0209] Methods are provided herein for sensing an inhalation by a
user and triggering a device. For example, an optical sensor that
uses a deformable member (e.g., a vane) that moves during
inhalation can be used to either open or close an optical path. In
some embodiments, a Hall effect sensor is used to measure
inhalation. In one embodiment, inhalation sensing is accomplished
using an optical signal wherein a unique pattern of light pulses is
sent along an optical path or light pipe and resent back along the
optical path to a light detector. In one embodiment, the optical
signal is sent from a controller into a dose cartridge whereby it
is resent back into the controller to a light detector. In one
embodiment, a vane is positioned in the path of an airway such that
when an inhalation occurs, the vane is deflected out of the way and
interrupts the optical signal. In this case, the device notes the
absence of the optical signal and triggers the creation of an
aerosol.
[0210] Methods are provided herein for inhalation flow control. In
some cases, a valve system to allow for a user to experience an
initial high pressure and low flow rates, followed by low pressure
is used. An initial high-pressure drop through the device to
facilitate the ejection of an agent (e.g., nicotine) from a dosing
mechanism can be used. The following high flow rate can facilitate
deep lung delivery. In one embodiment, a slide valve with an
attached piston mechanism is used to eject an agent (e.g.,
nicotine) from a dosing reservoir. In one embodiment, air flow over
a vaporizing agent (e.g., nicotine) formulation is regulated and
controlled to an optimum level using a valve system, resulting in
optimum particle sizing and dosing effectiveness. In a one
embodiment, a valve system is used to create an internal air or
inhalation resistance that is low (e.g., 0.08 to 0.12 (cm
H.sub.2O).sup.1/2/LPM).
[0211] In some cases, a device for generating a condensation
aerosol as provided herein can comprise a heater element. In some
cases, a device provided herein can comprise a passageway, wherein
the passageway comprises a heater element and a reservoir. In some
cases, the device comprises a passageway, a reservoir, and a
housing which comprises a heater element, wherein the passageway is
in fluid communication with the heater element. The passageway
comprising the heater element or in fluid communication with the
heater element can comprise an aerosol generation area or chamber.
In some cases, the aerosol generation area or chamber comprises the
heater element. In some cases, the aerosol generation area or
chamber comprises the heater element and a source of a formulation
comprising an agent as provided herein. The source can be a tube,
e.g., capillary tube, or a reservoir. The tube, e.g., capillary
tube can be coupled to the reservoir. The reservoir can comprise
the liquid formulation. The reservoir can be in fluid communication
with the heater element. The reservoir can serve to deliver the
liquid formulation to the heater element, wherein the liquid
formulation can wick onto the heater element. The reservoir can
comprise a tube, e.g., capillary tube, wherein the tube, e.g.,
capillary tube can deliver the liquid formulation onto the heater
element.
[0212] In some cases, a device for generating a condensation
aerosol as provided herein comprises an aerosol generation chamber.
The aerosol generation chamber can comprise a heater element. The
aerosol generation chamber can comprise a source of a liquid
formulation comprising a pharmaceutically active agent (e.g.
nicotine). In some cases, the aerosol generation chamber comprises
a heater element and a source of a liquid formulation comprising a
pharmaceutically active agent (e.g. nicotine). The aerosol
generation chamber can be within a primary flow-through passageway.
In some cases, a device for producing a condensation aerosol as
provided herein comprises a flow-through passageway, wherein the
flow-through passageway comprises an upstream opening and a
downstream opening, wherein the flow-through passageway comprises
an aerosol generation chamber between the upstream and downstream
openings of the flow-through passageway. The passageway can be a
primary flow-through passageway. The primary flow-through
passageway can be in fluid communication with a secondary
flow-through passageway as provided herein. In some cases, the
aerosol generation chamber further comprises a nozzle as provided
herein. In some cases, a device for generating a condensation
aerosol as provided herein comprises an aerosol generation chamber,
wherein the aerosol generation chamber is within a passageway
configured to limit the flow of a carrier gas through the aerosol
generation chamber to a flow rate effective for producing a
condensation aerosol comprising particles of a size suitable for
delivery to the deep lung of a subject. The flow rate can be
limited to about 1 to about 10 liters per minute (LPM) (a range
from about 1.667.times.10.sup.-5 m.sup.3/s to about
1.667.times.10.sup.-4 m.sup.3/s) at, e.g., a vacuum of about 1 to
about 15 inches of water (a range from about 249 Pa to about 3738
Pa).
[0213] In some cases, a device for producing a condensation aerosol
as provided herein comprises a primary flow-through passageway,
wherein the primary flow-through passageway comprises an upstream
opening and a downstream opening, wherein the upstream opening
comprises an inlet for a carrier gas (e.g., air) and the downstream
opening comprises an outlet for the carrier gas (e.g., air). The
passageway can be a primary flow-through passageway. The primary
flow-through passageway can be in fluid communication with a
secondary flow-through passageway as provided herein. The inlet can
comprise a flow restrictor configured to limit the flow of the
carrier gas through primary flow-through passageway to a flow rate
effective for producing a condensation aerosol comprising particles
of a size suitable for delivery to the deep lung of a subject. The
flow restrictor can limit the flow rate to about 1 to about 10
liters per minute (LPM) (a range from about 1.667.times.10.sup.-5
m.sup.3/s to about 1.667.times.10.sup.-4 m.sup.3/s), e.g., at a
vacuum of about 1 to about 15 inches of water (a range from about
249 Pa to about 3738 Pa). The flow restrictor can be a valve or an
orifice comprising dimensions that limit the flow of a carrier gas
(e.g., air) to a rate suitable for producing a condensation aerosol
comprising particles of a size suitable for delivery to the deep
lung of a subject.
[0214] An orifice for air that passes over the heater element can
have a diameter of about, more than, less than, or at least 0.01,
0.012, 0.015, 0.02, 0.022, 0.025, 0.03, 0.032, 0.035, 0.04, 0.042,
0.045, 0.05, 0.052, 0.055, 0.06, 0.062, 0.065, 0.07, 0.075, 0.08,
0.085, 0.09, 0.1, 0.105, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17,
0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28,
0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39,
0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5,
0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.6, 0.61,
0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72,
0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, or 0.8 inches (a range
from about 0.254 mm to about 20.32 mm). In some cases, an orifice
for air that passes over a heater element has a diameter of about
0.01 to about 0.12 inches, about 0.02 to about 0.1 inches, about
0.03 to about 0.09 inches, about 0.04 to about 0.08 inches, or
about 0.05 to about 0.07 inches, or about 0.15 to about 3 inches (a
range from about 0.254 mm to about 76.2 mm). An orifice for bypass
air (air that is routed around a heater element) can have a
diameter of about, more than, less than, or at least 0.02, 0.04,
0.06, 0.08, 0.1, 0.12, 0.14, 0.16, 0.18, 0.2, 0.22, 0.24, 0.26,
0.28, 0.3, 0.32, 0.34, 0.36, 0.38, 0.4, 0.42, 0.44, 0.46, 0.48,
0.5, 0.52, 0.54, 0.56, 0.58, 0.6, 0.62, 0.64, 0.66, 0.68, 0.7, 0.8,
0.9, 1, or 1.2 inches (a range from about 0.508 mm to about 30.48
mm). In some cases, an orifice for bypass air (air that is routed
around a heater element) has a diameter of about 0.05 to about 0.4
inches, about 0.1 to about 0.3 inches, or about 0.1 to about 0.4
inches (a range from about 1.27 mm to about 10.16 mm).
[0215] In some cases, a device for producing a condensation aerosol
as provided herein comprises a flow-through passageway, wherein the
flow-through passageway comprises an upstream opening and a
downstream opening, wherein the flow-through passageway is
configured to facilitate formation of a condensation aerosol
comprising particles of a size effective for delivery to the deep
lung of a subject. The particles can comprise an MMAD of about 1 to
about 5 .mu.m. The subject can be a human. The subject can be a
human who smokes and/or uses tobacco or nicotine containing
products. The condensation aerosol can comprise a pharmaceutically
active agent (e.g. nicotine). The passageway can be a primary
flow-through passageway. The primary flow-through passageway can be
in fluid communication with a secondary flow-through passageway as
provided herein. The upstream opening can be an inlet. The inlet
can comprise a flow restrictor as provided herein. The downstream
opening can comprise an outlet. The outlet can be a mouthpiece.
[0216] The flow-through passageway can be configured to form a
narrow channel between the upstream and downstream openings. The
passageway can be further configured to widen downstream of the
narrow channel prior to the downstream opening of the passageway.
The narrow channel can comprise an inner diameter and an outer
diameter (see, e.g., FIGS. 32 and 33). The inner diameter of the
narrow channel can be exactly, about, more than, less than, at
least or at most 0.01, 0.0125, 0.015, 0.0175, 0.02, 0.0225, 0.025,
0.0275, 0.03, 0.0325, 0.035, 0.0375, 0.04, 0.0425, 0.045, 0.0475,
0.05, 0.0525, 0.055, 0.0575, 0.06, 0.0625, 0.065, 0.0675, 0.07,
0.0725, 0.075, 0.0775, 0.08, 0.0825, 0.085, 0.0875, 0.09, 0.0925,
0.095, 0.0975, 0.1, 0.11, 0.115, 0.12, 0.125, 0.13, 0.135, 0.14,
0.145, or 0.15 inches (a range from about 0.254 mm to about 3.81
mm). The inner diameter of the narrow channel can be between
0.01-0.015, 0.015-0.02, 0.02-0.025, 0.025-0.03, 0.03-0.035,
0.035-0.04, 0.04-0.045, 0.045-0.05, 0.05-0.055, 0.055-0.06,
0.06-0.065, 0.065-0.07, 0.07-0.075, 0.075-0.08, 0.08-0.085,
0.085-0.09, 0.09-0.095, 0.095-0.1, 0.1-0.12, 0.12-0.13, 0.13-0.14,
or 0.14-0.15 inches (a range from about 0.254 mm to about 3.81 mm).
The inner diameter of the narrow channel can be about 0.01 to about
0.015, about 0.015 to about 0.02, about 0.02 to about 0.025, about
0.025 to about 03, about 0.03 to about 0.035, about 0.035 to about
0.04, about 0.04 to about 0.045, about 0.045 to about 0.05, about
0.05 to about 0.055, about 0.055 to about 0.06, about 0.06 to about
0.065, about 0.065 to about 0.07, about 0.07 to about 0.075, about
0.075 to about 0.08, about 0.08 to about 0.085, about 0.085 to
about 0.09, about 0.09 to about 0.095, about 0.095 to about 0.1, or
about 0.1 to about 0.15 inches (a range from about 0.254 mm to
about 3.81 mm). The outer diameter of the narrow channel can be
exactly, about, more than, less than, at least or at most 0.08,
0.0825, 0.085, 0.0875, 0.09, 0.0925, 0.095, 0.0975, 0.1, 0.11,
0.115, 0.12, 0.125, 0.13, 0.135, 0.14, 0.145, or 0.15 inches (a
range from about 2.0 mm to about 3.81 mm). The outer diameter of
the narrow channel can be between 0.08-0.085, 0.085-0.09,
0.09-0.095, 0.095-0.1, 0.1-0.12, 0.12-0.13, 0.13-0.14, or 0.14-0.15
inches (a range from about 2.0 mm to about 3.81 mm). The outer
diameter of the narrow channel can be about 0.08 to about 0.085,
about 0.085 to about 0.09, about 0.09 to about 0.095, about 0.095
to about 0.1, or about 0.1 to about 0.15 inches (a range from about
2.0 mm to about 3.81 mm). The inner diameter of the flow-through
passageway prior to and/or downstream of the narrow channel can be
exactly, about, more than, less than, at least or at most 0.2,
0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.35,
0.4, 0.45, or 0.5 inches (a range from about 5.08 mm to about 12.7
mm). The inner diameter of the flow-through passageway prior to
and/or downstream of the narrow channel can be between 0.2-0.21,
0.21-0.22, 0.22-0.23, 0.23-0.24, 0.24-0.25, 0.25-0.26, 0.26-0.27,
0.27-0.28, 0.28-0.29, 0.29-0.3, 0.3-0.35, 0.35-0.4, 0.4-0.45, or
0.45-0.5 inches (a range from about 5.08 mm to about 12.7 mm). The
inner diameter of the flow-through passageway prior to and/or
downstream of the narrow channel can be about 0.2 to about 0.25,
about 0.25 to about 0.3, about 0.3 to about 0.35, about 0.35 to
about 0.4, about 0.4 to about 0.45, or about 0.45 to about 0.5
inches (a range from about 5.08 mm to about 12.7 mm).
[0217] In some cases, a device for generating a condensation
aerosol comprising a primary flow-through passageway as provided
herein further comprises a secondary flow-through passageway. The
secondary flow-through passageway can be in fluid communication
with the primary flow through passageway. The secondary
flow-through passageway can comprise one or more channels. In some
cases, the secondary flow-through channel comprises a first, a
second, and a third channel. The first channel can be in fluid
communication with a primary flow-through chamber upstream of an
aerosol generation chamber as provided herein. The second channel
can be in fluid communication with a primary flow through
passageway between an aerosol generation chamber as provided herein
and a downstream opening of the primary flow through passageway.
The third channel can comprise a second inlet for a carrier gas
(e.g. air) and can be in fluid communication with the second
channel. The secondary flow-through passageway can also comprise an
articuable element. The articuable element can be a diaphragm. The
articuable element can be further connected to springs. The springs
can control the movement of the articuable element. The articuable
element can be articulated by changes in pressure within the
device. The pressure that articulates the articuable element can be
inhalation resistance or vacuum pressure. The inhalation resistance
can be a vacuum of about 1 to about 10 inches of H.sub.2O (a range
from about 249 Pa to about 2488 Pa). An increase in pressure can
compress the springs. Inhalation through a device for generating a
condensation aerosol as provided herein can increase the pressure
in the device. The articuable element can comprise a protruding
member. In some cases, one or more springs are located on a first
side of an articuable element, while the protruding member is
located on a second side opposite the first side. The protruding
member can be configured to enter and block the third channel. A
pressure differential between primary and secondary flow-through
passageways within the device can cause articulation or movement of
the articuable element. The pressure differential can be affected
by inhalation through the downstream opening of the primary flow
chamber. The pressure differential can be across the first channel
of the secondary flow chamber. Under conditions of low pressure or
inhalation resistance, the articuable element can block the third
channel, thereby preventing entry of the carrier gas (e.g. air).
Under conditions of increased pressure or inhalation resistance,
the articuable element can be articulated or removed from blocking
the third channel, thereby allowing the carrier gas to enter the
device. In some cases, inhalation through the downstream opening of
the primary flow-through passageway serves to articulate the
articuable element, whereby the articulation serves to open the
third channel, wherein the opening permits the carrier gas (e.g.
air) to flow through the third channel of the secondary
flow-through passageway and enter the primary flow through
passageway through the second channel in the secondary flow-through
passageway, thereby entraining the condensation aerosol in the
carrier gas from the secondary flow-through passageway. Additional
carrier gas entering the primary flow-through passageway through
the secondary flow-through passageway as described herein can
entrain the condensation aerosol in the carrier gas (e.g. air) to
produce a total flow rate of about 20 to about 80 LPM (a range from
about 3.times.10.sup.-4 m.sup.3/s to about 1.3.times.10.sup.-3
m.sup.3/s). The device can have an interior air resistance (to
inhalation) no greater than that of a cigarette. The device can
have an interior air resistance (to inhalation) of about 0.05 to
about 0.15 (cm H.sub.2O).sup.1/2/LPM.
[0218] A device for generating condensation aerosols comprising a
primary flow-through passageway as provided herein can further
comprise one or more additional sources of carrier gas, wherein the
additional sources permit the flow of carrier gas to enter the
device in addition to the carrier gas flowing through the primary
flow-through passageway. The one or more additional sources can be
inlets or channels. The one or more additional sources can be
bypass inlets or bypass channels, wherein carrier gas entering a
device through the bypass inlets or channels is bypass carrier gas.
The bypass carrier gas can be air. The one or more sources can be
within one or more walls of the primary flow-through passageway.
The one or more sources can be components of a secondary
flow-through passageway as provided herein, wherein the secondary
flow-through passageway can be in fluid communication with the
primary flow-through passageway. The one or more sources can be
within one or more walls of the secondary flow-through passageway.
The one or more sources can be within one or more walls of a
housing, wherein the housing surrounds or encompasses the primary
flow-through passageway. The one or more sources can be flow
regulators. The carrier gas entering the device through the one or
more sources can be the same type or a different type of carrier
gas as that flowing through a primary flow-through passageway. In
some cases, the carrier gas entering through the one or more
sources can be air. In some cases, the one or more sources permit
flow of carrier gas to enter the device downstream of a heater
element or aerosol generation chamber or area as provided herein.
The flow of carrier gas entering the device through the one or more
sources can mix with the carrier gas flowing through a primary flow
through passageway. The mixing can be downstream of a heater
element or aerosol generation chamber as provided herein but before
a downstream opening or outlet of a primary passageway comprising
the heater element or aerosol generation chamber. The mixing of the
carrier gases can produce a total flow rate exiting the device that
can be similar to normal breathing of a subject. The total flow
rate can be about 20 to about 80 LPM (a range from about
3.times.10.sup.-4 m.sup.3/s to about 1.3.times.10.sup.-3
m.sup.3/s). The subject can be a human. The subject can be a human
who smokes and/or uses tobacco or nicotine containing products.
[0219] FIG. 21 illustrates an embodiment of an electronic agent
(e.g., nicotine) delivery device comprising a valve system (2100)
for controlling air flow for deep lung delivery and rapid PK. Upon
inhalation, negative pressure in a mouthpiece (2102) increases
causing a pressure drop across a gas control valve (2104). An
increase in the pressure drop can cause the valve (2104) to close
and prevent airflow (2106) into an aerosol generating area (2108)
within a flow through chamber (2110). The aerosol generating area
(2108) can comprise an agent (e.g., nicotine) reservoir comprising
an agent (e.g., nicotine) formulation, any of the dosing mechanisms
described herein, and a heater for vaporizing an agent (e.g.,
nicotine) droplets that can be released from the dosing mechanism.
Closing of the valve (2104) can subsequently cause an increase in
airflow (2106) from an air inlet (2112) across a backflow valve
(2114) through a diversion air orifice (2116) and into a diversion
air channel (2118). In this manner, the airflow over a vaporizing
agent (e.g., nicotine) formulation can be regulated and controlled
to an optimal level in order to achieve optimum particle sizing and
dosing effectiveness. In one embodiment, the valve system produces
an inhalation resistance no greater than that of a cigarette. In
one embodiment, the valve system produces an inhalation resistance
no greater than 0.08 (cm H.sub.2O).sup.1/2/LPM.
[0220] FIG. 32 A-E illustrates multiple embodiments of a device for
regulating the flow of a carrier gas (e.g. air). In each
embodiment, the device comprises a primary flow-through passageway
(3202A-E) and one or more sources of bypass or additional carrier
gas (3204A-E). In each embodiment, the one or more sources of
bypass or additional carrier gas (3204A-E) permit an additional or
bypass flow of carrier gas (e.g. air) to mix with the carrier gas
flowing through the primary flow-through passageway (3202A-E). In
some cases, the mixing occurs downstream of an aerosol generation
chamber, thereby mixing a condensation aerosol produced in the
aerosol generation chamber with a larger volume of carrier gas
(e.g. air). The mixing can produce a total flow rate downstream of
the mixing of about 20 to about 80 liters per minute (LPM) (a range
from about 3.times.10.sup.-4 m.sup.3/s to about 1.3.times.10.sup.-3
m.sup.3/s). FIG. 32A shows a device comprising a primary
flow-through passageway (3202a) comprising an upstream and
downstream section comprising an inner diameter of 0.25 inches
(about 6.35 mm), and two secondary flow-through chambers (3204a),
wherein bypass or additional carrier gas enters the device through
two inlets (3206a) adjacent to the primary flow-through chamber
(3202a). The inner diameter of the primary flow through chamber
(3202a) narrows just prior to entry of the bypass carrier gas. In
some cases, the narrowing of the primary flow-through passageway
permits formation of condensation aerosol particles comprising
particles with an MMAD of about 1 to about 5 uM. The device in FIG.
32A can permit the mixing of the bypass carrier gas with the
carrier gas flow through the primary chamber at a ratio of
10:1.
[0221] FIG. 32B shows a device comprising a primary flow-through
passageway (3202b) comprising an upstream and downstream section
comprising an inner diameter of 0.25 inches (about 6.35 mm), and
two inlets (3204b) within the wall of the primary flow-through
chamber (3202b), wherein bypass or additional carrier gas enters
the device. The primary flow through chamber (3202b) narrows just
prior to entry of the bypass carrier gas to comprise an inner
diameter of 0.084 inches (about 2.13 mm) and an outer diameter of
0.108 inches (about 2.74 mm). In some cases, the narrowing of the
primary flow-through passageway (3202b) permits formation of
condensation aerosol particles comprising particles with an MMAD of
about 1 to about 5 um. The device in FIG. 32B can permit the mixing
of the bypass carrier gas with the carrier gas flow through the
primary chamber at a ratio of 7:1.
[0222] FIG. 32C shows a device comprising a primary flow-through
passageway (3202c) comprising an upstream and downstream section
comprising an inner diameter of 0.5 inches (about 12.7 mm), and two
inlets (3204c) within the wall of the primary flow-through chamber
(3202c), wherein bypass or additional carrier gas enters the
device. The primary flow through chamber (3202c) narrows just prior
to entry of the bypass carrier gas to comprise an inner diameter of
0.084 inches (about 2.13 mm) and an outer diameter of 0.108 inches
(about 2.74 mm). In some cases, the narrowing of the primary
flow-through passageway (3202c) permits formation of condensation
aerosol particles comprising particles with an MMAD of about 1 to
about 5 .mu.m. The device in FIG. 32C can permit the mixing of the
bypass carrier gas with the carrier gas flow through the primary
chamber at a ratio of 28:1.
[0223] FIG. 32D shows a device comprising a primary flow-through
passageway (3202d) comprising an upstream and downstream section
comprising an inner diameter of 0.25 inches (about 6.35 mm), and
two sets of two inlets (3204d) adjacent to the primary flow-through
chamber (3202d), wherein bypass or additional carrier gas enters
the device. The flow through chamber narrows just prior to entry of
the bypass carrier gas from each set of two inlets to comprise an
inner diameter of 0.096 inches (about 2.44 mm) and an outer
diameter of 0.125 inches (about 3.175 mm). Following the first set
of two inlets, the primary flow through passageway widens to an
inner diameter of 0.250 inches (about 6.35 mm), before narrowing
again. In some cases, the narrowing of the primary flow-through
passageway permits formation of condensation aerosol particles
comprising particles with an MMAD of about 1 to about 5 .mu.m. The
device in FIG. 32D can permit the mixing of the bypass carrier gas
with the carrier gas flow through the primary chamber at a ratio of
35:1.
[0224] The device in FIG. 32E is similar to the device in FIG. 32D,
wherein FIG. 32E shows a device comprising a primary flow-through
passageway (3202e) comprising an upstream and downstream section
comprising an inner diameter of 0.250 inches (about 6.35 mm), and
two sets of two inlets (3204e) adjacent to the primary flow-through
chamber (3202e), wherein bypass or additional carrier gas enters
the device. The primary flow through chamber (3202e) narrows just
prior to entry of the bypass carrier gas from the first set of two
inlets to comprise an inner diameter of 0.096 inches (about 2.44
mm) and an outer diameter of 0.125 inches (about 3.175 mm).
Following the first set of two inlets, the primary flow through
passageway (3202e) widens to an inner diameter of 0.250 inches
(about 6.35 mm) and an out diameter of 0.280 inches (about 7.112
mm). Subsequently, the primary flow-through passageway (3202e)
opens into a secondary housing (3206e), which has an inner diameter
of 0.466 inches (about 11.8 mm) In FIG. 32E, the second pair of
inlets (3204e) are located in the wall of a secondary housing
(3206e), which is coupled to and encompasses the primary
flow-through passageway.
[0225] FIG. 33 illustrates another embodiment of a device for
regulating the flow of a carrier gas (e.g. air). FIG. 33 shows a
device comprising a primary flow-through passageway (3302)
comprising an upstream and downstream section comprising an inner
diameter of 0.25 inches (about 6.35 mm), and two inlets (3306)
within the wall of the primary flow-through chamber (3302), wherein
bypass or additional carrier gas enters the device. The primary
flow-through chamber narrows (3302) just prior to entry of the
bypass carrier gas to comprise an inner diameter of 0.086 inches
(about 2.18 mm) and an outer diameter of 0.106 inches (about 2.69
mm). As depicted in FIG. 33, the section of the primary
flow-through chamber (3302) is coupled to and encased by a
secondary housing (3308). The secondary housing comprises a bypass
inlet (3304), which permits entry of bypass or additional carrier
gas (e.g. air) to enter the primary flow-through passageway through
the inlets (3306). In some cases, the narrowing of the primary
flow-through passageway permits formation of condensation aerosol
particles comprising particles with an MMAD of about 1 to about 5
.mu.m.
[0226] FIG. 35 illustrates another embodiment a device for
regulating the flow of a carrier gas (e.g. air). The device
comprises a primary airway (3504) that comprises an aerosol
generation chamber (3528) comprising a heater element (3502), a
restrictive orifice (3514) and a mouthpiece (3506). The heater
element (3502) comprises a coil. The heater element can be any
heater element comprising a coil as provided herein. The primary
airway (3504) is fluidically connected to a secondary airway
(3516), through a first channel (3518) located (disposed) between
the restrictive orifice (3514) and heater element (3502), and a
second channel (3520) located (disposed) between the heater element
(3502) and the mouthpiece (3506). The secondary airway (3516)
further comprises a third channel (3530) that is a secondary inlet
(3508) for a carrier gas (e.g. air) and a diaphragm (3510). The
diaphragm (3510) comprises a base member that is connected to a
pair of springs (3512) on a first side and a protruding member
(3524) on a second side. The springs (3512) are additionally
connected to a wall opposite the first side of the base member that
is part of the housing of the secondary airway (3516). The base
member of the diaphragm (3510) is also connected to a pair of
lateral springs (3526) on its lateral edges, which are further
connected to the walls of the housing of the secondary airway
(3516) opposite the lateral edges of the base member. The
restrictive orifice (3514) is configured to limit the flow rate of
the carrier gas (e.g. air) through the aerosol generation chamber
(3528) in order to allow for the condensation of a liquid
formulation comprising a pharmaceutically active agent as provided
herein vaporized by the heater element (3502) to particles
comprising about 1 to about 5 um MMAD. The restrictive orifice
(3514) limits the flow rate of the carrier gas (i.e. air) about 1
to about 10 liters per minute (LPM) (a range from about
1.667.times.10.sup.-5 m.sup.3/s to about 1.667.times.10.sup.-4
m.sup.3/s) at, e.g., a vacuum of about 1 to about 15 inches of
water (a range from about 249 Pa to about 3738 Pa). Inhalation
through the mouthpiece (3506) can produce a flow of carrier gas
(e.g. air) through the restrictive orifice (3514) that can produce
an inhalation resistance. The inhalation resistance produces a
pressure differential across the opening of the first channel
(3518) connecting the primary airway (3504) with the secondary
airway (3516). The inhalation resistance causes the springs (3512)
coupled to the first side of the diaphragm (3510) to compress and
the lateral springs (3526) coupled to the lateral edges of the
diaphragm (3510) to extend, whereby the protruding member of
coupled to the second side of the diaphragm (3510) is removed from
the third channel (3530) of the secondary airway (3516). Removal of
the protruding member (3524) causes an additional flow of carrier
gas (e.g. air) to enter the device. The additional flow of carrier
gas (e.g. air) then enters the primary airway (3504) downstream of
the heater element (3502) and aerosol generation area (3528)
through the second channel (3520). The additional flow of carrier
gas (e.g. air) can serve to mix or entrain the condensation aerosol
comprising particles of about 1 to about 5 .mu.m to produce a total
flow rate suitable for delivery of the particles to the deep lung
of a user of the device.
[0227] A device for producing a condensation aerosol as provided
herein can have an interior air resistance (to inhalation) no
greater than 0.08 (cm H.sub.2O).sup.1/2/LPM. The device can have an
interior air resistance (to inhalation) exactly, about, more than,
less than, at least, or at most 0.01, 0.02, 0.03, 0.04, 0.05, 0.06,
0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17,
0.18, 0.19, 0.20, or 0.25 (cm H.sub.2O).sup.1/2/LPM. The device can
have an interior air resistance (to inhalation) between 0.01-0.02,
0.02-0.03, 0.03-0.04, 0.04-0.05, 0.05-0.06, 0.06-0.07, 0.07-0.08,
0.08-0.09, 0.09-0.10, 0.1-0.11, 0.11-0.12, 0.12-0.13, 0.13-0.14,
0.14-0.15, 0.15-0.16, 0.16-0.17, 0.17-0.18, 0.18-0.19, 0.19-0.20,
or 0.20-0.25 (cm H.sub.2O).sup.1/2/LPM. The device can have an
interior air resistance (to inhalation) of about 0.01 to about
0.03, about 0.03 to about 0.05, about 0.05 to about 0.07, about
0.07 to about 0.09, about 0.09 to about 0.11, about 0.11 to about
0.13, about 0.13 to about 0.15, about 0.15 to about 0.17, about
0.17 to about 0.19, or about 0.19 to about 0.25 (cm
H.sub.2O).sup.1/2/LPM.
