U.S. patent application number 10/174000 was filed with the patent office on 2002-12-05 for system for effecting smoke cessation.
Invention is credited to Farr, Stephen J..
Application Number | 20020179102 10/174000 |
Document ID | / |
Family ID | 22507255 |
Filed Date | 2002-12-05 |
United States Patent
Application |
20020179102 |
Kind Code |
A1 |
Farr, Stephen J. |
December 5, 2002 |
System for effecting smoke cessation
Abstract
A system is disclosed which makes it possible for a patient to
be delivered gradually reduced amounts of nicotine over time
thereby allowing the patient to be gradually weaned off of
dependence on nicotine and quit smoking. The system is comprised of
a means for aerosolizing a formulation and containers of
formulation. The formulation is comprised of nicotine in a
pharmaceutically acceptable carrier. Preferably, a plurality of
containers are produced wherein the concentration of nicotine in
the different containers or different groups of containers is
reduced. The patient uses containers with the highest concentration
initially and gradually moves towards using containers with lower
and lower concentrations of nicotine until the patient's dependence
on nicotine is eliminated.
Inventors: |
Farr, Stephen J.; (Orinda,
CA) |
Correspondence
Address: |
BOZICEVIC, FIELD & FRANCIS LLP
200 MIDDLEFIELD RD
SUITE 200
MENLO PARK
CA
94025
US
|
Family ID: |
22507255 |
Appl. No.: |
10/174000 |
Filed: |
June 17, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10174000 |
Jun 17, 2002 |
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09611423 |
Jul 7, 2000 |
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60144140 |
Jul 16, 1999 |
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Current U.S.
Class: |
131/270 |
Current CPC
Class: |
A61M 2209/06 20130101;
A24F 40/10 20200101; A61M 15/06 20130101; A24F 40/42 20200101; A61M
15/009 20130101 |
Class at
Publication: |
131/270 |
International
Class: |
A24F 047/00 |
Claims
What is claimed is:
1. A system for aiding a patient in quitting smoking, comprising: a
device for aerosolizing a formulation; a first plurality of
containers which are designed for being loaded into the device for
aerosolizing formulation wherein the containers are comprised of
nicotine and a pharmaceutically acceptable carrier and wherein the
nicotine is present in a first concentration; a second plurality of
containers capable of being loaded into the device for aerosolizing
formulation wherein the formulation in the second plurality of
containers is comprised of nicotine and a pharmaceutically
acceptable carrier and further wherein the nicotine is present in
the formulation in a second concentration which is less than the
first concentration.
2. The system of claim 1, further comprising: a third plurality of
containers which are designed for being loaded into the device for
aerosolizing formulation wherein the containers are comprised of
nicotine and a pharmaceutically acceptable carrier and wherein the
nicotine is present in a third concentration which is less than the
second concentration.
3. The system as claimed in claim 1, wherein the formulation in the
first plurality of containers and the formulation in the second
plurality of containers is a liquid flowable formulation wherein
the nicotine is present in the formulation in a solution or
suspension.
4. The system as claimed in claim 3, wherein the first plurality of
containers comprises a porous membrane for each container and
further wherein the second plurality of containers comprises a
porous membrane for each container.
5. The system as claimed in claim 1, wherein the formulation in the
first plurality of containers and the formulation in the second
plurality of containers is a dry powder formulation.
6. The system as claimed in claim 1, wherein the first plurality of
containers comprises two or more canisters which canisters contain
the formulation in the form of nicotine and low boiling point
propellant and wherein the second plurality of containers comprises
two or more canisters wherein the formulation in the canisters
comprises nicotine and a low boiling point propellant.
7. The system as claimed in claim 1, wherein the device for
aerosolizing formulation is a hand-held, self-contained device.
8. The system as claimed in claim 1, wherein the first plurality of
containers each comprise a porous membrane wherein the pores have a
first average size, and wherein the second plurality of containers
each comprise a porous membrane wherein the pores have a second
average size which is larger than the first average size of the
pores in the membrane of the first plurality of containers.
9. A device for aerosolizing a nicotine formulation, comprising: a
means for aerosolizing formulation by applying force; and a means
for adjusting the means for aerosolizing formulation so that a
different amount of force can be applied based on the
adjustment.
10. The device as claimed in claim 9, further comprising: a
container loaded into the device which container is comprised of a
formulation comprised of nicotine and a pharmaceutically acceptable
carrier.
11. A kit for aiding a patient in quitting smoking, comprising: a
first plurality of containers having therein nicotine and a
pharmaceutically acceptable carrier, wherein the nicotine is
present in a first concentration; a second plurality of containers
having therein nicotine and a pharmaceutically acceptable carrier
wherein the nicotine is present in a second concentration which is
less than the first concentration.
12. The kit as claimed in claim 11, wherein the first plurality of
containers and second plurality of containers hold the nicotine and
pharmaceutically acceptable carrier in a liquid flowable form.
13. The kit as claimed in claim 11, wherein the first plurality of
containers and second plurality of containers each hold the
nicotine and pharmaceutically acceptable carrier in a dry powder
form.
14. A method of treatment, comprising: (a) aerosolizing a
formulation comprised of nicotine creating aerosolized particles
which are sufficiently small as to target the alveoli of a
patient's respiratory tract; (b) allowing the patient to inhale the
aerosolized particles of (a) thereby causing nicotine to enter the
patient's blood; (c) repeating (a) and (b) a plurality of times;
(d) aerosolizing a formulation comprised of nicotine creating
aerosolized particles which are sized in order to target the
bronchioles of the patient's respiratory tract; (e) allowing the
patient to inhale the aerosolized particles of (d) thereby
targeting the bronchioles of the respiratory tract; and (f)
repeating (d) and (e) a plurality of times.
15. The method of claim 14, further comprising: (g) aerosolizing a
formulation comprised of nicotine creating aerosolized particles
which are sized in order to target the bronchi of the patient's
respiratory tract; (h) allowing the patient to inhale the
aerosolized particles of (g) into the bronchi of the respiratory
tract; and (i) repeating (g) and (h) a plurality of times.
16. The method of claim 14, wherein the formulation is a liquid
formulation comprising nicotine and an excipient selected from the
group consisting of an aqueous solvent to form solutions and a
liquid to form suspensions.
17. The method of claim 14, wherein the formulation comprises a
solution or suspension of a nicotine and an aqueous solvent or
liquid carrier and the aerosolized particles are created by moving
the formulation through a porous membrane.
18. A method of treatment, comprising: (a) aerosolizing a
formulation comprising about 0.25 mg or more of nicotine to create
aerosolized particles which target an area of a patient's
respiratory tract; (b) allowing the patient to inhale the
aerosolized particles of (a) thereby causing nicotine to enter the
patient's blood; (c) repeating (a) and (b) a plurality of
times.
