U.S. patent application number 14/856116 was filed with the patent office on 2017-03-16 for system and method for controlling the harshness of nicotine-based dry powder formulations.
The applicant listed for this patent is Sansa Corporation (Barbados) Inc.. Invention is credited to Steven Ellis, Arthur Slutsky, Alex Stenzler, Noe Zamel.
Application Number | 20170071248 14/856116 |
Document ID | / |
Family ID | 58256847 |
Filed Date | 2017-03-16 |
United States Patent
Application |
20170071248 |
Kind Code |
A1 |
Stenzler; Alex ; et
al. |
March 16, 2017 |
System and Method for Controlling the Harshness of Nicotine-Based
Dry Powder Formulations
Abstract
A method of controlling or electing the harshness of inhaled
nicotine powder formulations is described. The method includes the
steps of identifying a concentration of nicotine for a subject to
inhale to achieve a desired level of harshness per inhalation,
identifying the total dose of nicotine to be inhaled by the
subject, and providing the subject with an amount of a formulation
comprising nicotine particles having the identified concentration
of nicotine, such that the total amount of nicotine particles in
the formulation equals the total dose of nicotine.
Inventors: |
Stenzler; Alex; (Long Beach,
CA) ; Zamel; Noe; (Ontario, CA) ; Slutsky;
Arthur; (Ontario, CA) ; Ellis; Steven;
(Ontario, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sansa Corporation (Barbados) Inc. |
Worthing |
|
BB |
|
|
Family ID: |
58256847 |
Appl. No.: |
14/856116 |
Filed: |
September 16, 2015 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/34 20180101;
A61K 31/465 20130101; A61K 9/0075 20130101; A24F 47/002
20130101 |
International
Class: |
A24F 47/00 20060101
A24F047/00; A24B 15/16 20060101 A24B015/16 |
Claims
1. A method of controlling the harshness of nicotine inhaled by a
subject, the method comprising the steps of: identifying a
concentration of nicotine for a subject to inhale to achieve a
desired level of harshness per inhalation, identifying the total
dose of nicotine to be inhaled by the subject, and providing the
subject with an amount of a formulation comprising nicotine
particles having the identified concentration of nicotine, such
that the total amount of nicotine particles in the formulation
equals the total dose of nicotine.
2. The method of claim 1, wherein the nicotine particles comprise
at least one nicotine salt.
3. The method of claim 2, wherein the at least one nicotine salt is
nicotine tartrate.
4. The method of claim 1, wherein the nicotine particles further
comprise at least one sugar.
5. The method of claim 4, wherein the at least one sugar is
lactose.
6. The method of claim 1, wherein the nicotine particles are
substantially between 2-5 micron in size.
7. The method of claim 1, wherein the concentration of nicotine is
between 1.5% and 20%.
8. The method of claim 1, wherein the formulation further comprises
a stabilizing agent.
9. The method of claim 1, wherein the formulation further comprises
a cough suppressant.
10. The method of claim 1, wherein the formulation is delivered to
a subject via a dry powder inhaler.
11. A method of delivering variable dosages of nicotine to a
subject over a number of doses while maintaining a substantially
constant level of harshness per inhalation for each dose, the
method comprising the steps of: identifying a concentration of
nicotine in a nicotine formulation for a subject to inhale to
achieve a desired level of harshness per inhalation, providing a
first dose comprising an amount of a formulation comprising
nicotine particles having the identified concentration of nicotine,
and providing at least one additional dose comprising an amount of
a formulation comprising nicotine particles having the identified
concentration of nicotine, wherein the amount of the formulation in
the at least one additional dose is less than the amount of the
formulation in the first dose.
12. The method of claim 11, wherein the total dose of nicotine is
decreased per dose, while the harshness of the administered doses
remains substantially constant.
13. A method of delivering reduced dosages of nicotine to a subject
over a number of doses, while increasing the level of harshness per
inhalation for each dose, the method comprising the steps of:
identifying a concentration of nicotine in a nicotine formulation
for a subject to inhale to achieve a desired level of harshness per
inhalation, providing a first dose comprising an amount of a
formulation comprising nicotine particles having the identified
concentration of nicotine, providing at least one additional dose
comprising an amount of a formulation comprising nicotine particles
having the identified concentration of nicotine, wherein the amount
of the formulation in the at least one additional dose is less than
the amount of the formulation in the first dose, and providing at
least one additional dose comprising an amount of a formulation
comprising nicotine particles having the identified concentration
of nicotine, wherein the amount of the formulation in the at least
one additional dose is less than the amount of the formulation in
the first dose.
14. A kit for controlling the harshness of inhaled nicotine, the
kit comprising at least an amount of a nicotine formulation
comprising nicotine particles, and an instruction material
identifying the method of claim 1.
15. The kit of claim 14, wherein the kit further comprises a dry
powder inhaler.
16. A dry powder nicotine formulation suitable for inhalation
comprising nicotine particles, wherein the nicotine particles are
substantially between about 1-10 micron in size.
17. The formulation of claim 16, wherein the nicotine particles are
substantially between about 2-5 micron in size.
18. The formulation of claim 16, wherein less than about 10% of the
nicotine particles are less than about 1 micron in size.
19. The formulation of claim 18, wherein less than about 10% of the
nicotine particles are less than about 2 micron in size.
20. The formulation of claim 16, wherein at least about 90% of the
nicotine particles are less than about 10 micron in size.
21. The formulation of claim 20, wherein at least about 90% of the
nicotine particles are less than about 5 micron in size.
22. The formulation of claim 16, wherein less than about 10% of the
nicotine particles are less than about 1 micron in size and wherein
at least about 90% of the nicotine particles are less than about 10
micron in size.
23. The formulation of claim 17, wherein less than about 10% of the
nicotine particles are less than about 2 micron in size and wherein
at least about 90% of the nicotine particles are less than about 5
micron in size.
24. A dry powder nicotine formulation suitable for inhalation
comprising: a nicotine based component having particles
substantially between about 1-10 micron in size; and a cough
suppressant component having particles substantially between about
5-10 micron in size.
25. The formulation of claim 24, wherein the cough suppressant
component comprises menthol or mint.
26. The formulation of claim 25, wherein the nicotine based
component particles are substantially between about 2-5 micron in
size and the cough suppressant component particles are
substantially between about 5-8 micron in size.
27. The formulation of claim 24, further comprising a cough
suppressant component having particles substantially between about
10-200 micron in size.
28. The formulation of claim 27, wherein the cough suppressant
component having particles substantially between about 10-200
micron in size comprises menthol or mint.
29. The formulation of claim 24, further comprising a flavor
component having particles substantially between about 10-1000
micron in size.
30. The formulation of claim 29, wherein the flavor component
comprises menthol or mint.
Description
BACKGROUND OF THE INVENTION
[0001] It is well known that inhaled cigarette smoke causes airway
irritation and cough, due largely to the fact that nicotine is one
of the most common inhaled irritants to the human respiratory
tract. This irritation results in a sensation of harshness when
nicotine is inhaled by a subject. Depending on the amount of
nicotine inhaled during inhalation and the frequency of nicotine
inhalation over time, a subject may develop a degree of tolerance
to the harshness experienced. Accordingly, the level of harshness
tolerated, or preferred, during nicotine inhalation can be very
different from one subject to the next.
[0002] Most regular smokers become addicted to, or dependent upon,
the pharmacological effects of nicotine in tobacco smoke. A common
strategy in overcoming nicotine addiction in general, and nicotine
cravings in particular, is the mimicking of cigarette smoking's
effects, followed by gradual reduction and, eventually, by complete
elimination.