[0228] A device for producing a condensation aerosol as provided
herein can produce a total flow rate of a carrier gas (e.g. air) of
exactly, about, more than, less than, at least, or at most 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,
22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,
39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,
56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,
73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,
90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 liters per min (LPM)
(a range from about 1.667.times.10.sup.-5 m.sup.3/s to about
1.667.times.10.sup.-3 m.sup.3/s). The total flow rate can be
between 1-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80,
80-90, or 90-100 LPM (a range from about 1.667.times.10.sup.-5
m.sup.3/s to about 1.667.times.10.sup.-3 m.sup.3/s). The total flow
rate can be about 1 to about 10, about 10 to about 20, about 20 to
about 30, about 30 to about 40, about 40 to about 50, about 50 to
about 60, about 60 to about 70, about 70 to about 80, about 80 to
about 90, or about 90 to about 100 LPM (a range from about
1.667.times.10.sup.-5 m.sup.3/s to about 1.667.times.10.sup.-3
m.sup.3/s). The device can comprise a primary flow-through
passageway for a carrier gas and one or more sources of additional
or bypass carrier gas as provided herein. These flow rates can be
at a vacuum of about 1 to about 15 inches of water (a range from
about 249 Pa to about 3738 Pa).
[0229] The one or more sources of additional or bypass carrier gas
(e.g. air) can be configured to limit the flow rate of additional
or bypass carrier gas to produce a total flow rate as provided
herein. The flow rate can be limited by using a restrictive orifice
on the one or more sources of additional or bypass carrier gas
(e.g. air). The restrictive orifice can comprise any valve or flap
as known in the art. The valve or flap can be moderated at specific
flow rates. The flow rates that moderate the valve or flap can be
the limited to flow rates provided herein. The valve or flap can be
opened at specific inhalation resistance levels. The restrictive
orifice can be opened at inhalation resistances comprising a vacuum
of about 1 to about 10 inches of water (a range from about 249 Pa
to about 2488 Pa).
[0230] A device for producing a condensation aerosol as provided
herein can be configured to limit the flow rate of a carrier gas
across or through a aerosol generation area or heater element as
provided herein to a flow rate of exactly, about, more than, less
than, at least, or at most 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5,
6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13,
13.5, 14, 14.5, 15, 15.5, or 16 liters per minute (LPM) (a range
from about 1.667.times.10.sup.-5 m.sup.3/s to about
2.667.times.10.sup.-4 m.sup.3/s). A device for producing a
condensation aerosol as provided herein can be configured to limit
the flow rate of a carrier gas across or through a aerosol
generation area or heater element to between 1-2, 2-4, 4-6, 6-8,
8-10, 10-12, 12-14, or 14-16 LPM a range from (about
1.667.times.10.sup.-5 m.sup.3/s to about 2.667.times.10.sup.-4
m.sup.3/s). A device for producing a condensation aerosol as
provided herein can be configured to limit the flow rate of a
carrier gas across or through a aerosol generation area or heater
element to about 1 to about 2, about 2 to about 4, about 4 to about
6, about 6 to about 8, about 8 to about 10, about 10 to about 12,
about 12 to about 14, or about 14 to about 16 LPM (a range from
about 1.667.times.10.sup.-5 m.sup.3/s to about
2.667.times.10.sup.-4 m.sup.3/s). The flow rate can be limited by
using a restrictive orifice on the inlet for a carrier gas (e.g.
air). The restrictive orifice can comprise any valve or flap as
known in the art. The valve or flap can be moderated at specific
flow rates. The flow rates that moderate the valve or flap can be
the limited flow rates provided herein. The valve or flap can be
opened at specific inhalation resistance levels. The restrictive
orifice can be opened at inhalation resistances comprising a vacuum
of about 1 to about 10 inches of water (a range from about 249 Pa
to about 2488 Pa). The restrictive orifice can be configured to
limit the flow rates to flow rates as provided herein. The
restrictive orifice can be configured into a slot as depicted in
FIG. 30B. An aerosol generation area or heater element as provided
herein can be within a flow-through passageway. The flow-through
passageway can be a primary flow through passageway.
[0231] A device for producing a condensation aerosol comprising a
primary flow-through passageway and one or more sources of
additional or bypass carrier gas (e.g. air) as provided herein can
produce a mixing ratio of bypass or additional carrier gas to
carrier gas flowing through the primary flow through chamber of
1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1,
13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1,
24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1,
35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1,
46:1, 47:1, 48:1, 49:1, or 50:1. The mixing ratio can be between
1:1 and 5:1, 5:1 and 10:1, 10:1 and 15:1, 15:1 and 20:1; 20:1 and
25:1, 25:1, and 30:1, 30:1, and 35:1, 35:1 and 40:1, 40:1 and 45:1,
or 45:1 and 50:1. The mixing ratio can be about 1:1 to about 5:1,
about 5:1 to about 10:1, about 10:1 to about 15:1, about 15:1 to
about 20:1; about 20:1 to about 25:1, about 25:1 to about 30:1,
about 30:1 to about 35:1, about 35:1 to about 40:1, about 40:1 to
about 45:1, or about 45:1 to about 50:1.
[0232] Device Dimensions
[0233] In some cases, an electronic agent (e.g., nicotine) delivery
device comprises the dimensions of an electronic cigarette. The
electronic agent (e.g., nicotine) delivery device can have an
overall cylindrical shape. The electronic agent (e.g., nicotine)
delivery device can resemble a combustible cigarette. An electronic
agent (e.g., nicotine) delivery device as provided herein can have
an outer diameter of about, more than, less than, or at least
0.001, 0.0015, 0.002, 0.0025, 0.003, 0.0035, 0.004, 0.0045, 0.005,
0.0055, 0.006, 0.0065, 0.007, 0.0075, 0.008, 0.0085, 0.009, 0.0095,
0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045, 0.05, 0.055,
0.06, 0.065, 0.07, 0.075, 0.08, 0.085, 0.09, 0.095, 0.1, 0.11,
0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22,
0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33,
0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44,
0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.54, 0.55,
0.56, 0.57, 0.58, 0.59, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66,
0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77,
0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88,
0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24, 25, 2627, 28, 29, or 30 cm. An electronic agent
(e.g., nicotine) delivery device as provided herein can have an
outer diameter of about 0.5 cm to about 1 cm, about 0.25 cm to
about 0.75 cm, about 0.25 cm to about 1 cm, or about 0.25 cm to
about 1.5 cm.
[0234] An electronic agent (e.g., nicotine) delivery device as
provided herein can have a length of about, more than, less than,
or at least 20, 21, 22, 23, 24, 25, 26 27, 28, 29, 30, 31, 32, 33,
34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,
51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,
68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84,
85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100,
101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113,
114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126,
127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139,
140, 141, 142, 143, 144, 145, 146, 147, 148, 149, or 150 mm. An
electronic agent (e.g., nicotine) delivery device as provided
herein can have a length of about 25 mm to about 75 mm, about 75 mm
to about 125 mm, about 125 mm to about 150 mm, or about 75 mm to
about 150 mm
[0235] An electronic agent (e.g., nicotine) delivery device as
provided herein can have a transverse dimension of about, more
than, less than, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 27, 28, 29,
30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 mm.
[0236] Agents
[0237] Any suitable agent (e.g., drug) can be used in the methods
and devices described herein. Agents (e.g., pharmaceutically active
agents) that can be used include, for example, drugs of one of the
following classes: anesthetics, antibiotic, anticonvulsants,
antidepressants, antidiabetic agents, antidotes, antiemetics,
antihistamines, anti-infective agents, antineoplastics,
antiparkisonian drugs, antirheumatic agents, antipsychotics,
anxiolytics, appetite stimulants and suppressants, blood modifiers,
cardiovascular agents, central nervous system stimulants, drugs for
Alzheimer's disease management, a cold medication, COPD (chronic
obstructive pulmonary disease) drug, cough medication, 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, drugs for treating
myocardial infarction, nonsteroidal anti-inflammatories, opioids,
other analgesics and stimulants, opthalmic preparations,
osteoporosis preparations, pain medication, panic medication,
prostaglandins, respiratory agents, sedatives and hypnotics, skin
and mucous membrane agents, smoking cessation aids, Tourette's
syndrome agents, urinary tract agents, insomnia medication, weight
loss drug, and vertigo agents. In some cases, an agent is an herb,
supplement, or vitamin.
[0238] An anesthetic can be ketamine, procaine, amethocaine,
cocaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine,
mepivacaine, dibucaine, or lidocaine. An anesthetic can be
desflurane, enflurane, halothane, isofurane, methoxyflurane, or
sevoflurane, amobaribital, methohexital, thiamylal, thiopental,
diazepam, lorazepam, midzolam, etomidate, or propofol. An
anesthetic can be atracurium, ciastracurium besyalte, rapacuronium,
rocuronium, succinylcholine, or suxamethonium chloride. An
anesthetic can be articaine, benzocaine, benzonatate, butacaine,
butanilicaine, chloroprocaine, cinchocaine, dimethocaine, eucaine,
etidocaine, hexylcaine, levobupivacaine, mepivacaine, meprylcaine,
metabutoxycaine, orthocaine, oxybuprocaine, phenacaine,
piperocaine, pramocaine, prilocaine, procaine, proparacaine,
propoxycaine, quinisocaine, ropivacaine, trimecaine, or
tetracaine.
[0239] An antibiotic can be an aminoglycoside (e.g., amikacin,
gentamicin, kanamycin, neomycin, netilmicin, tobramycin,
paromomycin, spectinomycin); an ansamycin (e.g., geldanamycin,
herbimycin, rifaximin, streptomycin); a carbacephem (e.g.,
loracarbef); a carbapenem (e.g., ertapenem, doripenem,
imipenem/cilastatin, meropenem); a cephalosporin (first generation)
(e.g., cefadroxil, cefazolin, cefalotin or cefalothin, cefalexin);
a cephalosporin (second generation) (e.g., cefaclor, cefamandole,
cefoxitin, cefprozil, cefuroxime); a cephalosporin (third
generation) (e.g., cefixime, cefdinir, cefditoren, cefoperazone,
cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime,
ceftriaxone); a cephalosporin (fourth generation) (e.g., cefepime);
a cephalosporin (fifth generation) (e.g., ceftaroline fosamil,
ceftobiprole); a glycopeptide (e.g., teicoplanin, vancomycin,
telavancin); a lincosamide (e.g., clindamycin, lincomycin); a
lipopeptide (e.g., daptomycin); a macrolide (e.g., azithromycin,
clarithromycin, dirithromycin, erythromycin, roxithromycin,
troleandomycin, telithromycin, spiramycin); a monobactam (e.g.,
aztreonam); a nitrofuran (e.g., furazolidone, nitrofurantoin); an
oxazolidonone (e.g., linezolid, posizolid, radezolid, torezolid); a
penicillin (e.g., amoxicillin, ampicillin, azlocillin,
carbenicillin, cloxacillin, dicloxacillin, flucloxacillin,
mezlocillin, methicillin, nafcillin, oxacillin, penicillin g,
penicillin v, piperacillin, penicillin g, temocillin, ticarcillin);
a penicillin combination (e.g., amoxicillin/clavulanate,
ampicillin/sulbactam, piperacillin/tazobactam,
ticarcillin/clavulanate); a polypeptide (e.g., bacitracin,
colistin, polymyxin b); a quinolone (e.g., ciprofloxacin, enoxacin,
gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic
acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin,
sparfloxacin, temafloxacin); a sulfonamide (e.g., mafenide,
sulfacetamide, sulfadiazine, silver sulfadiazine, sulfadimethoxine,
sulfamethizole, sulfamethoxazole, sulfanilimide (archaic),
sulfasalazine, sulfisoxazole, trimethoprim-sulfamethoxazole
(co-trimoxazole) (tmp-smx), sulfonamidochrysoidine (archaic)); a
tetracycline (e.g., demeclocycline, doxycycline, minocycline,
oxytetracycline, tetracycline); a drug against mycobacteria (e.g.,
clofazimine, dapsone, capreomycin, cycloserine, ethambutol,
ethionamide, isoniazid, pyrazinamide, rifampicin (rifampin in US),
rifabutin, rifapentine, streptomycin); or another antibiotic (e.g.,
arsphenamine, chloramphenicol, fosfomycin, fusidic acid,
metronidazole, mupirocin, platensimycin, quinupristin/dalfopristin,
thiamphenicol, tigecycline, tinidazole, trimethoprim).
[0240] An anticonvulsant can be an aldehyde (e.g., paraldehyde), an
aromatic allylic alcohol (e.g., stiripentol), a GABA analog (e.g.,
gabapentin, pregabalin); a barbiturate (e.g., pentobarbital,
methylpenobarital, or barbexaclone); a benzodiazepine (e.g.,
clonazepam, clobazam, clorazepate, diazepam, midazolam, nitrazepam,
temezepam, nimetazepam, or lorazepam); a bromide (e.g., potassium
bromide), a carbamate (e.g., felbamate), a caroxamide (e.g.,
carbamazepine, oxcarbazepine, eslicarbazepine acetate), a fatty
acid (e.g., vaproate (e.g., valproic acid, sodium valproate,
divalproex sodium), vigabatrin, progabide, or tiagabine), a
fructose derivative (e.g., topiramate), a hydantoin (e.g.,
phenyloin, ethotoin, mephenytoin, or fospheytoin); an
oxazolidinedione (e.g., paramethadoine, trimethadione, or
ethadione), a propionate (e.g., beclamide), a pyrimidinedione
(e.g., primidone), a pyrrolidine (e.g., brivaracetam,
levetiracetam, seletracetam), a succinimide (e.g., ethosuximide,
phensuximide, mesuximide), a sulfonamide (e.g., acetazoamide,
sultiame, methazolamide, or zonisamide), a triazine (e.g.,
lamatrigine), a urea (e.g., pheneturide, phenacemide), a
valproylamide (e.g., valpromide or valnoctamide), or a
phenyltriazine (e.g., lamotrigine).
[0241] An antidepressant can be a selective serotonin reuptake
inhibitor (SSRI, e.g., citalopram, escitalopram, paroxetine,
fluoxetine, fluvoxamine, sertraline), a norepinephrine reuptake
inhibitor (NRI, e.g., atomoxetine, reboxetine, viloxazine), a
noradrenergic and specific serotonergic antidepressant (NaSSA e.g.,
mianserin, mirtazapine), a serotonin-norepinephrine reuptake
inhibitor (SNRIs, e.g., desvenlafaxine, duloxetine, milnacipran,
venlafaxine), a serotonin antagonist and reuptake inhibitor (SARIs,
e.g., etoperidone, nefazodone, trazodone), a
norepinephrine-dopamine reuptake inhibitor (e.g., bupropion), a
selective serotonin reuptake enhancer (e.g., tianeptine,
amineptine), a norepinephrine-dopamine disinhibitor (NDDIs e.g.,
agomelatine), a tricyclic antidepressant (e.g., tertiary amine
tricyclic antidepressants (amitriptyline, clomipramine, doxepin,
imipramine, trimipramine) or secondary amine tricyclic
antidepressants (e.g., desipramine, nortriptyline, protriptyline)),
a monoamine oxidase inhibitor (MAOIs e.g., isocarboxazid,
mocolobemide, phenelzine, selegiline, tranylcypromine), nicotine,
caffeine, or lithium. In some cases, the antidepressant is
agomelatine, amitriptyline, amoxapine, atomoxetine, buspirone,
benmoxine, butriptyline, citalopram, clomipramine, desipramine,
dosulepin, doxepin, duloxetine, escitalopram, etoperidone,
femoxetine, fluovoxamine, imipramine, kitanserin, lofepramine,
medifoxamine, mianserin, maprotoline, mazindol, milnacipran,
mirtazapine, nefzaodone, nisoxetine, nomifensine, nortriptyline,
protriptyline, oxaprotiline, paroxetine, reboxetine, sertaline,
trazodone, trimipramine, venlafaxine, viloxazine, zimelidine,
citalopram, cotinine, duloxetine, fluoxetine, fluvoxamine,
milnacipran, nisoxetine, paroxetine, reboxetine, sertraline,
tianeptine, acetaphenazine, binedaline, brofaromine, cericlamine,
clovoxamine, iproniazid, isocarboxazid, moclobemide,
phenyhydrazine, phenelzine, selegiline, sibutramine,
tranylcypromine, ademetionine, adrafinil, amesergide, amisulpride,
amperozide, benactyzine, bupropion, caroxazone, gepirone, idazoxan,
metralindole, milnacipran, minaprine, nefazodone, nomifensine,
ritanserin, roxindole, S-adenosylmethionine, escitalopram,
tofenacin, trazodone, tryptophan, or zalospirone.
[0242] An antidiabetic agent can be insulin, a sufonylurea (e.g.,
tolbutamide, acetohexamide, tolazmide, chlorpropamide, glyburide,
glibenclamide, glimepiride, gliclazide, glycopyramide, gliquidone,
or glipizide), a biguanide (e.g., metformin, phenformin, or
buformin), an alpha-glucosidase inhibitor (e.g., acarbose,
miglitol, or voglibose), a meglitinide (e.g., repaglinide,
nateglinide), or a thiazolidinedione (e.g., pioglitazone
rosiglitazone, or troglitazone). An antidiabetic agent can be an
injectable glucagon-like peptide analog (e.g., exenatide,
liraglutide), or a dipeptidyl peptidase-4 inhibitor (e.g.,
vildagliptin, sitagliptin, saxagliptin, linagliptin, allogliptin,
septagliptin).
[0243] An antidote can be edrophonium chloride, flumazenil,
deferoxamine, nalmefene, naloxone, or naltrexone. An antidote can
be activated charcoal (e.g., with sortibal), adenosine, atropine,
beta blocker, calcium chloride, calcium gluconate, a chelator (e.g,
EDTA, dimercaptrol, penicillamine, EGTA, or 2,3-dimercaptosuccinic
acid), a cyanide antidote (amyl nitrite, sodium nitrite,
thiosulfate), cyproheptadine, deferoxamine mesylate, digoxin immune
Fab antibody, diphenhydramine hydrochloride, benztorpine mesylate,
ethanol, fomepizole, flumazenil, glucagon, insulin, insulin with
glucagon, leucovorin, methylene blude, naloxone hydrochloride,
N-acetylcysteine, octreotide, pralidoxime chloride (2-PAM),
protamine sulfate, Prussian blue, physostigmine sulfate,
pyridoxine, phytomenadione (vitamin K), or sodium bicarbonate.
[0244] An antiemetic can be a 5-HT3 receptor antagonist (e.g.,
dolasetron, granisetron, ondansetron, tropisetron, palonosetron, or
mirtazapine), a dopamine antagonist (e.g., doperidone, olanzapine,
droperidol, haloperidol, chlorpormaine, promethazine,
prochloperazine, alizapride, prochlorperazine, metoclopramide), an
NK1 receptor antagonist (e.g., aprepitant, casopitant), an
antihistamine (H1 histamine receptor antagonist; e.g., cyclizine,
diphenhydramine, dimenhydrinate, doxylamine, meclozine,
promethazine, hydroxyzine), a cannabinoid (e.g., cannabis,
dronabinol, nabilone, one of a JWH cannabinoid series), a
benzodiazepine (e.g., midazolam, lorazepam), an anticholinergic
(e.g., hyoscine), a steroid (e.g., dexamethasone),
trimethobenzamide, ginger, emetrol, propofol, peppermint, muscimol,
or ajwain. In some cases, the antiemetic is alizapride, azasetron,
benzquinamide, bromopride, buclizine, chlorpromazine, cinnarizine,
clebopride, cyclizine, diphenhydramine, diphenidol, dolasetron,
droperidol, granisetron, hyoscine, lorazepam, dronabinol,
metoclopramide, metopimazine, ondansetron, perphenazine,
promethazine, prochlorperazine, scopolamine, triethylperazine,
trifluoperazine, triflupromazine, trimethobenzamide, tropisetron,
domperidone, or palonosetron.
[0245] An antihistamine can be an H1-receptor antagonist (e.g.,
acrivastine, azelastine, bromopheniramine, buclizine,
bromodiphenhydramine, carbinoxamine, cetirizine, chlorpromazine,
cyclizine, chlorpheniramine, chlorodiphenhydramine, celmastine,
cyproheptadine, desloratadine, dexbrompheniramine,
dexchlorpheniramine, dimenhydramine, doxylamine, ebastine,
embramine, fexofenadine, levocetirizine, loratadine, meclozine,
mirtazapine, olopatadine, orphenadrine, pheninadamine, pheniramine,
phenyltooxamine, promethazine, pyrilamine, quetiapine, rupatadine,
tripelennamine, triprolidine), an H2-receptor antagonist (e.g.,
cimetidine, famotidien, lafutidien, mizatidine, ranitidine,
roxatidine), and H3-receptor antagonist (e.g., A-349,821, ABT-239,
ciproxifam, clobenpropit, conessine, thioperamide), or and
H4-receptor antagonist (e.g., thioperamide, JNJ 7777120, or
VUF-6002). In some cases, an antihistamine can be astemizole,
azatadine, brompheniramine, carbinoxamine, cetrizine,
chlorpheniramine, cinnarizine, clemastine, cyproheptadine,
dexmedetomidine, diphenhydramine, doxylamine, fexofenadine,
hydroxyzine, loratidine, hyroxyizine, promethazine, pyrilamine or
terfenidine.
[0246] A drug can be an allergy medication. In some cases, the
allergy medication can be an antihistamine, montelukast,
azelastine/fluticaseon propionate, beclomethasone dipropionate,
budesonide, ciclesonide, cromlyn sodium, flunisollide, fluticaonse
furoate, fluticasone propionate, ipratropium bromide, mometasone
furoate monohydrate, olopatadine, oxymetazoline, triamcinolone
acetonide, azelastine, cromolyn, emadastine, epinastine, ketorolac,
ketotifen, lodoxamine, loteprednol, naphazoline,
naphazoline/pheniramine, nedocromil, olopatadine, pemirolast,
epinephrine, aclometasone, fluocinolone, fluocinonide,
triamcinolone, desonide, fluocinolone, flurandrenolide,
fluandrenolide, fluticaonse, hydrocortisone butyrate,
hydrocortisone probuate, hydrocortisone valerate, mometasone,
prednicarbate, triamcinolone, amcinonide, betamethazone valerate,
desoximetasone, diflorasone, fluocinonide, halcononide,
triamcinolone, betamethasone bipropionate, clobetasol priopionate,
diflorasone, flurandrenolide, halobetasol propionate, doxepin,
pimecrolimus, tacrolimus, C1 inhibitor, ecallantide, cortisone
acetate, dexamethasone, hydrocortisone, methylprednisolone,
prednisolone, or prednisone.
[0247] An anti-infective agent can be selected from one of the
following classes: antivirals (e.g., abacavir, acyclovir,
acyclovir, adefovir, amadtadine, amprenavir, ampligen, arbidol,
atazanavir, atripla, balavir, boceprevirertet, cidofovir, combivir,
darunavir, delavirdine, didanosine, docosanol, edoxudine,
efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir,
fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir,
ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine,
lamivudine, lipinavir, loviride, maraviroc, moroxydine,
methisazone, nelfinavir, nevirapine, nexavir, oseltamivir,
peginterferon alpha-2a, penciclovir, peramivir, pleconaril,
podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir,
pyramidine, saquinavir, atavudine, teleprevir, tenofovir, tenofovir
disoproxil, tipranavir, trifluidine, trizivir, tromantadine,
truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine,
viramidine, zalcitabine, zanamivir, or zidovudine); AIDS adjunct
agents such as dapsone; aminoglycosides (e.g., streptomycin,
neomycin, framycetin, paromomycin, ribostamycin, kanamycin,
amikacin, arbekacin, bekanamycin, dibekacin, tobramycin,
spectinomycin, hygromycin B, paromoycin sulfate, gentamicin,
netilmicin, sisomicin, isepamicin, verdamicin, or astromicin);
antifungals (e.g., imidazoles, e.g., bifonazole, butoconazole,
clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole,
miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole,
or tioconazole; trizoles, e.g., albaconazole, fluconazole,
isavuconazole, itraconazole, posaconazole, ravuconazole,
terconazole, voriconazole; thiazoles e.g., abafungin; allyamines,
e.g., amorolfin, butenafine, naftifine, terbinafine; echinocandins
e.g., anidulafugin, caspofungin, micafungin; benzoic acid,
ciclopirox, flucytosine, griseofulvin, haloprogin, polygodial,
tolnaftate, undecylenic acid, or crystal violet); antimalarial
agents (e.g., quinine, chloroquine, amodiaquine, pyrimethamine,
proguanil, sulfadoxine, sulfamethoxypryidazine, mefloquine,
atovaquone, atovaquone-proguanil, primaquine, artemisinin,
artemether, artesuante, dihyroartemisinin, arteether, halofantrine,
doxycycline, clindamycin); antituberculosis agents (e.g.,
ethambutol, isoniazid, pyrazinamide, rifampicin); .beta.-lactams
(e.g., cefmetazole, cefazolin, cephalexin, cefoperazone, cefoxitin,
cephacetrile, cephaloglycin, cephaloridine; cephalosporins, such as
cephalosporin C, cephalothin; cephamycins such as cephamycin A,
cephamycin B, and cephamycin C, cephapirin, cephradine);
leprostatics (e.g., acedapsone, clofazimine, dapsone,
desoxyfructo-serotonin, diucifon, ethionamide, rifampicin,
rifapentine, sulfameter, thalidomide); penicillins (e.g.,
ampicillin, amoxicillin, hetacillin, carfecillin, carindacillin,
carbenicillin, amylpenicillin, azidocillin, benzylpenicillin,
clometocillin, cloxacillin, cyclacillin, methicillin, nafcillin,
2-pentenylpenicillin, penicillin N, penicillin O, penicillin S,
penicillin V, dicloxacillin; diphenicillin; heptylpenicillin; and
metampicillin); quinolones (e.g., cinoxacin, nalidixic acid,
oxolinic acid, piromidic acid, pipemidic acid, rosoxacin,
ciprofloxacin, enoxacin, fleroxacin, lomefloxacin, madifloxacin,
norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofoxacin,
clinafloxacin, difloxacin, grepafloxacin, levofloxacin,
pazufloxacin, sparfloxacin, tosufloxacin, norfloxacin, ofloxacine,
temafloxacin, clinafloxacin, gatifloxacin, gemifloxacin,
moxifloxacin, sitafloxacin, trovafloxacin, prulifloxacin);
tetracyclines (e.g., tetracycline, chlortetracycline,
demeclocycline, doxycycline, oxytetracycline, lymecycline,
meclocycline, methacycline, minocycline, rolitetracycyline,
tigecycline; miscellaneous anti-infectives such as linezolide,
trimethoprim and sulfamethoxazole.
[0248] An anti-neoplastic agent can be, e.g., lomustine,
carmustine, steptozocin, mechlorethamine, melphalan, uracil
nitrogen mustard, chlorambucil, cyclophosphamide, iphosphamide,
cisplatin, carboplatin, mitomycin, thiotepa, dacarbazin,
procarbazine, hexamethyl melamine, triethylene melamine, busulfan,
pipobroman, mitotane, methotrexate, trimetrexate, pentostatin,
cytarabine, Ara-CMP, fludarabine phosphate, hydroxyurea,
fluorouracil, floxuridine, chlorodeoxyadenosine, gemcitabine,
thioguanine, 6-mercaptopurine, bleomycin, toptecan, irinotecan,
camptothecin sodium salt, daunorubicin, doxorubicin, idarubicin,
mitoxantrone, teniposide, etoposide, dactinomycin, mithramycin,
vinblastine, vincristine, nvalebine, paclitaxel, docetaxel,
droloxifene, tamoxifen, or toremifene.
[0249] An antiparkisonian drug can be amantadine, baclofen,
biperiden, benztropine, orphenadrine, procyclidine,
trihexyphenidyl, levodopa, carbidopa, andropinirole, apomorphine,
benserazide, bromocriptine, budipine, cabergoline, eliprodil,
eptastigmine, ergoline, galanthamine, lazabemide, lisuride,
mazindol, memantine, mofegiline, pergolide, piribedil, pramipexole,
propentofylline, rasagiline, remacemide, ropinerole, selegiline,
spheramine, terguride, entacapone, or tolcapone.
[0250] An antirheumatic agent can be abatacept, adalimumab,
azathioprine, chloroquine, diclofenac, hydroxychloroquine,
methotrexate, ciclosporin, D-penicillamine, etanercept, golimumab,
infliximab, leflunomide, miocyline, rituximab, or sulfasalzine.
[0251] An antipsychotic can be acetophenazine, alizapride,
amisulpride, amoxapine, amperozide, aripiprazole, asenapine,
benperidol, benzquinamide, bromperidol, buramate, butaclamol,
butaperazine, carphenazine, carpipramine, chlorpromazine,
chlorprothixene, clocapramine, clomacran, clopenthixol,
clospirazine, clothiapine, clopenthixol, clozapine, cyamemazine,
droperidol, flupenthixol, fluphenazine, fluspirilene, haloperidol,
loxapine, melperone, mesoridazine, levomepromazine, pimozide,
metofenazate, molindrone, olanzapine, paliperidone, lloperidone,
lurasidone, penfluridol, periciazine, perphenazine, pimozide,
pipamerone, piperacetazine, pipotiazine, prochlorperazine,
promazine, quetiapine, remoxipride, risperidone, sertindole,
spiperone, sulpiride, thioridazine, thiothixene, trifluperidol,
triflupromazine, trifluoperazine, ziprasidone, zotepine, or
zuclopenthixol.
[0252] An anxiolytic can be a benzodiazepine (e.g., alprazolam,
chlordiazepoxide, clonazepam, diazepam, etizolam, lorazepam,
oxazepam); tofisopam; a selective serotonin reuptake inhibitor
(SSRI); afobazole; selank; bromantane; an azapirone (e.g.,
buspirone, tandospirone, gipeirone); a barbiturate; hydroxyzine;
pregalalin; validol; an herbal treatment (e.g., Bacopa monnieri,
Lactuca virosa, Rohodiola rosea, Hypericum perforatum, Matricaria
recutita, Passiflora incarnate, Piper methysticum; Sceletium
tortuosum, Scutellaria lateriflora; Valeriana officinalis; Salvia
splendens; Coriandrum sativum; Myristica; Salvia elegans; Inositol;
Cannabidiol); an over-the counter pharmaceutical drug (e.g.,
picamilon; chlorpheniramine; diphenhydramine; melatonin); BNC210;
CL-218,872; L-838,417; SL-651,498; or aloradine. In some cases, an
anxiolytic can be alprazolam, bromazepam, oxazepam, buspirone,
hydroxyzine, mecloqualone, medetomidine, metomidate, adinazolam,
chlordiazepoxide, clobenzepam, flurazepam, lorazepam, loprazolam,
midazolam, alpidem, alseroxlon, amphenidone, azacyclonol,
bromisovalum, captodiamine, capuride, carbcloral, carbromal,
chloral betaine, enciprazine, flesinoxan, ipsapiraone, lesopitron,
loxapine, methaqualone, methprylon, propanolol, tandospirone,
trazadone, zopiclone, or zolpidem.