19. The method of claim 18, further comprising: (d) aerosolizing a
formulation comprising about 0.25 mg or more of nicotine to create
aerosolized particles which target a second area of the patient's
respiratory tract; (e) allowing the patient to inhale the
aerosolized particles of (d) to the second area of the patient's
respiratory tract; and (f) repeating (d) and (e) a plurality of
times.
20. A method comprising the steps of: (a) aerosolizing a
formulation comprised of nicotine creating aerosolized particles
having a diameter of 0.5 .mu. to about 2 .mu.; (b) allowing the
patient to inhale the aerosolized particles of (a) into the
patient's respiratory tract; (c) repeating (a) and (b) a plurality
of times; (d) aerosolizing a formulation comprised of nicotine
creating aerosolized particles having a diameter of 2 .mu. to about
4 .mu.; (e) allowing the patient to inhale the aerosolized
particles of (d) into the patient's respiratory tract; and (f)
repeating (d) and (e) a plurality of times.
21. The method of claim 20, further comprising the steps of: (g)
aerosolizing a formulation comprised of nicotine creating
aerosolized particles having a diameter of 4 .mu. to about 8 .mu.;
(h) allowing the patient to inhale the aerosolized particles of (g)
into the patient's respiratory tract; and (i) repeating (g) and (h)
a plurality of times.
Description
CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/144,140, filed Jul. 16, 1999, which application
is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention relates generally to a method for treating
conditions responsive to nicotine therapy. More specifically, the
invention relates to pulmonary administration of nicotine to effect
smoking cessation.
BACKGROUND OF THE INVENTION
[0003] Diseases related to cigarette smoking, such as lung disease,
heart disease and cancer, claim an estimated 400,000 lives each
year. The combustion of tobacco produces poisons and carcinogens
that present a significant health hazard for smokers and
non-smokers alike. Nicotine is a principal component of tobacco,
and the most pharmacologically active. It is physically addictive,
making it extremely difficult for a smoker to quit.
[0004] Smoking a cigarette delivers nicotine vapors to the lungs,
where nicotine is rapidly absorbed through the arteries and
delivered to the brain. Nicotine interacts with nicotinic
cholinergic receptors in the brain to induce the release of
neurotransmitters and produce an immediate reward--the "rush" that
smokers experience--that is associated with a rapid rise in blood
level. A persistent stimulus is also produced, and is associated
with a high blood level of nicotine. Complex behavioral and social
aspects of smoking, e.g., the hand-to-mouth ritual, etc., are also
habit-forming.
[0005] A therapeutic approach to aid in smoking cessation is to
provide the smoker with nicotine from sources other than
cigarettes. A number of nicotine replacement therapies have been
developed to accomplish this result. Commercially available
therapies deliver nicotine to the systemic circulation via
absorption through mucosal membranes or the skin. These include
nicotine-containing chewing gum, sachets, transdermal patches,
capsules, tablets, lozenges, nasal sprays and oral inhalation
devices.
[0006] Nicotine delivery via inhalation offers the benefit of
addressing the psychological component of cigarette smoking in
addition to the physiological dependence on nicotine. Nicotine
inhalation systems release nicotine as a vapor (see U.S. Pat. Nos.
5,167,242; 5,400,808; 5,501,236; 4,800,903; 4,284,089; 4,917,120;
4,793,366), aerosol (see U.S. Pat. Nos. 5,894,841; 5,834,011) or
dry powder (see U.S. Pat. No. 5,746,227) when air is inhaled
through the inhaler. A droplet ejection device (U.S. Pat. No.
5,894,841) has also been described that delivers a controlled dose
of nicotine via inhalation. These systems deliver low doses of
nicotine to the mouth and throat, where nicotine is absorbed
through the mucosal membranes into the circulation. Some inhalation
therapies feature devices that simulate or approximate the look,
feel and taste of cigarettes.
[0007] Currently available nicotine replacement therapies, such as
transdermal and buccal systems, provide a low, steady-state blood
level of nicotine to the patient. The need remains for an smoking
cessation therapy that delivers a precise dose of nicotine to the
lungs in a profile that mimics the blood levels achieved by
cigarette smoking--providing an initial sharp rise in blood level
followed by a slow release of nicotine--making it possible for the
user to be weaned off of nicotine and to quit smoking.
SUMMARY OF THE INVENTION
[0008] A system for aiding a patient in quitting smoking is
disclosed. The system is comprised of a means for the delivery of
aerosolized nicotine which makes it possible to gradually decrease
the amount of nicotine that the patient receives. The system
comprises a means for aerosolizing a formulation comprised of
nicotine and a means for decreasing the amount of nicotine
formulation which is aerosolized and/or the amount which actually
reaches the patient's circulatory system. The amount of nicotine
aerosolized or effectively delivered to the patient can be changed
in several different ways using either the device aerosolization
mechanism, the formulation or formulation containers loaded into
the device.
[0009] A preferred system of the invention aerosolizes the liquid
formulation by applying force to a container of nicotine
formulation and causing the nicotine formulation to be moved
through a porous membrane which results in creating particles of
nicotine formulation which are inhaled by the patient. This system
modifies the amount of nicotine aerosolized by providing a
plurality of different containers or different groups of containers
wherein the different containers or groups of containers contain
different concentrations of nicotine. A patient using the system
can utilize packets of nicotine formulation containing a high
concentration initially and then gradually switch towards lower and
lower concentrations so that the patient receives essentially the
same amount of aerosolized formulation but receives gradually
reduced amounts of nicotine due to the reduced concentration of the
nicotine in the formulation.
[0010] The same procedure described above can also be carried with
a dry powder inhaler (DPI). Using the dry powder inhaler technology
the packets of dry powder nicotine formulation loaded into the
device can initially contain a relatively high concentration of
nicotine. Thereafter, the concentration of nicotine in the dry
powder formulation added into the device is gradually decreased.
Thus, using this system the same amount of dry powder is
aerosolized, but the amount of nicotine is gradually decreased by
decreasing the concentration or simply the total amount of nicotine
in the dry powder package loaded into the device. The same
procedure can be utilized with a conventional metered dose inhaler
(MDI) device. It is somewhat more difficult to utilize the
invention with an MDI device. However, small pressurized canisters
conventionally used with MDIs can contain different concentrations
of nicotine along with the propellant. By using a first container
which includes the highest concentration of nicotine and gradually
changing to lower and lower concentrations of nicotine in the
pressurized canister the desired result of reducing the amount of
nicotine delivered to the patient can be obtained. The same results
could be obtained by gradually decreasing the amount of formulation
released when the value of a container is opened.