[0003] There are several effects of smoking which a potential
therapeutic formulation or method would seek to mimic. Among the
most important effects of smoking are the chemical and mechanical
impact of cigarette smoke on airway receptors of the subject, and
the absorption of nicotine into the subject's blood. The chemical
and mechanical impact of cigarette smoke on the airways of the
subject results in a certain level of satisfaction experienced by
the subject, and it is also associated with the perceived harshness
of the smoke inhalation upon the airways of the subject. The
absorption of nicotine into the subject's blood results in nicotine
reaching various receptors in the central nervous system of the
subject, which in turn affects the perceived nicotine cravings
experienced by the subject. Both effects can potentially be
mimicked by the administration of nicotine formulation doses to a
subject seeking smoking cessation therapy. By gradually reducing
the doses, until complete elimination, nicotine addiction can be
treated.
[0004] There is a need in the art for methods of delivering
nicotine-based dry powder formulations which can achieve effective
blood nicotine concentrations while at the same time allowing for
controlling the satisfaction and harshness of the chemo-mechanical
impact of the formulations on the airways of the subject. Ideally,
such methods of delivery and harshness control would provide
flexibility in delivering the necessary amount of nicotine, while
at the same time allowing for a modulation on the degree of
harshness experienced by the subject. The present invention
satisfies this need.
SUMMARY OF THE INVENTION
[0005] A method of controlling the harshness of inhaled nicotine is
described. The method comprises the steps of identifying a
concentration of nicotine for a subject to inhale to achieve a
desired level of harshness per inhalation, identifying the total
dose of nicotine to be inhaled by the subject, and providing the
subject with an amount of a formulation comprising nicotine
particles having the identified concentration of nicotine, such
that the total amount of nicotine particles in the formulation
equals the total dose of nicotine. In one embodiment, the nicotine
particles used comprise at least one nicotine salt. In one
embodiment, the at least one nicotine salt is nicotine tartrate. In
one embodiment, the nicotine particles further comprise at least
one sugar. In one embodiment, the at least one sugar is lactose. In
one embodiment, the nicotine particles are substantially between
2-5 micron in size. In one embodiment, the concentration of
nicotine is about 1.5% to about 20%. In one embodiment the
formulation further comprises a stabilizing agent. In one
embodiment the formulation is inhaled using an inhaler.
[0006] Also described is a method of delivering variable dosages of
nicotine to a subject over a number of doses while maintaining a
substantially constant level of harshness per inhalation for each
dose. The method includes the steps of identifying a concentration
of nicotine in a nicotine formulation for a subject to inhale to
achieve a desired level of harshness per inhalation, providing a
first dose comprising an amount of a formulation comprising
nicotine particles having the identified concentration of nicotine,
and providing at least one additional dose comprising an amount of
a formulation comprising nicotine particles having the identified
concentration of nicotine, wherein the amount of the formulation in
the at least one additional dose is less than the amount of the
formulation in the first dose. In one embodiment, the total dose of
nicotine is decreased per dose, while the harshness of the
administered doses remains substantially constant.
[0007] Also described is a method of delivering reduced dosages of
nicotine to a subject over a number of doses, while increasing the
level of harshness per inhalation for each dose. The method
includes the steps of identifying a concentration of nicotine in a
nicotine formulation for a subject to inhale to achieve a desired
level of harshness per inhalation, providing a first dose
comprising an amount of a formulation comprising nicotine particles
having the identified concentration of nicotine, providing at least
one additional dose comprising an amount of a formulation
comprising nicotine particles having the identified concentration
of nicotine, wherein the amount of the formulation in the at least
one additional dose is less than the amount of the formulation in
the first dose, and providing at least one additional dose
comprising an amount of a formulation comprising nicotine particles
having the identified concentration of nicotine, wherein the amount
of the formulation in the at least one additional dose is less than
the amount of the formulation in the first dose.
[0008] Also described is a kit for controlling the harshness of
inhaled nicotine is described, the kit comprising at least an
amount of a nicotine formulation comprising nicotine particles, and
an instruction material for the use therewith. In one embodiment,
the kit comprises a dry powder inhaler.
[0009] Also described is a dry powder nicotine formulation suitable
for inhalation comprising nicotine particles, wherein the nicotine
particles are substantially between about 1-10 micron in size. In
one embodiment, the nicotine particles are substantially between
about 2-5 micron in size. In another embodiment, less than about
10% of the nicotine particles are less than about 1 micron in size.
In another embodiment, less than about 10% of the nicotine
particles are less than about 2 micron in size. In another
embodiment, at least about 90% of the nicotine particles are less
than about 10 micron in size. In another embodiment, at least about
90% of the nicotine particles are less than about 5 micron in size.
In another embodiment, less than about 10% of the nicotine
particles are less than about 1 micron in size and wherein at least
about 90% of the nicotine particles are less than about 10 micron
in size. In another embodiment, less than about 10% of the nicotine
particles are less than about 2 micron in size and wherein at least
about 90% of the nicotine particles are less than about 5 micron in
size.
[0010] Also described is a dry powder nicotine formulation suitable
for inhalation. The formulation includes a nicotine based component
having particles substantially between about 1-10 micron in size,
and a cough suppressant component having particles substantially
between about 5-10 micron in size. In one embodiment, the cough
suppressant component comprises menthol or mint. In another
embodiment, the nicotine based component particles are
substantially between about 2-5 micron in size and the cough
suppressant component particles are substantially between about 5-8
micron in size. In another embodiment, the formulation further
includes a cough suppressant component having particles
substantially between about 10-200 micron in size. In another
embodiment, the cough suppressant component having particles
substantially between about 10-200 micron in size comprises menthol
or mint. In another embodiment, the formulation includes a flavor
component having particles substantially between about 10-1000
micron in size. In another embodiment, the flavor component
comprises menthol or mint.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] The following detailed description of preferred embodiments
of the invention will be better understood when read in conjunction
with the appended drawings. For the purpose of illustrating the
invention, there are shown in the drawings embodiments which are
presently preferred. It should be understood, however, that the
invention is not limited to the precise arrangements and
instrumentalities of the embodiments shown in the drawings.
[0012] FIG. 1 is a chart depicting exemplary preparations for
achieving various levels of harshness by adjusting one or both of
the total amount of powder formulation and the concentration of
nicotine in the powder formulation, while maintaining constant the
total dose of nicotine delivered within the amount of powder
formulation.
[0013] FIG. 2 is a chart depicting exemplary preparations for
achieving decreasing total doses of nicotine delivered within the
amount of powder formulation, by adjusting the total amount of
powder formulation containing nicotine particles to maintain a
substantially constant level of harshness across the variable doses
of nicotine.
[0014] FIG. 3 is a chart depicting exemplary preparations for
achieving decreasing total doses of nicotine delivered within the
amount of powder formulation, by adjusting the total amount of
powder formulation containing nicotine particles to increase the
level of harshness across the variable doses of nicotine.
[0015] FIG. 4 is a flowchart of an exemplary method of controlling
the harshness of nicotine inhaled by a subject.
[0016] FIG. 5 is a flowchart of an exemplary method for delivering
reduced dosages of nicotine to a subject over a number of doses,
while maintaining a substantially constant level of harshness per
inhalation for each dose.
[0017] FIG. 6 is a flowchart of an exemplary method for delivering
reduced dosages of nicotine to a subject over a number of doses,
while increasing the level of harshness per inhalation for each
dose.
[0018] FIG. 7 is a flowchart depicting an exemplary method of
manufacturing a formulation of the present invention comprising dry
mixing.
[0019] FIG. 8 is a flowchart depicting an exemplary method of
manufacturing a formulation of the present invention comprising wet
mixing.
DETAILED DESCRIPTION
Definitions
[0020] 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 present
invention, the preferred methods and materials are described.
[0021] As used herein, each of the following terms has the meaning
associated with it in this section.
[0022] The articles "a" and "an" are used herein to refer to one or
to more than one (i.e., to at least one) of the grammatical object
of the article. By way of example, "an element" means one element
or more than one element.