[0253] An appetite stimulant (orexigenic) can be ghrelin, orexin,
neuropeptide Y; a 5-HT2c receptor antagonist (e.g., mirtazapine,
alanzapine, quetiapin, amitriptyline, cyrpoheptadine); an H1
receptor antagonist (e.g., mirtazapine, olanzapine, quetiapine,
amitriptyline, cyproheptadine); a dopamine antagonist (e.g.,
haloperidol, chlorpromazine, olanzapine, risperidone, quetiapine);
an adrenergic antagonist (e.g., carvedilol, propranolol;
alpha2-adrenergi agonist (e.g., clonidine); a CB1 receptor agonist
(e.g., THC/dronabinol, nabilone); a corticosteroid (e.g.,
dexamethasone; prednisone, hydrocortisone); a pregnene steroid
(e.g., oxandrolone, nandrolone, testosterone); a sufonylurea (e.g.,
glibenclamide, chlopropamide).
[0254] An appetite suppressant can be diethylpropion, rimonabant,
oxymetazoline, fenfluramine, phentermine, sibutramine, benfluorex,
butenolide, cathine, diethylpropion, FG-7142, phenmetrazine,
phenylpropanolamine, pryoglutamyl-histidyl-glycine, amfepramon,
amphetamine, benzphetamine, dexmethylphenidate, dextroamphetamine,
glucagon, lisdexamfetamine, methamphetamine, methylphenidate,
phendimetrazine, phenethylamine, or bupropion.
[0255] A blood modifier can be an anticoagulant (e.g., heparin);
colony stimulating factor (e.g., fligrastim, pegfilgrastim;
sargramostim); phytonadione (Vitamin K); iron; iron combination
(e.g., iron+vitamin C) cilostazol, dipyridamol, abbokinase,
abciximab, activase, advate, aggrastat, aggrenox, agrylin, albumin,
alteplase, amicar, aminocaproic acid, anadrol, anagrelide,
angiomax, anti-inhibitor coagulant complex; antihemophilic factor,
antithrombin III, aprotinin, aquamephyton, aranesp, argtroban,
arixtra, aspirin, aspirin+dipryidamole, benefix, bivalirudin,
buminate 25%, buminate 5%, cathflo activas, clopidogrel,
Coagulation Factor IX, Coagulation Factor IX Human, Coagulation
Factor VIIA, Coumadin, Cyanocobalamin Nasal, cykokapron,
Dalteparin, Ddavp, drotrecogin alpha, ecotrin, eltrombopag,
enoxaparin, epoetin alpha, epogen, epoprostenol, eptifibatide,
erythropoiesis stimulating protein, feiba VH, ferrlecit, fibrinogen
human, flolan, fondaparinux subcutaneous, fragmin, gammaplex,
hemofil M, human immunoglobulin G, infed, integrilin, iron dextran,
jantoven, kinlytic, koate-DVI, kogenate, lepirudin, leukine,
lovenox, mephyton, mononine, mozobil, nascobal, neulasta, neumega,
novoseven, nplate, oprelvekin, pegfilgrastim, pentoxifylline,
pentoxil, persantine, phytondione, plasbumin-25, pasbumin-5, plasma
protein fraction, plasmanate, plavix, plerixafor, pletal, procrit,
promacta, recombinate, refacto, refludan, reopro, riastap,
romiplostim, sargramostim, sodium ferric gluconate, tenecteplase,
thrombate III, thrombin, ticlid, ticlopidien, tirofiban, tnkase,
tranexamic acid, trasylol, trental, urokinase, vitamin K1,
warfarin, or xigris.
[0256] An asthma agent can be fluticaone, budeonside, mometasone,
beclomethasone, zariflukast, zileuton, flunisolide, ciclesonide,
triamcinolone, ipratropium, dyphylllin/guaifenesin, dexamethasone,
prednisone, methylprednisolne, formoterol/mometeasone,
triamcinolone, montelukast, isoetharine, dyphylline, salmeterol,
budeonside/formoterol, mometasone/formoterol, theophylline,
albuterol, levabulterol, ipratropium, omalizumab, or
guaifenesin/theophylline. In some cases, the asthma medication can
be an inhaled corticosteroid (e.g., beclomethasone propionate,
budesonide, budesonide/formoterol, ciclesonide, blunisolide,
fluticasone propionate, fluticaonse/salmeterol, mometasone,
memetasone/formoterol, or triamcinolone acetonide). In some cases
the asthma agent can be a long-acting beta-agonist (LABA; e.g.,
albuterol sulfate, formoterol fumarate, salmeterol xinafoate, or
arformoterol tartrate). In some cases, the asthma agent can be
cromolyn sodium or theophylline. In some cases an asthma agent can
be a leukotriene modifier (e.g., montelukast, zafirlukast,
zileuton). In some cases, an asthma agent can be an immunomodulator
(e.g., omalizumab). In some cases, an asthma agent can be a
short-acting beta-agonist (SABA; e.g., albuterol sulfate,
ipratropium bromide/albuterol sulfate, ipratropium bromide HFA,
levalbuterol HCl, pirbuterol, tiotropium bromide). In some cases,
an asthma agent is duplilumab. In some cases, the asthma agent is
bambuterol, bitolerol, doxofylline, ephedrine,
epinephrine/chlorpheniramine, erythromycin, hydrocortisone,
ipratropium bromide, isoetharine, isoprenaline, isoproterenol,
ketotifen, metaproterenol, mometasone furoate and formoterol
fumarate, nedocromil, oxtriphylline, salmeterol/fluticasone,
terbutaline, tinocordin, triamcinolone, zafirlukast, or
zileuton.
[0257] A cardiovascular agent can be fenoldopam, diazoxide,
nitroprusside, ambrisentan, epoprostenol, treprostinil, sildenafil,
bosentan, iloprost, treprostinil, epoprostenol; an aldosterone
receptor antagonist (e.g., spironolactone, eplerenone); an
angiotensin converting enzyme inhibitor (e.g., fosinopril,
ramipril, captopril, trandolapril, moexipril, lisinopril,
quinapril, enalapril, lisinopril, perinodpril, benazepril); an
angiontensin II inhibitor (e.g., eprosartan, olemsartan, azilsartan
medoxomil, telmisartan, losartan, valsartan, candesartan,
irbesartan); an antiadrenergic agent, centrally acting (e.g.,
clonidine, fuanfacine, methyldopa, guanabenz); an antiadrenergic
agent, peripherally acting (e.g., doxazosin, prazosin, terazosin,
silodosin, alfuzosin, tamsulosin, dutasertide/tamsulosin,
guanadrel, mecemylamine, guanethidine); an antianginal agent (e.g.,
nitroglycerin, ranolazine, isosorbide mononitrate, isosorbide
dinitrate); an antiarrhythmic agent (e.g., group I (e.g.,
moricizine, guanidine, disopyramide, phenytoin, propafenone,
flecainide, disopyramide, phenytoin, mexiletine, quinidine,
tocainide, lidocaine, procainamide); group II (e.g., propranolol,
esmolol, acebutolol); group III (e.g., amiodarone, sotalol,
dofetilide, dronedarone, amiodarone, sotalol, ibutilid); group IV
(e.g., ditiazem, verapamil); group V (e.g., adenosine, digoxin);
and anticholinergic chronotropic agent (e.g., atropine); an
antihypertensive combination (e.g., bendroflumethiazide/nadolol,
eprosartan/hydrochlorothiazide,
amlodipine/hydrochlorothiazide/valsartan, amplodipine/atorvastatin,
hydrochlorothiazide/telmisartan, trandolapriVverapamil;
hydrochlorthiazide/irbesartan, hydralazine/hydrochlorothiazide,
hydrochlorothiazide/triamterene, diltiazem/enalapril,
aliskiren/hdrochlorothiazise, amlodipine/telmisartan,
amlodipine/olmesartan, atenolol/chlorthalidone,
hydrochlorothiazide/moexipril, hydrochlorothiazide/olmesartan,
hydrochlorothiazide/lisinopril, hydrochlorothiazide/valsartan,
hydrochlorothiazide/losartan, hydrochlorthiaxide/quinapril,
hyrodchlorothiazide/spironolactone, azilsartan
medoxomil/chlorthalidone, amlodipine/benazepril,
amiloride/hydrochlorothiazise, hydrochlrothiazide/lisinopril,
amlodipine/hydrochorothiazide/olmesartan, amlodipine/valsartan,
aliskirne/valsartan, hydrocholorthiazide/triamterene,
bisoprolol/hydrochlorothiazide, candesartan/hydrochlorothiazide,
chrlorthiazide/methyldopa, hydrochlorothiazide/triamterene,
hydroclorothiazide/methyldopa, chlorothiazide/methyldopa,
hydrochlrothiazide/methyldopa, amlodipine/benazepril,
aliskiren/amlodipine/hydrochlorothiazide,
hydrazine/hydrochlorothiazide, hydralazine/isosrbide dinitrate,
captopril/hydrochlorothiazide, chlorthalidone/clonidine,
bendroflumethiazide/nadolol, bendrofluemethiazide/nadolol,
chlorthalidone/reserpine,
hydralazine/hydrochlorothiazide/reserpine,
hydrochlorothiazide/metoprolol, deserpidine/methyclothiazide,
guanethidine/hydrochlorothiazide, hydrochlorothiazide/propranolol,
enalapril/felodipine, polythiazide/prazosin,
amiloride/hydrochlorothiazise, fosinopril/hydrochlorothiazide,
hydrochlorothiazide/quinapril, chlorthalidone/reserpine,
polythiazide/reerpine, aliskiren/amlodipine,
atenolol/chlorthalidone, hydrochlorothiazide/timolol); a
beta-adrenergic blocking agent (e.g., cardioselective beta blocker
(e.g., betaxolol, bisoprolol, atenolol, metoprolol, nibivolol,
esmolol, acebutolol); non-cardioselective beta blocker (e.g.,
propranolol, nadolol, sotalol, carvedilol, labetalol, timolol,
carteolol, penbutolol, pindolol)); a calcium channel blocking agent
(e.g., nifedipine, diltiazem, nimodipine, verapamil, felodipine,
nicardipine, isradipine, nisoldipine, clevidipine, bepridil); a
peripheral vasodilator (e.g., cyclandelate, papverine,
isoxsuprine); a catecholamine (e.g., epinephrine, isoproterenol,
norepinephrine); a diuretic (e.g., carbonic anhydrase inhibitor
(e.g., acetazolamide, dichlophenamide, methazolamide), loop
diuretic (e.g., torsemide, furosemide, bumetanide, ethacrynic
acid); pamabrom, mannitol; a potassium-sparing diuretic (e.g.,
triamterene, spironolactone, amiloride); a thiazide diuretic (e.g.,
indapamide, hydrochlorothiazide, metolazone, methylclothizode,
hydrochlorothiazide, chlorothiazide, methyclothizide, metolazone,
bendroflumethiazide, polythiazide, hydrofluemethiazide,
chlorthalidone)); a inotropic agent (e.g., digoxin, dobutamine,
milrinone); icatibant, cilostazol, midodrine, metyrosine,
phenoxybenzamine, EDTA, phentolamine; rennin inhibitor (e.g.,
aliskiren); a peripheral vasodilator (e.g., cyclandelate,
papaverine, isoxsuprine); a sclerosing agent (e.g., laureth-9,
ethanolamine oleate, morrhuate sodium, sodium tetrdecyl sulfate); a
vasodilator (e.g., nitroglycerin, alprostadil, hydralazine,
minoxidil, mesiritide, nitroprusside); a vasopression antagonist
(e.g., conivaptan, tolvaptan); or a vasopressor (e.g., epinephrine,
isoproterenol, phenylephrine, norepinephrine, dobutamine,
isoproterenol). In some cases, the cardiovascular agent can be
benazepril, captopril, enalapril, quinapril, ramipril, doxazosin,
prazosin, clonidine, labetolol, candesartan, irbesartan, losartan,
telmisartan, valsartan, disopyramide, flecanide, mexiletine,
procainamide, propafenone, quinidine, tocamide, amiodarone,
dofetilide, ibutilide, adenosine, gemfibrozil, lovastatin,
acebutalol, atenolol, bisoprolol, esmolol, metoprolol, nadolol,
pindolol, propranolol, sotalol, diltiazem, nifedipine, verapamil,
spironolactone, bumetanide, ethacrynic acid, furosemide, torsemide,
amiloride, triamterene, or metolazone.
[0258] A central nervous system stimulant can be phendimetrazine,
methamphetamine, diethylpropion, amphetamine/dextroamphetamine,
benzphetamine, phendimetrazine, lisdexamfetamine, diethylpropion,
phendimetrazine, dexmethylphenidate, armodafinil, atomexetine,
doxapram, amphetamine, brucine, caffeine, dexfenfluramine,
dextroamphetamine, ephedrine, fenfluramine, mazindol,
methyphenidate, pemoline, phentermine, sibutramine, or
modafinil.
[0259] An agent for Alzheimer's disease management can be
donepezil, galanthamine, rivastigmine, tacrine, or memantine.
[0260] An agent for cystic fibrosis management can be an antibiotic
(e.g., ciprofloxacin, tobramycin); a bronchodilator (e.g.,
albuterol or salmeterol); an anticholinergic (e.g., atrovent); a
DNase (e.g., pulmozyme); a mucolytic (e.g., acetylcysteine); a
saltwater solution (e.g., hypertonic saline); a nonsteroidal
anti-inflammatory (NSAID; e.g., ibuprofen); a corticosteroid (e.g.,
fluticasone or prednisone); an enzyme replacement therapy (e.g.,
creon or pancreaze); CPX, IBMX, XAC and analogues; 4-phenylbutyric
acid; genistein and analogous isoflavones; azithromycin, aztreonam,
pancrelipase, gentamicin, ivacaftor, azithromycin, vitamin E,
pancreatin, or milrinone.
[0261] A diagnostic agent can be adenosine or aminohippuric
acid.
[0262] A homeopathic cold medication can be Aconitum napellus,
Allium cepa, Antimonium tartaricum, Apsi mellifica, Arsenicum
album, Arum triphyllum, Belladonna, Bryonia alba, Dulcamara,
Eupatorium perforliaturn, Euphrasia, Ferrum phosphoricum,
Gelsemium, Hepar sulphuris, Kali bichromicum, Mercurius solubilis,
Natrum muriaticum, Nux vomica, Oscillococinum (Anas barbariase),
phosphorus, Rhus toxicodendron, sulphur, or Pulsatilla Sticta.
[0263] A COPD drug can be montelukast, budesonide/formoterol,
roflumilast, aclidinium, prednisone, isoetharine, dyphylline,
guaifenesin/theophylline, or fluticasone/vilanterol. In some cases,
a COPD drug is a bronchodilator (e.g., albuterol, levabuterol,
ipratropium; or a long-acting bronchodilator (e.g., tiotropium,
salmeterol, formoterol, arformoterol, indacaterol, aclidinium). In
some cases, a COPD drug is a steroid (e.g., fluticasone,
budesonide). In some cases, a COPD drug is a combination (e.g.,
salmeterol/fluticasone and formoterol/budesonide). In some cases a
COPD drug is a phosphodiesterase-4 inhibitor (e.g., roflumilast).
In some cases, a COPD drug is theophylline or an antibiotic.
[0264] A cough medication can be guaifenesin/hydrocodone,
acetaminophen/codeine, diphenhydramine, guaifenesin/potassium
guaiacolsulfonate, carbetapentane/guaifenesin, codeine/guaifenesin,
dextromethorphan/guaifenesin, guaifenesin,
carbinoxamine/dextromethorphan/pseudoephedrine, dextromethorphan,
brompheniramine/codeine,
carbetapentane/chlorpheniramine/phenylephrine,
benzocaine/dextromethorphan, menthol,
acetaminophen/dextromethorphan, chlophedianol/guaifenesin,
acetaminophen/dextromethrophan/doxylamine,
aceteaminophen/hydrocodone, glycerin,
acetaminophen/dextromethorphan/phenylephrine,
dexbrompheniramine/hydrocodone/phenylephrine, hydromorphone,
acetaminophen/chlorpheniramine/dextromethorphan/phenylephrine,
guaifenesin, carbetapentane/guaifenesin,
carbinoxamine/dextromethorphan/pseudoephredrine,
chlorpheniramine/dextromethorphan/methscopolamine,
guaifenesin/potassium guaiacolsulfonate, homatropine/hydrocodone,
dihdrocodeine/guaifenesin/pseudoephredrine,
chlropheniramine/hydrocodone, codeine/guaifenesin, potassium
iodide, dihydrocodeine/guaifenesin, dihydrocodeine/hydrocodone,
acetaminophen/hydrocodone, chlorcyclizine/codeine/phenylephrine,
codeine/pseudoephedrine/pyrilamine, hydromorphone,
dihydrocodeine/guaifensesin/pseudoephedrine,
chlophedianatriprolidine, dextromethorphan/promethazine,
codeine/promethazine, dextromethorphan/promethazine,
carbetapentane/guaifenesin, carbetapentane/guaifenesine,
dextromethorphan/guaifenesin, dextromethorphan/doxylamine,
carbetapentanse, dyclonine/menthol, dextromethorphan/guaifenesin,
benzonatate, acetaminophen/dextromethorphan/phenylephrine,
guaifenesin/hydrocodone,
carbinoxamine/hydrocodone/pseudeoephedrine, codeine/guaifenesin,
guaifenesin/hydrocodoen, homatropine/hydrocodone,
chlorpheniramine/hydrocodone, carbetapentane/guaifenesin,
acetaminophen/dextromethorphan/doxylamine/phenylephrine,
acetaminophen/dextromethorphan,
acetaminophen/dextromethorphan/phenylephrine,
acetaminophen/hydrocodone,
dihydrocodein/guaifenesin/pseudoephedrine, or benzonatate. In some
cases, the cough medication can be dextromethorphan, codeine,
noscapine, bromhexine, acetylcysteine, ephedrine, guaifenesin,
honey, cinnaomon, honey/cinnamon, lemon, elderberry syrup, tea,
Slippery Elm, peppermint, Chinese Hot Mustard, cayenne pepper
(capsaicin), apple cider vinegar, wasabi, horseradish, Echinacea,
vitamin c, zinc, ginger (zingiber officinale), vinegar, water, red
onion, garlic, hyssop, or mullein. In some cases, a cough
medication can be an antihistamine, decongestant, inhaled asthma
drug, antibiotic, acid blocker, or cough suppressant. In some
cases, a cough medication is licorice, horehound, mullein,
peppermint, elderflower, yarrow, Belladonna, bryonia, Gelsemium,
Coccus catcti, Drosera, Dulcamara, Eupatorium, Euphrasia, hepar
suphuratum, Kali bic, Nux vomica, phosphorus, Pulsatilla,
Antimonium tartaricu, Rhus tox, Spongia, or Vincetoxicum.
[0265] A dietary supplement can be acai, aloe vera, an anabolic
steroid, astragalus, vitamin A, bilberry, beta carotene, bitter
orange, Black Cohosh, Butterbur, vitamin B12, vitamin B6, calcium,
carnitine, cartilage, cat's claw, chamomile, chasteberry,
chondroitin, chromium, cinnamon, coenzyme Q10, colloidal silver,
cranberry, vitamin C, dandelion, vitamin C, Echinacea, ephedra,
essiac/flor-essence, European elder, evening primrose oil, vitamin
E, fenugreek, feverfew, fish oil, flaxseed, folate, folic acid,
garlic, ginger, ginkgo, ginseng, glucosamine, glucosamine with
chondroitin sulfate, goldenseal, grape seed extract, green tea,
hawthorn, hoodia, horse chestnut, iodine, iron, kava, vitamin K,
lavender, licorice root, L-lysine, magnesium, melatonin, milk
thistle, mistletoe, noni, omega-3 fatty acids, PC-SPES, peppermint
oil, red clover, sage, S-adenosyl-L-methionine, saw palmetto,
selenium, soy, St. John's Wort, tea, thunder god vince, turmeric,
valerian, vitamin A, vitamin B1, vitamin B12, vitamin B6, vitamin
C, vitamin D, vitamin E, vitamin K, yohimbe, or zinc.
[0266] An agent for erectile dysfunction can be tadalafil,
sildenafil, vardenafil, alprostadil, avanafil, apomorphine,
apomorphine diacetate, phentolamine, and yohimbine.
[0267] A gastrointestinal agent can be a 5-aminosalicylate (e.g.,
mesalamine, balsalazide, sulfasalazine, olsalazine), an antacid
(e.g., aluminum hydroxide/magnesium hydroxide/simethicone; sodium
barcarbonate, magaldrate/simethicone, calcium carbonate, aluminum
hydroxide/magnesium hydroxide/simethicone, magnesium hydroxide,
aluminum hydroxide/magnsesium hydroxide, magnesium hydroxide,
alginic acid/aluminum hydroxide/magnesium trisilicate, alginic
acid/aluminum hydroxide/magnesium carbonate, aluminum
hydroxide/magnesium hydroxide/simethicone, calcium
carbonate/magnesium hydroxide, magaldrate, magaldrate/simethicon),
an antidiarrheal (e.g., bismuth subsalicylate, atropine/difenoxin,
attapulgite, lactobacillus acidophilus, loperamide,
atropine/diphenoxylate, saccharomyces boulardii lyo, crofelemer
systemic, kaolin/pectin systemic, kaolin systemic, lactobacillus
acidophilus/lactobacillus bulgaricus, loperamide/simethicone
systemic), a digestive enzyme (e.g., pancrelipase,
amylase/cellulose/hyoscyamine/lipase/phenyltoloxamine/protease,
pancreatin, lactase), a functional bowel disorder agent (e.g., an
antichoinergic/antispasmodic, e.g., hyoscyamine,
atropine/hyoscyamine/Phenobarbital/scopolamine, methscopolamine,
scopolamine, chlordiazepoxide/clidinium, dicyclomine,
glycopyrrolate, belladonna, atropine,
atropine/hyoscyamin/Phenobarbital/scopolamine,
belladonna/ergotamine/phenobarbital, mepenzolate,
hyoscyamine/phenyltoloxamine), a chloride channel activator (e.g.,
lubiprostone), a guanylate cyclase-C agonist (e.g., linaclotide), a
peripheral opioid receptor antagonist (e.g., methylnaltrexone,
alivmopan); a serotoninergic neuroenteric modulator (e.g.,
tegaserod, alosetron), a gallstone solubilizing agent (e.g.,
ursodiol, chenodeoxycholic acid), a gastrointestinal stimulant
(e.g., metoclopramide, cisapride, choline bitartrate/dexpanthenol),
H. pylori eradication agent (e.g.,
amoxicillin/clarithromycin/lansoprazole, bismuth subcitrate
potassium/metronidazole/tetracycline, bismuth
subsalicylate/metronidazole/tetracycline,
amoxicillin/clarithromycin/omeprazole), an H2 antagonist (e.g.,
nizatidine, cimetidine, ranitidine, famotidine, cimetidine, calcium
carbonate/famotdine/magnesium hydroxide), a laxative (e.g.,
magnesium citrate, polyethylene glycol 3350, lactulose, senna,
bisacodyl, psyllium, methylcellulose, docusate, polycarbophil,
sodium biphophate/sodium phosphate, docusate/senna, sodium
biphosphate/sodium phosphate, polyethylene glycol 3350 with
electrolytes, bisacodyl/polyethylene glycol 3350/potassium
chloride/sodium bicarbonate/sodium chloride, magnesium sulfate,
polycarbophil, magnesium hydroxide, mineral oil), citric
acid/simethicone/sodium bicarbonate, simethicone, misoprostol,
charcoal/simethicone, sucralfate, teduglutide; or a proton pump
inhibitor (e.g., pantoprazole, omeprazole/sodium bicarbonate,
rebeprazole, esomeprazole, lansoprazole, dexlansoprazole). In some
cases, the gastrointestinal agent can be loperamide, atropine,
hyoscyamine, famotidine, lansoprazole, omeprazole, or
rebeprazole.
[0268] A hormone can be estrogen, progesterone, hydrocortisone,
fludocortisone, throxine, progestin, testosterone, estradiol,
cortisone, 1-androstendediol, 1-androstenedione, bolandiol,
bolasterone, boldenone, boldione, calusterone, clostebol, danazol,
dehydrochlormethyltestosterone, desoxymethyltestosterone,
drostanolone, ethylestrenol, fluoxymesterone, formeboone,
furazabol, gestrinone, 4-hydroxytestosterone, mestanolone,
mesterolone, meenolone, methandienone, methandriol, methasterone,
methyldienolone, methyl-1-testosterone, methylnortestosterone,
methyltestosterone, mitribolone, mibolerone, nandrolone,
19-noradrostenedione, norboletone, norclostebol, norethandrolone,
oxabolone, oxandrolone, oxymesterone, oxymetholone, prostanozol,
quinbolone, stnozolol, stenbolone, 1-testosterone,
tetrhydrogestrinone, trenbolone, androstenediol, androstenedionne,
dihydrotestosterone, or prasterone.
[0269] An agent for the treatment of alcoholism can be naloxone,
naltrexone, acamprostate, or disulfuram.
[0270] An agent for the treatment of addiction can be disulfiram,
naltrexone, acamprosate, methadone, levo-alph acetyl methadol
(LAAM), or buprenorphine.
[0271] An immunosupressive can be a glucocorticoid, a cytostatic
(e.g., alkyating agent, antimetabolite (e.g., methotrexate,
azathiopurine, mercaptopurine, fluorouracil, a cytotoxic antibiotic
(e.g., dactinomycin, an antracycline, mitomycin C, bleomycin,
mithramycin), an antibody (e.g., a monoclonal antibody (e.g., IL-2
receptor directed antibody, CD3 directed antibody; a T-cell
receptor directed antibody (e.g., muromonab-CD3)), a drug acting on
immunophilin (e.g., ciclosporin, tacrolimus, sirolimus), other
drugs (e.g., an interferon, an opioid, a TNF binding protein, a
mycophenolate). In some cases, the immunosuppressive is
mycophenolic acid, cyclosporin, azathioprine, tacrolimus,
everolimus, or rapamycin. In some cases, the immunosuppressive
agent is a calcineurin inhibitor (e.g., cyclosporine, tacrolimus),
an interleukin inhibitor (e.g., rilonacept, tocilizumab, anakinra,
ustekinumab, canakinumab, basiliximab, daclizumab), omalizumab,
lenalidomide, azathioprine, methotrexate, pomalidomide,
thalidomide, alefacept, efalizumab, mycophenolic acid,
mycophenolate mofetil, fingolimod, natalizumab, belimumab,
lefunomide, abatacept, lymphocyte immune globulin anti-thy
(equine), teriflunomide, belatacept, muromonab-cd3, eculizumab,
anti-thymocyte globulin (rabbit), or a TNF alpha inhibitor (e.g.,
infliximab, adalimumab, etanercept, certolizumab, golimumab).
[0272] A mast cell stabilizer can be cromolyn, pemirolast, or
nedocromil.
[0273] An agent for migraine headache can be naproxen, ibuprofen,
acetaminophen, almotriptan, alperopride, codeine,
dihydroergotamine, ergotamine, eletriptan, frovatriptan,
isometheptene, lidocaine, lisuride, metoclopramide, naratriptan,
oxycodone, propoxyphene, rizatriptan, sumatriptan, tolfenamic acid,
zolmitriptan, amitriptyline, atenolol, clonidine, cyproheptadine,
diltiazem, doxepin, fluoxetine, lisinopril, methysergide,
metoprolol, nadolol, zolmitriptan, nortriptyline, paroxetine,
pizotifen, pizotyline, propanolol, protriptyline, sertraline,
timolol, ergotamine/caffeine, isometheptine/dichlorphenazone/apap,
or verapamil.
[0274] An agent that can be used to treat motion sickness can be
diphenhydramine, dimehydrinate, cinnaizine, meclozine,
promethazine, metoclopramide, prochlorperazine, ginger root, or
scopolamine
[0275] An agent for managing multiple sclerosis can be
corticotropin, dalfampridine, teriflunomide, interferon beta-1a,
interferon beta-1b, glatiramer, cyclophosphamide, dexamethasone,
prednisone, fingolimod, azathioprine, natalizumab, bencyclane,
methylprednisolone, azathioprine, mitoxantrone, or
prednisolone.
[0276] A muscle relaxant can be a neuromuscular blocking agent
(e.g., succinylcholine, mivacurium, cisatracurium, vecuronium,
doxacurium, pancuronium, atracurium); a skeletal muscle relaxant
combination (e.g., aspirin/caffeine/orphenadrine,
aspirin/carisoprodol, aspirin/carisoprodol/codeine,
aspirin/methocarbamol, aspirin/meprobamate); or a skeletal muscle
relaxant (e.g., dantrolene, botulinum toxin type b, carisprodol,
onabotulinumtoxin A, cyclobenzaprine, chlorzoxazone, chlrophenesin,
tizanidine, baclofen, cyclobenzaprine, metaxalone, methocarbamol,
cyclobenzaprine, orphenadrine, carisoprodol, incobotulinumtoxinA).
In some cases, the muscle relaxant is decamethonium, rapacuronium,
atracurium, rocuronium, alcuronium, gallamine, metocurine,
pipecuronium, bubocurarine, baclofen, chlorzoxazone,
cyclobenzaprine, methocarbamol, orphenadrine, quinine,
carisoprodol, gabapentin, metaxalone, diazepam, dantrolene,
botulinum toxin type b, onabotulinumtoxinA, chloroxazone,
chlorphenesin, baclofen, methocarbamol, or ortizanidine.