[0011] When using a dry power inhaler or a system which aerosolizes
a liquid formulation by moving the formulation through a porous
membrane it is possible to decrease the amount of nicotine
gradually by making changes in the device, or more specifically the
operation of the device. For example, a dry powder inhaler often
utilizes a burst of air in order to aerosolize the dry powder. The
burst of air could be decreased so that not all of the powder is
fully aerosolized or so that the powder is not aerosolized in a
completely efficient manner. In a more preferred embodiment the
system for aerosolizing liquid formulation is adjusted at different
points so that different amount of pressure are applied to the
formulation making it possible to aerosolize decreasing amounts of
formulation and allowing the patient to be gradually weaned off of
nicotine.
[0012] The most preferred embodiment of the invention involves the
use of a system which aerosolizes liquid formulations of nicotine
contained within individual packets which packets include a porous
membrane. As indicated above the amount of nicotine that can be
changed by changing the amount of or concentration of nicotine in
the packets. However, it is also possible to decrease the amount of
nicotine actually delivered to the patient's circulatory system by
changing the size of the pores in the membrane. When the pore size
is in a preferred range then a relatively high concentration of the
formulation aerosolized will reach the patient's lungs and move
from the lungs into the patient's circulatory system. However, by
making the pores larger the aerosolized particles created also
become larger. The larger particles will not move into the lungs as
efficiently as the smaller particles. Further, the larger particles
may be deposited in areas where they are not readily absorbed into
the patient's circulatory system. Thus, in accordance with a
preferred embodiment of the invention a plurality of different
containers are produced. The containers are different from each
other in that they contain different amounts or concentrations of
nicotine. Alternatively, the containers are different from each
other in that they have different porous membranes on them which
make it possible to aerosolize the formulation in a somewhat less
efficient manner over time. It is possible to combine both or all
three features together. More specifically, it is possible to
produce containers which contain (1) smaller concentrations of
nicotine; (2) smaller amounts of nicotine; or (3) have porous
membranes which have different size or amounts of pores so as to
less efficiently aerosolize the formulation present in the
container.
[0013] A method for aiding in smoking cessation and for treating
conditions responsive to nicotine therapy by the administration of
nicotine is disclosed. A formulation comprised of nicotine is
aerosolized. The aerosol is inhaled into the lungs of the patient.
Once inhaled, particles of nicotine deposit on lung tissue and from
there enter the patient's circulatory system. Because delivery is
to the lungs, the patient's serum nicotine level is quickly raised
to a desired level--as quickly as if the user were smoking. The
methods of the invention produce arterial concentrations of
nicotine similar to cigarette smoking.
[0014] Subsequently, the patient's dependence on nicotine is
reduced by gradually reducing the dose of nicotine. The dose of
nicotine is reduced by progressively increasing the size
distribution of the aerosolized nicotine particles delivered to the
patient. This decreases the amount of nicotine delivered to the
patient's lungs, with the result that nicotine absorption is less
immediate and the blood plasma level is lower.
[0015] A method of treatment is disclosed, comprising:
[0016] (a) aerosolizing a formulation comprised of nicotine
creating aerosolized particles which are sufficiently small as to
enter the alveolar ducts;
[0017] (b) allowing a patient to inhale the aerosolized particles
of (a) thereby causing nicotine to enter the patient's blood at
air/blood diffusion membranes;
[0018] (c) repeating (a) and (b) a plurality of times;
[0019] (d) aerosolizing a formulation comprised of nicotine
creating aerosolized particles which are too large to enter
alveolar ducts but sufficiently small to enter primary and
secondary bronchioles;
[0020] (e) allowing the patient to inhale the aerosolized particles
of (d) into primary and secondary bronchioles; and
[0021] (f) repeating (d) and (e) a plurality of times.
[0022] The method is preferably further comprised of:
[0023] (g) aerosolizing a formulation comprised of nicotine
creating aerosolized particles which are too large to enter primary
and secondary bronchioles but sufficiently small to enter the small
bronchi;
[0024] (h) allowing the patient to inhale the aerosolized particles
of (g) into small bronchi; and
[0025] (i) repeating (g) and (h) a plurality of times.
[0026] An aspect of the invention is a method of treatment whereby
nicotine or a nicotine substitute is aerosolized, inhaled into
areas of the respiratory tract including the lungs and provided to
the circulatory system of the patient at levels sufficient to
simulate cigarette smoking.
[0027] An advantage of the invention is that the nicotine levels
are raised almost immediately on administration.
[0028] Another advantage of the invention is that the patient can
gradually be weaned off of the immediate effect of nicotine
obtained via smoking and gradually weaned off of the need of
nicotine by, respectively, increasing particle size and decreasing
dose size or concentration.
[0029] A feature of the invention is that aerosolized particles of
nicotine having a diameter of about 0.5 to 8 microns (.mu.) are
created and inhaled deeply into the lungs, thereby enhancing the
speed and efficiency of administration.
[0030] It is an object of this invention to describe the utility of
delivering nicotine by inhalation as a means of treating conditions
responsive to nicotine therapy, and particularly for smoking
cessation therapy.
[0031] It is another object of this invention to describe the
utility of varying the distribution of aerosolized particles of
nicotine inhaled as a means of treating smokers wishing to
quit.
[0032] It is another object of this invention to describe liquid
formulations (which includes suspensions) of nicotine and
derivatives thereof appropriate for pulmonary delivery.
[0033] It is another object of this invention to describe how
nicotine delivered via the lung can quickly increase blood plasma
levels.
[0034] An aspect of the invention is a method whereby larger and
larger particles of aerosolized nicotine are administered to a
patient over time in order to first wean a smoking patient off of
the addiction to immediate nicotine and thereafter reduce the
amount of nicotine in order to wean the patient completely off of
the addiction to nicotine, thereby allowing the patient to quit
smoking.
[0035] A feature of this invention is that it allows for the
formation of nicotine particles in different sizes designed for
delivery to different areas of a patient's lungs.
[0036] An advantage of the invention is that it allows the patient
to be weaned off of (1) the need for immediate nicotine delivery as
obtained when smoking, and (2) the need for nicotine at all.
[0037] These and other aspects, objects, advantages, and features
of the invention will become apparent to those skilled in the art
upon reading this disclosure.
BRIEF DESCRIPTION OF THE DRAWINGS
[0038] FIG. 1 is a schematic view of a human lung branching
pattern.
[0039] FIG. 2 is a schematic view of a human respiratory tract.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0040] Before the devices, formulations, and methodology of the
present invention are described, it is to be understood that this
invention is not limited to the particular device, components,
formulations and methodology described, as such may, of course,
vary. It is also to be understood that the terminology used herein
is with the purpose of describing particular embodiments only, and
is not intended to limit the scope of the present invention which
will be limited only by the appended claims.
[0041] It must be noted that as used herein and in the appended
claims, the singular forms "a," "and," and "the" include plural
referents unless the context clearly dictates otherwise. Thus, for
example, reference to "a formulation" includes mixtures of
different formulations and reference to "the method of treatment"
includes reference to equivalent steps and methods known to those
skilled in the art, and so forth.