[0023] "About" as used herein when referring to a measurable value
such as an amount, a temporal duration, and the like, is meant to
encompass variations of .+-.20% or .+-.10%, more preferably .+-.5%,
even more preferably .+-.1%, and still more preferably .+-.0.1%
from the specified value, as such variations are appropriate to
perform the disclosed methods.
[0024] As used herein the terms "nicotine dose" and "total nicotine
dose" refer to the total amount of nicotine to be delivered to a
subject in order to achieve a target nicotine blood
concentration.
[0025] As used herein the term "formulation amount" refers to the
total amount of a dry powder formulation packed in a disposable
container, such as a capsule or blister pack, to be used with a dry
powder inhaler, or to the total amount of a bulk dry powder
formulation that can be loaded into a delivery chamber or
compartment of a dry powder inhaler. The term also refers to the
total amount of a dry powder formulation containing a nicotine dose
to be delivered to a subject in order to achieve a particular blood
nicotine concentration. Accordingly, the formulation amount
includes the total dose of nicotine and may further include any
additional pharmaceutically acceptable material, composition or
carrier.
[0026] As used herein, the term "harshness" refers to the sensation
or perception of irritation in a subject's airways after inhaling
nicotine particles.
[0027] As used herein the term "inhalation" refers to the single
act of inhaling an amount of a nicotine dry powder formulation,
typically from a dry powder inhaler. The duration of an inhalation
can be limited either by the control of the subject over the
inhaler, such as by the physical act of continuously inhaling for a
period of time and then stopping, or by a physical attribute of the
inhaler.
[0028] Unless stated otherwise, the described size or size range of
a particle should be considered as the mass median aerodynamic
diameter (MMAD) of the particle or set of particles. Such values
are based on the distribution of the aerodynamic particle diameters
defined as the diameter of a sphere with a density of 1 gm/cm.sup.3
that has the same aerodynamic behavior as the particle which is
being characterized. Because the particles described herein may be
in a variety of densities and shapes, the size of the particles is
expressed as the MMAD and not the actual diameter of the
particles.
[0029] The term "pharmaceutically acceptable" refers to those
properties and/or substances that are acceptable to the patient
from a pharmacological/toxicological point of view and to the
manufacturing pharmaceutical chemist from a physical/chemical point
of view regarding composition, formulation, stability, patient
acceptance and bioavailability. "Pharmaceutically acceptable" may
also refer to a carrier, meaning a medium that does not interfere
with the effectiveness of the biological activity of the active
ingredient(s) and is not toxic to the host to which it is
administered. Other additional ingredients that may be included in
the pharmaceutical compositions used in the practice of the
invention are known in the art and described, for example in
Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing
Co., 1985, Easton, Pa.), which is incorporated herein by
reference.
[0030] As used herein, the term "composition" refers to a mixture
of at least one compound or molecule useful within the invention
with one or more different compound, molecule, or material.
[0031] As used herein, an "instructional material" includes a
physical or electronic publication, a recording, a diagram, or any
other medium of expression which can be used to communicate the
usefulness of the composition and method of the invention for its
designated use. The instructional material of the kit of the
invention may, for example, be affixed to a container which
contains the composition or be shipped together with a container
which contains the composition. Alternatively, the instructional
material may be delivered separately from the container with the
intention that the instructional material and the composition be
used cooperatively by the recipient.
[0032] Ranges: throughout this disclosure, various aspects of the
invention can be presented in a range format. It should be
understood that the description in range format is merely for
convenience and brevity and should not be construed as an
inflexible limitation on the scope of the invention. Accordingly,
the description of a range should be considered to have
specifically disclosed all the possible subranges as well as
individual numerical values within that range. For example,
description of a range such as from 1 to 6 should be considered to
have specifically disclosed subranges such as from 1 to 3, from 1
to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as
well as individual numbers within that range, for example, 1, 2,
2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of
the range.
Description
[0033] In existing nicotine delivery systems and treatment
protocols, nicotine blood levels are ultimately controlled by the
total dose of inhaled nicotine delivered to the airways of a
subject in a specified formulation, and the harshness of the
formulation is determined solely by the characteristics of the
nicotine. As a consequence to this design, the harshness
experienced by the subject during any single inhalation is fixed,
meaning the level of harshness cannot be increased or decreased
without discontinuing, or improperly administering, the dose. This
significantly limits the user experience associated with an inhaled
nicotine product.
[0034] However, as demonstrated herein, a total dose of nicotine
necessary for achieving a specified nicotine blood level can
instead be formulated into powder doses having various
concentrations within various total formulation amounts. For
example, a formulation powder of low nicotine concentration will
result in a low level of harshness during inhalation, and may be
delivered in a relatively larger total amount of powder in order to
achieve the desired blood nicotine level. Similarly, a formulation
powder of high nicotine concentration will result in a high level
of harshness during inhalation, but can be delivered in a
relatively smaller amount of powder in order to achieve the desired
blood nicotine level.
[0035] Accordingly, the harshness experienced by a subject when
inhaling a nicotine-based dry powder formulation can be altered by
changing one or both of: 1) the total powder formulation amount,
and 2) the concentration of nicotine within the total powder
formulation amount. To implement this, dry powder inhalers designed
specifically for delivering a powder formulation dose across
multiple inhalations may be used. Examples of such dry powder
inhalers can be found in co-owned U.S. Patent Application Ser. Nos.
62/147,798; 62/147,803; 62/147,806; 62/147,808; and 62/148,030, the
entire disclosures of which are each incorporated by reference
herein in their entirety. As contemplated herein, the dry powder
formulation may be placed in a sealed storage chamber, such as a
capsule or a blister pack, which can be loaded into any of the
devices described in the aforementioned, co-owned patent
applications.
[0036] For example, as shown in FIG. 1, three different
formulations are outlined, where each formulation is designed to
deliver the same total dose of nicotine (1 mg). To achieve a base
level of harshness (Formulation 1), the total dose of nicotine
forms part of a 10 mg total formulation amount of powder, which
results in a nicotine concentration of 10% in the formulation
amount. Assuming that approximately 1 mg of powder can be inhaled
per inhalation, this means that about 0.10 mg of nicotine is
inhaled per inhalation, and the total dose of nicotine is
administered after completion of about 10 inhalations to take up
the 10 mg of formulation powder. To achieve a decreased level of
harshness (Formulation 2) when delivering 1 mg of nicotine, the
total dose of nicotine forms part of a 20 mg total formulation
amount of powder, which results in a nicotine concentration of 5%
in the formulation amount. Again, assuming that approximately 1 mg
of powder can be inhaled per inhalation, this means that about 0.05
mg of nicotine is inhaled per inhalation, and the total dose of
nicotine is administered after completion of about 20 inhalations
to take up the 20 mg of formulation powder. By taking up a reduced
amount of nicotine per inhalation, the user experiences a decreased
level of harshness. To achieve an increased level of harshness
(Formulation 3) when delivering 1 mg of nicotine, the total dose of
nicotine forms part of a 5 mg total formulation amount of powder,
which results in a nicotine concentration of 20% in the formulation
amount. Again, assuming that approximately 1 mg of powder can be
inhaled per inhalation, this means that about 0.20 mg of nicotine
is inhaled per inhalation, and the total dose of nicotine is
administered after completion of about 5 inhalations to take up the
5 mg of formulation powder. By taking up an increased amount of
nicotine per inhalation, the user experiences an increased level of
harshness.
[0037] By controlling the level of harshness of the inhaled
nicotine formulation, the nicotine formulation can be uniquely
designed to achieve a specific level of harshness suitable for use
with any subject, no matter what tolerance to harshness or irritant
a subject may have. In other words, the nicotine powder formulation
may be specifically tailored and administered to more accurately
mimic the harshness experienced by a subject when smoking For
example, if a subject is being treated with a smoking cessation
therapy, the total dose of nicotine can be gradually reduced while
maintaining the harshness experienced throughout the process. As
shown in FIG. 2, three different formulations are outlined, where
each formulation is designed to deliver a different (smaller) total
dose of nicotine. Starting with Formulation 4, assume that the
targeted level of harshness is achieved by inhalation of 0.1 mg of
nicotine per inhalation.