[0277] A drug for treating mycocardial infarction can be urokinase,
perindopril, alteplase, ramipril, aspirin, aluminum
hydroxide/aspirin/calcium carbonate/magnesium hydroxide, timolol,
magnesium chloride, warfarin, dalteparin, heparin, propranolol,
eptifibatide, metoprolol, enoxaparin, trandolapril, nitroglycerin,
clopidogrel, lisinopril, reteplase, streptokinase, atenolol,
tenecteplase, or moexipril. In some cases, the drug for treating
myocardial infarction can be a vasodilator. A vasodilator can be an
alpha-adrenoceptor antagonist (e.g., prazosin, terazosin,
doxazosin, trimazosin, phentolamine, phenoxybenzamine); an
angiotensin converting enzyme (ACE) inhibitor (e.g., benazepril,
captopril, enalapril, fosinopril, lisinopril, moexipril, quinapril,
ramipril); an angiotensin receptor blocker (ARB) (e.g.,
candesartan, eprosartan, irbesartan, losartan, olmesartan,
telmisartan, valsartan); a beta2-adrenoceptor agonist
(beta2-agonist) (e.g., epinephrine, norepinephrine, dopamine,
dobutamin, isoproterenol); a calcium-channel blocker (CCB) (e.g.,
amlodipine, felodipine, isradipine, nicardipine, nifedipine,
nimodipine, nitrendipine); a centrally acting sympatholytic (e.g.,
clonidine, guanabenz, guanfacine, alpha-methyldopa); a direct
acting vasodilator (e.g., hydralazine); an endothelin receptor
antagonist (e.g., bosetan); a ganglionic blocker (e.g.,
trimethaphan camsylate); a nitrodilator (e.g., isosorbide
dinitrate, isosorbide mononitrate, nitroglycerin, erhthrityl
tetranitrate, pentaerythritol tetranitrate, sodium nitroprusside);
a phosphodiesterase inhibitor (e.g., a PDE3 inhibitor (e.g.,
milrinone, inamrinone, cliostazol; a PDE5 inhibitor (e.g.,
sildenafil, tadalafil)); a potassium-channel opener (e.g.,
minoxidil); or a rennin inhibitor (e.g., aliskiren). In some cases,
a drug for treating myocardial infarction can be a cardiac
depressant drug (e.g., a beta-adrenoceptor antagonist
(beta-blocker), e.g., a non-selective beta1/beta2 drug (e.g.,
carteolol, carvedilol, labetalol, nadolol, penbutolol, pindolol,
propranolol, sotalol, timolol) or a beta1-selective drug (e.g.,
acebutolol, atenolol, betaxolol, bisoprolol, esmolol, metoprolol,
nebivolol); a calcium-channel blocker (e.g., amlodipine,
felodipine, isradipine, nicardipine, nifedipine, nimodipine,
nitrendipine); or a centrally acting sympatholytic (e.g.,
clonidine, guanabenz, guanfacine, alpha-methyldopa). In some cases,
a drug for treating myocardial infarction can be an antiarrhythmic
drug (e.g., Class I--sodium-channel blocker (e.g., Class 1A (e.g.,
quinidine, procainamide, disopryamide); Class 1B (e.g., lidocaine,
tocainide, mexiletine); Class 1C (e.g., flecainide, propafenone,
moricizine); Class II--beta blocker (e.g., a non-selective
beta1/beta2 drug (e.g., carteolol, carvedilol, labetalol, nadolol,
penbutolol, pindolol, propranolol, sotalol, timolol) or a
beta1-selective drug (e.g., acebutolol, atenolol, betaxolol,
bisoprolol, esmolol, metoprolol, nebivolol); a Class III--potassium
channel blocker (e.g., amiodarone, dronedarone, bretylium, sotalol,
ibutilide, dofetilide); a Class IV calcium channel blocker (e.g.,
amlodipine, felodipine, isradipine, nicardipine, nifedipine,
nimodipine, nitrendipine); adenosine, an electrolyte supplement
(e.g., magnesium, potassium); a digitalis compound (e.g., digoxin,
digitoxin, ouabain); or atropine. In some cases, the drug for
treating myocardial infarction is a thrombolytic drug (e.g., a
tissue plasmiogen activator (e.g., alteplase, retaplase,
tenecteplase); streptokinase, anistreplase, or urokinase.
[0278] A nonsteroidal anti-inflammatory can be a salicylate (e.g.,
aspirin (acetylsalicylic acid), diflunisal, salsalate); a propionic
acid derivative (e.g., ibuprofen, dexibuprofen, naproxen,
fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin,
loxoprofen); an acetic acid derivative (e.g., indomethacin,
tolmetin, sulindac, etodolac, ketorolac, diclofeanc, nabumetone) a
enolic acid (oxicam) derivative (e.g., piroxicam meloxicam,
tenoxicam, droxicam, lornoxicam, isoxicam); a fenamic acid
derivative (fenamate; e.g., mefenamic acid, meclofenamic acid,
flufenamic acid, tolfenamic acid); a selective COX-2 inhibitor
(coxib; e.g., celecoxib, rofecoxib, vadexocib, parecoxib,
lumiracoxib, etoricoxib, firoxib); a sulphonanilide (e.g.,
nimesulide); licofelone, lysine clonixinate, hyperforin, figwort,
calcitriol (vitamin D). In some cases, a nonsteroidal
anti-inflammatory can be aceclofenac, alminoprofen, amfenac,
aminopropylon, amixetrine, aspirin, benoxaprofen, bromfenac,
bufexamac, carprofen, celecoxib, choline salicylate, cinchophen,
cinmetacin, clopriac, clometacin, diclofenac, diclofenac potassium,
diclofenac sodium, diclofenac sodium with misoprostol, diflunisal,
etodolac, fenoprofen, fenoprofen calcium, flurbiprofen, ibuprofen,
indomethacin, indoprofen, ketoprofen, ketorolac, magnesium
salicylate, mazipredone, meclofenamate, meclofenamate sodium,
mefanamic acid, meloxicam, nabumetone, naproxen, naproxen sodium,
oxaprozin, parecoxib, piroxicam, pirprofen, rofecoxib, salsalate,
sodium salicylate, sulindac, tolfenamate, tolmetin, tolmetin
sodium, or valdecoxib.
[0279] An opioid, opioid antagonist, or inverse agonist can be an
opium alkaloid (e.g., codeine, morphine, oripavine, pseudomorphine,
thebaine); an alkaloid salt mixture (e.g., pantopon, papaveretum);
14-hydroxymorphine, 2,4-dinitorphenylmorphe,
6-methyldihydromorphine, 6-methylenedihydrodesoxymorphine,
acetyldihydromorphine, azidomorphine, chlornaltrexamine,
chloroxymorphamine, desomorphine, dihydromorphine,
ehtyldihydromorphine, hydromorphinol, methyldesorphine,
N-henethylnormorphine, RAM-378, 6-nicotinoyldihydromorphine,
acetlypropionylmorphin, diacetyldihydromorphine, dibutyrylmorphine,
dibenzoylmorphine, diformylmorphine, dipropanoylmorphine, heroin,
nicomorphine, 6-Monoacetylcodeine, Benzylmorphine, Codeine
methylbromide, Desocodeine, Dimethylmorphine (6-O-Methylcodeine),
Ethyldihydromorphine, Methyldihydromorphine (dihydroheterocodeine),
Ethylmorphine (dionine), Heterocodeine, Isocodeine, Pholcodine
(morpholinylethylmorphine), Myrophine, Nalodeine
(N-allyl-norcodeine), Transisocodeine, 14-Cinnamoyloxycodeinone,
14-Ethoxymetopon, 14-Methoxymetopon, 14-Phenylpropoxymetopon,
7-Spiroindanyloxymorphone, 8,14-Dihydroxydihydromorphinone,
Acetylcodone, Acetylmorphone, .alpha.-hydrocodol (Dihydrocodeine),
Bromoisopropropyldihydromorphinone, Codeinone, Codorphone, Codol
(Codeine Phosphate), Codoxime, IBNtxA, Thebacon
(acetyldihydrocodeinone, dihydrocodeinone enol acetate),
Hydrocodone, Hydromorphone, Hydroxycodeine, Metopon
(Methyldihydromorphinone), Morphenol Morphinone, Morphol,
N-Phenethyl-14-ethoxymetopon, Oxycodone, Oxymorphol, Oxymorphone,
Pentamorphone, Semorphone, .alpha.-chlorocodide (Chlorocodide),
.beta.-chlorocodide, .alpha.-chloromorphide (Chloromorphide),
Bromocodide, Bromomorphide, Chlorodihydrocodide, Chloromorphide,
Codide, 14-Hydroxydihydrocodeine, Acetyldihydrocodeine,
Dihydrocodeine, Dihydrodesoxycodeine (desocodeine),
Dihydroisocodeine, Nicocodeine, Nicodicodeine, 1-Nitrocodeine cas,
Codeine-N-oxide, Morphine-N-oxide, Oxymorphazone, 1-Bromocodeine,
1-Chlorocodeine, 1-Iodomorphine, Codeine-N-oxide (genocodeine),
Heroin-7,8-oxide, Morphine-6-glucuronide, 6-Monoacetylmorphine,
Morphine-N-oxide (genomorphine), Naltrexol, Norcodeine,
Normorphine, Levomethorphan, 4-chlorophenylpyridomorphinan,
Cyclorphan, Dextrallorphan, Levargorphan, Levorphanol,
Levophenacylmorphan, Levomethorphan, Norlevorphanol,
N-Methylmorphinan, Oxilorphan, Phenomorphan, Methorphan
(racemethorphan), Morphanol (racemorphanol), Ro4-1539,
Stephodeline, Xorphanol, 1-Nitroaknadinine, 14-episinomenine,
5,6-Dihydronorsalutaridine, 6-Keto Nalbuphine, Aknadinine,
Butorphanol, Cephakicine, Cephasamine, Cyprodime, Drotebanol,
Fenfangjine G, Nalbuphine, Sinococuline, Sinomenine (cocculine),
Tannagine, 5,9 alpha-diethyl-2-hydroxybenzomorphan (5,9-DEHB),
8-Carboxamidocyclazocine (8-CAC), Alazocine, Anazocine,
Bremazocine, Butinazocine, Carbazocine, Cogazocine, Cyclazocine,
Dezocine, Eptazocine, Etazocine, Ethylketocyclazocine, Fedotozine,
Fluorophen, Gemazocine, Ibazocine, Ketazocine, Metazocine,
Moxazocine, Pentazocine, Phenazocine, Quadazocine, Thiazocine,
Tonazocine, Volazocine, Zenazocine, Pethidine, 4-Fluoromeperidine,
Allylnorpethidine, Anileridine, Benzethidine, Carperidine,
Difenoxin, Diphenoxylate, Etoxeridine (carbetidine), Furethidine,
Hydroxypethidine (bemidone), Morpheridine, Meperidine-N-oxide,
Oxpheneridine (carbamethidine), Pethidine (meperidine), Pethidine
intermediate A, Pethidine intermediate B (norpethidine), Pethidine
intermediate C (pethidinic acid), Pheneridine, Phenoperidine,
Piminodine, Properidine (ipropethidine), Sameridine, Allylprodine,
(.alpha./.beta.)-Meprodine, Desmethylprodine (MPPP), PEPAP,
(.alpha./.beta.)-Prodine, Prosidol, Trimeperidine (promedol),
Acetoxyketobemidone, Droxypropine, Ketobemidone,
Methylketobemidone, Propylketobemidone, Alvimopan, Loperamide,
Picenadol, Methadone, Dextromethadone, Dipipanone, Isomethadone,
Levoisomethadone, Levomethadone, Methadone, Methadone intermediate,
Normethadone, Norpipanone, Phenadoxone (heptazone), Pipidone
(Dipipanone Hydrochloride)
(6-piperidine-4,4-diphenyl-5-methyl-hexanone-3 hydrochloride),
Alphaacetylmethadol, Dimepheptanol (racemethadol),
Levacetylmethadol, Noracetylmethadol, Desmethylmoramide,
Dextromoramide, Levomoramide, Moramide intermediate, Racemoramide,
Diethylthiambutene, Dimethylthiambutene, Ethylmethylthiambutene,
Piperidylthiambutene, Pyrrolidinylthiambutene, Thiambutene,
Tipepidine, Dextropropoxyphene (propoxyphene), Dimenoxadol,
Dioxaphetyl butyrate, Levopropoxyphene, Norpropoxyphene,
Diampromide, Phenampromide, Propiram, IC-26, Isoaminile,
Lefetamine, R-4066, Fentanyl, 3-Allylfentanyl, 3-Methylfentanyl,
3-Methylthiofentanyl, 4-Phenylfentanyl, Alfentanil,
Alphamethylacetylfentanyl, Alphamethylfentanyl,
Alphamethylthiofentanyl, Benzylfentanyl, Betahydroxyfentanyl,
Betahydroxythiofentanyl, Betamethylfentanyl, Brifentanil,
Carfentanil, Fentanyl, Lofentanil, Mirfentanil, Ocfentanil,
Ohmefentanyl, Parafluorofentanyl, Phenaridine, Remifentanil,
Sufentanil, Thenylfentanyl, Thiofentanyl, Trefentanil,
Thienorphine, 7-PET, Acetorphine, Alletorphine
(N-allyl-noretorphine), BU-48, Buprenorphine, Cyprenorphine,
Dihydroetorphine, Etorphine, Homprenorphine,
18,19-Dehydrobuprenorphine (HS-599),
N-cyclopropylmethylnoretorphine, Nepenthone, Norbuprenorphine,
Thevinone, Thienorphine, Ethoheptazine, Meptazinol, Metheptazine,
Metethoheptazine, Proheptazine, Bezitramide, Piritramide,
Clonitazene, Etonitazene, Nitazene, 18-Methoxycoronaridine,
7-Acetoxymitragynine, 7-Hydroxymitragynine, Akuammidine, Akuammine,
Eseroline, Hodgkinsine, Mitragynine, Pericine, Pseudoakuammigine,
BW373U86, DPI-221, DPI-287, DPI-3290, SNC-80, .beta.-neo-endorphin,
dynorphin, Big dynorphin, Dynorphin A, Dynorphin B, Endorphin,
Beta-endorphin, Alpha-endorphin, Gamma-endorphin,
.alpha.-neo-endorphin, .beta.-neo-endorphin, Enkephalin,
DADLE.cndot.DAMGO.cndot.Dermenkephalin, Met-enkephalin,
Leu-enkephalin, Adrenorphin, Amidorphin, Casomorphin, DALDA
(Tyr-D-Arg-Phe-Lys-NH2), Deltorphin, Dermorphin, DPDPE,
Endomorphin, Gliadorphin, Morphiceptin, Nociceptin, Octreotide,
Opiorphin, Rubiscolin, TRIMU
5,3-(3-Methoxyphenyl)-3-ethoxycarbonyltropane, AD-1211, AH-7921,
Azaprocin, BDPC, Bisnortilidine, BRL-52537, Bromadoline, C-8813,
Ciramadol, Doxpicomine, Enadoline, Faxeladol, GR-89696, Herkinorin,
ICI-199,441, ICI-204,448, J-113,397, JTC-801, Ketamine, KNT-42,
LPK-26, Methopholine, MT-45, Desmethylclozapine, NNC 63-0532,
Nortilidine, 0-Desmethyltramadol, Phenadone, Phencyclidine,
Prodilidine, Profadol, Ro64-6198, Salvinorin A, SB-612,111,
SC-17599, RWJ-394,674, TAN-67, Tapentadol, Tecodine (Oxycodone),
Tifluadom, Tilidine, Tramadol, Trimebutine, U-50,488, U-69,593,
Viminol,
1-(4-Nitrophenylethyl)piperidylidene-2-(4-chlorophenyl)sulfonamide
(W-18), 5'-Guanidinonaltrindole, .beta.-Funaltrexamine,
6.beta.-Naltrexol, Alvimopan, Binaltorphimine, Chlornaltrexamine,
Clocinnamox, Cyclazocine, Cyprodime, Diacetylnalorphine,
Difenamizole, Diprenorphine (M5050), Fedotozine, JDTic,
Levallorphan, Methocinnamox, Methylnaltrexone, Nalfurafine,
Nalmefene, Nalmexone, Naloxazone, Naloxonazine, Naloxone, Naloxone
benzoylhydrazone, Nalorphine, Naltrexone, Naltriben, Naltrindole,
Norbinaltorphimine, Oxilorphan,
S-allyl-3-hydroxy-17-thioniamorphinan (SAHTM), Alimadol,
Anilopam+HCl, Asimadoline, FE 200665, Fedotozine, MCOPPB,
Nalfurafine, Nalorphine, Nalorphine dinicotinate, or SoRI-9409 In
some cases, the opioid can be alfentanil, allylprodine,
alphaprodine, anileridine, benzylmorphine, bezitramide,
buprenorphine, butorphanol, carbiphene, cipramadol, clonitazene,
codeine, dextromoramide, dextropropoxyphene, diamorphine,
dihydrocodeine, diphenoxylate, dipipanone, fentanyl, hydromorphone,
L-alpha acetyl methadol, lofentanil, levorphanol, meperidine,
methadone, meptazinol, metopon, morphine, nalbuphine, nalorphine,
oxycodone, papaveretum, pethidine, pentazocine, phenazocine,
oxymophone, remifentanil, sufentanil, or tramadol.
[0280] An analgesic can be merperidine, hydromorphone, fentanyl,
codeine, methadone, morphine, oxycodone, oxycodone and ASA,
oxycodone and acetaminophen, pentazocine,
acetaminophen/caffeine/codeine, acetaminophen/codeine,
acetaminophen, acetylsalicylic acid, ibuprofen, naproxen sodium,
naproxen, indomethacin, diclofenac, mefenamic acid, ketorolac,
celecoxib, erotamin, sumatriptan, butorphanol, zolmitriptan,
naratriptan, rizatriptan, almotriptan, apazone, benzpiperylon,
benzydramine, caffeine, clonixin, ethoheptazine, flupirtine,
nefopam, orphenadrine, propacetamol, or propoxyphene.
[0281] An opthalmic preparation can be an anti-angiogenic
ophthalmic agent (e.g., aflibercept, ranibizumab, pegaptanib);
cysteamine, ocriplasmin, mitomycin, dapiprazole; a mydriatic (e.g.,
cyclpentolate, phenylephrine, atropine,
cyclopentolate/phenylephrine, homatropine, scopolamine,
phenylephrine/scopolamine, tropicamide,
hydroxyamphetamine/tropicamide, tropicamide); an ophthalmic
anesthetic (e.g, lidocaine, proparacaine, tetracaine); ophthalmic
anti-infectives (e.g., levofloxacin, natamycin,
bactiracin/neomycin/polymyxin b, bactiracin/polymyxin b,
tobramycin, moxifloxacin, ciprofloxacin, gatifloxacin,
azithromycin, idoxuridine, besifloxacin, norfloxacin,
chloramphenicol, bacitracin/polymyxin b, sulfacetamide sodium,
chloramphenicaol, boric acid, erythromycin, sulfisoxazole,
gentamin, gramicidin/neomycin/polymyxin b, bacitracin, ofloxacin,
polymyxin b/trimethoprim, levofloxacin, sulfacetamide sodium,
oxytetracycline/polymyxin b, tobramycin, vidarabine, trifluridine,
ganciclovir, gatifloxacin); an ophthalmic anti-inflammatory agent
(e.g., bromfenac, nepafenac, ketorolac, cyclosporine, fluriprofen,
suprofen, diclofenac, bromfenac); ophthalmic antihistamine and
decongestant (e.g., ketotifen, nedocromil, azelastine, epinastine,
olopatadine, naphazoline/pheniramine, olopatadine, alcaftadine,
cromolyn, bepotastine, pemirolast, tetrhydrozolien,
tetrahydrozoline/zinc sulfate, iodoxamide, naphazoline,
phenylephrine, tetrhydrozoline, naphazoline/zinc sulfate,
emedastine, naphazoline/pheniramine, levocabastine); an ophthalmic
glaucoma agent (e.g., travoprost, dorzolamide/timolol, bimatoprost,
latanoprost, brimonidine, brimonidine/timolol, timolol,
levobunolol, brinzolamide, levobetaxolol, carbachol,
dorzolamide/timolo, epinephrine/pilocarpine, epinephrine,
demecarium bromide, apraclonidine, pilocarpine, acetylcholine,
metipranolol, echothiophate iodide, dipivefrin, unoprostone,
dorzolamide, tafluprost); an ophthalmic steroid (e.g.,
dexamethasone, fluocinolone, loteprednol, difluprednate,
fluorometholone, loteprednol, prednisolone, medrysone,
triamcinolone, rimexolone); an opthlamic steroid with an
anti-infective (e.g., fluorometholone/sulfacetamide sodium,
dexamethasone/meomycin, dexamethasone/tobramycin,
dexamethasone/neomycin/polymyxin b), or orbetaxolol.
[0282] An osteoporosis preparation can be alendronate, ibandronate,
calcium carbonate, calcium/vitamin D, estradiol, teriparatide,
hydrochlorothiazide, calcitonin, conjugated estrogens, conjugated
estrogens/medroxyprogesterone, denosumab, zoledronic acid,
ibandronate, calcium glubionate, dihydrotachysterol, etidronate,
esterified estrogens, raloxifene, alendronate/cholecalciferol,
calcium phosphate tribasic, conjugated
estrogens/medroxyprogesterone, calcium lactate, estropitate,
risedronate or raloxifene.
[0283] A pain medication can be ibuprofen, hydroxyzine, celecoxib,
meperidien, hydromorphone, amitriptyline,
acetaminophen/hydrocodone, acetaminophen/codeine, tapentadol,
acetaminophen/diphenhydramine, oxymorphone, oxycodone,
acetaminophen, ketorolac, tramadol, diclonfenac,
diphenhydramine/ibuprofen, naproxen,
acetaminophen/phenyltoloxamine, aspirin/hydrocodone,
acetaminophen/pheyltoloxamine, aspirin/caffeine, lidocaine,
flurbiprofen, fentanyl, ketoprofen, aluminum
hydroxide/aspirin/calcium carbonate/magnesium, trolamine
salicylate, morphine, nortriptyline, capsaicin,
aspirin/hydrocodone, magnesium salicylate,
aspirin/caffeine/salicylamide, benzocain, camphor/menthol,
valdecoxib, buprenorphine, aspirin/butalbital/caffeine,
acetaminophen/caffeine/phenyltoloxamine/salicylamide,
acetaminophen/codeine, clonidine, celecoxib,
benzocaine/dextromethorphan, benzocaine, cholline
salicylcate/magnesium salicylate,
acetaminophen/dextromethorphan/doxylamine, sulindac, methol,
ibuprofen/oxycodone, acetaminophen/gauifenesin,
acetaminophen/diphenhydramine, pramoxine, aspirin/hydrocodone,
acetaminophen/propoxyphene, propoxylphene,
aspirin/caffeine/propoxyphene, oxycodone, meperidine, morphine
liposomal, diphenhydramine, hydromorphone,
diphenhydramine/magnesium salicylate, diflunisal, methadone,
capsaicin, acetaminophen/phenyltoloxamine/salicylamide,
acetaminophen/caffeine/magnesium, morphine/naltrexone,
aspirin/codeine, acetaminophen/oxycodone, aspirin/meprobamate,
acetaminophen/aspirin, acetaminophen/caffeine, bupivacaine
liposome, aspirin/butalbital/caffeine, piroxicam,
pentafluoropropane/tetrafluoroethane, indomethacin,
acetaminophen/aspirin/caffeine/salicylamide, levorphanol, etodolac,
meclofenamate, meperidine/promethazine, fenoprofen, nalbuphine,
tapentadol, oxymorphone, acetaminophen/caffeine/dihydrocodeine,
aspirin/caffeine/propxoyphene, menthol, mefenamic acid,
propoxyphene, pramoxine, ziconotide, butorphanol,
acetaminophen/pentazocine, pentazocine, naloxone/pentazocine,
imipramine, tolmetin, acetaminophen/tramadol,
acetaminophen/dextromethorphan, choline salicylate/magnesium
salicylate, hydrocodone/ibuprofen, rofecoxib, or diclofenac. A pain
medication can be a nonsteroidal anti-inflammatory drug (NSAID), a
corticosteroid, an opoid, a muscle relaxant, an anti-anxiety drug,
an antidepressant, or an anticonvulsant.
[0284] An anti-anxiety or panic disorder medication can be
alprazolam, clomipramin, lorazepma, nortriptyline, buspirone,
venlafaxine, clonazepam, lorazepam, maprotiline, paroxetine,
fluoxetine, nefazodone, imipramine, sertraline; a serotonin and
norepinephrine reuptake inhibitor (e.g., venlafaxine
hydrochloride); a benzodiazepine (e.g., alprazolam, clonazepam, or
lorazepam); or a selective serotonin reuptake inhibitor (SSRI;
e.g., fluoxetine, paroxetine, or sertraline). A panic disorder
medication can be a tricyclic antidepressant (TCA; imipramine
hydrochloride, desipramine, clomipramine) or a monoamine oxidase
inhibitor (MAOI; e.g., isocaroxazid, phenelzine, tranylcypromine).
An anti-anxiety or panic medication can be lemon balm (Melissa
officinalis), ibergoast (caraway, chamomile, licorice, milk
thistle, and peppermint), hops (Humulus lupulus), lemon juice,
ground ginger, honey, catnip, chamomile (Matricaria recutita),
fennel, L-theanine, Kava Kava, Motherwort, Passionflower, Skullcap
(Scutellaria lateriflora), omega-3, Valerian (Valeriana
officinalis), lavender (Lavandula hybrida), St. John's Wort,
magnesium vitamin B12, vitamin B1, Aconitum napellus, Argentum
nitricum, Arsesnicum album, Gelsemium sempervirens, Natrum
muriaticum, Calcarea carbonica, Ignatia amara, Kali arsenicosum,
Kali phosphoricum, Lycopodium clavatum, Natrum muriaticum,
phosphorus, Pulsatilla, Silicea (Silica), Aconite (Aconitum
napellus), Ignatia amara, Mercurius solubilis, phosphorus, sulphur,
borax, Bryonia, Casticum, Anacardium, or Valerian Root.
[0285] A prostaglandin can be epoprostanol, dinoprostone,
misoprostol, or alprostadil.
[0286] A respiratory agent can be an antiasthmatic combination
(e.g., dyphylline/guaifensin, guaifenesin/theophylline), an
antihistamine (e.g., fexofenadine, loratadine, phenindamine,
dexchlorpheniramine, terfenadine, triprolidine, promethazine,
brompheniramine, chlorpheniramine, cetirizine, diphenhydramine,
carbinoxamine, diphenhydramine, chlorpheniramine, cyproheptadine,
levocetirizine, desloratadine, clemastine, astemizole,
tripelennamine, carboxamine,
pheniramine/phenyltoloxamine/pyrilamine); an antitussive (e.g.,
carbetapentane, benzonatate, dextromethorphan); a bronchodilator
(e.g., an adrenergic bronchodilator (e.g., epinephrine,
isoproterenol, salmeterol, levalbuterol, arformoterol,
metaproterenol, terbutaline, pirbuterol, albuterol, formoterol,
indacaterol, racepinephrine, isoetharine, isoproterenol,
bitolterol); an anticholinergic bronchodilator (e.g., ipratropium,
aclidinium, tiotropium, ipratropium); a bronchodilator combination
(e.g., fluticasone/salmeterol, albuterol/ipratropium,
budesonide/formoterol, formoterol/mometasone,
isoproterenol/phenylephrine); a methylxanthine (e.g., theophylline,
oxtriphylline, dyphylline, aminophylline)); a decongestant (e.g.,
pseudoephedrine, phenylephrine, phenylpropanolamine,
pseudophedrine); an expectorant (e.g., guaifenesin, potassium
iodide, carbocysteine, or potassium guaiacolsulfonate); a
leukotriene modifier (e.g., zafirlukast, monteukast, zileuton); a
lung surfactant (e.g., poractant, calfactant, lucinactant,
beractant); alpha 1-proteinase inhibitor, dornase alpha, sodium
chloride, nitric oxide); an inhaled anti-infective (e.g.,
tobramycin, ribavirin, zanamivir, pentamidine); an inhaled
corticosteroid (e.g., flunisolide, budesonide, fluticasone,
beclomethasone, mometasone, ciclesonide); a mast cell stabilizer
(e.g., cromolyn, nedocromil); a mucolytic (e.g., acetylcysteine); a
selective phosphodiesterase-4 inhibitor (e.g., roflumilast);
loratadine/pseudoephedrine,
acetaminophen/chlorpheniramine/pseudoephedrine,
chlorpheniramine/phenylephrine,
acetaminophen/diphenhydramine/phenylephrine,
brompheniramine/pseudoephedrine, codeine/guaifenesin,
chlorpheniramine/dextromethorphan/phenylephrine,
dextromethorphan/phenylephrine/pyrilamine,
acetaminophen/chlorpheniramide/pheylephrine,
guaifenesin/pseudoesphedrine, chlorpheniramine/phenylpropanolamine,
carbetapentane/pseudoephedrine/pyrilamine,
acetaminophen/chlorpheniramine/codeine,
chlorpheniramine/dextromethorphan/pseudoephedrine,
chlorcyclizine/phenylephrine, chlorpheniramine/pseudoephedrine, or
chlorpheniramine/phenylpropanolamine. In some cases, the
respiratory agent is albuterol, ephedrine, epinephrine, fomoterol,
metaproterenol, terbutaline, budesonide, ciclesonide,
dexamethasone, flunisolide, fluticasone propionate, triamcinolone
acetonide, ipratropium bromide, pseudoephedrine, theophylline,
montelukast, zafirlukast, ambrisentan, bosentan, enrasentan,
sitaxsentan, tezosentan, iloprost, treprostinil, or
pirfenidone.