[0042] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
any methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the invention, the
preferred methods and materials are now described. All publications
mentioned herein are incorporated herein by reference to describe
and disclose specific information for which the reference was cited
in connection with.
Definitions
[0043] The term "nicotine" is intended to mean the naturally
occurring alkaloid known as nicotine, having the chemical name
S-3-(1-methyl-2-pyrrolidinyl)pyridine, which may be isolated and
purified from nature or synthetically produced in any manner. This
term is also intended to encompass the commonly occurring salts
containing pharmacologically acceptable anions, such as
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or
bisulfate, phosphate or acid phosphate, acetate, lactate, citrate
or acid citrate, tartrate or bitartrate, succinate, maleate,
fumarate, gluconate, saccharate, benzoate, methanesulfonate,
ethanesulfonate, benzenesulfonate, p-toluene sulfonate, camphorate
and pamoate salts. Nicotine is a colorless to pale yellow, strongly
alkaline, oily, volatile, hygroscopic liquid having a molecular
weight of 162.23 and the formula: 1
[0044] Structure and ionisation of nicotine. Nicotine is
approximately 10% of the particulate weight in cigarette smoke.
Brand differences change this percentage. It is monoprotonated at
most physiological pH values. The diprotonated ion would exist at
pH values found in the stomach. Metabolism is largely due to
oxidation. Cotinine is a major metabolite; however, there are at
least 4 primary metabolites of nicotine and all are encompassed by
the use of this term herein.
[0045] The term "nicotine" further includes any pharmacologically
acceptable derivative, metabolite or analog of nicotine which
exhibits pharmacotherapeutic properties similar to nicotine. Such
derivatives and metabolites are known in the art, and include
cotinine, norcotinine, nornicotine, nicotine N-oxide, cotinine
N-oxide, 3-hydroxycotinine and 5-hydroxycotinine or
pharmaceutically acceptable salts thereof A number of useful
derivatives of nicotine are disclosed within the Physician's Desk
Reference (most recent edition) as well as Harrison's Principles of
Internal Medicine. In addition, applicants refer to U.S. Pat. Nos.
5,776,957; 4,965,074; 5,278,176; 5,276,043; 5,227,391; 5,214,060;
.5,242,934; 5,223,497; 5,278,045; 5,232,933; 5,138,062; 4,966,916;
4,442,292; 4,321,387; 5,069,094; 5,721,257; all of which are
incorporated herein by reference to disclose and describe nicotine
derivatives and formulations.
[0046] The physiologically active form of nicotine is the
S-(-)-isomer. Certain compounds of the present invention may exist
in particular geometric or stereoisomeric forms. The present
invention contemplates all such compounds, including cis and trans
isomers, R and S enantiomers, diastereomers, the racemic mixtures
thereof, and other mixtures thereof, as falling within the scope of
the invention. Additional asymmetric carbon atoms may be present in
a substituent such as an alkyl group. All such isomers, as well as
mixtures thereof, are intended to be included in this
invention.
[0047] The term "upper airways" and the like are used
interchangeably herein to define an area of the respiratory system
which includes the oropharyngeal region and trachea. This area is
the first area which air enters upon inhalation (see FIG. 1).
[0048] The terms "central airways," "bronchial airways" and the
like are used interchangeably herein to refer to a region of the
respiratory system that includes generations 1 through 16 of the
airways (see FIG. 1) which removes particles larger than 3 .mu. in
diameter. They are the conductive airways that also clean particles
from the lung using a mucosal clearance mechanism. Upon inhalation,
air passes through the upper airways into the central airways.
[0049] The terms "pulmonary region," "peripheral region" and the
like are used interchangeably herein to define a region of the
respiratory system where gas exchange occurs between the lungs and
the circulatory system, i.e., where oxygen enters the blood and
carbon dioxide leaves the blood. The peripheral region includes
generations 17 through 23 of the airways (see FIG. 1). Drugs
delivered to this area generally have a systemic effect.
[0050] The terms "alveolar ducts," "alveoli" and the like refer to
components in the pulmonary region of the lung which are
approximately 3 .mu. in diameter where gas exchange occurs between
the air in the lungs and the circulatory system.
[0051] The term "diameter" is used herein to refer to particle size
as given in the "aerodynamic" size of the particle. The aerodynamic
diameter is a measurement of a particle of unit density that has
the same terminal sedimentation velocity in air under normal
atmospheric conditions as the particle in question. This is pointed
out in that it is difficult to accurately measure the diameter of
small particles using current technology and the shape of such
small particles may be continually changing. Thus, the diameter of
one particle of material of a given density will be said to have
the same diameter as another particle of the same material if the
two particles have the same terminal sedimentation velocity in air
under the same conditions. In connection with the present
invention, it is important that particles, on average, have the
desired diameter so that the particles can be inhaled and targeted
to a specific area of the lungs. It is also important not to have
particles which are too small in that such particles would be
inhaled into the lungs and then exhaled without depositing on the
lung tissue in the same manner that particles of smoke can be
inhaled and exhaled with only a small amount of the particles being
deposited on the lung tissue. An acceptable range for particle
diameter varies depending on the area of the respiratory tract
being targeted. To target the alveolar ducts and alveoli the
particles should have a diameter in a range of about 0.5 .mu. to
about 2 .mu.. To target the area above the alveolar ducts and below
the small bronchi the diameter should be in the range of from about
2 .mu. to about 4 .mu., and to target the small bronchi and above
the particles should have a diameter of from about 4 .mu. to about
8 .mu..
[0052] The term "porous membrane" shall be interpreted to mean a
membrane of material in the shape of a sheet having any given outer
perimeter shape, but preferably covering a package opening which is
in the form of an elongated rectangle, wherein the sheet has a
plurality of openings therein, which openings may be placed in a
regular or irregular pattern, and which openings have a diameter in
the range of 0.25 .mu. to 4 .mu. and a pore density in the range of
1.times.10.sup.4 to about 1.times.10.sup.8 pores per square
centimeter. Alternatively, the porous membrane may be merely an
area of the package which has pores therein wherein the pores have
a size and a density as described above. The configuration and
arrangement of the pore density may be changed so as to provide
pores which are capable of creating the desired amount of aerosol.
For example, the porous membrane or area of the container may have
some 10 to 10,000 pores therein which pores are positioned in an
area of from about 1 mm.sup.2 to about 1 Cm.sup.2. The membrane is
preferably comprised of a material having a density in the range of
0.25 to 3.0 mg/Cm.sup.2, more preferably 1.7 mg/Cm.sup.2, and a
thickness of about 2 .mu. to 20 .mu., more preferably about 8 .mu.
to 12 .mu.. The membrane material is preferably hydrophobic and
includes materials such as polycarbonates and polyesters which may
have the pores formed therein by any suitable method including
anisotropic etching or by etching through a thin film of metal or
other suitable material. Pores can be created in the membrane which
may be an area of the container by use of techniques such as
etching, plating or laser drilling. The membrane materials may have
pores with a conical configuration and have sufficient structural
integrity so that it is maintained intact (will not rupture) when
subjected to force in the amount of about 20 to 200 psi while the
formulation is forced through the pores. The membrane functions to
form an aerosolized mist when the formulation is forced through it.