[0038] Accordingly, 1 mg total dose of nicotine must form part of a
10 mg total formulation amount of powder, which results in a
nicotine concentration of 10% in the formulation amount. Assuming
that approximately 1 mg of powder can be inhaled per inhalation,
this means that about 0.10 mg of nicotine is inhaled per
inhalation, and the total dose of nicotine is administered after
completion of about 10 inhalations at the desired level of
harshness. Formulation 5 is designed for delivery of a total dose
of 0.8 mg of nicotine. Accordingly, 0.8 mg total dose of nicotine
must form part of an 8 mg total formulation amount of powder, which
again results in a nicotine concentration of 10% in the formulation
amount. Assuming that approximately 1 mg of powder can be inhaled
per inhalation, this means that about 0.10 mg of nicotine is
inhaled per inhalation, and the total dose of nicotine is
administered after completion of about 8 inhalations at the same
level of harshness as was experienced when administering
Formulation 4. Likewise, Formulation 6 is designed for delivery of
a total dose of 0.6 mg of nicotine. Accordingly, 0.6 mg total dose
of nicotine must form part of a 6 mg total formulation amount of
powder, which again results in a nicotine concentration of 10% in
the formulation amount. Assuming that approximately 1 mg of powder
can be inhaled per inhalation, this means that about 0.10 mg of
nicotine is inhaled per inhalation, and the total dose of nicotine
is administered after completion of about 6 inhalations at the same
level of harshness as was experienced when administering
Formulations 4 and 5. Thus, a subject can gradually step down the
total dose of nicotine administered by subsequently administering
Formulations 4-6, while more accurately mimicking the same level of
harshness the subject experienced throughout the reduction in
delivered nicotine.
[0039] In yet another embodiment, the total dose of nicotine can be
gradually reduced while also altering the harshness experienced.
For example, as shown in FIG. 3, three different formulations are
outlined, where each formulation is designed to deliver a different
(smaller) total dose of nicotine with slightly increased levels of
harshness experienced. Starting with Formulation 7, assume that the
initial level of harshness is achieved by inhalation of 0.1 mg of
nicotine per inhalation. Accordingly, 1 mg total dose of nicotine
must form part of a 10 mg total formulation amount of powder, which
results in a nicotine concentration of 10% in the formulation
amount. Assuming that approximately 1 mg of powder can be inhaled
per inhalation, this means that about 0.10 mg of nicotine is
inhaled per inhalation, and the total dose of nicotine is
administered after completion of about 10 inhalations at the
initial level of harshness. Formulation 8 is designed for delivery
of a total dose of 0.8 mg of nicotine with slightly increased
harshness. Accordingly, 0.8 mg total dose of nicotine may form part
of a 7 mg total formulation amount of powder, which results in a
nicotine concentration of about 11.4% in the formulation amount.
Assuming that approximately 1 mg of powder can be inhaled per
inhalation, this means that about 0.114 mg of nicotine is inhaled
per inhalation, and the total dose of nicotine is administered
after completion of about 7 inhalations at a slightly increased
level of harshness than was experienced when administering
Formulation 7. Formulation 9 is designed for delivery of a total
dose of 0.6 mg of nicotine with again slightly increased harshness.
Accordingly, 0.6 mg total dose of nicotine may form part of a 5 mg
total formulation amount of powder, which results in a nicotine
concentration of about 12% in the formulation amount. Assuming that
approximately 1 mg of powder can be inhaled per inhalation, this
means that about 0.12 mg of nicotine is inhaled per inhalation, and
the total dose of nicotine is administered after completion of
about 5 inhalations at a slightly increased level of harshness than
was experienced when administering Formulation 8. Thus, a subject
can gradually step down the total dose of nicotine administered by
subsequently administering Formulations 7-9, while experiencing an
increased level of harshness throughout the reduction in delivered
nicotine.
[0040] Accordingly, the present invention may include methods for
controlling the harshness of nicotine inhaled by a subject,
including increasing, decreasing or maintaining the harshness of a
nicotine powder formulation inhaled by a subject. For example, as
shown in FIG. 4, method 400 includes the steps of identifying a
concentration of nicotine for a subject to inhale to achieve a
desired level of harshness per inhalation 410, identifying the
total dose of nicotine to be inhaled by the subject 420, and
providing the subject with an amount of a formulation comprising
nicotine particles having the identified concentration of nicotine,
such that the total amount of nicotine particles in the formulation
equals the total dose of nicotine 430.
[0041] In another example, as shown in FIG. 5, method 500 may be
used for delivering reduced dosages of nicotine to a subject over a
number of doses, while maintaining a substantially constant level
of harshness per inhalation for each dose. Method 500 may include
the steps of identifying a concentration of nicotine in a nicotine
formulation for a subject to inhale to achieve a desired level of
harshness per inhalation 510, providing a first dose comprising an
amount of a formulation comprising nicotine particles having the
identified concentration of nicotine 520, and providing at least
one additional dose comprising an amount of a formulation
comprising nicotine particles having the identified concentration
of nicotine, wherein the amount of the formulation in the at least
one additional dose is less than the amount of the formulation in
the first dose 530.
[0042] In another example, as shown in FIG. 6, method 600 may be
used for delivering reduced dosages of nicotine to a subject over a
number of doses, while increasing the level of harshness per
inhalation for each dose. Method 600 may include the steps of
identifying a first concentration of nicotine in a nicotine
formulation for a subject to inhale to achieve a first level of
harshness per inhalation 610, identifying at least one additional
concentration of nicotine in a nicotine formulation for a subject
to inhale to achieve a level of harshness per inhalation that is
greater than the level of harshness achieved via the first
concentration of nicotine 620, providing a first dose comprising an
amount of a formulation comprising nicotine particles having the
identified first concentration of nicotine 630, and providing at
least one additional dose comprising an amount of a formulation
comprising nicotine particles having the identified additional
concentration of nicotine, wherein the amount of the formulation in
the at least one additional dose is less than the amount of the
formulation in the first dose 640.
[0043] Again, it should be appreciated that any manner of
increasing, decreasing or maintaining the total dose of nicotine in
a nicotine formulation can be combined with any manner of
increasing, decreasing or maintaining the level of harshness
experienced by the subject inhaling the nicotine formulation.
[0044] As contemplated herein, there is no limitation to the
particular formulation amount of powder or the concentration of
nicotine within the total formulation amount, but rather, the
present invention relates to the ability to alter one or both of
these parameters when delivering a total dose of nicotine to a
subject via a dry powder inhaler. Further, there is no limitation
to the actual amount of powder inhaled per inhalation. Such amounts
can be dependent on the functionality of the dry powder inhaler
used, or it can be user performance dependent, where a user elects
to take a shallower, or deeper, inhalation through the dry powder
inhaler used. Furthermore, by administering the total dose of
nicotine across multiple inhalations, the subject can more
consistently insure uptake of the total dose of nicotine, as any
user error occurring during a single inhalation is ultimately
corrected through one or more subsequent inhalations.
[0045] In one embodiment, a nicotine therapy course may last a
number of days. In one embodiment, the course of nicotine therapy
lasts between about 7 days, to about 30 days. In another
embodiment, the course of nicotine therapy lasts between about 10
days, to about 45 days. In another embodiment, the course of
nicotine therapy lasts between about 15 days, to about 60 days. In
another embodiment, the course of nicotine therapy lasts between
about 30 days, to about 90 days. In a preferred embodiment, the
course of nicotine therapy lasts about 30 days. In another
preferred embodiment, the course of nicotine therapy lasts about 45
days. In another preferred embodiment, the course of nicotine
therapy lasts about 60 days. In another preferred embodiment, the
course of nicotine therapy lasts about 90 days.