[0287] A sedative or hypnotic can be a barbiturate (e.g.,
amobarbital, pentobarbital, secobarbital, phenobarbitol); a
benzodiazepine (e.g., clonazepam, diazepam, estrazolam,
flunitrazepam, lorazepam, midazolam, nitrazepam, oxazepma,
trazolam, temazepma, chlordiazepoxide, alprazolam,); an herbal
sedative (e.g., ashwagandha, Duboisia hopwoodii, Prosanthera
striatiflora, catnip, kava, mandrake, valerian, marijuana); a
non-benzodiazpein "z-drug" sedative (e.g., eszopiclone, zaleplon,
zolpidem, zopiclone); an antihistamine (e.g., diphenhydramine,
dimenhydrinate, doxylamine, pheneragn, promethazine), chloral
hydrate, or alcohol. In some cases, the sedative or hypnotic is
butalbital, chlordiazepoxide, diazepam, estazolam, flunitrazepam,
flurazepam, lorazepam, midazolam, temazepam, triazolam, zaleplon,
zolpidem, zolpidem tartrate, butisol sodim, pentobarbital or
zopiclone.
[0288] A skin or mucous membrane agent can be an antibiotic (e.g.,
bacitracin, bacitracin zinc/polymyxin B sulfate; clindamycin
phosphate, erythromycin/tretinoin, fusidate sodium, fusidic acid;
gramicidin/polymyxin B sulfate; mupirocin; polymyxin B
sulfate/bacitracin); an antiviral (e.g., acyclovir, idoxuridine);
an antifungal (e.g., clotrimazole, ketoconazole, miconazole
nitrate, nystatin, terbinafine HCl, terconazole, tolnaftate); a
scabicide or pediculicide (e.g., crotamiton, isopropyl myristate,
lindane, permethrin; piperonyl butoxide/pyrethrins); benzoyl
peroxide, chlorheidine acetate, chorhexidine gluconate, hydrogen
peroxide, metronidazole; metronidazole/avobenzone/octinoxate,
metronidazole/nystatin, povidone-iodine, selenium sulfide, silver
sulfadiazine, triclosan; an anti-inflammatory agent (e.g.,
amcinonide, beclomethasone dipropionate, betamethaseon dipropionate
in propylene glycol, betamethasone dipropionate/clotrimazole,
betamethasone dipropionate/salicyclic acid, betamethasone valerate,
budesonide, clobetasol propionate, clobetasone butyrate, desonide,
desoximetasone, diflucortolone valerate, diflucortolone
valerate/salicyclic acid, fluocinolone acetonide, fluocinonide,
fluticasone propionate, halobetasol propionate, hydrocortisone,
hydrocortisone acetate, hydrocortisone acetate/zince sulfate,
hydrocortisone acetate/zinc sulfate/prmoxine HCl, hydrocortisone
valerate, hydrocortisone/dibucaine HCVesculin/framycetin sulfate;
hydrocortisone/urea, mometasone furoate, triamcinolone acetonide);
an anipruritic or local anesthetic (e.g., lidocaine HCl,
lidocaine/prilocaine); a cell stimulate or proliferant (e.g.,
tretinoin); a basic ointment or protectant (e.g., dimethicone,
petrolatum, zinc oxide); a keratolytic agent (e.g., adapalene,
canthadridin/podphyllin/salicyclic acid, dithranol,
formaldehyde/lactic acid/salicyclic acid, latic acid/salicyclic
acid, podofilox, podophyllin, salicyclic acid); a keratoplastic
agent (e.g., coal tar, coal tar/juniper tar/pine tar; coal
tar/juniper tar/pine tar/zinc pyrithione, coal tar/salicylic acid,
coal tar/salicyclic acid/sulfur); a pigmenting agent (e.g.,
methoxsalen); acitretin, azelaic acid, calcipotriol, capsaicin,
collagenase, fluorouracil, iostretinoin, pimecrolimus, tacrolimus,
tazarotene, or vitamin E. In some cases, a skin or mucous membrane
agent is isotretinoin, bergapten or methoxsalen.
[0289] A smoking cessation aid can be topiramate, fluphenazine,
varenicline, nortriptyline, bupropion, clonidine, nicotine, or
tryptophan.
[0290] A Tourette's syndrome agent can be pimozide, topiramate,
olanzapine, clonidine, guanfacine, haloperidol, botulinum toxin
type A, methylphenidate, dextroamphetamine, or pergolide.
[0291] A urinary tract agent can be lactobacillus acidophilus,
amoxicillin, cefazolin, amoxicillin/clavulante,
sulfamethoxazole/trimethoprim, cefuroxime, ciprofloxacin,
ertapenem, levofloxacin, nitrofurantoin, ceftriaxone, cefixime,
ampicillin/sulbactam, doxycycline, piperacillin/tazobactam,
hyoscyamine/methenamine/methylene blue/phenyl salicylate,
doripenem, cefadroxil, acetohydroxamic acid, nitrofurantoin,
methenamine, lomefloxacin, cefepime, cefoxitin, tolteridine,
darifenicin, propantheline bromide, or oxybutynin.
[0292] A vertigo agent can be promethazine, diphenidol, betahistine
or meclizine.
[0293] An insomnia medication can be 5-hydroxytryptophan,
diphenhydramine/ibuprofen, zolpidem, lorazepam, flurazepam,
amitriptyline, triazolam, eszopiclone, estazolam, temezepam,
ramelteon, doxepin, doxylamine, zaleplon,
acetaminophen/diphenhydramine, diphenhydramine,
5-hydroxytryptophan, tryptophan, chloral hydrate,
diphenhydramine/magnesium salicylate, quazepam, eszopiclone,
secobarbital, doxepin, olanzapine, clonazepam, quazepam, lorazepam,
alprazolam, oxazepam, prazepam, flunitrazepam, melatonin, valerian
root, chamomile tea, lemon balm, or 5-L-5-hydroxytryptophan.
[0294] A weight loss drug can be megestrol, phentermine/topirmate,
phentermine, phenylpropanolamine, lorcaserin, oxandrolone,
megestrol, mazindol, orlistat, sibutramine, rimonabant, metformin,
exenatide, pramlintide, conjugated linoleic acid, green tea
extract, khat, lipoic acid, ECA stack, or raspberry ketone.
[0295] An herb, supplement, or vitamin can be aloe, arginine,
beta-carotene, black cohosh, chocolate, chondriotin sulfate, coca,
coenzyme Q10, cranberry, creatine, DHEA (dehydroepiandrosterone),
dong quai, Echinacea, ephedra, evening primrose oil, flaxseed,
flaxseed oil, folate, ginkgo, glucosamine, honey, Lactobacillus
acidophilus, lycopene, marijuana, melatonin, milk thistle, niacin,
omega-3 fatty acid, fish oil, alpha-linolenic acid, red yeast rice,
SAMe (adenosylmethionine), saw palmetto, soy, St. John's wort, tea
tree oil, thiamin, vitamin A, vitamin B12, vitamin B6, vitamin C,
vitamin D, vitamin E, whey protein, or zinc. An herb can be a
medicinal herb. A medicinal herb can be absinthe wormwood
(Artemisia absinthium), agrimony (Agrimonia eupatoria), aloe vera
(Aloe barbadensis Miller), alpine rose (Rhododendron ferrugineum),
angelica (Angelica silvestris), anise (Pimpinella anisum), arnica
(Arnica montana), ash (Fraxinus excelsior), asparagus (Asparagus
officinalis), barberry (Berberis vulgaris), barley (Hordeum
sativum), basil (Ocimum basilicum), bean (Phaseolus vulgaris),
bearberry (Arctostaphylos uva ursi), beet (Beta vulgaris), betony
(Betonica officinalis), bilberry (Vaccinium myrtillus), birch
(Betula pendula), birdweed (Polygonum aviculare), bistort
(Polygonum bistorta), bitter dock (Rumex obtusifolis), bitter root
(Gentiana lutea), bitterwort (Gentiana lutea), blackberry (Rubus
fruticosus), black chokeberry (Aronia melanocarpa), black currant
(Ribes nigrum), black locust (Robinia pseudoacacia), blackthorn
(Prunus spinosa), blue gum tree (Eucalyptus globulus), borage
(Borago officinalis), broadleaf dock (Rumex obtusifolis),
broad-leaved dock (Rumex obtusifolis), broccoli (Brassica oleracea
var. botrytis), burdock (Arctium lappa), burnet saxifrage
(Pimpinella saxifraga), butcher's broom (Ruscus aculeatus), calamus
(Acorus calamus), calendula (Calendula officinalis), cannabis
(Cannabis sativa), caraway (Carum carni), canine thistle (Carlina
acaulis), carrot (Daucus carota), cat's claw (Uncaria tomentosa),
celery (Apium graveolens), centaury (Centaurium umbellatum),
chamomile (Matricaria chamomilla), chasteberry (Vitex
agnus-castus), chickory (Cichorium intybus), christ's thorn
(Paliurus spina-christi), church steples (Agrimonia eupatoria),
cinnamon (Cinnamomum zeylandicum), cinquefoil (Potentilla reptans),
cleavers (Galiuma aparine), clove (Syzygium aromaticum), clubmoss
(Lycopodium clavatum), coltsfoot (Tussilago farfara), comfrey
(Symphytum officinale), common ivy (Hedera helix), common polypody
(Polypodium vulgare), coriander (Coriandrum sativum), corn (corn
silk) (Zea mays), couch grass (Agropyron repens), cowslip (Primula
veris), cranberry (Vaccinium oxycoccos), cranesbill (Geranium
macrorrhizum), creeping cinquefoil (Potentilla reptans), creeping
thyme (Thymus serpyllum), cross gentian (Gentiana cruciata), daisy
(Bellis perennis), dandelion (Taraxacum officinale), dill (Anethum
graveolens), dog rose (Rosa canina), dogwood (Cornus mas), dwarf
everlast (Helichrysum arenarium), echinacea (Echinacea
angustifolia), elder (Sambucus nigra), elderberry (Sambucus nigra),
elecampane (Inula helenium), european cornet (Cornus mas), european
wild ginger (Asarum europaeum), evening primrose (Oenothera
biennis), evening star (Oenothera biennis), everlasting flower
(Helichrysum arenarium), eyebright (Euphrasia officinalis), fennel
(Foeniculum vulgare), fenugreek (Trigonella foenum-graecum), fig
(Ficus carica), flax (Linum usitatissimum), garden nasturtium
(Tropaeolum majus), garlic (Allium sativum), garland thorn
(Paliurus spina-christi), ginger (Zingiber officinalis), ginkgo
(Ginkgo biloba), ginseng (Araliaceae>Panax), glossy buckthorn
(Rhamnus frangula), goat willow (Salix caprea), goosegrass (Galiuma
aparine), goldenrod (Solidago virgaurea), gotu kola (Centella
asiatica), grape vine (Vitis vinifera), greater celandine
(Chelidonium majus), great sallow (Salix caprea), great yellow
gentian (Gentiana lutea), green tea (Camellia sinensis),
green-winged orchid (Orchis morio), ground ivy (Glechoma
hederacea), gypsyweed (Veronica officinalis), haselwort (Asarum
europaeum), hawthorn (Crataegus laevigata), heartsease (Viola
tricolor), hibiscus (Hibiscus), hops (Humulus lupulus), horehound
(Marrubium vulgare), horse chestnut (Aesculus hippocastanum),
horse-heal (Inula helenium), horsetail (Equisetum arvense),
houseleek (Sempervivum tectorum), hyssop (Hyssopus officinalis),
iceland moss (Cetraria islandica), indian cress (Tropaeolum majus),
ivy (Hedera helix), johnny jump up (Viola tricolor), juniper
(Juniperus communis), kidney vetch (Anthyllis vulneraria),
knotgrass (Polygonum aviculare), lady's bedstraw (Galium verum),
lady's mantle (Alchemilla vulgaris), larch (Larix europaea),
large-leaved lime (Tilia platyphyllos), large-leaved linden (Tilia
platyphyllos), lavender (Lavandula angustifolia), lemon balm
(Melissa officinalis), lemon, citron (Citrus medica), lily of the
walley (Convallaria majalis), linseed (Linum usitatissimum),
liquorice (Glycyrrhiza glabra), loosestrife (Lythrum salicaria),
lovage (Levisticum officinale), lungwort (Pulmonaria officinalis),
mallow (Malva silvestris), marigold (Calendula officinalis),
marjoram (Majorana hortensis), marshmallow (Althaea officinalis),
melilot, yellow (Melilotus officinalis), milk thistle (Silybum
marianum), mint (Mentha piperita), mistletoe (Viscum album), monks
cress (Tropaeolum majus), mountain germander (Teucrium montanum),
mouse-ear hawkweed (Pilosella officinarum), mulberry, black (Morus
nigra), mulberry, white (Morus alba), mullein (Verbascum thapsus),
mustard, black (Brassica nigra), mustard, white (Sinapis alba), oak
(Quercus), oat (Avena sativa), olive (Olea europaea), onion (Allium
cepa), orchid (Orchis morio), oregano (Origanum vulgare), parsley
(Petroselinum hortense), peach (Prunus persica), peppermint (Mentha
piperita), pigweed (Polygonum aviculare), pink ip (Tabebuia
impetiginosa), plantain, greater (Plantago major), plantain,
ribwort (Plantago lanceolata), plum (Prunus domestica), polypody
(Polypodium vulgare), pomergranate (Punica granatum), pumpkin
(Cucurbita pepo L), purple chokeberry (Aronia prunifolia), pussy
willow (Salix caprea), quackgrass (Agropyron repens), quince
(Cydonia oblonga), radish (Raphanus sativus), raspberry (Rubus
idaeus), ramsons (Allium ursinum), red chokeberry (Aronia
arbutifolia), red currant (Ribes rubrum), rest harrow (Ononis
spinosa), rose de mai (Rosa centifolia), rosemary (Rosmarinus
officinalis), rupturewort (Herniaria glabra), rustyback (Ceterach
officinarum), sage (Salvia officinalis), salad burnet (Sanguisorba
minor), saw palmetto (Serenoa Repens), scots pine (Pinus
silvestris), senna (Cassia angustifolia), sesame (Sesamum indicum),
shepard's purse (Capsella bursa-pastoris), silver thistle (Carlina
acaulis), speedwell (Veronica officinalis), starflower (Borago
officinalis), sticklewort (Agrimonia eupatoria), stickyweed
(Galiuma aparine), stickywilly (Galiuma aparine), stinging netle
(Urtica dioica), st john's wort (Hypericum perforatum), strawberry
(Fragaria), stone fern (Ceterach officinarum), sunflower
(Helianthus annuus), sweetclover, yellow (Melilotus officinalis),
sweet flag (Acorus calamus), sweet woodruff (Asperula odorata),
taheebo tea (Tabebuia impetiginosa), tarragon (Artemisia
dracunculus), thyme (Thymus vulgaris), tetterwort (Chelidonium
majus), toadflax (Linaria vulgaris), tormentil (Potentilla
tormentilla), valerian (Valeriana officinalis), vervian (Verbena
officinalis), violet (Viola odorata), wall germander (Teucrium
chamaedrys), walnut (Juglans regia), water dropwort (Oenanthe
aquatica), waterlily (Nymphaea alba), white lotus (Nymphaea alba),
wild apple (Malus sylvestris), wild cherry (Prunus serotina), wild
ginger (Asarum europaeum), wild pansy (Viola Tricolor), wild pear
(Pyrus piraster), wild strawberry (Fragaria vesca), wild thyme
(Thymus serpyllum), willow herb (Epilobium parviflorum), winter
savory (Satureja montana), woodruff (Asperula odorata), wormwood
(Artemisia absinthium), woundwort (Solidago virgaurea), yarrow
(Achilea millefolium), yellow sweetclover (Melilotus officinalis),
or yucca (Agavaceae).
[0296] An agent can be one that is, or can be made to be,
vaporizable. In some cases, the drug can be a heat stable drug.
Exemplary drugs include acebutolol, acetaminophen, alprazolam,
amantadine, amitriptyline, apomorphine diacetate, apomorphine
hydrochloride, atropine, azatadine, betahistine, brompheniramine,
bumetanide, buprenorphine, bupropion hydrochloride, butalbital,
butorphanol, carbinoxamine maleate, celecoxib, chlordiazepoxide,
chlorpheniramine, chlorzoxazone, ciclesonide, citalopram,
clomipramine, clonazepam, clozapine, codeine, cyclobenzaprine,
cyproheptadine, dapsone, diazepam, diclofenac ethyl ester,
diflunisal, disopyramide, doxepin, estradiol, ephedrine, estazolam,
ethacrynic acid, fenfluramine, fenoprofen, flecainide,
flunitrazepam, galanthamine, granisetron, haloperidol,
hydromorphone, hydroxychloroquine, ibuprofen, imipramine,
indomethacin ethyl ester, indomethacin methyl ester, isocarboxazid,
ketamine, ketoprofen, ketoprofen ethyl ester, ketoprofen methyl
ester, ketorolac ethyl ester, ketorolac methyl ester, ketotifen,
lamotrigine, lidocaine, loperamide, loratadine, loxapine,
maprotiline, memantine, meperidine, metaproterenol, methoxsalen,
metoprolol, mexiletine HCl, midazolam, mirtazapine, morphine,
nalbuphine, naloxone, naproxen, naratriptan, nortriptyline,
olanzapine, orphenadrine, oxycodone, paroxetine, pergolide,
phenyloin, pindolol, piribedil, pramipexole, procainamide,
prochloperazine, propafenone, propranolol, pyrilamine, quetiapine,
quinidine, rizatriptan, ropinirole, sertraline, selegiline,
sildenafil, spironolactone, tacrine, tadalafil, terbutaline,
testosterone, thalidomide, theophylline, tocamide, toremifene,
trazodone, triazolam, trifluoperazine, valproic acid, venlafaxine,
vitamin E, zaleplon, zotepine, amoxapine, atenolol, benztropine,
caffeine, doxylamine, estradiol 17-acetate, flurazepam,
flurbiprofen, hydroxyzine, ibutilide, indomethacin norcholine
ester, ketorolac norcholine ester, melatonin, metoclopramide,
nabumetone, perphenazine, protriptyline HCl, quinine, triamterene,
trimipramine, zonisamide, bergapten, chlorpromazine, colchicine,
diltiazem, donepezil, eletriptan, estradiol-3,17-diacetate,
efavirenz, esmolol, fentanyl, flunisolide, fluoxetine, hyoscyamine,
indomethacin, isotretinoin, linezolid, meclizine, paracoxib,
pioglitazone, rofecoxib, sumatriptan, tolterodine, tramadol,
tranylcypromine, trimipramine maleate, valdecoxib, vardenafil,
verapamil, zolmitriptan, zolpidem, zopiclone, bromazepam,
buspirone, cinnarizine, dipyridamole, naltrexone, sotalol,
telmisartan, temazepam, albuterol, apomorphine hydrochloride
diacetate, carbinoxamine, clonidine, diphenhydramine, thambutol,
fluticasone proprionate, fluconazole, lovastatin, lorazepam
N,O-diacetyl, methadone, nefazodone, oxybutynin, promazine,
promethazine, sibutramine, tamoxifen, tolfenamic acid,
aripiprazole, astemizole, benazepril, clemastine, estradiol
17-heptanoate, fluphenazine, protriptyline, ethambutal,
frovatriptan, pyrilamine maleate, scopolamine, and triamcinolone
acetonide or pharmaceutically acceptable analogs or equivalents
thereof.
[0297] In some cases, an agent is a parasympathomimetic alkaloid.
In some cases, the parasympathomimetic alkaloid is nicotine,
arecoline, muscarine, or pilocarpine.
[0298] In some cases, an agent is a nicotinic acetylcholine
receptor agonist. In some cases, the nicotinic acetylcholine
receptor agonist is nicotine, acetylcholine, choline, epibatidine,
lobeline, or varenicline.
[0299] In some cases, an agent inhibits chromatin modifying enzymes
(e.g., class I and II histone deaceytlases). In some cases, an
agent that inhibits chromation modifying enzymes is nicotine.
[0300] In some cases, an agent is a nicotine analog or derivative.
In some cases, the nicotine analog is EVP-6124. In some cases, a
nicotine analog or derivative is described, e.g., in U.S. Patent
Application Publication Nos. 20130157995, 20090234129, 20080108822,
20070186940, or 20080227088 or U.S. Pat. Nos. 4,243,605, 5,015,741,
6,503,922, 6,995,265, or 7,132,545.
[0301] In some cases, a combination of at least or at most 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20
agents is used. In some cases, a combination of between 1-2, 2-4,
4-6, 6-8, 8-10, 10-12, 12-14, 14-16, 16-18, or 18-20 agents is
used. In some cases, a combination of between 1-5, 5-10, 10-15, or
15-20 agents is used.
[0302] Formulations
[0303] Any agent as provided herein for use in the methods and
devices described herein can be in a formulation comprising one or
more additional substances as provided herein. In some cases, the
formulation comprising an agent (e.g., nicotine) and one or more
additional substances is a liquid formulation. In some cases, the
formulation is liquid at room temperature. In some cases, the
liquid formulation is contained in a reservoir as provided herein
in a device as provided herein and is liquid at an operating
temperature of the device. The operating temperature of any of the
devices as described herein can be at, below, or above room
temperature. In some cases, the liquid formulation comprising a
pharmaceutically active agent (e.g., nicotine) as provided herein
is delivered as a liquid to a heater element as provided herein in
a device as provided herein when a user inhales from the outlet or
mouthpiece of the device. In some cases, the liquid formulation is
not a viscous liquid. In some cases, the liquid formulation is not
gel-like or a gel. In some cases, a liquid formulation comprising a
pharmaceutically active agent (e.g., nicotine) as provided herein
is not coated as a solid or film of any thickness onto a heater
element as provided herein. In some cases, a liquid formulation
comprising nicotine for use in the methods and devices described
herein is not admixed with thickening agents and thereby has a
viscosity that is reduced or is less than a liquid formulation
comprising nicotine that has been admixed with a thickening agent.
In some cases, a liquid formulation for use in the methods and
devices as provided herein is not applied to or coated on a heater
element as provided herein prior to use of the device by a user or
subject as provided herein. In some cases, the liquid formulation
comprising a pharmaceutically active agent is delivered as a liquid
to a heater element in a device as provided herein only upon use of
the device. Use of the device can be a user as provided herein
inhaling or drawings on an outlet or mouthpiece on a device as
provided herein. In some cases, inhalation on the outlet or
mouthpiece draws carrier gas (e.g., air) ino the device through an
inlet on the device as provided herein, wherein the flow of the
carrier gas (e.g., air) through the inlet triggers delivery of a
liquid formulation comprising a pharmaceutically active agent
(e.g., nicotine) by any of the means provided herein to a heater
element contained within the device. The device can comprise one or
more inlets as provided herein, wherein inhalation on an outlet
draws carrier gas (e.g., air) through the one or more inlets
simultaneously.
[0304] In some cases, one or more carriers or excipients is added
to a liquid formulation to change a property of the formulation.
One or more carrriers can be used to change the density,
compressibility, specific weight, viscosity, surface tension, or
vapor pressure of a liquid formulation.
III. eHealth tools
[0305] Overview
[0306] Provided herein are eHealth tools which can include mobile
devices, web-based devices, computer readable medium, and an
eHealth-enabled electronic agent (e.g., nicotine) delivery
platform. In some cases, an eHealth-enabled electronic nicotine
delivery platform can help a smoker transition to clean nicotine
delivery by delivering a pre-determined nicotine dose with a
pre-determined nicotine particle size at a pre-determined time for
an individual user of a device. The eHealth-enabled electronic
nicotine delivery platform can provide nicotine to an individual
user on a particular schedule, which may involve varying the number
of doses per day, timing of doses within the day, or amount of
nicotine per dose over time. In one embodiment, the eHealth-enabled
electronic nicotine delivery platform is used to achieve full
smoking cessation. In another embodiment, the eHealth-enabled
electronic nicotine delivery platform is used to achieve full
nicotine or smoking cessation without relapse to smoking. In
another embodiment, the eHealth-enabled electronic nicotine
delivery platform is used to achieve full nicotine withdrawal
without nicotine withdrawal symptoms. In another embodiment, the
eHealth-enabled electronic nicotine delivery platform is used in
conjunction with other nicotine replacement therapies, nicotinic
agonist or partial agonists (e.g., varenicline or any other
.alpha..sub.4.beta..sub.2 subtype of the nicotinic acetylcholine
receptor) to help achieve a particular smoking goal (e.g., complete
cessation). In another embodiment, the eHealth tools can help to
ensure user safety when administering doses of nicotine from an
electronic nicotine delivery device, so as to prevent overdose.
[0307] The methods can be applied to a variety of types of
classifications of users of combustible tobacco products, including
a new smoker, a trough maintainer smoker, an intermittent smoker, a
light smoker, a weight-loss smoker, a heavy smoker, or a very heavy
smoker. An intermittent smoker can be an individual who does not
smoke every day. A light smoker can be an individual who smokes 1
to 9 cigarettes per day. A moderate smoker can be an individual who
smokes 10 to 19 cigarettes a day. A heavy smoker can be an
individual who smokes 20 to 29 cigarettes per day. A very heavy
smoker can be an individual who smokes 30 or more cigarettes per
day. Different smokers may require different approaches to
facilitate their transition from smoking.
[0308] Provided herein is a method for managing treatment of a
condition. The method can comprise providing a device for
generating a condensation aerosol comprising a pharmaceutically
active agent. The pharmaceutically active agent can be an agent as
provided herein. In some cases, the condition is smoking or
nicotine addiction. In some cases, the pharmaceutically active
agent is nicotine. The device for generating the condensation
aerosol can be device as provided herein. The device can comprise a
heater element. The heater element can be any heater element as
provided herein. The heater element can vaporize a composition
comprising the pharmaceutically active agent. In some cases, the
formulation is a liquid formulation. The heater element can be in
fluid communication with a source of the formulation. The source of
the formulation can be a reservoir. The heater element can be in
fluid communication with a passageway configured for permiting the
condensation of the vaporized formulation to produce particles
comprising a size effective for deep lung delivery. The size of the
particles can have an MMAD of about 1 to about 5 um. The device can
further comprise a programmable controller, wherein the
programmable controller comprises a non-transitory computer
readable medium comprising one or more algorithms, and an interface
for communicating with the programmable controller, wherein the
interface is capable of receiving information from and/or
transmitting information to a source. The source can be a user of
the device, a healthcare provider and/or a counselor. The methods
provided herein can include inputting, receiving and/or recording
data on the device; analyzing the data; and regulating a dosage,
frequency of administration and/or delivery schedule of the
condensed formulation comprising the pharmaceutically active agent
based on the analysis of the data by the one or more algorithms.
The method as provided herein can also comprise adjusting the
dosage, frequency of administration and/or delivery schedule of the
condensed formulation comprising the pharmaceutically active agent
based on the information received from the source. The inputting,
analysis, regulating, and, optionally, adjusting can be repeated in
order to manage treatment of the condition. Prior to a user
engaging in a method or using a device as provided herein for a
first time, the dosage, frequency of administration and/or delivery
schedule of the condensed formulation comprising the
pharmaceutically active agent can be pre-set by a source. The
analysis of the data can be performed by the one or more
algorithms. The regulation the dosage, frequency of administration
and/or delivery schedule of agent as provided herein can be based
on an analysis of the data by the one or more algorithms.
[0309] Provided herein is a method for facilitating smoking
cessation. The method can comprise providing any device for
generating a condensation aerosol comprising a pharmaceutically
active agent as provided herein, wherein the device comprises a
programmable controller. The pharmaceutically active agent can be
nicotine. In some cases, the subject inhales the condensation
aerosol produced by the device a plurality of times, wherein
inhaling a plurality of times produces a desired nicotine blood
concentration. The desired nicotine plasma concentration can be a
plasma concentration. In some cases, the desired plasma
concentration can be an arterial plasma concentration. In some
cases, the desired plasma concentration can be a venous plasma
concentration. The desired nicotine plasma concentration can be
about, more than, less than, or at least 1%, 2%, 3%, 4%, 5%, 6%,
7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%,
30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%,
43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%,
56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%,
69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%,
82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%, 96%, 97%, 98%, 99%, or 100% of the nicotine plasma
concentration achieved by smoking a cigarette. The desired nicotine
plasma concentration can be between 1%-10%, 10%-20%, 20%-30%,
30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, or 90%-100%
of the nicotine plasma concentration achieved by smoking a
cigarette. The desired nicotine plasma concentration can be about
1% to about 10%, about 10% to about 20%, about 20% to about 30%,
about 30% to about 40%, about 40% to about 50%, about 50% to about
60%, about 60% to about 70%, about 70% to about 80%, about 80% to
about 90%, or about 90% to about 100% of the nicotine plasma
concentration achieved by smoking a cigarette. Smoking a single
cigarette can produce peak increments of plasma nicotine
concentration of 5-30 ng/ml. The peak increments of plasma nicotine
concentration from smoking a cigarette can be achieved within 10
minutes. The methods provided herein further comprise altering the
dosage, frequency of administration, and/or delivery schedule of
the condensation aerosol in order to alter the arterial nicotine
plasma concentration. The alteration of the dosage, frequency of
administration, and/or delivery schedule of the condensation
aerosol can facilitate smoking cessation. In some cases, the dosage
of the pharmaceutically active agent inhaled during each of the
plurality of inhalations can be a percentage of a total dosage
required for a specific period of time. The period of time can be a
day, wherein each inhalation of the plurality of inhalations can be
a percentage of the daily dosage. Each inhalation can be about,
more than, less than, or at least 1%, 5%, 10%, 15%, 20%, 25%, 30%,
33%, 50%, or 100% of a total dosage.
[0310] An eHealth tool can be a healthcare practice supported by
electronic processes and/or communication. In some cases, eHealth
tools comprise healthcare practice using the Internet. The eHealth
tools can be formatted for use by different types of smokers,
including a new smoker, a weight loss smoker, a trough maintainer,
a light smoker, a heavy smoker, or a very heavy smoker. The eHealth
tools can be formatted for use by different types of patients who
may be using nicotine to enhance their cognition or otherwise
improve other symptoms of their illness (ulcerative colitis). In
some cases the eHealth tools can communicate with a device
described herein (e.g., through Bluetooth connectivity), or eHealth
tools can be incorporated into a device described herein.