Those skilled in the art may contemplate other materials which
achieve this function as such materials are intended to be
encompassed by this invention.
[0053] The terms "treatment," "treating," and the like are used
interchangeably herein to generally mean obtaining a desired
pharmacological and/or physiological effect. The terms are used in
a manner somewhat differently than the terms are typically used in
that what is intended by the method of treatment of the invention
is to allow a patient to overcome an addiction to nicotine and
thereby allow the patient to quit smoking. The treating effect of
the invention provides a psychological effect in that the invention
originally delivers high doses of nicotine in a manner that
simulates the nicotine delivery obtained from a cigarette. The
patient then becomes accustomed to relying on the methodology of
the invention to provide an immediate "rush" of nicotine.
Thereafter, the particles of the aerosol are made larger. This
prevents the particles from penetrating deeply into the lung and,
therefore, to some extent, diminishes the "rush" of nicotine.
However, the same amount of nicotine is still given to the patient
in order to satisfy the overall nicotine craving. Eventually, the
treatment of the invention reduces the amount of nicotine so as to
allow the patient to completely "wean" off of nicotine and to quit
smoking.
[0054] All publications mentioned herein are incorporated herein by
reference to described and disclose specific information for which
the reference was cited in connection with. The publications
discussed herein are provided solely for their stated disclosure
prior to the filing date of the present application. Nothing herein
is to be construed as an admission that the invention is not
entitled to antedate such publications by virtue of prior
invention. Further, the actual publication date may be different
from that stated on the publication and as such may require
independent verification of the actual publication dates.
General Methodology
[0055] The steady state delivery of nicotine as therapy for smokers
wishing to quit is characterized by slow absorption and low blood
levels of nicotine, which limits its utility. The present invention
replaces the nicotine that a smoker receives from smoking a
cigarette in a therapeutically effective manner by providing a
rapid pulse of bioavailable nicotine to the smoker on demand.
[0056] One means currently available for a true pulsatile, rapid
onset replacement therapy is intravenous administration. Although
preparations of nicotine appropriate for intravenous administration
have been available for some time, intravenous cannulation as a
means for gaining access to the circulation for the administration
of nicotine on demand is not a socially acceptable alternative to
cigarette smoking.
[0057] The treatment methodology of the present invention creates
an aerosol of nicotine particles. The nicotine particles may be
formed from any liquid containing nicotine including a solution or
suspension of nicotine and aerosolized in any known manner
including (1) moving the formulation through a porous membrane in
order to create particles or (2) a dry powder where the particles
of powder have been designed to have a desired diameter. The rate
of particle absorption is directly proportional to the surface area
of the tissue on which the particles are deposited. Accordingly,
nicotine is absorbed more slowly through the mucosal membranes of
the upper respiratory tract which have a smaller surface area than
through the airways in the lower respiratory tract which have a
larger surface area. Thus, the overall effect of increasing the
size of the nicotine particles is to reduce the rate at which
nicotine is absorbed into the circulation, thereby reducing the
smoker's physiological dependence on the quick rush of nicotine
experienced when smoking.
Method of Treatment
[0058] The penetration of aerosolized nicotine particles into the
respiratory tract is determined largely by the size distribution of
the particles formed. Larger particles, i.e., particles with a
diameter .gtoreq.5 .mu., deposit on the upper airways of the lungs
(see FIG. 1). Particles having a diameter in a range of about >2
.mu. to <5 .mu. penetrate to the central airways. Smaller
particles having a diameter .ltoreq.2 .mu. penetrate to the
peripheral region of the lungs.
[0059] An important feature of the invention is that the treatment
methodology begins with particles of a given size, carries out
treatment for a given period of time after which the particles are
increased in size. The particles initially administered to the
patient penetrate deeply into the lung, i.e., the smallest
particles (e.g. 0.5 to 2 .mu.) target the alveolar ducts and the
alveoli. When the deepest part of the lung is targeted with the
smallest particles the patient receives an immediate "rush" from
the nicotine delivered which closely matches that received when
smoking a cigarette. These small particles can be obtained by
milling powder into the desired size and inhaling the powder or by
creating a solution or suspension and moving the solution or
suspension through the pores of a membrane. In either case, the
desired result is to obtain particles which have a diameter in the
range of 0.5 .mu. to about 2 .mu.. Those skilled in the art will
understand that some of the particles will fall above and below the
desired range. However, if the majority of the particles (50% or
more) fall within the desired range then the desired area of the
lung will be correctly targeted.
[0060] The patient is allowed to continually, from time to time,
target the outermost area of the lung with the smallest particles.
For example, the patient would be instructed to repeatedly
administer the smallest size particles when the patient would
normally smoke a cigarette. In this manner, the patient will become
accustomed to finding that the device administers nicotine into the
patient in the same manner that a cigarette does. In one embodiment
of the invention the concentration of the nicotine in the liquid
formulation could be reduced gradually over time. This could be
done over a sufficiently long period of time so as to allow the
patient to "wean" off of nicotine. However, in a more preferred
embodiment of the invention the amount of nicotine is kept
substantially constant but the size of the aerosolized particles
created are increased.
[0061] The second phase of the treatment methodology is to increase
the size of the particles so as to target the respiratory tract
above the alveolar ducts and below the small bronchi. This can
generally be accomplished by creating aerosolized particles of
nicotine which have a size and range of about 2 .mu. to about 4
.mu.. Administration is carried out in the same manner as described
above. Specifically, the patient administers the aerosolized
nicotine at the same time when the patient would be smoking a
cigarette. Since the patient has become adjusted to receiving the
nicotine "rush" from the smaller sized particles, the patient will
expect and is therefore likely to experience the same "rush" when
administering the slightly larger particles. However, the effect
will be less immediate. This procedure is carried out over a period
of time, e.g., days or weeks. In one embodiment of the invention it
is possible to reduce the dose of aerosolized nicotine delivered to
the patient during this second phase. However, the dose may remain
constant.