[0046] In another embodiment, the present invention may further
include a set of instructions for using or electing a particular
nicotine-based powder formulation to achieve a desired level of
harshness upon inhalation. For example, the set of instructions may
be conveyed to the subject in the form of an "instruction
material," such as a pamphlet, manual, or any electronic file
format, such as an email, web page, SMS or the like, which can
further be part of a kit or associated therewith.
[0047] Accordingly, the present invention may further include a
nicotine therapy kit, including, but not limited to, smoke
cessation kits. In one embodiment, the kit may include a plurality
of nicotine-based powder formulation doses contained in a sealed
storage chamber, such as a capsule or a blister pack. As
contemplated herein, at least two of the formulation doses have
equal amounts of a total nicotine, but at different nicotine
concentrations. In other embodiments, the kit comprises at least
two sets of bulk nicotine-based powder having different
concentrations of nicotine, and means for measuring set amounts of
the powders, such as a scoop or a graduated measuring container,
that can be loaded into the storage chamber of a dry powder
inhaler. In other embodiments, the kit comprises a dry powder
inhaler with one or more reservoirs or other compartments suitable
for holding one or more bulk nicotine-based powder formulations,
and further may optionally include a metering mechanism for
dispensing or loading a designated amount of formulation for
inhalation.
[0048] In another embodiment, the kit includes pre-filled powder
capsules for a set course of nicotine therapy or treatment, such as
for example a 30 day course of treatment. The capsules can be filed
with various amounts of powder of various nicotine concentrations,
to achieve variable levels of harshness while delivering the same
total nicotine dose per the therapy regimen. In other embodiments,
the kit includes instructional materials which describe the steps
for a method for nicotine therapy, including, but not limited to,
smoke cessation therapy. The steps of the method can include a
starting dose, regular doses thereafter, such as multiple daily
doses for example, and a final dose, to be administered by means of
loading the dry powder formulation doses into a dry powder inhaler.
The instruction material may also include steps for modulating or
electing the harshness of inhalation for any particular
administered dosage, such that the subject of the therapy may
select the level of harshness experienced by administering the
sealed formulation dose corresponding to the level of harshness
desired.
[0049] In another embodiment, the instruction material may instruct
the user on a set number of days course of nicotine therapy, in
which the daily nicotine dose may be modulated, while the harshness
of the administered doses remains about the same. In one
embodiment, the course of nicotine therapy lasts between about 7
days, to about 30 days. In another embodiment, the course of
nicotine therapy lasts between about 10 days, to about 45 days. In
another embodiment, the course of nicotine therapy lasts between
about 15 days, to about 60 days. In another embodiment, the course
of nicotine therapy lasts between about 30 days, to about 90 days.
In a preferred embodiment, the course of nicotine therapy lasts
about 30 days. In another preferred embodiment, the course of
nicotine therapy lasts about 45 days. In another preferred
embodiment, the course of nicotine therapy lasts about 60 days. In
another preferred embodiment, the course of nicotine therapy lasts
about 90 days. In one embodiment, the daily nicotine dose is
increased daily, while the harshness of the administered doses
remains about the same. In another embodiment, the daily nicotine
dose is increased daily for a period of time, then decreased daily
for a period of time, while the harshness of the administered doses
remains about the same. In a preferred embodiment, the daily
nicotine dose is decreased daily, while the harshness of the
administered doses remains about the same.
[0050] In one aspect, the present invention provides compositions
and methods related to a dry powder nicotine formulation suitable
for inhalation. In one embodiment, the formulation is comprised of
nicotine particles and at least one sugar. In one embodiment, the
nicotine particles are comprised of a nicotine salt. The present
invention also provides methods for producing formulations of the
invention.
[0051] The present invention relates to dry powder formulations of
nicotine, and optionally other selected materials, wherein the
nicotine component and optional additional components fall within
controlled particle size ranges. For example, in one embodiment,
the formulation includes nicotine particles (also referred to
herein as the nicotine-based component) sized substantially between
about 1-10 microns, based on the MMAD of the particles. In yet
another embodiment, the formulation includes nicotine particles
sized substantially between about 1-7 microns. In another
embodiment, the formulation includes nicotine particles sized
substantially between about 2-5 microns. In yet another embodiment,
the formulation includes nicotine particles sized substantially
between about 2-3 microns. By selectively limiting or excluding
nicotine particles below about 1 micron in size, or below about 2
microns in size, the formulations of the present invention remove
or at least reduce a subject's ability to exhale nicotine back into
the environment, thereby effectively reducing or removing the
production of the nicotine contained in second hand smoke. Further,
by selectively limiting or excluding non-respirable nicotine
particles, the formulations of the present invention reduce
unwanted irritation caused by nicotine particles trapped in the
larger airways, oro-pharynx, the glottis vocal cords and other
anatomic regions more proximal or closer to the mouth. Accordingly,
in some embodiments, the smallest particles within the nicotine
particle size range are at least about 1 micron, at least about 1.1
microns, at least about 1.2 micron, at least about 1.3 micron, at
least about 1.4 micron, at least about 1.5 micron, at least about
1.6 micron, at least about 1.7 micron, at least about 1.8 micron,
at least about 1.9 micron, or at least about 2 micron. In some
embodiments, the largest particles within the nicotine particle
size range are no greater than about 10 micron, no greater than
about 7 micron, no greater than about 6 micron, no greater than
about 5 micron, no greater than about 4.5 micron, no greater than
about 4 micron, no greater than about 3.5 micron, or no greater
than about 3 micron. In certain embodiments, no more than about 10%
of the nicotine particles are less than about 1 micron. In certain
embodiments, no more than about 10% of the nicotine particles are
less than about 2 micron. In other embodiments, at least 90% of the
nicotine particles are less than about 10 micron. In other
embodiments, at least 90% of the nicotine particles are less than
about 7 micron. In other embodiments, at least 90% of the nicotine
particles are less than about 5 micron. In one embodiment, no more
than about 10% of the nicotine particles are less than about 1
micron and at least 90% of the nicotine particles are less than
about 10 micron. In one embodiment, no more than about 10% of the
nicotine particles are less than about 1 micron and at least 90% of
the nicotine particles are less than about 7 micron. In one
embodiment, no more than about 10% of the nicotine particles are
less than about 2 micron and at least 90% of the nicotine particles
are less than about 5 micron. In one embodiment, no more than about
10% of the nicotine particles are less than about 2 micron and at
least 90% of the nicotine particles are less than about 3
micron.
[0052] As would be understood by a person skilled in the art, the
particle size ranges described herein are not absolute ranges. For
example, a nicotine particle mixture of the present invention with
a size range of about 2-5 microns can contain a portion of
particles that are smaller or larger than the about 2-5 micron
range. In one embodiment, the particle size value as presented for
any particular component of the formulations of the present
invention represents a D90 value, wherein 90% of the particles
sizes of the mixture are less than the D90 value. In another
embodiment, the particle size range represents a particles size
distribution (PSD) wherein a percentage of the particles of the
mixture lie within the listed range. For example, a nicotine
particle size range of about 2-5 microns can represent a mixture of
nicotine particles having at least 50% of the particles in the
range of about 2-5 microns, but more preferably a higher
percentage, such as, but not limited to: 60%, 70%, 80%, 90%, 95%,
97%, 98% or even 99%.
[0053] In another example, the formulation of the present invention
may optionally include a cough suppressant component having
particles sized substantially between 5 and 10 microns. In one
embodiment, the cough suppressant component is menthol or mint. In
another embodiment, the cough suppressant component may include
benzocaine. It should be appreciated that the cough suppressant
component can include any compound approved for suppressing cough.