[0311] The eHealth tools provided herein include mechanisms for
tracking use of a device. For example, the frequency of use of a
device can be tracked. Also, provided herein are algorithms for
analyzing the use of a device. The algorithms can be used to
generate goals for a user of the device. In some cases, the
algorithms can suggest a recommended dose of an agent (e.g.,
nicotine) for a user. The algorithms can suggest an agent (e.g.,
nicotine) delivery schedule for a user. Algorithms provided herein
can change over time based on input from a device or feedback from
the user over time. An eHealth nicotine delivery platform described
herein can track use of a nicotine delivery device, assess the user
in terms of their subjective nicotine craving, mood, or other
psychological or behavioral parameters, and adjust nicotine
delivery to accomplish desired effects. Smoking behavior can be
tracked, as can other symptoms of a disease where nicotine is being
used either as a treatment or to enhance deficiencies in cognition
associated with a specific illness.
[0312] A smoking pattern of a user can be monitored, or use of a
device described herein can be monitored. For example, tools
provided herein can be used to determine if smoking or use of a
device provided herein was used to satisfy a morning craving,
determine if smoking occurred, or a device was used, while a
subject was bored, drinking, under stress. Tools can be used to
assess whether a subject smoked or used a device described herein
alone or in the presence of others (e.g., friends), or whether the
dose of nicotine administered was successful in enhancing cognition
or improving another target medical or psychiatric symptom.
[0313] One or more algorithms can be used to devise a plan (e.g.,
nicotine dose, nicotine delivery schedule) for a user. In some
cases, web-based tools can be used to transition a smoker to use of
an electronic nicotine delivery device described herein along with
customized behavioral input.
[0314] The eHealth tools provided herein can be used to enable
smoking cessation, partial smoking cessation (e.g., use of an
electronic nicotine delivery device at work, in public places, or
on a plane), or full nicotine cessation. eHealth tools provided
herein can be used to engage smokers, including teenagers and a
person in their 20s to alter their smoking habits.
[0315] In some cases, the eHealth tools are web-based tools. The
web-based tools can enable an appropriate dosing of nicotine for a
user of a device described herein. In some cases, the web-based
tools can track experiences of a user. In some cases, a web-based
tool can track success in making a transition from smoking.
Web-based tools described herein can track health benefits derived
from using devices described herein. Such tracking can enable
generation of rewards (e.g., decreased health premiums). Web-based
tools can enable development of constantly-improving use algorithms
by obtaining use profiles from a multitude of users in the field,
and can provide feedback to users. In some cases, web-based tools
described herein can leverage social media to produce ideal health
outcomes. The social media can be a social networking site (e.g.,
Facebook, Google+, MySpace, Bebo), blog or microblog (e.g.,
Twitter), a content community (e.g., YouTube), a virtual social
world (e.g., Second Life), a virtual game world (e.g., World of
Warcraft), or a collaborative project (e.g., Wikipedia). Social
media can include technologies such as a blog, picture-sharing,
vlog, wall-posting, email, instant messaging, music-sharing,
crowdsourcing, voice over IP, Internet forums, weblog, social blog,
microblog, wiki, podcast, and social bookmarking. The customized
feedback can also be specific for users suffering from a medical or
psychiatric disorder. For example, nicotine has been shown to have
beneficial effects on cognition among patients with schizophrenia.
The device could be used to deliver nicotine and also provide
therapeutic input to patients to help them manage their nicotine
intake in such a way as to provide maximum therapeutic advantage to
their cognition or psychiatric symptom control. Other disorders
where nicotine has been shown to have beneficial effects on
cognition include Parkinson's disease, attention deficient
disorder, mild cognitive impairment, and Alzheimer's disease.
[0316] In some cases, an eHealth tool is a mobile device. In some
cases, the mobile device is an electronic nicotine delivery device.
The mobile device can ensure dosing occurs at an appropriate time.
The mobile device can comprise on-board tracking of dosing, can
provide reminders to a subject, and can provide nicotine craving
assessments. Also, a mobile device can comprise complementary
advertising opportunities.
[0317] The devices provided herein can comprise electronics that
control for variability in battery condition and ensure consistent
heating.
[0318] Identifying Individualized User Goals
[0319] Customized goals can enable the same nicotine delivery
platform to be used to achieve multiple beneficial health benefits
for different smokers, from full smoking cessation, to partial
cessation (e.g., no smoking during the workday), to partial or full
nicotine cessation (i.e., stopping nicotine intake entirely), to
cognition remediation. In one embodiment, the customized goals
enable the same nicotine delivery platform to be used to achieve
full smoking cessation. In another embodiment, the customized goals
enable the same nicotine delivery platform to be used to achieve
full nicotine or smoking cessation without relapse. In another
embodiment, the customized goals enable the same nicotine delivery
platform to be used to achieve full nicotine withdrawal without
nicotine withdrawal symptoms.
[0320] eHealth tools can include Web based and mobile tools. For
example, for web-based tools, self-report measures can be used to
help a smoker or new user of a device provided herein identify a
target goal based on their degree of nicotine dependency, health
status, health goals, economic goals (i.e., decrease the amount of
money spent on cigarettes), target body weight or change in body
weight, or other factors. Tests of attentional bias for smoking
stimuli, and other cognitive measures of nicotine dependency, can
be assessed on the web backend or an electronic nicotine delivery
device to assess risk for relapse upon smoking cessation, which can
then be used to identify a pattern of use that will minimize the
odds of relapse to smoking. In some cases, biomarkers, such as
nicotine receptor polymorphisms, information can also be added to a
user's profile to help identify the optimal outcome for an
individual user.
[0321] When a mobile device is used, smoking patterns can be
tracked prior to the transition to an electronic nicotine delivery
platform, which can enable a real world, ecologically valid
assessment of actual behavior to be used as a foundation for a
subsequent prescribed pattern of use of an electronic nicotine
delivery device.
[0322] Algorithm Development
[0323] The high rates of smoking relapse upon cessation (often
greater than 90%) reflect the tremendous heterogeneity in the ways
in which smoking quit attempts fail, even when using NRTs like a
nicotine gum or patch. By systematically tracking user
characteristics at the outset of a quit attempt, tracking their
actual use of the electronic nicotine delivery device over time in
terms of patterns of dosing, and real world risk factors associated
with a smoking relapse, algorithms can be generated that can be
used to suggest an optimal pattern of use, dose, pH, particle size,
and other characteristics (e.g., flavoring) of the electronic
nicotine delivery device to maintain use and minimize the risk of
smoking relapse. These algorithms can be constantly enhanced
through additional user experience, adding to the empirical
foundation of the algorithms and enabling more robust and
finer-grained algorithms to be customized to an individual user's
nicotine dependency and health goals.
[0324] For a mobile device, data can be captured from individual
users in the field and can be sent to a backend web-based central
database for algorithm development. The mobile device can also
assess the ecological risk factors for relapse and adjust the dose
or dose characteristics of nicotine accordingly to help achieve the
desired outcome. An initial trial of several different types of
dose characteristics may also be helpful in determining the ideal
use algorithm.
[0325] In a web-based method, data from real world use of the
electronic nicotine delivery device can be collected and used to
predict outcomes. Users can also pick from one of several
established algorithms that they think will best suit their health
or other goals. The central database can issue instructions back to
the electronic nicotine device, either in the form of explicit
compliance reminders to use the device to achieve the optimal
nicotine absorption, or implicit dosing instructions to the device
to gradually taper the dose (or other characteristics of the
nicotine dose, including its concentration, pH, particle size,
flavorings, or flow characteristics coming from the device which
can affect back of the throat impaction, which in turn can affect
subjective sensations associated with the nicotine dose (i.e.,
tingling or burning in the back of the throat)) over the days or
weeks to help achieve various health or nicotine-related goals.
[0326] Matching Users to Algorithms
[0327] A user's goal when transitioning off of combustible tobacco
products may change over time (e.g., a user initially wanting to
quit smoking only at work may come to choose full cessation over
time). By carefully matching users to an initial use and dose
algorithm, and then monitoring their progress over time,
adjustments can be made to ensure the maximal probability of
success in their individual goals.
[0328] For a mobile device, feedback from the mobile device, both
in terms of use patterns as well as real-time self-reports of
cravings, environmental risk factors for smoking relapse, and
on-going tests of psychological dependency can be used help
identify an initial use algorithm, as well as make changes to the
use algorithm or switch to a new algorithm entirely.
[0329] For a web-based device, as new data is used to refine use
algorithms, a web-based backend database can communicate subtle
and/or gross changes in prescribed use algorithms to the device to
help enhance the probability that a target goal will be achieved.
In this way, each user can become part of a community helping to
refine his/her own and others optimal algorithms to achieve a
variety of goals.
[0330] Customized Dose, pH, Particle Size, Etc.
[0331] By systematically varying different dose characteristics
(e.g., dose, particle size, pH, amount of nicotine in the gas vs.
particulate phase, air speed velocity coming out of a nicotine
delivery device, flavorings, etc.), a differentially reinforcing
subjective reward from the nicotine can be created. The probability
that certain goals will be achieved (e.g., smoking cessation) can
be maximized by varying dose characteristics of nicotine.
[0332] Relying on use algorithms matched to individual users
regarding their stated goals, physical or psychological nicotine
dependency characteristics, and/or biomarkers, the electronic
nicotine delivery device can modify dose characteristics of
nicotine. These modifications can occur gradually over time (e.g.,
slowly decreasing the dose of nicotine over days or weeks) to
eventually help the user stop all nicotine intake or transition to
other forms of nicotine replacement. In some cases, the
modifications can change in response to environmental triggers
(e.g., by altering the mean particle size of the dose to provide an
especially reinforcing dose if the subject reports on the
electronic nicotine delivery device a strong craving to return to
smoking, or if their pattern of use is indicative of someone likely
to return to smoking). In some cases, the modifications can change
to help the initial transition off of combustible tobacco (e.g., by
altering the pH or flavor of the dose to help match previous
stimulus characteristics of smoking).
[0333] Administering Nicotine Challenge Doses
[0334] Routine administration of nicotine doses does not allow
users to assess their level of nicotine dependency, nor to
challenge themselves to achieve certain goals (e.g., full or
partial nicotine cessation). An electronic nicotine delivery device
can be used to administer challenge doses of nicotine to a user in
order to assess their readiness to change use algorithms, assess
physical and psychological aspects of nicotine dependency, or, for
example, to demonstrate to users that they are increasingly able to
wean themselves off of nicotine administration entirely.
[0335] As part of a behavioral program to achieve certain health or
other nicotine-related goals, the electronic nicotine delivery
device can administer one or more nicotine challenge doses. These
challenge doses may contain no nicotine, less nicotine than
previous doses, or doses of nicotine that vary in regards to other
important characteristics (e.g., dose, particle size, pH, amount of
nicotine in the gas vs. particulate phase, air speed velocity
coming out of a nicotine delivery device, flavorings, etc). An
electronic nicotine delivery device can then assess self-reported
cravings or changes in a pattern of use that suggests increased or
decreased nicotine administration. This feedback can then be used
as real world data to help maintain or change the use algorithm to
increase the probability that the user will achieve certain health
or other nicotine-related goals.
[0336] Customized Feedback
[0337] By systematically tracking nicotine administration using an
electronic nicotine delivery device described herein, and
communicating these results to a web-based backend database,
feedback to the user can be customized to help promote the
achievement of certain health goals. This customized feedback can
be used in multiple ways. For example, achieving certain use
patterns (e.g., sufficient nicotine administration to forestall
strong cravings after initially transitioning from smoking, or
administering a new minimum amount of nicotine in accordance with a
planned taper to nicotine cessation) can result in a virtual credit
or actual monetary reward that can reinforce the user's pattern of
nicotine administration.
[0338] Customized feedback can also be used to leverage
psychological principles important in smoking cessation. For
example, a user could be given feedback that his/her pattern of use
is consistent with his/her goals (e.g., quitting smoking) or aim to
enhance his/her self-efficacy by demonstrating that the user is
becoming less dependent on nicotine based on a real world nicotine
challenge presented by an electronic nicotine delivery device
described herein (e.g., by administering a test dose containing no
nicotine or less nicotine than the user had been administering and
demonstrating that their nicotine craving did not increase, or
significantly increase, after that challenge dose; see FIG. 19).
Feedback could also engage users using game theory, including the
earning of virtual points, which, for example, can be used to
enable other actions of the device or to enhance one's standing in
a virtual online world, or be redeemed for real-world
reinforcements.
[0339] In some cases, the electronic nicotine delivery device or
web backend system can reinforce a user's self-efficacy by giving
him/her feedback that his/her pattern of use is indicative of other
users who successfully abstain from smoking. In some cases, an
electronic nicotine delivery device or web backend system can give
the user feedback that his/her mean nicotine dose is decreasing
over time, despite it initially remaining constant or nearly
constant, so as to enhance self-efficacy and increase his/her
resilience in the face of environmental smoking cues that could
otherwise trigger a smoking lapse or relapse (FIG. 20).
[0340] "About" can mean a referenced numeric indication plus or
minus 10% of that referenced numeric indication. For example, the
term about 4 can include a range of 3.6 to 4.4.
[0341] FIG. 39 illustrates an example environment 3900 for
implementing devices and methods described herein in accordance
with an embodiment. As illustrated, one or more user devices 3902
connect via a network 3904 to an electronic agent (e.g., nicotine)
delivery device 3906 as provided herein which can be configured to
produce a condensation aerosol comprising a pharmaceutically active
agent (e.g., nicotine) as provided herein. The electronic agent
(e.g., nicotine) delivery device 3906 can comprise a controller,
which can be programmable, as provided herein and the electronic
agent (e.g., nicotine) delivery device 3906 can be connected to the
network 3904 through the programmable controller. In some cases,
the condensation aerosol comprising the pharmaceutically active
agent (e.g., nicotine) is produced from a liquid formulation
comprising the pharmaceutically active agent (e.g., nicotine) as
provided herein. In various embodiments, the user devices 3902 can
include any device capable of communicating with the network 3904,
such as personal computers, workstations, laptops, smartphones,
mobile phones, tablet computing devices, smart TVs, game consoles,
internet-connected set up boxes, and the like. In some embodiments,
the user devices 3902 can include applications such as web browsers
and/or applications (e.g., mobile apps) that are capable of
communicating with the electronic agent (e.g., nicotine) delivery
device 3906 and/or a system that uses the electronic agent (e.g.,
nicotine) delivery device 3906. In some cases, the user devices
3902 communicate with the electronic agent (e.g., nicotine)
delivery device 3906 via the programmable controller as provided
herein. The user can be a patient, and/or a healthcare provider
(e.g., physician, physician's assistant, nurse, nurse practitioner,
pharmacist or other medical professional). In some cases, a first
user uses the device, while a second user uses the other user
devices 3902. In some cases, a first user uses the device and the
other user devices 3902, while the second user also uses the user
devices 3902.
[0342] In some embodiments, the electronic agent (e.g., nicotine)
delivery device 3906 can communicate with a data store 3908 in
order perform the functionalities described herein (e.g., track
device usage, adjust dose, frequency of administration, delivery
schedule, customize feedback, administer challenge doses, etc.).
For example, the data store 3908 can be used to store historical
(e.g. user use history, dosage history, delivery schedule history,
frequency of administration history, etc.), evaluation rules, and
the like.
[0343] In some embodiments, the data store 3908, or any other data
stores discussed herein, can include one or more data files,
databases, (e.g., SQL database), data storage devices (e.g., tape,
hard disk, solid-state drive), data storage servers, or the like.
The data store 3908 can be connected to the electronic agent (e.g.,
nicotine) delivery device 3906 locally or remotely via a network.
In some embodiments, data store 3908, or any other data stores
discussed herein, can comprise one or more storage services
provisioned from a "cloud storage" provider, for example, Amazon
Simple Storage Service ("Amazon S3"), provided by Amazon.com, Inc.
of Seattle, Wash., Google Cloud Storage, provided by Google, Inc.
of Mountain View, Calif., and the like.
[0344] In various embodiments, the network 3904 can include the
Internet, a local area network ("LAN"), a wide area network
("WAN"), a cellular network, wireless network or any other public
or private data and/or telecommunication network.
[0345] FIG. 40 illustrates example components of an electronic
agent (e.g., nicotine) delivery system 4000, in accordance with an
embodiment. In this example, the electronic agent (e.g., nicotine)
delivery system 4000 includes a data collector 4002 residing on a
user or client device 4004. The system further comprises an
electronic agent (e.g., nicotine) delivery device 4006, which can
be the same as 3906 as depicted in FIG. 39. The electronic agent
(e.g., nicotine) delivery device 4006 can comprise a programmable
controller, wherein the data collector resides on the programmable
controller. The data collector can be implemented as a browser
script using JavaScript or any other scripting language. The data
collector can be configured to communicate with a web-based backend
database. For example, the data collector can be configured to
collect parameter information about the electronic agent (e.g.,
nicotine) delivery device 4006 such as discussed herein and
transmit such parameter information to the web-based backend
database, for example, using an application programming interface
(API) provided by the user device 4004. In some embodiments, the
collection and/or communication with the user device 4004 can be
triggered by an event on the electronic agent (e.g., nicotine)
delivery device 4006. For example, the event can include a click on
a portion (e.g., a button or a link) of a user display on the
electronic agent (e.g., nicotine) delivery device 4006, use of the
delivery device by a user or patient, and the like. The user
display can be on the programmable controller as provided
herein.
[0346] In some embodiments, the electronic agent (e.g., nicotine)
delivery device 4006 can be configured to receive parameter
information (e.g., dosage, frequency of administration, dosing
schedule, etc.) provided by the data collector of the user device
and to compare and/or analyze the parameter information received
from the data collector of the user device to the parameter
information from use of the electronic agent (e.g., nicotine)
delivery device 4006. To that end, the electronic agent (e.g.,
nicotine) delivery device 4006 can utilize an evaluation engine
4008. The evaluation engine 4008 can be configured to analyze the
parameter information in order to customize or adjust output
parameters of the electronic agent (e.g., nicotine) delivery device
4006. In some embodiments, the evaluation engine 4008 can be
implemented using one or more server-side library files. In some
embodiments, the evaluation engine 4008 can be implemented using
one or more algorithms as provided herein for analyzing the
respective parameter.
[0347] In some embodiments, customized feedback or a treatment
regimen (e.g., agent dosage, frequency of administration and/or
delivery schedule) can be evaluated based on some or all of the
parameters as provided herein. For example, a lookup table (e.g.,
stored in memory) can be used to determine the weight values
associated with some or all of the parameters. The weight values
may or may not be further weighted, combined or otherwise processed
to derive a final customized feedback or treatment regimen. In some
embodiments, the lookup table and the one or more algorithms for
deriving the customized feedback or treatment regimen can be
included on one or more rules that are pre-determined based on
historical data such as past usage and/or user activities. In some
embodiments, analysis of parameter information and/or generation of
customized feedback or treatment regimen can be performed in real
time or nearly real time with respect to the receipt of the
parameter information. In other embodiments, any or all of the
above operations may be performed in an asynchronous mode, for
example, using batch processing.
[0348] In some embodiments, the generated feedback and/or treatment
regimen can be stored in a data store 4010. In some embodiments,
the data store 4010 can include a memory of a server, one or more
data storage device (e.g., SSD, hard disk, taps), or a cloud-based
storage service such as discussed in connection with FIG. 39. The
data store 4010 may or may not be owned and/or operated by the same
as the provider of the electronic agent (e.g., nicotine) delivery
device 4006.
[0349] FIG. 41 illustrates example components of a computer device
4100 for implementing aspects of devices and methods described
herein, in accordance with an embodiment. In another embodiment,
the computer device 4100 may be configured to implement a user
device such as a user device 3902 discussed in connection with FIG.
39 and/or components or aspects of the electronic agent (e.g.,
nicotine) delivery device 3906 such as described in connection with
FIGS. 39 and 40. In some embodiments, computing device 4100 can
include many more components than those shown in FIG. 4100.
However, it is not necessary that all of these components be shown
in order to disclose an illustrative embodiment.
[0350] As shown in FIG. 41, computing device 4100 includes a
network interface 4102 for connecting to a network such as
discussed above. In some cases, the computing device 4100 is housed
on a programmable controller on an electronic agent (e.g.,
nicotine) delivery device as provided herein. In various
embodiments, the computing device 4100 may include one or more
network interfaces 4102 for communicating with one or more types of
networks such as the Internet, wireless networks, cellular
networks, and any other network.
[0351] In an embodiment, computing device 4100 also includes one or
more processing units 4104, a memory 4106, and an optional display
or user interface as provided herein 4108, all interconnected along
with the network interface 4102 via a bus 4110. The processing
unit(s) 4104 can be capable of executing one or more methods or
routines stored in the memory 4106. The display 4108 can be
configured to provide a graphical user interface to a user
operating the computing device 4100 for receiving user input,
displaying output, and/or executing applications. In some cases,
such as when the computing device 4100 is a server, the display
4108 may be optional.
[0352] The memory 4106 can generally comprise a random access
memory ("RAM"), a read only memory ("ROM"), and/or a permanent mass
storage device, such as a disk drive. The memory 4106 may store
program code for an operating system 4112, one or more agent (e.g.,
nicotine) delivery routines 4114, and other routines. In various
embodiments, the program code can be stored on a computer-readable
storage medium, for example, in the form of a computer program
comprising a plurality of instructions executable by one or more
processors. The computer-readable storage medium can be
non-transitory. The one or more agent (e.g., nicotine) delivery
routines 4114, when executed, can provide various functionalities
associated with the electronic agent (e.g., nicotine) delivery
device as described herein.
[0353] In some embodiments, the software components discussed above
can be loaded into memory 4106 using a drive mechanism associated
with a non-transient computer readable storage medium 4118, such as
a floppy disc, tape, DVD/CD-ROM drive, memory card, USB flash
drive, solid state drive (SSD) or the like. In other embodiments,
the software components can alternatively be loaded via the network
interface 4102, rather than via a non-transient computer readable
storage medium 4118. In an embodiment, the computing device 4100
can also include an optional time keeping device (not shown) for
keeping track of the timing of usage of the electronic agent (e.g.,
nicotine) delivery device.
[0354] In some embodiments, the computing device 4100 also
communicates via bus 4110 with one or more local or remote
databases or data stores such as an online data storage system via
the bus 4110 or the network interface 4102. The bus 4110 can
comprise a storage area network ("SAN"), a high-speed serial bus,
and/or via other suitable communication technology. In some
embodiments, such databases or data stores may be integrated as
part of the computing device 4100.
EXAMPLES
Example 1
Effect of Changes in Air Flow Rate, Electrical Current, Duration of
Heating, and Thickness of Heater Element on Particle Size of a
Aerosol Generated from a Propylene Glycol Formulation
[0355] This example describes how changes in specific parameters
(i.e. air flow rate, electrical current to a heater element, and
thickness of a heater element) affect the size of aerosol particles
generated by a test apparatus designed to comprise components
and/or parameters of a nicotine delivery device as described
herein. FIG. 26 shows a schematic of the entire test apparatus
while FIG. 27 shows alternates views of the test airway used in the
test apparatus. The test bed has an airway created between a block
of Delrin (bottom) and a sheet of clear plexiglass (top) with brass
sides used to clamp and make electrical contact with a heater
element. The heater element is a stainless steel foil of variable
thickness (0.0005 inches (about 0.013 mm) or 0.001 inches (about
0.025 mm)), and the formulation used to generate an aerosol is
composed of propylene glycol. FIG. 27A shows a top view, with
airflow (2702a) into an an inlet (2704a). A hole to deposite drug
(2706a) is provided and foil is shown (2708a). Brass contacts
(2710a) are provided. The length of the device is 6 inches (about
152.4 mm), and the width is 2.25 inches (about 57.15 mm) FIG. 27B
shows a side view of the inlet (2704b), foil (2708b), brass
electrical contacts (2710b), and outlet (2712b). FIG. 27C shows and
end view of the foil (2708c) and (2712c). FIG. 27D shows an
isometric view. Table 2 shows the results of altering heater
element thickness, air flow rate, current, and duration of heating
on particle size distribution. Based on the results in Table 2, as
the air flow rate is increased, the particle size diameter (PSD)
decreases when the other parameters are held constant.
TABLE-US-00002 TABLE 2 Propylene glycol aerosol data from test
airway Heater Duration Particle Element Air Flow of Size Thickness
Rate Dose Current Heating Diameter Sequence Material (inches)
(Liters/min) (mg) (Amps) (seconds) (microns) 1 PG 0.0005 1 1 8 0.5
2 2 PG 0.0005 1 1 6 1 2.1-3 3 PG 0.001 1 1 8 0.7 1 4 PG 0.001 3 1 7
1 1.8 5 PG 0.001 3 1 7 1 2 6 PG 0.001 3 1 7 1 2 7 PG 0.001 3 1 7 1
1.5-1.8 8 PG 0.001 3 1 7 1 1.4-1.8 9 PG 0.001 3 1 7 1 2 10 PG 0.001
3 1 10 1 1 11 PG 0.001 3 1 10 1 0.9 12 PG 0.001 6 1 10 1 0.6 13 PG
0.001 6 1 10 1 0.6-0.8 14 PG 0.001 12 1 10 1 0.5 15 PG 0.001 12 1
10 1 0.5
Example 2
Effect of Changes in Air Flow Rate, Electrical Current, Duration of
Heating, and Thickness of Heater Element on Particle Size of an
Aerosol Generated from a Nicotine/Propylene Glycol Formulation
[0356] This example describes how changes in specific parameters
(i.e. air flow rate, and electrical current to a heater element)
affect the size of aerosol particles generated from a 10%
nicotine/propylene glycol formulation by a test apparatus as
described in Example 1. Table 3 shows the results of altering
heater element thickness, air flow rate, current, and duration of
heating on particle size distribution. As shown in Table 3, when
air flow rate is altered while other parameters are held constant,
the higher the air flow rate, the smaller the average particle size
diameter (PSD).
TABLE-US-00003 TABLE 3 Nicotine/propylene glycol mixture (10%)
aerosol data from test airway Average Heater Duration Particle
Element Air Flow of Size Thickness Rate Dose Current Heating
Diameter Sequence Material (inches) (Liters/min) (mg) (Amps)
(seconds) (microns) 1 Nic/PG 0.001 4 1 9 1 1.35 2 Nic/PG 0.001 4 1
9 1 1.45 3 Nic/PG 0.001 4 1 9 1 1.45 4 Nic/PG 0.001 2 1 9 1 1.85 5
Nic/PG 0.001 2 1 9 1 2.3 6 Nic/PG 0.001 2 1 9 1 2.3 7 Nic/PG 0.001
4 1 10 1 1.55 8 Nic/PG 0.001 4 1 10 1 1.2 9 Nic/PG 0.001 4 1 10 1
1.325
Example 3
Particle Size Diameter Ranges of Aerosols Generated from a Test
Apparatus Using a Heater Element Comprising a Wire Coil
[0357] This example describes the particle size diameters of
aerosols generated from either a PG formulation or 10% nicotine/PG
formulation using a test apparatus as shown in FIGS. 26 and 27 and
described in Example 1. In this example, the heater element is a
stainless steel coil comprising 3.5 coils and a diameter of 0.10
inches (about 2.54 mm). The heater element is heated using a
current of 2.5 Amps and the air flow rate is 4 Liters/min (about
6.7.times.10.sup.-5 m.sup.3/s). Table 4 shows the results.
TABLE-US-00004 TABLE 4 Air Flow Duration Particle Rate of Size
(Liters/ Dose Current Heating Diameter Sequence Material min) (mg)
(Amps) (seconds) (microns) 1 PG 4 1 2.5 1 1.5-2.2 2 PG 4 1 2.5 1
1.5-2.2 3 Nic/PG 4 1 2.5 1 1.57-2.2 4 Nic/PG 2 1 2.5 1 1.6-2.8 5
Nic/PG 2 1 2.5 1 1.52-2.2 6 PG 2 1 2.5 1 1.5-2.2 7 PG 4 1 2.5 1
1.5-2.3 8 PG 4 1 2.5 1 2.4-1.5
Example 4
Particle Size Diameters of Aerosols Generated from Commercially
Available e-Cigarettes (eCigs)
[0358] This example describes the particle size diameters of
aerosols generated from either one of two brands of eCigs (Finiti
and BLU). In this example, a 50 ml volume of an aerosol was pulled
from either one of the two brands of eCigs over a period of 3
seconds in order to simulate a human breath. The collected aerosol
was then injected into a laser particle size detector set at a flow
rate of 14 Liters/min (about 2.33.times.10.sup.-4 m.sup.3/s). Table
5 shows the particle size diameter of the aerosols generated from
two brands of eCigs. FIG. 28 shows a comparison of the particle
size distribution for aerosols created by eCigs vs. aerosol created
by devices provided herein (devices). As shown in FIG. 28, the
particle size distribution of aerosols generated by devices
provided herein is shifted toward larger particle sizes vs. those
generated by eCigs.
TABLE-US-00005 TABLE 5 Test Particle Size Number Brand Low End High
End Average 1 Finiti 0.5 0.5 0.5 2 Finiti 0.5 0.6 0.55 3 Finiti 0.5
0.5 0.5 4 Finiti 0.5 0.5 0.5 5 BLU 0.5 0.5 0.5 6 BLU 0.5 0.8
0.65
Example 5
Effect of Changes in Valve Material, and the Diameter of a Bypass
Orifice on Particle Size of a Aerosol Generated from a Propylene
Glycol Formulation
[0359] This example describes how changes in specific parameters
(i.e. valve material and diameter of a bypass orifice) affect the
size of aerosol particles generated by a test apparatus designed to
comprise components and/or parameters of a device for generating
condensation aerosols as described herein. FIG. 29A shows a
schematic of the entire test apparatus while FIG. 29B shows an
internal view of the valve (2904a) used in the test apparatus. The
valve flap (2902b) has a 3/4 inch diameter and the diameter of the
channel downstream of the valve is 0.375 inches (about 9.53 mm) in
length and 0.090 inches (about 2.29 mm) in width. The test bed has
a primary airway (2906a), and a bypass airway (2908a), an aerosol
generation chamber (2912a) and vacuum source (2910a). The aerosol
generation chamber comprises a heater element. The inlet to the
bypass airway is a slot of varying dimensions (L.times.W). Table 6
shows the results using a valve of 3/4 inch (about 19.05 mm)
diameter and altering valve material and bypass orifice diameter.