[0062] The treatment can be completed after any phase, e.g. after
the second phase. However, in accordance with a more preferred
embodiment of the invention a third phase of treatment is carried
out. Within the third phase the particle size of the aerosolized
nicotine is increased again. The particles are increased to a size
in a range from about 4 .mu. to about 8 .mu. or, alternatively,
perhaps as large as 12 .mu.. These larger particles will target the
upper airways. The larger particles will give a very small
immediate "rush" but will still be absorbed through the mucous
membranes of the patient's respiratory tract. Accordingly, the
patient will be administering nicotine doses which may be the same
as those doses administered at the beginning of treatment. At this
point the treatment can take a number of different directions. The
patient can attempt to stop administration by immediate and
complete cessation of nicotine delivery. Alternatively, the patient
can try to wean off of nicotine by delivering fewer doses during a
given time period. In another alternative, the same size dose
(volume of aerosol formulation) is administered and delivered,
creating the same amount of aerosol, but wherein the aerosolized
particles contain progressively less nicotine (i.e., more dilute
concentration). The amount of nicotine can be decreased until the
patient is receiving little or no nicotine. Those skilled in the
art reading this disclosure will recognize variations on the
overall method and methods for stopping treatment.
[0063] There are a number of aspects of the invention which will
result in the ability of the smoker to use the invention and,
eventually, quit smoking. Firstly, the invention is particularly
suited for smokers in that smokers are accustomed to inhaling their
source of nicotine. Other treatments such as those involving the
transdermal delivery of nicotine via a nicotine "patch" or buckle
delivery via a nicotine "gum" do not match the means which a smoker
usually obtains nicotine.
[0064] Further, the present invention provides a method wherein the
patient obtains an influx of nicotine into the circulatory system
at a rate which substantially matches the rate which nicotine would
enter the circulatory system when smoking. This is obtained
because, at least at first, the invention provides sufficiently
small particles such that they are inhaled deeply into the lung,
i.e. 50% or more of the particles are inhaled deeply into the lung
and thereby quickly enter the patient's circulatory system.
[0065] Thirdly, the present invention is advantageous in that the
rate at which the delivered nicotine enters the circulatory system
can be gradually decreased by gradually increasing the size of the
aerosolized particles delivered to the patient. This can be done
over any desired period of time and in any desired number of
phases.
[0066] Lastly, the invention provides a means whereby the amount of
nicotine delivered to the patient can be gradually decreased in a
number of different ways. Firstly, it can be decreased by
decreasing the concentration of nicotine in the aerosolized
formulation. Secondly, it can be decreased by merely decreasing the
number of administrations of aerosolized doses. Thirdly, it can be
decreased by decreasing the size of the dose aerosolized and
inhaled by the patient.
[0067] One aspect of the invention is a method of treatment,
comprising:
[0068] (a) aerosolizing a formulation comprised of nicotine
creating aerosolized particles which are sufficiently small to
target a particular lower area of the respiratory tract such as the
alveoli. The particles targeting this area will have a relatively
small size, e.g. 0.5 micron to about 2 microns in diameter.
[0069] (b) in the next step the patient inhales the aerosolized
particles of (a) into the respiratory tract, preferably targeted to
a specific area of the lower respiratory tract where the deposited
particles cross into the patient's circulatory system.
[0070] In step (c), steps (a) and (b) are repeated a plurality of
times. Specifically, the patient may repeat these steps any number
of times such as every time the patient would normally smoke a
cigarette. At this point the patient could continue the treatment
protocol in this manner and gradually decrease the number of times
the patient administers aerosolized nicotine until the patient is
no longer addicted to nicotine. Decreasing the amount of
aerosolized nicotine could also be done by decreasing the
concentration of nicotine within the aerosolized particles
decreasing the concentration of nicotine in the formulation and/or
decreasing the size of the aerosolized dose.
[0071] Preferably the method of the invention continues with a step
(d) which involves aerosolizing formulation comprised of nicotine
in order to create aerosolized particles which are larger in size
than the aerosolized particles produced in step (a). These larger
particles are directed towards a particular area of the patient's
respiratory tract, e.g. the mid-region of the patient's respiratory
tract. (See FIGS. 1 and 2) These particles could have a size in the
range of about 2 microns to about 4 microns.
[0072] In the following step (d) the patient inhales the
aerosolized particles of (d) thereby targeting the particular
desired area of the patient's respiratory tract such as the mid
region. Thereafter, steps (d) and (e) are repeated a plurality of
times. At this point the patient can decrease the amount of
nicotine being delivered as indicated in the same manner as
indicated above step (c). Alternatively, the method of the
invention can be continued so that a third phase of treatment can
be carried out which phase is similar to the two phases described
above. In accordance with the above invention it is possible to
carry out the treatment in any number of phases. For example, the
treatment could involve as many as 24 phases which target specific
defined regions of a patients respiratory tract using particles
which are continually larger in size in each of the 24 phases (see
FIG. 1 and Table 1 below). Because it may not be practical to
specifically design the particles so that they are all larger in
each of the phases the formulations may be designed so that a
certain percentage of the particles within each phase of delivery
is larger than the particles in the preceding phase.
[0073] The method of the invention can be carried out using 1 to 24
different phases with each phase targeting a higher level of the
respiratory tract (See Table 1). The higher levels of the
respiratory tract can be targeted using larger and larger
particles.
1TABLE 1 Subdivision of the Respiratory Tree Generation Name 0
Trachea 1 Primary bronchi 2 Lobar bronchi 3 Segmental bronchi 4
subsegmental bronchi 5 Small bronchi .dwnarw. 10 11 Bronchioles,
primary and secondary .dwnarw. 13 14 Terminal bronchioles .dwnarw.
15 16 Respiratory bronchioles .dwnarw. 18 19 Alveolar ducts
.dwnarw. 23 24 Alveoli
Nicotine Delivery Devices
[0074] Precision delivery of small molecule drugs via the lung for
systemic effect is possible. An electronic inhaler capable of
delivering a liquid formulated drug stored in a unit dose packages
has been described and disclosed in U.S. Pat. No. 5,718,222
entitled "Disposable Package for Use in Aerosolized Delivery of
Drugs," and is incorporated herein by reference. A formulation of
nicotine can be prepared for delivery with this system.
Quantitative delivery of nicotine on demand provides a mechanism
for nicotine replacement therapy which is unlikely to be associated
with recidivism precipitated by the symptoms of physical
withdrawal.
[0075] In the present invention, a nicotine formulation is forced
through the openings or pores of a porous membrane to create an
aerosol. In the preferred embodiment, the openings are all uniform
in size and are positioned at uniform distances from each other.
However, the openings can be varied in size and randomly placed on
the membrane. If the size of the openings is varied, the size of
the particles formed will also vary. In general, it is preferable
to maintain uniform opening sizes in order to create uniform
particle sizes, and it is particularly preferable to have the
opening sizes within the range of about 0.25 .mu. to about 6 .mu.
which will create particle sizes of about 0.5 .mu. to 12 .mu. which
are preferred with respect to inhalation applications. When the
openings have a pore size in the range of 0.25 .mu. to 1 .mu. they
will produce an aerosol having particle sizes in the range of 0.5
.mu. to 2 .mu., which is particularly useful for delivering
nicotine to the alveolar ducts and alveoli. Pore sizes having a
diameter of about 1 .mu. to 2 .mu. will produce particles having a
diameter of about 2 .mu. to 4 .mu., which are particularly useful
for delivering nicotine to the area above the alveolar ducts and
below the small bronchi. A pore size of 2 .mu. to 4 .mu. will
create particles having a diameter of of 4 .mu. to 8 .mu., which
will target the area of the respiratory tract from the small
bronchi upward.