By selectively including menthol or mint particles between 5-10
microns, these non-respirable menthol or mint particles can reduce
cough by soothing irritation in the subject's upper airways.
Accordingly, in some embodiments, the smallest particles within the
cough suppressant component particle size range are at least about
5 micron, at least about 6 micron, at least about 7 micron, or at
least about 8 micron. In some embodiments, the largest particles
within the cough suppressant component particle size range are no
greater than about 10 micron, no greater than about 9 micron, no
greater than about 8 micron, or no greater than about 7 micron. In
certain embodiments, no more than about 10% of the cough
suppressant particles are less than about 5 micron. In other
embodiments, at least 90% of the cough suppressant particles are
less than about 10 micron. In other embodiments, at least 90% of
the cough suppressant particles are less than about 8 micron. In
one embodiment, no more than about 10% of the cough suppressant
particles are less than 4 micron and at least 90% of the cough
suppressant particles are less than about 10 micron. In one
embodiment, no more than about 10% of the cough suppressant
particles are less than about 5 micron and at least 90% of the
cough suppressant particles are less than about 8 micron. Although
in the preferred embodiment the cough suppressant component is
composed of particles substantially in the range of 5-10 micron,
the cough suppressant component can comprise particles in a broader
range. In one embodiment, the cough suppressant component can
comprise particles in the range of 5-25 micron. In another
embodiment, the cough suppressant component comprises particles
substantially in the range of 5-50 micron. In yet another
embodiment, the cough suppressant component comprises particles
substantially in the range of 5-100 micron.
[0054] In another example, the formulation of the present invention
may optionally include a cough suppressant component having
particles sized substantially between 10-200 microns. This cough
suppressant component can be added to the formulation instead of,
or in addition to, the cough suppressant component in the range of
5-10 previously discussed. Accordingly, the formulation of the
present invention can comprise two cough suppressant components,
wherein each cough suppressant component has a substantially
different particle size distribution. The 10-200 micron cough
suppressant component may reduce a cough caused by irritation of
the oro-pharynx, the glottis vocal cords and other anatomic regions
more proximal or closer to the mouth that contain receptors that
can trigger cough or trigger other unwanted sensations. As
contemplated herein, these larger particles are substantially
prohibited from entering the sub-glottic airways. Accordingly, in
some embodiments, the smallest particles within the cough
suppressant component particle size range are at least about 10
micron, at least about 12 micron, at least about 20 micron, at
least about 30 micron, or at least about 50 micron. In some
embodiments, the largest particles within the cough suppressant
component particle size range are no greater than about 200 micron,
no greater than about 150 micron, no greater than about 120 micron,
no greater than about 100 micron, no greater than about 90 micron,
or no greater than about 80 micron. In certain embodiments, no more
than about 10% of the cough suppressant component particles are
less than about 10 micron. In certain embodiments, no more than
about 10% of the cough suppressant component particles are less
than about 20 micron. In other embodiments, at least 90% of the
cough suppressant component particles are less than about 200
micron. In other embodiments, at least 90% of the cough suppressant
component particles are less than about 150 micron. In other
embodiments, at least 90% of the cough suppressant component
particles are less than about 100 micron. In one embodiment, no
more than about 10% of the cough suppressant component particles
are less than 10 micron and at least 90% of the cough suppressant
component particles are less than about 200 micron. In one
embodiment, no more than about 10% of the cough suppressant
component particles are less than about 12 micron and at least 90%
of the cough suppressant component particles are less than about
100 micron. In one embodiment, the cough suppressant component
includes menthol or mint particles between about 10-200 microns in
size, which may provide a soothing effect in areas of particle
impact. In another embodiment, the cough suppressant component
having particles between about 10-200 microns in size may include
benzocaine. It should be appreciated that the cough suppressant
component having particles between about 10-200 microns in size can
include any compound approved for suppressing cough. In another
example, the addition of at least one component in the formulation
of the present invention other than the nicotine component may act
to dilute the nicotine containing particles and decrease cough
caused by nicotine irritating the oro-pharynx, vocal cords and
other anatomic regions proximal to the trachea.
[0055] In another example, the formulation of the present invention
may optionally include a flavor component having particles sized
substantially between about 10-1000 microns. In one embodiment, the
flavor component is composed of particles substantially in the
range of about 10-200 micron. In a preferred embodiment, the flavor
component is composed of particles substantially in the range of
about 10-100 micron. This flavor component utilizes such embedded
larger particles that may impact the subject in the oral cavity to
produce a desired flavor. Further, by limiting such flavor
component particles to larger than about 10 microns in size, these
particles are limited in their ability to enter into the subject's
lungs. Accordingly, in some embodiments, the smallest particles
within the flavoring component particle size range are at least
about 10 micron, at least about 12 micron, at least about 20
micron, at least about 30 micron, or at least about 50 micron. In
some embodiments, the largest particles within the flavoring
component particle size range are no greater than about 1000
micron, no greater than about 500 micron, no greater than about 200
micron, no greater than about 150 micron, no greater than about 120
micron, no greater than about 100 micron, no greater than about 90
micron, or no greater than about 80 micron. In certain embodiments,
no more than about 10% of the flavor component particles are less
than about 10 micron. In certain embodiments, no more than about
10% of the flavor component particles are less than about 20
micron. In other embodiments, at least 90% of the flavor component
particles are less than about 1000 micron. In other embodiments, at
least 90% of the flavor component particles are less than about 500
micron. In other embodiments, at least 90% of the flavor component
particles are less than about 200 micron. In other embodiments, at
least 90% of the flavor component particles are less than about 150
micron. In other embodiments, at least 90% of the flavor component
particles are less than about 100 micron. In one embodiment, no
more than about 10% of the flavor component particles are less than
10 micron and at least 90% of the flavor component particles are
less than about 1000 micron. In one embodiment, no more than about
10% of the flavor component particles are less than 10 micron and
at least 90% of the flavor component particles are less than about
200 micron. In one embodiment, no more than about 10% of the flavor
component particles are less than about 10 micron and at least 90%
of the flavor component particles are less than about 100 micron.
In one embodiment, the flavor component is menthol. In other
embodiments, the flavor component may include tobacco, mint, fruit
flavors, or food grade flavorings used in candy or baking. It
should be appreciated that the flavor compound may be any flavoring
compound known in the art, preferably a regulatory-approved
flavoring compound.
[0056] As shown in FIG. 2, the present invention includes a dry
process or method of producing any one of the formulations
described herein. For example, in step 110, nicotine tartrate is
dry milled. At step 120, nicotine is mixed with lactose. In some
embodiments, the nicotine or nicotine salt is not bound to any
other components of the formulation. That is, the formulation
contains distinct particles of nicotine or a nicotine salt, and
distinct particles of other components of the formulation, such as
a sugar. In one embodiment, the nicotine is not bound to the
lactose particles. Alternatively, nicotine tartrate and lactose may
be first dry mixed, such as in step 115, and co-milled in step 125.
At step 130, the particles of the resulting formulation are
filtered, such as with a sieve, to remove any particles larger than
a threshold size value. At step 140, the particles of the resulting
formulation are filtered again to remove any particles smaller than
a threshold size value, resulting in the final dry powder
formulation. In some embodiments, only one filtering step is
needed. In other embodiments, two or more filtering steps are
needed. Optionally at step 160, a cough suppressant component may
be added to final formulation 150. Step 160 may contain any number
of processing steps needed to obtain the desired particle size
(e.g., 1-10 micron) for the cough suppressant component being
added. Optionally at step 170, a cough suppressant component may be
added to final formulation 150. Step 170 may contain any number of
processing steps needed to obtain the desired particle size (e.g.,
10-200 micron) for the cough suppressant component being added.
Optionally at step 180, a flavor component may be added to final
formulation 150. Step 180 may contain any number of processing
steps needed to obtain the desired particle size (e.g., 10-1000
micron) for the flavor component being added.