As shown in Table 6, regardless of valve material type and bypass
orifice diameter, above inhalation pressures of about 2 inches of
H.sub.2O (about 498 Pa), the primary flow remains relatively
constant, while the bypass flow increases with increasing vacuum
pressure. Table 7 shows the results using a valve of 3/8 inch
diameter, a bypass orifice of varying dimensions, and altering the
orifice dimensions for the inlet of the primary airway. As shown in
Table 7, reducing the size of the orifice of the primary airway
consistently reduces the flow rate through the primary airway
regardless of varying vacuum pressure, dimensions of the bypass
orifice, or varying the valve material
TABLE-US-00006 TABLE 6 Testing of Flow Control with the device of
FIG. 29. Flow Flow Total Valve Bypass Primary .DELTA. P Vac Flow
Bypass .phi. Material (LPM) (LPM) (inches H.sub.2O) (LPM) (inches)
.0045'' Brown 15.4 4.9 2.11 20.03 .149 .0045'' Brown 18.6 5.6 3
.149 .0045'' Brown 21.5 6.39 4.2 .149 .0045'' Brown 24.2 6.94 5.5
.149 .0045'' Brown 28.75 7.62 8 .149 .0045'' Brown 31.7 7.9 9.6
.149 .0045'' Brown 34.6 8.2 11.3 .149 .0045'' Brown 38.2 8.5 14
.149 Green 9.5 1.99 .3 .199 17.08 3.49 .93 .199 24.80 4.39 2.0 .199
31.7 4.80 3.2 .199 38.2 5.0 4.7 .199 44.2 5.11 6.3 .199 49.4 5.18
8.2 .199 53 5.10 9.8 .199 Valve Bypass Primary Valve Slot Size
Bypass .phi. Flow Flow .DELTA. P Vac Mate- (inches) (inches) (LPM)
(LPM) (inches H.sub.2O) rial .300 .199 6.0 2.9 .1 Green .300 .199
9.2 4.2 .28 Green .300 .199 14.1 6.2 .65 Green .300 .199 17.5 7.4
.99 Green .300 .199 24.4 7.6 1.9 Green .300 .199 28.9 7.5 2.7 Green
.300 .199 33.9 6.3 3.7 Green .300 .199 38.0 5.46 4.8 Green .300
.199 46.7 4.76 7.5 Green .300 .199 50.3 4.6 8.5 Green .300 .199 54
4.6 9.8 Green .300 1.99 5.9 2.6 .1 Brown .300 1.99 7.9 3.6 .2 Brown
.300 1.99 11.8 5.4 .45 Brown .300 1.99 17.7 7.9 1.0 Brown .300 1.99
23.9 10.48 1.9 Brown .300 1.99 28.59 11.76 2.7 Brown .300 1.99 33.2
11.9 3.7 Brown .300 1.99 38.5 10.9 5.0 Brown .300 1.99 42.8 10.3
6.0 Brown .300 1.99 45.5 10.2 6.8 Brown .300 1.99 48.6 9.6 7.9
Brown .300 1.99 49.5 9.7 8.3 Brown
TABLE-US-00007 TABLE 7 Re-lay out of valve with 3.8 radius and
smaller slot (device of FIG. 29). Bypass .phi. Primary Slot Bypass
Flow Primary Flow .DELTA. P Vac Flap Material (inches) Size
(inches) (LPM) (LPM) (inches H.sub.2O) (Color) .265 .04 .times.
.150 8.75 .65 .13 Brown .265 .04 .times. .150 12.5 .95 .23 Brown
.265 .04 .times. .150 18.0 1.4 .45 Brown .265 .04 .times. .150 40.3
3.14 2.02 Brown .265 .04 .times. .150 25.0 1.99 .84 Brown .265 .04
.times. .150 64.0 4.5 Brown .199O Equivalent .04 .times. .150 18.7
2.82 1.38 Green (EQUI) SLOT .199O EQIU SLOT .04 .times. .150 21.8
3.19 1.8 Green .199O EQIU SLOT .04 .times. .150 25.5 3.68 2.54
Green .199O EQIU SLOT .04 .times. .150 29.5 4.07 3.26 Green .199O
EQIU SLOT .04 .times. .150 34.1 4.45 4.19 Green .199O EQIU SLOT .04
.times. .150 38.7 4.75 5.21 Green .199O EQIU SLOT .04 .times. .150
43.3 4.88 6.2 Green .199O EQIU SLOT .04 .times. .150 46.2 4.97 7.0
Green .199O EQIU SLOT .04 .times. .150 54.1 4.79 9.12 Green .199O
EQIU SLOT .04 .times. .150 55.0 4.69 9.9 Green .199O EQIU SLOT .04
.times. .150 19.8 1.05 1.5 .001 KAPTON .199O EQIU SLOT .04 .times.
.150 28.6 1.37 3.17 .001 KAPTON .199O EQIU SLOT .04 .times. .150
35.7 1.10 4.56 .001 KAPTON .199O EQIU SLOT .04 .times. .150 41.7
.97 5.8 .001 KAPTON .199O EQIU SLOT .04 .times. .150 46.7 .94 7.1
.001 KAPTON .199O EQIU SLOT .04 .times. .150 60.8 .94 11.5 .001
KAPTON Bypass .phi. Primary Slot Bypass Flow Primary Flow .DELTA. P
Vac Valve (inches) Size (inches) (LPM) (LPM) (inches H.sub.2O)
Material .199 "SLOT" .040 .times. .275 16.7 1.79 1.08 .001 KAPTON
.199 "SLOT" .040 .times. .275 18.1 1.87 1.3 .001 KAPTON .199 "SLOT"
.040 .times. .275 25.3 2.12 3.48 .001 KAPTON .199 "SLOT" .040
.times. .275 35.7 2.7 4.6 .001 KAPTON .199 "SLOT" .040 .times. .275
43.5 2.8 6.4 .001 KAPTON .199 "SLOT" .040 .times. .275 50.2 2.8
8.34 .001 KAPTON .199 "SLOT" .040 .times. .275 54.0 2.72 9.67 .001
KAPTON .199 "SLOT" .040 .times. .275 56.3 2.64 10.4 .001 KAPTON
VALVE REVERSED .199 "SLOT" .040 .times. .275 19.4 1.5 1.45 .001
KAPTON .199 "SLOT" .040 .times. .275 24.8 1.89 2.3 .001 KAPTON .199
"SLOT" .040 .times. .275 36.2 2.36 4.7 .001 KAPTON .199 "SLOT" .040
.times. .275 41.3 2.5 5.8 .001 KAPTON .199 "SLOT" .040 .times. .275
50.4 2.6 8.3 .001 KAPTON .199 "SLOT" .040 .times. .275 55.9 2.6 9.6
.001 KAPTON RETEST .199 "SLOT" .040 .times. .275 12.4 1.56 0.6 .001
KAPTON .199 "SLOT" .040 .times. .275 21.1 1.65 1.71 .001 KAPTON
.199 "SLOT" .040 .times. .275 30.2 2.0 3.4 .001 KAPTON .199 "SLOT"
.040 .times. .275 41.5 2.08 6.0 .001 KAPTON .199 "SLOT" .040
.times. .275 50.1 2.03 8.4 .001 KAPTON .199 "SLOT" .040 .times.
.275 57.5 1.65 11.0 .001 KAPTON .199 "SLOT" .040 .times. .275 46.0
1.64 7.5 .001 KAPTON .199 "SLOT" .040 .times. .275 33.7 1.55 4.32
.001 KAPTON .199 "SLOT" .040 .times. .275 19.5 1.36 1.48 .001
KAPTON .199 "SLOT" .040 .times. .275 30.0 1.76 9.39 .001 KAPTON
Example 6
Particle Size Diameters of Aerosols Generated from Devices
Comprising Wire Coil Heater Elements and Bypass Inlets
[0360] This example describes the particle size diameters (PSD) of
aerosols generated from a device comprising a heater element
comprising a wire coil. An example of this type of device is shown
in FIGS. 31A-D. FIG. 31A depicts a device designated ENT-100-A,
(two inches (about 50.8 mm) long) comprising a primary carrier gas
inlet (3112a), positive and negative brass contacts (3110a), a
heater element (3106a) comprising a coil located distally from the
inlet to the primary airway (3112a) and two bypass inlets (3104a)
located (disposed) downstream of the heater element but prior to
the outlet (3102a). FIG. 31B depicts a device designated ENT-100-B,
which is the same as ENT-100-A except that the heater element has
been moved to be proximal to the inlet of the primary airway
(3112b). FIG. 31C depicts a device designated ENT-100-C, which is
similar to the ENT-100-A device except that the wire coil heater
element has been moved to an intermediate position relative to the
location of the coil in ENT-100-A and ENT-100-B. Any of the devices
depicted in FIG. 31A-C can comprise the wire coil heater element
designated "A Coil" (3114e) or "B Coil" (3116e) as illustrated in
FIG. 31E. The coil in both types of heater elements comprise inner
diameter of 0.26 inches (about 6.604 mm). The "A Coil" comprises a
stretch of coil followed by a straight lead on either end of the
coil which connects to the brass contacts. The "B Coil" comprises a
stretch of coil, wherein the coil itself connects to the brass
contacts. Tables 8-12 shows the particle size diameter of the
aerosols generated from the devices depicted in FIG. 31A-C. Table 8
shows the PSD of particles generated using an ENT-100-A device with
the "B Coil". Table 9 shows the PSD of particles generated using an
ENT-100-B device with the "A Coil". Table 10 shows the PSD of
particles generated using an ENT-100-B device with the "B Coil".
Table 11 shows the PSD of particles generated using an ENT-100-C
device with the "A-Coil". Table 12 shows the PSD of particles
generated using an ENT-100-C device with the "B-Coil".
TABLE-US-00008 TABLE 8 Testing of ENT-100-A, B prototype Dose = 2
mg (propylene glycol formulation), current = 3 amps, duration = 1
sec. Total Primary Bypass Flow Flow Flow PSD (LPM) (LPM) (LPM)
(microns) Notes 9.7 N/A N/A 1.7-1.8 ENT-100-A Device 9.7 N/A N/A
1.5-2.1 2.2 1.67 0.4-0.5 ENT-100-A Device 2.2 1.67 0.38-0.5 w/o
screen in flow 2.2 .7 1.7-1.5 valve 2.2 2.3 0.4 w/screen 32 1.6 N/A
0.4 ENT-100-B (heater O 0.7 N/A 1.7-2.0 coil moved aft) O 0.66 N/A
1.4-1.5 1.7 O 0.5-1.0 Bypass taped over ENT- 100-B 1.7 O 0.5-1.0
Bypass taped over ENT- 100-B 1.7 O 0.5-1.0 Bypass taped over ENT-
100-B 1.7 O 0.5-1.0 Bypass taped over ENT- 100-B 0.5 O 3 Bypass
taped over ENT- 100-B 0.51 O 2.9 Bypass taped over ENT- 100-B .82 O
3.3/1.8 Bypass taped over ENT- 100-B .84 O 3.2-3.3 Bypass taped
over ENT- 100-B 1.1 O 2.7 Bypass taped over ENT- 100-B 1.11 O
2.7-2.8 Bypass taped over ENT- 100-B 1.38 O 2.1-2.3 Bypass taped
over ENT- 100-B 1.42 O 2.2-2.4 Bypass taped over ENT- 100-B 1.72 O
1.7 Bypass taped over ENT- 100-B 1.72 O 1.7-1.75 Bypass taped over
ENT- 100-B 2.04 O .5-1.0 Bypass taped over ENT- 100-B Primary
Bypass Flow Flow PSD (LPM) (LPM) (microns) Notes 1.45 O 2.3
ENT-100-B Device 1.45 O 2.2-2.4 Flap removed from flow 1.74 O
1.95-2.0 valve 1.75 O 1.8-1.9 2.04 O 1.7-1.8 2.04 O 1.6-1.7 3.0 O
0.5-1.0 3.0 O 0.5-1.0 3 O .sup. 0.5-1.0 ST Flow control valve
removed/ 3 O 2.0-2.3 replaced with Black Delyrn 3 O 2.3-2.4 W
O.196.phi. hole 1.04 O No trigger 2.0 O 3.8 2.04 O 0.5-1.0 With
foam (open cell packing 2.04 O .sup. 0.5-1.0 ST foam used to even
out air 1.05 O 1.8-2.1 flow, placed upstream from 1.05 O 2.0-2.1
the heater element), no 1.5 O .79-1.0 valve 1.49 O 1.6 1.25 O 1.6
1.24 O 0.7-1.2 1.24 O 0.7-1.2 2.0 O 0.5-1.0 2.0 O 0.5-1.0
TABLE-US-00009 TABLE 9 Testing of ENT-100-B device with "A Coil"
heater element Dose = 2 mg (propylene glycol formulation), 1 sec
duration, current 3.1 amps Flow PSD (LPM) (Microns) Notes 1.01
3.4-3.6 1.01 3.1-3.5 1.51 2.6-2.7 1.51 2.5-2.7 2.06 2.6-2.3 2.12
2.15-2.2 2.48 1.9-2.2 2.49 1.85-1.9 3.02 1.5-1.6 3.02 1.4-1.5 3.02
1.35-1.45 3.04 1.45-1.6 3.26 1.4-1.6 3.27 1.3-1.5 4.25
TABLE-US-00010 TABLE 10 Testing of ENT-100-B device with "B Coil"
heater element Dose = 2 mg (propylene glycol formulation), Duration
1 sec, current 2.0 amps Dose Flow PSD (mg) (LPM) (microns) Notes 2
1.5 2.9-3.1 With foam 2 1.53 2.6-2.8 2 1.53 2.8-2.9 2 2.49 1.8-1.9
2 2.49 1.7-1.8 2 3.01 1.4 2 3.01 1.4-1.5 2 3.49 2 1.55 2.5 With
stainless steel (SS) screen to 1.56 2.6-2.9 even flow 1.56 .sup.
2-2.5 Taped up bypass 2.52 1.5-1.6 2.56 1.5 2.35 1.8-2.0 With foam
(taped up bypass) 2.51 1.9-2.0 2.48 1.9 1.48 2.9-3.0 1.50 2.8-3.0
1.5 1.8-1.9 Bypass untaped Total flow ~8.5 LPM 1.52 1.7-1.8 1.48
1.2-1.1 With 0.42 .phi. orifice added to primary inlet (Total flow
= 24) 1.5 1.7-1.8 With heater element moved aft 1.60 1.7-1.75 B
configuration (Total flow 12 LPM)
TABLE-US-00011 TABLE 11 Testing of ENT-100-C with "A Coil" heater
element, which has 7 coils Current set @ 2.0 amps, 1 sec, 2 mg dose
(propylene glycol formulation) Primary .DELTA. P Inlet orifice Flow
PSD Vac (inches (inches) (LPM) (microns) H.sub.2O) Notes .04 1.01
4.6-5.sup. 2.48 No adder .04 1.00 4.3-4.7 2.50 0.250 straight tube
.04 3.00 1.7-1.8 17.5 2.4 amps .04 3.00 1.6-1.7 17.2 2.4 amps .04
4.85 ~1.0 LIMIT .020 + 0.98 2.2-2.4 .45 2.4 amps - No adder FOAM
.020 + 1.00 3.5-4.0 .46 2.4 amps - No adder FOAM .020 + 1.00
4.2-4.7 .46 2.4 amps - No adder FOAM .020 + 1.00 4.0-5.7 .46 2.4
amps - No adder FOAM .020 + 1.00 3.0-4.3 .46 2.4 amps - No adder
FOAM .020 + 2.09 2.2 1.52 2.4 amps - No adder FOAM .020 + 2.07
2.4-2.5 1.51 2.4 amps - No adder FOAM .020 + 2.07 2.2-2.4 1.48 2.4
amps - No adder FOAM .020 + 2.08 2.4-2.5 1.53 2 amps FOAM .020 +
2.08 2.1-2.3 1.53 2 amps FOAM .020 + 2.09 2.5-2.6 1.53 2 amps
FOAM
TABLE-US-00012 TABLE 12 Testing of ENT-100-C with "B Coil" heater
element, with 0.050 spacer between contacts then spread to .200 in
Current set @ 2.0 amps, 1 sec, 2 mg dose (propylene glycol
formulation) .DELTA. P Vac Flow PSD (inches Current (LPM) (microns)
H.sub.2O) (amps) Notes .94 3.0-3.2 .67 2.4 .94 2.4-2.5 .67 2.8 .95
2.5-3.1 .67 2.8 .95 3.3-3.4 .67 2.8 .95 2.7-3.4 .67 2.8 2.11
2.3-2.4 2.58 2.8 2.11 2.3-2.7 2.58 2.8 2.11 2.6-2.7 2.58 2.8 New
Heater Element .040 ID 1.91 1.7-2.0 .86 2.4 1.91 2.4-2.5 .86 2.6
1.97 2.6-2.7 .86 2.6 1.91 2.4-2.5 .86 2.6 1.91 2.5-2.6 .86 2.6 1.91
2.4-2.5 .86 2.8 2.04 1.8-2.0 .96 2.8 2.04 2.4-2.7 .96 2.8 2.04
2.0-1.9 .96 2.8 New Heater Element .032 ID 0.100 stretch 2.04
2.0-2.5 .93 2.6 2.04 2.0-2.2 .96 2.6 2.04 2.1-2.3 .96 2.6 Spit
(nicotine/propylene glycol was heated under conditions (air flow,
heating rate) that lead to the mixture being boiled off of the
heater element and "spit" off of the heater element) 2.04 2.1-2.2
.89 2.6 spit
Example 7
Particle Size Diameters of Aerosols Generated from Heater Element
Comprising a Center Exit Wire Lead
[0361] This example describes the particle size diameters (PSD) of
aerosols generated from a heater element comprising a wire wherein
one end of the wire wraps around another segment of the wire,
wherein a wire coil is formed with an end of the wire passes
through the center of the wire coil. An example of this type of
heater element is shown in FIGS. 36-38. In this example, the heater
element is inserted into the device depicted in FIG. 31D. FIG. 31D
depicts a device designated ENT-100-D with a primary passageway for
air to flow through, brass contacts (+/-) embedded within the wall
of the primary passageway, and a heater element as described in
this example. The wire of the heater element has a diameter of 0.10
inches (about 2.54 mm). The wire coil of the heater element has 9
coils, and the wire coil has an inner diameter of 0.032 inches
(about 0.813 mm). In this example, the liquid formulation comprises
propylene glycol and it wicks onto the ends of the wire of the
heater element and onto the brass contacts. Table 13 shows the
particle size diameter of the aerosols generated from a device
comprising the heater element. As shown in Table 13, the particle
size distribution of aerosols generated by devices with the heater
element is unaffected by alterations in current used to heat the
wire.
TABLE-US-00013 TABLE 13 Propylene glycol (dose: 2 mg) found to wick
to ends of heater element and onto brass contacts ENT-100-D Heater
Element .032 10, 010 wire, 9 turn, center exit .DELTA. P Vac Flow
PSD (inches Current (LPM) (microns) H.sub.2O) (amps) Notes 2.01
.sup. 2-2.2 1.14 2.2 Foam 2.00 .sup. 2-2.2 1.14 2.2 2.00 2.0-2.2
1.14 2.0 2.0 2.1-2.2 1.14 2.0 2.0 1.8-2.1 1.14 1.8 2.0 1.9-2.1 1.14
1.8 0.99 5.0-5.3 .34 1.8 1.00 5.0-5.2 .34 1.8 1.52 2.6-2.8 .71 2.0
1.52 2.6-2.7 .71 2.0 1.53 2.4-2.7 .71 1.8 1.53 2.5-2.7 .71 1.8 2.02
2.1-2.2 2.0 3.0 1.2-1.4 2.43 2.0 3.0 0.8-1.4 2.43 2.0 3.0 .90-1.3
2.43 2.2 3.0 .6-1.3 2.43 2.2
Example 8
Particle Size Diameters of Aerosols Generated from Heater Element
Comprising a Center Exit Wire Lead when the Length of the Leads are
Increased
[0362] This example describes the particle size diameters (PSD) of
aerosols generated from a heater element as described in FIG. 36.
In this example, the length of the leads connecting the wire coil
to the brass contacts are increased as shown in FIG. 37. The length
of the leads in this example is 0.70 inches (about 17.78 mm). The
heater element is inserted into the device depicted in FIG. 31D.
FIG. 31D depicts a device designated ENT-100-D with a primary
passageway for air to flow through, brass contacts (+/-) embedded
within the wall of the primary passageway, and a heater element as
described in this example. In some cases, the diameter of the inlet
is varied from 0.060 inches to either 0.070, 0.071, or 0.041 inches
(a range from about 1.524 mm to either 1.78, 1.80, or 1.04 mm. The
wire of the heater element has a diameter of 0.10 inches (about
0.254 mm). The wire coil of the heater element has a reduced number
of coils, and the wire coil has an inner diameter of 0.032 inches
(about 0.813 mm). In this example, the liquid formulation comprises
propylene glycol and it wicks onto the ends of the wire of the
heater element and onto the brass contacts. Table 14 shows the
particle size diameter of the aerosols generated from a device
comprising the heater element. As shown in Table 14, the particle
size distribution of aerosols generated by device with the heater
element is unaffected by alterations in current used to heat the
wire. Table 14 also shows the effects of altering the airway
configuration in the ENT-100-D device. As shown in Table 14,
altering the configuration of the airway of the ENT-100-D device by
adding the airway depicted in FIG. 32E (designated the MARK V
adders in Table 14) downstream of the heater element produces
particles with a PSD of about 1 to about 2 .mu.m.
TABLE-US-00014 TABLE 14 Heater element leads lengthened .DELTA. P
Vac Flow PSD (inches Current (LPM) (microns) H.sub.2O) (amps) Notes
2.0 3.1-3.2 .96 2.0 2.0 3.1-3.2 .96 2.0 2.01 3.1-3.2 .96 1.8 2.01
3.1-3.2 .96 1.8 2.02 3.0-3.2 .96 2.2 Orifice .060 2.02 2.9-3.0 .96
2.2 Test of .DELTA.P affecting PSD 2.06 3.3-3.4 1.74 2.0 Orifice
size = .060 2.04 3.2-3.3 .96 2.0 .071 2.04 3.0-3.2 7.00 2.0 .041
2.04 3.1-3.2 7.08 2.0 .041 Test to see affect of foam 2.06 2.4-2.5
6.65 2.0 Foam removed 2.06 2.4-2.5 6.65 2.0 2.0 2.7-2.9 1.63 2.0
Original foam 2.05 2.7-2.8 1.63 2.0 Replaced orifice .070 2.05
2.7-2.8 1.70 2.0 New foam 2.06 2.7 1.70 2.0 2.06 2.9-3.0 1.05 2.0
New foam rotated 90.degree. 2.04 2.7-2.9 .98 2.0 2.0 2.6 1.47 2
Foam rotated 2.0 2.6 1.47 2 again 90.degree. Foam replaced w/SS
screen 2.05 2.6-2.8 .63 2 2.04 2.7-3.0 .63 2 2.04 2.8-3.0 .63 2
2.06 2.8-3.0 .65 2 New screen 2.06 3.0-3.1 .65 2 New heater element
2.03 3.0-3.2 .62 2 2.04 2.7-2.8 .62 2 2.04 2.7-2.8 .62 2 2.04
2.9-3.0 .62 2 2.50 2.7-2.9 .9 2 2.50 2.4-2.6 .9 2 2.54 2.6-2.8 .9 2
2.54 2.6-2.9 .9 2 3.52 1.9 1.60 2 3.51 2.1 1.60 2 4.53 1.8-1.9 2.54
2 4.51 1.8-1.9 2.54 2 Heater element broke 2.02 2.8-3.0 .61 2
Heater replaced 4.52 1.9 2.53 2 4.53 1.9 2.53 2 6.10 1.3-1.5 4.33 2
6.10 1.4-1.5 4.35 2 7.03 1.1-1.2 5.68 2 .DELTA. P Vac Flow PSD
(inches (LPM) (microns) H.sub.2O) Notes 1.48 2.8-3.sup. .34 1.48
3.2-2.4 .34 1.48 2.6-2.9 .34 1.48 2.4-2.7 .34 2.04 .sup. 3-3.2 .62
2.04 .sup. 3-3.2 .62 .95 3.9-4.2 0.14 .95 3.9-4.2 0.14 Bypass Adder
used (Mark V) 2.08 1.4-1.8 1.06 14.9 2.08 1.9-2.1 1.06 14.9 2.08
2.0-2.1 1.06 14.9 2.08 2.0-2.1 1.06 14.9 3.02 1.7-1.8 2.06 21.0
3.02 1.8 2.06 21.09 4.48 1.3-1.4 4.22 30.4 4.48 1.2-1.4 4.22 30.1
2.0 1.9-2.sup. 1.08 Flow meter taped up 2.0 2 1.08 on bypass 2.0
2.4-2.5 1.08 2.01 2.2-2.3 1.08
Example 9
Particle Size Diameters of Aerosols Generated from Heater Element
Comprising a Center Exit Wire Lead when the Length of the Leads are
Decreased
[0363] This example describes the particle size diameters (PSD) of
aerosols generated from a heater element as described in FIG. 36.
In this example, the length of the leads connecting the wire coil
to the brass contacts is 0.30 inches (about 0.762 mm). The heater
element is inserted into the device depicted in FIG. 31D. FIG. 31D
depicts a device designated ENT-100-D with a primary passageway for
air to flow through, brass contacts (+/-) embedded within the wall
of the primary passageway, and a heater element as described in
this example. The wire of the heater element has a diameter of 0.10
inches (about 2.54 mm). The wire coil of the heater element has an
increased number of coils relative to example 8, and the wire coil
has an inner diameter of 0.032 inches (about 0.813 mm). In this
example, the liquid formulation comprises propylene glycol and it
wicks onto the ends of the wire of the heater element and onto the
brass contacts. The dose of the formulation is 2 mg. Table 15 shows
the particle size diameter of the aerosols generated from the
device described in this example. As shown in Table 15, the
particle size diameter distribution of aerosols generated by this
device is unaffected by alterations in current used to heat the
wire.
TABLE-US-00015 TABLE 15 Testing using ENT-100-D (side mount)
(w/bottom leads) with leads shortened. Dose 2 mg, current 2.00 amps
(U.N.O.) Primary .DELTA. P Vac Flow (LPM) PSD (microns) (inches
H.sub.2O) Current (amps) 2.02 3.0-3.2 .62 2.0 2.02 2.9-3.2 .62 2.0
1.48 2.3-2.5 .37 2.0 1.48 2.0-2.4 .37 2.0 1.48 2.0-2.6 .37 1.8 1.48
2.0-2.5 .37 1.8 1.10 2.8-4.1 .20 1.8 1.10 2.3-3.4 .20 1.8 2.0
3.1-3.2 .62 2.0 2.12 2.2 1.16 2.0 2.12 2.2 1.16 2.0 1.01 2.8 .30
1.8 1.01 2.8-3.0 .30 1.8 .49 4.7-5.4 .08 1.8 .49 4.5-4.8 .09 1.8
4.50 1.4-1.6 4.14 2.0
Example 10
Particle Size Diameters of Aerosols Generated from a Device
Comprising a Heater Element Comprising a Center Exit Wire Lead
[0364] This example describes the particle size diameters (PSD) of
aerosols generated from a device comprising a heater element as
described in FIG. 36. In this example, the heater element is
inserted into the device depicted in FIG. 31D. FIG. 31D depicts a
device designated ENT-100-D with a primary passageway for air to
flow through, brass contacts (+/-) embedded within the wall of the
primary passageway, and a heater element as described in this
example. The wire of the heater element has a diameter of 0.10
inches (about 2.54 mm). The wire coil of the heater element has an
inner diameter of 0.032 inches (about 0.813 mm). In this example,
the liquid formulation comprises propylene glycol and it wicks onto
the ends of the wire of the heater element and onto the brass
contacts. The dose of the formulation in this example is 2 mg.