[0076] Increasing the size of the openings of the porous membranes
produces nicotine particles of increasing size. A strategy in which
the blood level of nicotine is reduced gradually will be the most
effective in treating the symptoms of withdrawal, and thereby
increase the chances of successful smoking cessation. In one
embodiment of the invention, the size of the aerosolized nicotine
particles is increased in a stepwise manner by using porous
membranes that create "monodisperse" aerosols, wherein all the
particles within the aerosol created have essentially the same
particle size. Nicotine particles of increasing size are produced
by using membranes of increasing pore sizes.
[0077] In another embodiment, the size of the aerosolized nicotine
particles is increased in gradient fashion by using porous
membranes that create "multi-disperse" aerosols, wherein the
particles within the aerosol created have different particle sizes.
Membranes which have an increasing range of pore sizes are used to
produce nicotine particles of increasing size.
[0078] Nicotine can be administered orally. However, after oral
administration it is absorbed from the gut into the portal blood
and degraded promptly by the liver. Thus, insignificant amounts
reach the patient's systemic circulation. Nicotine can also be
administered parenterally. However, when so administered it is
rapidly absorbed and metabolized making it difficult to sustain
therapeutic levels in plasma over time. In view of such, effective
therapy has been carried out using other means of delivery (e.g.,
transdermal patches, gum). The present invention uses
intrapulmonary delivery to avoid first pass liver metabolism and to
obtain quick infusion into the patient's systemic circulatory
system. The present invention administers sufficient nicotine by
inhalation to temporarily produce a rapid increase in the patient's
blood level, and thereafter allow the patient's nicotine level to
return to a therapeutically effective level.
[0079] Because intrapulmonary administration is not 100% efficient,
the amount of drug aerosolized will be greater than the amount that
actually reaches the patient's circulation. For example, if the
inhalation system used is only 50% efficient then the patient will
aerosolize a dose which is twice that needed to raise the patient's
nicotine level to the extent needed to obtain the desired results.
More specifically, when attempting to administer 1 mg of nicotine
with a delivery system known to be 50% efficient, the patient will
aerosolize an amount of formulation containing about 2 mg of
nicotine.
[0080] A device comprised of a container that includes an opening
covered by a porous membrane, such as the device disclosed in U.S.
Pat. No. 5,906,202, may be used to deliver nicotine. The device may
be designed to have the shape and/or bear the markings of a pack of
cigarettes, and may include the scent of tobacco. These features
and others that address the behavioral component of cigarette
smoking may enhance the effectiveness of the method described
herein.
Dosing
[0081] Cigarettes contain 6 to 11 mg of nicotine, of which the
smoker typically absorbs 1-3 mg; see Henningfield N Engl J Med
333:1196-1203 (1995). Factors influencing nicotine absorption
include subject-dependent factors, such as smoking behavior, lung
clearance rate, etc., morphological factors, and physiological
factors, such as tidal volume, inspiratory and expiratory flow
rate, particle size and density. See Darby et al., Clin
Pharmacokinet 9:435-439 (1984). The systemic dose of nicotine per
puff is extremely variable, however, peak plasma concentrations of
25-40 ng/mL of nicotine, achieved within 5-7 minutes by cigarette
smoking, are believed typical. In accordance with the present
invention, 0.1 mg to 10 mg, preferably 1 to 3 mg, and more
preferably about 2 mg of nicotine are delivered to the lungs of the
patient in a single dose to achieve peak blood plasma
concentrations of 15-40 ng/mL.
[0082] The amount of a nicotine administered will vary based on
factors such as the age, weight and frequency of smoking or
nicotine tolerance of the smoker. Other factors, such as daily
stress patterns, demographic factors may also determine, in part,
the amount of nicotine sufficient to satisfy the smoker's craving
for nicotine. Administering nicotine using the methods of the
present invention can involve the daily administration of anywhere
from 5 mg to 200 mg of nicotine, but more preferably involves the
administration of approximately 10 to 100 mg per day.
[0083] It is noted that nicotine can be administered in toxic
amounts. Care should be taken not to overdose the patient. The
amount of nicotine which an individual can tolerate will vary on a
number of factors including size, sex, weight and amount of
cigarette smoking the patient is accustomed to. In order to avoid
overdosing it is possible to program a lock-out system into the
delivery device which prevents administration of acrosolized doses
beyond a given point. Such a system is described within U.S. Pat.
No. 5,735,263 issued Apr. 7, 1998 and incorporated herein by
reference in its entirety to disclose drug delivery devices and
lock-out systems used in connection therewith.
[0084] The nicotine is in a liquid form or is dissolved or
dispersed within a pharmaceutically acceptable, liquid excipient
material to provide a liquid, flowable formulation which can be
readily aerosolized. The container will include the formulation
having nicotine therein in an amount of about 10 mL to 300 mL, more
preferably about 200 mL. The large variation in the amounts which
might be delivered is due to different delivery efficiencies for
different devices. Administration may involve several inhalations
by the patient, with each inhalation providing nicotine from the
device. For example, the device can be programmed so as to release
the contents of a single container or to move from one container to
the next on a package of interconnected containers. Delivering
smaller amounts from several containers can have advantages. Since
only small amounts are delivered from each container and with each
inhalation, even a complete failure to deliver nicotine with a
given inhalation is not of great significance and will not
seriously disturb the reproducibility of the dosing event. Further,
since relatively small amounts are delivered with each inhalation,
the patient can safely administer a few additional micrograms (or
milligrams) of nicotine without fear of overdosing.
[0085] In one embodiment of the invention the patient is treated in
the three different phases. In the first phase the aerosolized
liquid particles or dry powder particles have a size and a range of
0.5 .mu. to about 2 .mu.. The particles of nicotine having this
size are administered in a dosage amount which is substantially
equivalent to the doses or amount which the patient would received
from a single cigarette or, alternatively, the dosage amount which
the patient would received from a single puff on a single
cigarette. Assuming that the patient receives the dosage amount of
a single cigarette then the patient will be administered
approximately 1 to 3 mg of nicotine each time the formulation is
aerosolized. The particles having a size of 0.5 .mu. to about 2
.mu. will be administered to the patient over a plurality of days
(e.g., 2 to 7 days) or perhaps a plurality of weeks (e.g., 2 to 4
weeks). If the device and/or dosage containers are designed to
deliver a dosage equivalent to a puff on a cigarette then
substantially smaller doses are delivered. If each dose corresponds
to a puff on a cigarette then a patient may be directed to
continually take aerosolized doses equivalent to a cigarette puff
over a period of one to ten minutes or any period of time
equivalent to what that patient normally takes to smoke one
cigarette. This constitutes the first phase of treatment.