[0057] As shown in FIG. 3, the present invention also includes a
wet process or method of producing any one of the formulations
described herein. For example, in step 210, nicotine tartrate is
admixed with a carrier, such as lactose, to form a flowable
mixture. At step 220, the mixture is atomized. At step 230, the
mixture is dried, such as via a spray drier. Alternatively, the
process may optionally be performed via fluid bed drying, wherein
nicotine tartrate can instead be spray dried onto the lactose. At
step 240, the resulting nicotine particles are filtered, such as
with a sieve, to remove any particles larger than a threshold size
value. At step 250, the resulting nicotine particles are filtered
again to remove any particles smaller than a threshold size value,
resulting in the final dry powder formulation. In some embodiments,
only one filtering step is needed. In other embodiments, two or
more filtering steps are needed. Optionally at step 270, a cough
suppressant component may be added to final formulation 260. Step
270 may contain any number of processing steps needed to obtain the
desired particle size (e.g., 1-10 micron) for the cough suppressant
component being added. Optionally at step 280, a cough suppressant
component may be added to final formulation 260. Step 280 may
contain any number of processing steps needed to obtain the desired
particle size (e.g., 10-200 micron) for the cough suppressant
component being added. Optionally at step 290, a flavor component
may be added to final formulation 260. Step 290 may contain any
number of processing steps needed to obtain the desired particle
size (e.g., 10-1000 micron) for the flavor component being
added.
[0058] In one embodiment, the nicotine-based component may include
nicotine and a pharmaceutical grade sugar prepared as solid
discrete flowable particles, which may be entrained in the air
inhaled by a subject so as to travel to the alveoli and smaller
airways of the lungs. Further, the dried nicotine-sugar particles
may be filtered, such as via one or more sieving steps, to isolate
and segregate the desired particle sizes from those particles being
removed.
[0059] In one embodiment, initial particles of the nicotine-based
component may be produced via the methods as described in U.S.
Patent Application Publication No. 20120042886, which is
incorporated by reference herein in its entirety. For example, in a
first step, nicotine and a pharmaceutical grade sugar, such as
lactose, can be mixed with a liquid carrier so as to form a
flowable mixture.
[0060] As contemplated herein, any form of nicotine may be used as
the nicotine-based component. Preferably the form of nicotine used
is one which achieves the fast uptake into the lungs of the
patient. A form of nicotine which can be milled, or co-milled with
a sugar or other components, is preferable. In another embodiment,
the nicotine is blended with a sugar or other components. In one
embodiment, the nicotine is a salt, which, at room temperature, is
a solid. The nicotine may further be a pharmacologically active
analog or derivative of nicotine or substance that mimics the
effect of nicotine, either alone or in combination with other
active substances. If the nicotine is a base, then it may be added
to a liquid carrier, such as water, and mixed to produce a
generally homogeneous liquid mixture, which can then be dried by
various method to form a dry particulate formulation. In other
embodiments a form of nicotine which is soluble in or miscible with
a liquid carrier may also be used. For example, the nicotine may be
a nicotine base, which, at room temperature, is a liquid that is
miscible in water. Alternatively, the nicotine base may be an oil
formulation.
[0061] Accordingly, in one embodiment, nicotine is present in the
formulation as a free base. In another embodiment, the formulation
may comprise a nicotine salt. In one such embodiment, the nicotine
salt is nicotine tartrate. In another embodiment, the nicotine salt
is nicotine hydrogen tartrate. In other embodiments, the nicotine
salt can be prepared from any suitably non-toxic acid, including
inorganic acids, organic acids, solvates, hydrates, or clathrates
thereof. Examples of such inorganic acids are hydrochloric,
hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic,
hexafluorophosphoric, citric, gluconic, benzoic, propionic,
butyric, sulfosalicylic, maleic, lauric, malic, fumaric, succinic,
tartaric, amsonic, pamoic, p-toluenenesulfonic, and mesylic.
Appropriate organic acids may be selected, for example, from
aliphatic, aromatic, carboxylic and sulfonic classes of organic
acids, examples of which are formic, acetic, propionic, succinic,
camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic,
malic, mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic,
maleic, furoic, glutamic, benzoic, anthranilic, salicylic,
phenylacetic, mandelic, embonic (pamoic), methanesulfonic,
ethanesulfonic, pantothenic, benzenesulfonic (besylate), stearic,
sulfanilic, alginic, galacturonic, and the like.
[0062] As contemplated herein, the sugar is an inhalable sugar, and
is generally solid at room temperature. The sugar can be milled
into a particulate formulation, either by itself, or co-milled with
a nicotine component. The sugar may also be soluble in a liquid
carrier, such as water. Without limitation, examples of suitable
sugars are lactose, sucrose, raffinose, trehalose, fructose,
dextrose, glucose, maltose, mannitol, or combinations thereof. In
one embodiment, the sugar is lactose. In another embodiment, the
lactose is coarse lactose. In another embodiment, the sugar is
alpha monohydrate lactose. The sugar may be a natural or a
synthetic sugar, and may include any analogs or derivatives of
sugars. It should be appreciated that any form of sugar approved as
an excipient may be used as a carrier in the production of the
nicotine-based component. While not required, the sugar is
preferably of a pharmaceutical grade as would be understood by
those skilled in the art. Preferably, the pharmaceutical grade
sugar used to be milled by itself, co-milled with a nicotine
component or to create the flowable mixture is a non-spheronized
sugar. The pharmaceutical grade sugar may be prepared in a
non-spheronized form prior to dry or wet admixture with nicotine.
For example, the pharmaceutical grade sugar may be first prepared
in a non-spheronized form by freeze drying, milling, micronizing or
the like. In certain embodiments, the pharmaceutical grade sugar
may be subjected to milling, bashing, grinding, crushing, cutting,
sieving or other physical degradation process as understood by
those skilled in the art, which ultimately reduces the particle
size of the sugar and results in a non-spheronized sugar.
[0063] In various embodiments, the formulation can further comprise
any pharmaceutically acceptable material, composition or carrier,
such as a liquid or solid filler, stabilizer, dispersing agent,
suspending agent, diluent, excipient, thickening agent, solvent or
encapsulating material, involved in carrying or transporting a
compound useful within the invention within or to the subject such
that it may perform its intended function. In one embodiment, the
formulation is further comprised of a stabilizing agent. Each
material must be "acceptable" in the sense of being compatible with
the other ingredients of the formulation, including nicotine, and
not injurious to the subject. Some materials that may useful in the
formulation of the present invention include pharmaceutically
acceptable carriers, for example sugars, such as lactose, glucose
and sucrose; starches, such as corn starch and potato starch;
cellulose, and its derivatives, such as sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered
tragacanth; malt; gelatin; talc; excipients, such as cocoa butter,
lecithin, and suppository waxes; oils, such as peanut oil,
cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and
soybean oil; glycols, such as propylene glycol; polyols, such as
glycerin, sorbitol, mannitol and polyethylene glycol; esters, such
as ethyl oleate and ethyl laurate; agar; buffering agents, such as
magnesium hydroxide and aluminum hydroxide; surface active agents;
alginic acid; pyrogen-free water; isotonic saline; Ringer's
solution; ethyl alcohol; phosphate buffer solutions; and other
non-toxic compatible substances employed in pharmaceutical
formulations. Other pharmaceutically acceptable materials that can
be useful in the formulation include any and all coatings,
antibacterial and antifungal agents, and absorption delaying
agents, and the like that are compatible with the activity of
nicotine or any other compound useful within the invention, and are
physiologically acceptable to the subject. Supplementary active
compounds, including pharmaceutically acceptable salts of those
compounds, may also be incorporated into the compositions. Other
additional ingredients that may be included in the compositions
used in the practice of the invention are known in the art and
described, for example in Remington's Pharmaceutical Sciences
(Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa.), which is
incorporated herein by reference.