Table 16 shows the particle size diameter of the aerosols generated
from a device comprising the heater element described in this
example. As shown in Table 16, the particle size distribution of
aerosols generated by devices with the heater element is unaffected
by alterations in current used to heat the wire. Also as shown in
Table 16, altering the configuration of the airway of the ENT-100-D
device by adding the airway depicted in FIG. 33 (designated the
MARK VI adder in Table 15) downstream of the heater element
produces particles with a PSD of about 1 to about 2 uM, which
matches the PSD of the particles generated without the MARK VI
adder. The MARK VI adder comprises a primary airway with an
internal diameter of 0.25 inches (about 6.35 mm), which narrows to
an airway comprising an internal diameter of 0.086 inches (about
2.18 mm) and an external diameter of 0.106 inches (about 2.69
mm)
TABLE-US-00016 TABLE 16 Testing of ENT-100-D device Dose = 2 mg;
Current 2 amps; 1 sec duration .DELTA. P Vac P Flow B Flow PSD
(inches (LPM) (LPM) (microns) H.sub.2O) Notes 1.97 3.0-3.1 .58
Straight tube 1.52 2.0-2.5 .37 1.52 2.4 .36 1.0 3.2-3.7 .17 3.0
2.0-2.3 1.21 3.0 2.3-2.4 1.22 4.53 1.6-1.8 2.52 4.53 1.3-1.5 2.50
6.08 1.2-1.3 4.23 6.08 0.8-1.3 4.23 6.11 .sup. 0.7-1.2 (ST) 7.13
w/SS needle in 6.11 .6-1.2 7.13 .250 tube 4.48 1.5-1.6 4.14 4.48
1.6-1.7 4.14 3.01 1.7-1.9 2.05 3.01 1.7-1.8 2.05 2.01 2.2 1.04 2.01
2.2-2.7 1.04 1.47 2.0-2.1 .6 1.47 2.1 .6 0.98 2.8-3.0 .29 0.98
2.7-3.0 .29 .48 4.7-5.2 .07 .48 4.4-5.1 .07 1.5 2.1 .6 Delrin
"double cone" 1.5 2.1-2.2 .64 2.05 2.3 1.04 2.05 2.2 1.08 2.5
2.1-2.2 1.48 3.0 1.9-2.0 2.04 3.0 1.9-2.0 2.04 1.0 2.9-3.1 .29 1.24
2.6-2.7 .43 1.25 2.5-2.7 .43 1.75 2.3-2.4 .76 1.75 2.3 .76 1.49
2.1-2.2 .6 Current changed to 2.2 1.49 2.1-2.2 2.41 Back to 2.0
amps orifice changed Adder installed .250 w/SS needle 6 slots .100
long x .080 3.0 21.16 1.8 1.98 3.0 21.16 1.8-1.9 1.98 7x Adder 2.0
14.13 2.0-2.1 1.0 Mark VI 2.0 14.13 2.0-2.1 1.0 .98 7.06 2.7-2.8
.28 .98 7.00 2.8-2.9 .29 1.5 10.49 2.1-2.2 .63 1.53 10.62 2.0-2.2
.63 .49 3.45 4.3-4.5 .07 4.51 31.4 1.5-1.6 4.09 4.51 31.4 1.5-1.6
4.04 6.1 4.2 1.2 7.0 1.98 3.98 2.3-2.5 .98 1.98 3.98 2.3-2.4 .98
2.02 0 2.3-2.4 1.03 2 28 2 3.52 2 28 2.0-2.1 3.52
Example 11
Particle Size Diameters of Aerosols Generated from Device
Comprising a Bypass Inlet for Mixing the Condensation Aerosol in a
Larger Volume of Carrier Gas
[0365] In this example, the particle size diameters (PSD) of a
condensation aerosol generated by a device comprising the airway
configuration depicted in FIG. 33 are tested. The device comprises
a primary airway with an internal diameter of 0.25 inches (about
6.35 mm), which narrows to an airway comprising an internal
diameter of 0.086 inches (about 2.18 mm) and an external diameter
of 0.106 inches (about 2.69 mm). The airway configuration is
coupled to a heater element comprising a wire coil, wherein the
heater element vaporizes a liquid formulation comprising propylene
glycol upstream of where the primary airway narrows. The vaporized
formulation then enters the narrowed airway and condenses into
particles. The narrowed primary airway is designed to carry the
vaporized formulation in a carrier gas (e.g. air) at a flow rate
suitable for condensing the vapor into particles of a desired size
(e.g. an MMAD of about 1 to about 5 um). In this example, the
narrowed primary airway opens up into a wide downstream airway
comprising an internal diameter of 0.25 inches (about 6.35 mm) and
the condensed particles are mixed with bypass carrier gas (e.g.
air) that enters the widened primary airway from inlets located
(disposed) in the walls of the primary airway. The carrier gas
entering through the inlets is fed from a bypass inlet which is in
a wall of a secondary housing that encompasses the primary airway.
In this example, the effect of varying the flow rates of the bypass
gas (B flow) on the PSD of the condensed is examined Table 17 shows
the results. As shown in Table 17, different rates of B flow have
no effect on the PSD. Moreover, the PSD at each B flow rate is
between 1 and 3 uM. Table 18 shows the effect on PSD of limiting
the flow of bypass carrier gas through the bypass inlet on the
secondary housing. The flow of bypass gas through the bypass inlet
is limited by using either a valve or by altering the geometry of
the orifice (i.e. forming a slot of different dimensions. As shown
in Table 18, either the use of a valve or slot to control the flow
of bypass gas is effective in producing particles with a PSD of
about 1 to about 5 .mu.m.
TABLE-US-00017 TABLE 17 Characterization of Primary Flow (P flow),
Bypass Flow (B Flow), and particle size diameter of device
comprising Mark VI Adder .DELTA. P Vac P Flow B Flow PSD (inches
(LPM) (LPM) (microns) H.sub.2O) Notes 1.01 7 2.7-2.8 .29 1.02 14.2
2.5-2.8 1.99 1.0 14.03 2.5-2.7 2.11
TABLE-US-00018 TABLE 18 Characterization of Primary Flow (P flow),
Bypass Flow (B Flow), and particle size diameter of device
comprising Mark VI Adder with addition of Flap valve to bypass
inlet .DELTA. P P Flow B Flow Vac (inches Orifice (LPM) (LPM)
H.sub.2O) (inches) Valve 0 0 0 .060 Clear 1.48 .64 1 .060 Slot .080
2.20 1.58 2 .060 x 240 2.81 2.70 3.14 .060 3.23 3.72 4 .060 3.66
5.10 5 .060 4.42 7.3 7 .060 5.3 10.48 10 .060 1.48 4.86 1 Tee slot
1.83 6.74 1.48 2.25 9.02 2.08 2.50 10.6 2.53 2.79 12.6 3.07 3.38
17.2 4.32 4.14 23.7 6.24 5.32 34.6 10.0 1.47 5.05 1.01 Internal
radius 1.86 6.34 1.51 valve 2.23 7.7 2.06 Blue material 2.52 8.7
2.56 1.5 5.75 1 Internal radius 2.2 9.2 2 Green 2.75 12.94 3 3.27
17.5 4.06 4.2 26.2 6.4 5.4 38.7 10.5
Example 12
Effects of Gravity on Particle Size Diameters of Aerosols Generated
from an ENT-100-D Device
[0366] In this example, the effects of gravity on the particle size
diameters (PSD) of a condensation aerosol generated by an ENT-100-D
device as depicted in FIG. 31D are tested. The ENT-100-D device is
loaded with 2 mg of a liquid propylene glycol formulation and the
device is rotated during the use of the device. The device is
rotated 90 degrees in all dimensions from a stable baseline
position. The particle size diameter is measured at each rotation
and found not to change. As a result, the device produces particles
of a consistent size regardless of the orientation in space of the
device.
Example 13
Study of the Safety, Tolerability, Pharmacokinetics, and
Pharmacodynamics of the eNT-100 Nicotine Inhaler Among Healthy
Volunteer Cigarette Smokers
[0367] In this example, a study will be conducted to examine the
safety, tolerability, pharmacokinetics, and pharmacodynamics of
condensation aerosol comprising nicotine produced from a liquid
nicotine formulation using the ENT-100 nicotine inhaler. One
primary objective is to establish the maximally tolerated dose in
the range of 25-100 .mu.g of a condensation aerosol comprising
nicotine and propylene glycol (PG) from the eNT-100 nicotine
inhaler. A second primary objective is to establish the plasma
level-time profiles of nicotine administered as 10 inhalations
(single dose) using .mu.g doses from the eNT-100 nicotine inhaler.
The study will be conducted in two parts: Part 1 will be a
single-blind, placebo and vehicle-controlled, escalating, single
dose design to assess the safety, tolerability, nicotine
concentrations, and pharmacodynamics of a condensation aerosol
comprising nicotine produced from a liquid nicotine formulation
using the eNT-100 nicotine inhaler. Subjects will be abstinent from
smoking for at least 12 hours prior to the experimental session.
Groups of 12 subjects will be assigned to one of up to seven
experimental groups, depending on the maximally tolerated dose
within the predetermined range of 25-100 .mu.g of nicotine per
inhalation (less than a typical cigarette inhalation per puff).
Subjects will complete predose assessments of their exhaled CO,
smoking urge, nicotine concentrations, spirometry, and pulse
oximetry, and a brief training including practice inhalations, and
then complete 10 inhalations from the eNT-100 inhaler at
approximately 30-second intervals over a 4.5-minute period.
Postdose assessments will include nicotine concentrations, safety,
tolerability, liking, smoking urge, spirometry, and pulse oximetry
assessments. Subjects will receive a follow-up phone call
approximately 24 hours after dosing to assess any adverse events
(AEs) that have occurred since dosing. Escalation to the next dose
group will not take place until adequate safety and tolerability
from the previous group has been demonstrated.
[0368] During the escalating-dose sequence portion of the study
(see FIG. 43), 1.0 mg of total solution (nicotine+PG) will be
aerosolized in the vehicle and nicotine dose groups. Then, the
final MTD nicotine group (e.g., Group #7), will participate to
evaluate the nicotine concentration for the eNT-100 with the
nicotine concentration based on the safety and tolerability from
the previous groups. Upon reaching the maximally tolerated dose
(within the predetermined range of 25-100 .mu.g of nicotine per
inhalation), a final cohort of subjects will be run at the same
nicotine dose, but at twice the nicotine concentration (e.g., if
100 .mu.g of nicotine is well tolerated within 1 mg of PG, [i.e.,
10% solution], then an additional group would be run using 100
.mu.g of nicotine within 0.5 mg of PG [i.e., 20% solution]). Part 2
will be a randomized, single-blind, within-subject, 5-way
crossover, vehicle-, e-cig-, and combustible cigarette-controlled
design to assess the safety, tolerability, pharmacokinetics and
pharmacodynamic effects of the eNT-100 nicotine inhaler. The
selected nicotine aerosol concentrations and doses to be
administered during Part 2 will be determined upon completion of
Part 1 of the study. Subjects will complete predose assessments of
exhaled CO, their smoking urge, nicotine PK, spirometry, and pulse
oximetry, and a brief training including practice inhalations. Each
administration of the study products will include 10 inhalations at
approximately 30-second intervals over a 4.5-minute period (or
completion of one conventional cigarette). Postdose assessments
will include nicotine PK, safety, tolerability, liking, smoking
urge, exhaled CO, spirometry, and pulse oximetry assessments. A
36-hour wash-out from nicotine will be required prior to each
product administration. See FIG. 43 for the trial design of this
portion of the trial.
[0369] Study Population and Sample Size
[0370] Parts 1 and 2 will include approximately 48-84 (depending on
the maximally tolerated aerosol administration) and 15 subjects,
respectively.
[0371] Subjects will be healthy, adult males and females, 21-65
years of age inclusive, who smoke at least 10 cigarettes per day
(CPD) for the last 12 months. Ideally, subjects participating in
Part 1 will serve as the pool of subjects for Part 2; however,
additional subjects will be recruited following completion of Part
1 if necessary to better ensure that 15 subjects are administered
study product in Part 2. Potential subjects must fulfill all of the
following inclusion criteria to be eligible for participation in
the study. Inclusion criteria include: 1. Healthy adult male and
female smokers, 21 to 65 years of age, inclusive, at Screening. 2.
At least a 12-month smoking history prior to Check-in with a
cigarette smoked per day average of 10 or more manufactured
cigarettes per day (no restriction on brand). Brief periods (up to
7 consecutive days) of non-smoking (e.g., due to illness, trying to
quit, participation in a study where smoking was prohibited) will
be permitted at the discretion of the PI. A history of occasional
use of e-cigs is allowed, but the subjects should confirm that
their primary source of nicotine consumption is smoking
conventional cigarettes. 3. Positive urine cotinine at Screening
(>500 ng/mL). 4. Exhaled CO>12 ppm at Screening. 5. Female
subjects who are heterosexually active and of childbearing
potential (e.g., not surgically sterile [bilateral tubal ligation,
hysterectomy, or bilateral oophorectomy at least 6 months prior to
Check-in] or at least 2 years naturally postmenopausal) must have
been using one of the following forms of contraception and agree to
continue using it through completion of the study: hormonal method
(e.g., oral, vaginal ring, transdermal patch, implant, or
injection) consistently for at least 3 months prior to Check-in;
double barrier method (i.e., condom with spermicide or diaphragm
with spermicide) consistently for at least 2 weeks prior to
Check-in; intrauterine device for at least 3 months prior to
Check-in; Essure.RTM. procedure at least 6 months prior to
Check-in; have a partner who has been vasectomized for at least 6
months prior to Check-in. 6. Female subjects of childbearing
potential who are not currently engaging in heterosexual
intercourse must agree to use one of the above methods of birth
control, in the event that they have heterosexual intercourse
during the course of the study. 7. Voluntary consent to participate
in this study documented on the signed informed consent form (ICF).
8. Willing to comply with the requirements of the study and willing
to consider using alternative inhaled forms of nicotine other than
conventional cigarettes. 9. Forced Expiratory Flow (FEF) (25-75%)
at least 70% of the normal values predicted for that individual
based on age, gender, and height.
[0372] Subjects may be excluded from the study if there is evidence
of any of the following criteria at Screening, Check-in, or at any
time during the study as appropriate, in the opinion of the
principal investigator (PI): History or presence of clinically
significant gastrointestinal, renal, hepatic, neurologic,
hematologic, endocrine, oncologic, urologic, pulmonary (especially
bronchospastic diseases), immunologic, psychiatric, or
cardiovascular disease, or any other condition that, in the opinion
of the PI, would jeopardize the safety of the subject or impact the
validity of the study results; (Part 2 only) clinically significant
abnormal findings on the physical examination, ECG, or clinical
laboratory results, in the opinion of the PI; (Part 2 only)
positive test for human immunodeficiency virus (HIV), hepatitis B
surface antigen (HbsAg), or hepatitis C virus (HCV); positive urine
screen for alcohol or drugs of abuse at Screening or any Check-in;
history of drug or alcohol abuse within 24 months of Check-in; an
acute illness (e.g., upper respiratory infection, viral infection)
requiring treatment within 2 weeks prior to Check-in; fever
(>100.2.degree. F.) at Screening or at Check-in; systolic blood
pressure>150 mmHg, diastolic blood pressure>95 mmHg, or pulse
rate>99 bpm at Screening; body mass index (BMI)<19 kg/m2 or
>35 kg/m2 at Screening; female subjects who are pregnant,
lactating, or intend to become pregnant from Screening through
completion of study; consumption of xanthines/caffeine, alcohol, or
grapefruit juice within 24 hours of Check-in and during
confinement; use of any OTC or prescription smoking cessation
treatments, including, but not limited to, nicotine replacement
therapies (gum, patches, lozenges, nasal spray, or inhalers),
varenicline (Chantix.RTM.), or buproprion (Zyban.RTM.) within 3
months prior to screening and throughout the study; use of
prescription anti-diabetic medication and/or insulin therapy within
12 months of Check-in and throughout the study; concomitant use of
inhalers for any reason within 3 months prior to screening and
throughout the study; plasma donation within 7 days prior to
Check-in, or donation of blood or blood products, had significant
blood loss, or received whole blood or a blood product transfusion
within 56 days prior to Check-in; participation in a previous
clinical study for an investigational drug, device, or biologic
within 30 days prior to either Check-in; use of nicotine-containing
products other than manufactured cigarettes and occasional e-cig
use (e.g., roll-your-own cigarettes, bidis, snuff, nicotine
inhaler, pipe, cigar, chewing tobacco, nicotine patch, nicotine
spray, nicotine lozenge, or nicotine gum) within four weeks prior
to Check-in or during study; or self-reported puffers (i.e., adult
smokers who draw smoke from the cigarette into the mouth and throat
but do not inhale); FTND score of <6.
[0373] Study Restrictions:
[0374] Concomitant Medications
[0375] Stable doses (i.e., no dosage adjustments within 30 days
prior to Check-in) of prescription or over-the-counter medications
required to treat a PI-approved disease or condition (e.g.,
hypertension) are permitted at the discretion of the PI. Hormonal
contraceptives (e.g., oral, transdermal patch, implant, injection)
and hormonal replacement therapy are permitted. Occasional use of
over-the-counter analgesics (e.g., acetaminophen, ibuprofen),
antihistamines, and nasal decongestants are permitted. Exceptions
may be permitted at the discretion of the PI in consultation with
the Sponsor, providing the medication in question would have no
impact on the study. Any exceptions will be documented. All
concomitant medications (and reasons for their use) taken by
subjects during the study will be recorded and coded using the most
updated version of the WHO Drug Dictionary available at Celerion
(e.g., September 2013 or later). During the study, up to 2 g per
day of acetaminophen may be administered at the discretion of the
PI for intercurrent illness or adverse events. If other drug
therapy is required, a joint decision will be made by the PI and
Sponsor to continue or discontinue the subject.
[0376] Foods and Beverages
[0377] Consumption of foods and beverages containing the following
substances will be prohibited as indicated: Xanthines/caffeine: 24
hours prior to Check-in and during confinement; alcohol: 24 hours
prior to Check-in and during confinement; or grapefruit or
grapefruit juice: 24 hours prior to Check-in and during
confinement.
[0378] Activity
[0379] Subjects will not engage in strenuous activity in the 48
hours prior to and at any time during the confinement period.
[0380] Subject Numbering
[0381] Subjects will be assigned a unique screening number and
subject numbers for each part of the study.
[0382] In Part 1, once enrolled for study conduct, subjects in the
first enrollment cohort will be numbered 101-112, subjects in the
second enrollment cohort will be numbered 113-124, etc.
[0383] In Part 2, once enrolled for study conduct, subjects will be
assigned a subject number from 201-215.
[0384] Replacement subjects, if used, will be assigned a number
1000 higher than the subject being replaced (e.g., Subject 1110
would replace Subject 110).
[0385] Eligibility for inclusion into Part 1 will be based on a
screening visit(s) to assess medical history, concomitant
medications, demographics, and smoking history (including the
Fagerstrom Test for Nicotine Dependence [FTND]), an exhaled CO
test, urine cotinine and drugs of abuse test, urine pregnancy test,
vital signs, and BMI determination.
[0386] Subjects participating in Part 2 will complete additional
screening events including a physical examination, ECG, clinical
laboratory, and serology evaluations. If the pool of subjects from
Part 1 is deemed not sufficient to successfully complete Part 2,
then additional subjects will be recruited.
[0387] However, these subjects must also complete all applicable
screening procedures.
[0388] Duration of Study Conduct
[0389] Part 1 will be completed during a Screening visit, a single
study visit and a follow-up phone call. Subjects entering into Part
2 will complete an additional 11-day in-clinic confinement. Overall
the study is expected to take place over approximately 10
weeks.
[0390] Study Products
[0391] Part 1:
[0392] Placebo (eNT-100 inhaler delivering air only); Vehicle
control (eNT-100 inhaler delivering PG only); and eNT-100 Nicotine
Inhaler (potential nicotine concentration range depending on
tolerability: 1.25-20% nicotine solution in PG vehicle)
[0393] Part 2:
[0394] Vehicle control (eNT-100 inhaler delivering PG only);
eNT-100 Nicotine Inhaler (potential nicotine concentration range
depending on tolerability: 1.25-20% nicotine solution in PG
vehicle); NJOY King Bold e-cig (4.5% nicotine solution); and
subject's usual brand of combustible cigarette
[0395] Product Administration/Experimental Sessions
[0396] Part 1:
[0397] Subjects will participate in one of the experimental groups
using the eNT-100 nicotine inhaler involving 10 inhalations
resulting in the total nicotine delivery as listed in Table 19
below.
TABLE-US-00019 TABLE 19 Experimental Groups (Part 1) Group (Total
Total Amount Total Amount of of Solution Nicotine Nicotine Nicotine
Nicotine Aerosolized per over 10 Concen- Over 10 per Inhalation
Inhalation Inhalations tration Inhalations) (.mu.g) (.mu.g) (.mu.g)
(%) Group #1: 0 0 0 0 Placebo (air only) Group #2: 1000 0 0 0
Vehicle (PG) Group #3: 1000 25 250 2.5 250 .mu.g Group #4: 1000 50
500 5.0 500 .mu.g Group #5: 1000 75 750 7.5 750 .mu.g Group #6:
1000 100 1000 10.0 1000 .mu.g Group 500-2000 MTD TBD (range: TBD
(range: #{TBD}: MTD 250-1000) 1.25-20.0)
[0398] If deemed appropriate, in order to identify a dose that is
both well-tolerated while minimizing the total amount of chronic
exposure to PG that would be expected from eventual chronic use of
the eNT inhaler, the total amount of solution aerosolized (starting
at 1.0 mg but adjustable to a minimum of 0.5 mg or a maximum of 2.0
mg of total nicotine plus PG solution), as well as the nicotine
concentration of the aerosol, can be adjusted following a review of
the safety and tolerability from the previous group.
[0399] For Groups 2 through 6, Table 20 below highlights using
alternative experimental groups. Initially, subjects will be dosed
with 1 mg of total solution being aersolized. If that appears to be
poorly tolerated in the vehicle condition, then 0.5 mg of solution
will be evaluated. If, on the other hand, the PG appears to be well
tolerated but the nicotine concentrations are not well tolerated
(e.g., as reflected in AEs at the 25 .mu.g dose), then 2.0 mg of
solution may be evaluated, which would enable evaluation of lower
concentrations of nicotine solution. Thus, the total amount of
solution to be aerosolized will range from 0.5 to 2 mg, while the
nicotine concentration range will be from 1.25 to 20%.
TABLE-US-00020 TABLE 20 Alternative Experimental Groups (Part 1)
Total Amount of eNT Solution Nicotine (nicotine + PG) Dose (.mu.g)
Experimental Aerosolized per (Concen- Solution Groups Inhalation
(mg) tration %) Placebo Group 1 0.0 0.0 (air only) Vehicle Group 2
0.5-2 0.0 (Propylene Glycol only) Nicotine & Groups 3-6: Doses
0.5 25 (5.0%) Propylene to be evaluated if 0.5 50 (10.0%) Glycol
(PG) 1.0 mg of PG is 0.5 75 (15.0%) not well tolerated 0.5 100
(20.0%) Groups 3-6: Planned 1 25 (2.5%) starting doses 1 50 (5.0%)
1 75 (7.5%) 1 100 (10.0%) Groups 3-6: Doses 2 25 (1.25%) to be
evaluated if 2 50 (2.5%) nicotine concentration 2 75 (3.75%) is not
well tolerated 2 100 (5.0%)
[0400] The final maximally tolerated dose (MTD) nicotine group
(e.g., Group #7), will evaluate the nicotine concentration for the
eNT-100 with the nicotine concentration based on the safety and
tolerability from the previous groups. The maximum nicotine
concentration that would be evaluated in any scenario is 20.0%.
[0401] Dose-escalation decisions within part 1 will be made based
on evaluation of safety data, AEs, and the pharmacodynamic (PD)
assessments.
[0402] Part 2:
[0403] Subjects will participate in all the experimental sessions
according to the randomization schedule outlined in Table 21.
TABLE-US-00021 TABLE 21 Experimental Products (Part 2) Total Total
Amount Nicotine Nicotine Nicotine of Solution per over 10 Concen-
Aerosolized per Inhalation Inhalation tration Product Inhalation
(.mu.g) (.mu.g) (.mu.g) (%) Vehicle 500-2000 0 0 0 (propylene
glycol only) eNT-100: 500-2000 TBD TBD TBD (range: TBD .mu.g dose
1.25-20.0) eNT-100: 500-2000 TBD TBD TBD (range: TBD .mu.g dose
1.25-20.0) e-Cig Variable ~113 ~1130 4.5 (NJOY King Bold, 4.5%
concentration) Combustible N/A 145-199 ~1450-199 N/A cigarette
[0404] The selected nicotine aerosol concentration and doses to be
administered during Part 2 (TBD) will be determined upon completion
of Part 1.
[0405] Note: % nicotine is % by volume.
[0406] Pharmacokinetic Sample Collection, Parameters, and
Analysis:
[0407] During Part 1, serial blood samples will be collected within
15 minutes prior to product administration, and at approximately 5
and 10 minutes after the start of each product administration, and
will be used to determine plasma nicotine concentrations. Table 22
outlines the blood sample collection protocol for Part 1.
TABLE-US-00022 TABLE 22 Part 1 Blood Sample Collection Protocol
Approximate Number of Approximate Sample Volume Time Volume per
Time Over Course Sample Type Points Point* (mL) of Study (mL) PK 3
4 12 Total Blood Volume 12 for Study (mL) .fwdarw.
[0408] During Part 2, serial blood samples will be collected within
15 minutes prior to product administration and at approximately 3,
5, 10, 15, 20, 25, 30, and 60 minutes after the start of each
product administration and will be used to determine plasma
nicotine concentrations. Table 23 outlines the blood sample
collection protocol for Part 2.
TABLE-US-00023 TABLE 23 Part 2 Blood Sample Collection Protocol
Approximate Number of Approximate Sample Volume Time Volume per
Time Over Course Sample Type Points Point* (mL) of Study (mL)
Screening laboratory 1 12.5 12.5 safety tests (including
hematology, serum chemistry, serology). On-study hematology 1 12.5
12.5 and serum chemistry (including serum pregnancy for women) PK
45 4 180 Total Blood Volume 205 for Study (mL) .fwdarw.
[0409] For Part 2, noncompartmental PK parameters of C5, C.sub.max,
t.sub.max, and AUC.sub.0-t will be calculated from plasma
concentrations of nicotine. Additional PK parameters may be
calculated if deemed appropriate.
[0410] Nicotine concentrations and PK parameters will be summarized
by study product using descriptive statistics.
[0411] Analyses of variance (ANOVA) or other appropriate
statistical tests will be performed on the PK parameters. The ANOVA
model will include sequence, study product, and period as fixed
effects, and subject nested within sequence as a random effect.
Sequence will be tested using subject nested within sequence as the
error term. Each ANOVA will include calculation of least-squares
means (LSM), differences between product LSM, and the standard
error associated with these differences. The above statistical
analyses will be performed using the appropriate SAS
procedures.
[0412] Pharmacodynamic Assessment and Analysis
[0413] Smoking urge, aversion/tolerability, respiratory tract
sensations, and subjective effects will be evaluated via
patient-reported outcome (PRO) measures following product
administration in both Part 1 and Part 2.
[0414] All pharmacodynamic data obtained during both parts of the
study will be listed by subject and time point. The data will be
summarized by time point using descriptive statistics and an
appropriate statistical method (ANOVA or an appropriate
non-parametric test as required by the type of data) will be used
to characterize the between-group comparisons.
[0415] Safety Assessments and Analysis
[0416] Prior to inclusion into Part 1 of the study, medical
history, vital signs, urine drug and alcohol screen, and pregnancy
test (females only) will be performed. Part 1 Check-in evaluations
will include vital signs, urine drug and alcohol screen, and a
pregnancy test (females only).
[0417] Additional safety evaluations performed prior to inclusion
in Part 2 will include a physical examination, electrocardiogram
(ECG), clinical laboratory (clinical chemistry, hematology,
urinalysis), and serology. Part 2 Check-in evaluations will include
a brief physical examination (symptom-driven), vital signs,
clinical laboratory (clinical chemistry, hematology, and
urinalysis), urine drug and alcohol screen, and a pregnancy test
(females only). End-of-Study (or Early Termination) evaluations
will include a brief physical examination (symptom-driven) and
vital signs.
[0418] In addition, vital signs will be evaluated before and after
study product administration.
[0419] Adverse events (AEs) spontaneously reported by the subjects
or observed by the PI or other study personnel will be monitored
and followed up until the symptoms or values return to normal or
acceptable levels or until lost to follow-up, as appropriate in the
opinion of the PI or his designee.
[0420] Other Non-Safety Assessments and Analysis
[0421] Spirometry, pulse oximetry, and expired CO values for both
Part 1 and Part 2 will be listed by subject and time point.
Postdose to predose difference in each assessment will be
summarized by time point using descriptive statistics and analyzed
using an appropriate statistical method.
[0422] The dependent measures related to the spirometry device
attached to the eNT-100 inhaler used to characterize subjects'
inhalations will be listed by subject.
[0423] Description of the eNT-100 Nicotine Inhaler
[0424] The aerosol is created inside the eNT-100 inhaler, which is
itself inside a small cylindrical plastic housing that is used to
blind the test subject from the test article. The test subject will
inhale from a plastic tube that slides over the stainless-steel
mouthpiece shown. Inside of the aerosol-generating inhaler is a
small heater element that is used to vaporize the nicotine solution
under flow conditions that result is a 1.4 to 2.5 micron aerosol
particle. The nicotine inhaler further comprises a positive
displacement pump to meter out a dose of the nicotine solution onto
the heater element.
[0425] The eNT-100 is designed to create the aerosol when the
inhalation rate reaches 20 lpm (about 3.times.10.sup.-4 m.sup.3/s).
At that flow rate the aerosol produced has a particle size of 2.5
micron volume median diameter (VMD) with a GSD of 1.6. The upper
end of the inhalation flow rate is determined by the flow rate that
can be produced under what is considered an upper limit of vacuum
that the human lung can produce by inhalation (13 inches of water
is considered that upper limit (about 3235 Pa)). At that vacuum,
the inhalation flow rate is 50 lpm (about 8.33.times.10.sup.-4
m.sup.3/s) and the particle size is 1.4 micron VMD with a GSD of
1.2.
[0426] The bulk of the aerosol is created within 1 second of the
inhaler being breath-activated. Within 1.4 seconds the entire
aerosol is created. An estimate of the aerosol produced between the
1 second and the 1.4 second time point is around 5-10% of the total
amount of the aerosol. As a result, the bulk of the aerosol is
delivered to the respiratory tract in the first 1/3 to 1/2 of the
volume of the total inhalation volume, thereby allowing the aerosol
to be "chased" down into the deep lung by the balance of the
inhalation.
[0427] The eNT-100 system can generate an emitted dose of +/-20% of
the dose (or loaded dose). The dose (or loaded dose) can be the
amount of nicotine solution pumped onto the heater element prior to
the creation of the aerosol and can be +/-2% of the target dose
(the label claimed dose or goal dose). The emitted dose can be 92%
to 97% of the dose. For example, the amount actually delivered to
the lung if the label claim dose is 100 .mu.g would be between 90%
and 99%.
[0428] While preferred embodiments have been shown and described
herein, it will be obvious to those skilled in the art that such
embodiments are provided by way of example only. Numerous
variations, changes, and substitutions will now occur to those
skilled in the art. It should be understood that various
alternatives to the embodiments of the invention described herein
may be employed. It is intended that the following claims define
the scope of the invention and that methods and structures within
the scope of these claims and their equivalents be covered
thereby.
* * * * *