[0086] After completing the first phase of the treatment the method
of the invention may be completed. However, as indicated above the
method may be continued by repeating phases such as the first phase
using continually larger particles and/or continuing more dilute
solutions of nicotine and/or smaller doses of nicotine.
[0087] Within the second phase of treatment the patient is
preferably administered the same dosage amount of nicotine with
each inhalation, e.g., the patient is administered 1 to 3 mg of
nicotine each time formulation is aerosolized. However, during the
second phase the size of the particles is increased to a size and
range from 2 .mu. to about 4 .mu.. The particle size is increased
in order to target an area of the lungs where the nicotine will be
absorbed into the circulatory system more slowly. Specifically, the
larger particles target an area of the lungs above the alveolar
ducts and below the small bronchi. Administration is carried out
over a plurality of days or a plurality of weeks in the same manner
as indicated above. Within all phases the patient preferably
administers nicotine from a device of the invention when the
patient would normally smoke a cigarette. The treatment can be
completed pursuant to the present invention by using only the two
phases. However, it is preferable to include three or more
phases.
[0088] In accordance with the third phase, the same dose is
administered each time nicotine formulation is aerosolized.
Accordingly, 1 to 3 mg of nicotine is delivered to the patient at
each dose. However, the dose is delivered by using aerosolized
particles which have a diameter of 4 .mu. or more, e.g., in the
range of from 4 .mu. to about 8 .mu.. These larger particles are
designed to target the area of the respiratory tract at the small
bronchi or higher. When the nicotine targets the upper airways it
will not immediately enter the patient's circulatory system.
However, the nicotine will, eventually, cross the mucous membranes
of the upper respiratory tract and enter the circulatory system.
Thus the patient will be administered nicotine but will become less
accustomed to having the immediate "rush" obtained from smoking.
Thus, within the third phase the patient has been weaned away from
the need for the "rush" of nicotine. The third phase is then used
to continually reduce the number of administrations needed and
thereby reduce the amount of nicotine administered. By this process
the patient's dependency on nicotine is slowly reduced and then
eliminated thereby allowing the patient to quit smoking.
[0089] When nicotine enters the circulatory system of a human
patient it is oxidized to cotinine within four to six hours. The
present invention includes the administration of cotinine and other
nicotine derivatives provided such derivatives do not result in
unacceptable adverse effects.
Indications
[0090] The method of the invention has applicability to smokers
wishing to quit or trying to quit who have experienced all or any
of the nicotine withdrawal symptoms associated with smoking
cessation, such as craving for nicotine, irritability, mood
ability, frustration or anger, anxiety, drowsiness, sleep
disturbances, impaired concentration, nervousness, restlessness,
decreased heart rate, increased appetite and weight gain.
[0091] While particularly applicable to smoking cessation,
pulmonary administration of nicotine could be of value for the
treatment of other diseases, such as for patients suffering from
neurodegenerative diseases, psychiatric disorders and other central
nervous system disorders responsive to nicotinic receptor
modulation (see U.S. Pat. Nos. 5,187,169; 5,227,391; 5,272,155;
5,276,043; 5,278,176; 5,691,365; 5,885,998; 5,889,029; 5,914,328).
Such diseases include, but are not limited to, senile dementia of
the Alzheimer's type, Parkinson's disease, schizophrenia,
obsessive-compulsive behavior, Tourette's Syndrome, depression,
attention deficit disorder, myasthenia gravis and drug
addiction.
Formulations
[0092] Pharmaceutical grade nicotine can be produced as a colorless
to pale yellow liquid. The pure liquid could be aerosolized and
inhaled by itself. Alternatively, a formulation may include a
buffer to enhance absorption. Any absorption enhancers including
ammonia could be used with the formulation. However, a typical
formulation is only nicotine dissolved in water or dry powder
nicotine. Methods of formulating liquids and liquid inhalers are
disclosed in U.S. Pat. Nos. 5,364,838; 5,709,202; 5,497,763;
5,544,646; 5,718,222; 5,660,166; 5,823,178; and 5,910,301; all of
which are incorporated by reference to describe and disclose such.
Formulations of nicotine include aqueous formulations, aqueous
saline formulations, and ethanol formulations. All of these
formulations may be included with additional components such as
permeation enhancers, buffers, preservatives and excipient and
carrier components and additives normally included within
formulations for aerosolized drug delivery.
[0093] Nicotine is freely soluble in water. An aqueous nicotine
solution may be readily aerosolized and inhaled. The nicotine
solution can be placed in a low boiling point propellant in a
pressurized canister and released using a conventional metered dose
inhaler (MDI) device. Preferably, the MDI device is modified so
that the aerosolized dose is released each time at the same
inspiratory flow rate and inspiratory volume. When this is done the
patient is more likely to receive the same dose each time. A device
for obtaining repeating dosing with an MDI canister is taught in
U.S. Pat. No. 5,404,871.
[0094] In accordance with the present invention it is preferable to
load the nicotine solution into a container which opens to a porous
membrane. When the formulation is forced through the membrane it is
aerosolized. Such a container is taught in U.S. Pat. No. 5,497,763
and is loaded into a device and delivered via a method as taught in
U.S. Pat. No. 5,823,178. Both patents are incorporated herein by
reference to describe and disclose containers, devices and methods
of drug delivery by inhalation.
[0095] A dry powder formulation comprising a pharmacologically
acceptable salt of nicotine alone or with additives such as
components to prevent the particles from sticking together may be
used.
Supplemental Treatment Methodology
[0096] Smokers wishing to quit may be treated solely with
respiratory nicotine as indicated above, i.e. by intrapulmonary
delivery. However, it is possible to treat such patients with a
combination of pulmonary administration and other means of
administration, such as transdermal administration. Transdermal
nicotine is preferably administered to maintain a steady state
level of nicotine within the circulatory system. Nasal or buccal
formulation could be used for nasal or buccal delivery which could
supplement aerosolized delivery.
[0097] Based on the above, it will be understood by those skilled
in the art that a plurality of different treatments and means of
administration can be used to treat a single patient. For example,
a patient can be simultaneously treated with nicotine by
transdermal administration, nicotine via pulmonary administration,
in accordance with the present invention, and nicotine which is
administered to the mucosa.
[0098] The instant invention is shown and described herein in a
manner which is considered to be the most practical and preferred
embodiments. It is recognized, however, that departures may be made
therefrom which are within the scope of the invention and that
obvious modifications will occur to one skilled in the art upon
reading this disclosure.
* * * * *