[0064] Any method of blending particles in and for the methods and
formulations of the present invention is contemplated here. The
blending can be conducted in one or more steps, in a continuous,
batch, or semi-batch process. For example, if two or more
excipients are used, they can be blended together before, or at the
same time as, being blended with the pharmaceutical agent
microparticles.
[0065] The blending can be carried out using essentially any
technique or device suitable for combining the microparticles with
one or more other materials (e.g., excipients) effective to achieve
uniformity of blend. The blending process may be performed using a
variety of blenders. Representative examples of suitable blenders
include V-blenders, slant-cone blenders, cube blenders, bin
blenders, static continuous blenders, dynamic continuous blenders,
orbital screw blenders, planetary blenders, Forberg blenders,
horizontal double-arm blenders, horizontal high intensity mixers,
vertical high intensity mixers, stirring vane mixers, twin cone
mixers, drum mixers, and tumble blenders. The blender preferably is
of a strict sanitary design required for pharmaceutical
products.
[0066] Tumble blenders are often preferred for batch operation. In
one embodiment, blending is accomplished by aseptically combining
two or more components (which can include both dry components and
small portions of liquid components) in a suitable container. One
example of a tumble blender is the TURBULA.TM., distributed by Glen
Mills Inc., Clifton, N.J., USA, and made by Willy A. Bachofen AG,
Maschinenfabrik, Basel, Switzerland.
[0067] For continuous or semi-continuous operation, the blender
optionally may be provided with a rotary feeder, screw conveyor, or
other feeder mechanism for controlled introduction of one or more
of the dry powder components into the blender.
[0068] The milling step is used to fracture and/or deagglomerate
the blended particles, to achieve a desired particle size and size
distribution, as well as to enhance distribution of the particles
within the blend. Any method of milling can be used to form the
particles of the invention, as understood by one of ordinary skill
in the art. A variety of milling processes and equipment known in
the art may be used. Examples include hammer mills, ball mills,
roller mills, disc grinders, jet milling and the like. Preferably,
a dry milling process is used.
[0069] As contemplated herein, any liquid carrier may be used in
the wet process. Preferably, the liquid carrier is one in which
both the pharmaceutical grade sugar and the nicotine tartrate or
the nicotine base are soluble. For example, in one embodiment, the
liquid carrier is water. While water is the preferred liquid
carrier, other liquids in combination with or in place of water may
be used. For example, the liquid carrier may comprise a mixture of
an alcohol and water to form an azeotropic liquid carrier. If an
alcohol is used, the alcohol is preferably a primary alcohol. In
one embodiment, the alcohol is preferably a lower alkyl alcohol
(i.e. C.sub.1 to C.sub.5), such as ethanol. In such embodiments,
any ratio of water to alcohol may be used, and may be determined
when balancing the solubility of the mixture components with the
desired drying rate of the final mixture. In some embodiments, the
ratio of alcohol to water in the liquid carrier may be from about
1:1 to 1:10, preferably from about 1:2 to 1:8 and more preferably
from about 1:5 to 1:7 parts by weight. Accordingly, the liquid
carrier may be any liquid or liquids with which nicotine may be
admixed with sugar to form a flowable mixture which is preferably
of a generally uniform composition.
[0070] It should be appreciated that there are no limitations to
the ratio of nicotine to sugar, or other components used, and the
actual ratio used will be based on the concentration of nicotine
desired in the nicotine based component particles. In one
embodiment the percentage of nicotine in the formulation is between
1.5% and 20%. In one embodiment, the percentage of nicotine in the
formulation is between 0.5% and 5%. In some embodiments, the
percentage of nicotine in the formulation is between 1.5% and 2.5%.
In other embodiments, the percentage of nicotine in the formulation
is between 0.5% and 2.5%. In yet other embodiments the percentage
of nicotine in the formulation is between 1.5% and 5%. In one
embodiment, the percentage of nicotine in the formulation is about
2.5%. In another embodiment, the percentage of nicotine in the
formulation is about 5%. In other embodiments the concentration of
nicotine is between about 5-10%. In another embodiment, the
percentage of nicotine in the formulation is about 10%. In one
embodiment the ratio of sugar to nicotine in the dry mixture or the
wet flowable mixture may vary from about 1:100 to about 100:1, or
from about 3:7 to about 3:2 or alternatively, from about 4:6 parts
by weight. Further, the concentration of sugar in the dry mixture
or the wet flowable mixture may vary from about 1 to about 10 w/v
(g/100 ml), from about 2 to about 5 w/v (g/100 ml) or from about 3%
w/v (g/100 ml).
[0071] As mentioned previously, in the wet process the
nicotine-sugar flowable mixture is dried, such as via a spray
drier, to produce composite particles of nicotine-sugar that are
suitable for delivery to the alveoli and lower airways of a
subject. It should be appreciated that there is no limitation to
the method of drying the flowable mixture. While a preferred method
utilizes a spray drier, other drying techniques capable of
producing appropriately sized particles may be used, such as
fluidized bed drying. In one embodiment, the mixture is finely
divided via passage through an orifice upon on entry to a spray
dryer. In another embodiment, the flowable mixture may be passed
through an atomizer, such as a rotary atomizer, to feed the
flowable liquid into a spray dryer. Further still, any rate of
drying may be used (e.g., slow or rapid rate drying), provided such
rate of drying results in the formation of dry particles of the
desired size range. Prior to the segregation of the desired
particle size of the nicotine-based component, the resultant
particles formed via the spray drier may have a particle size from
about 0.1 to about 5 micron.
[0072] Additional segregation/filtering of selected particle sizes
may be performed both in the dry and the wet process. In the wet
process, the operating conditions of the spray dryer may be
adjusted so to produce particles which are sized so as to be able
to travel to the alveoli and smaller airways of the lungs. For
example, a rotary atomizer may be operated at a liquid feed rate
from about 2 to about 20 ml/min, or from 2 to about 10 ml/min, or
from about 2 to about 5 ml/min. Further, the rotary atomizer may be
operated from about 10,000 to about 30,000 rpm, from about 15,000
to about 25,000 rpm, or from about 20,000 to about 25,000 rpm. It
should be appreciated that particles of various sizes may be
obtained by spray drying, and particles having the desired particle
size may be more specifically selected when filtered, such as via
one or more sieving steps, as described elsewhere herein. The spray
dryer may be operated at temperatures sufficiently high to cause
the liquid carrier to rapidly evolve without raising the
temperature of the sugar and nicotine within the mixture to a point
at which these compounds begin to degrade. Accordingly, the spray
dryer may be operated with an inlet temperature from about
120.degree. C. to about 170.degree. C., and an outlet temperature
from about 70.degree. C. to about 100.degree. C.
[0073] It should be appreciated that the nicotine-based component
particles may be spherical or of any other shape desired. In one
embodiment of the wet process, by evolving the liquid carrier
sufficiently rapidly during the spray drying process, the particles
may be produced with an uneven or a "dimpled" surface. In such
embodiments, the uneven surface may produce a relative turbulence
as the particles travel through the air, thus providing the
particles with aerodynamic lift. In such embodiments, particles
having such shape may be more readily entrained, and to remain
entrained, in the air inhaled by a subject, thereby improving the
ability of the nicotine-based component particles to travel to the
alveoli and smaller airways.
[0074] As mentioned previously, the present invention includes
formulations having components characterized by particular particle
size ranges. For example, the formulations of the present invention
can include nicotine-based particles sized substantially between
about 1-10 microns, and preferably between about 2-5 microns. In
other embodiments, the formulations can optionally include a cough
suppressant component (such as menthol or mint) having particles in
the size range of about 1-100 microns. In other embodiments, the
formulations can optionally include a second cough suppressant
component having particles in the size range of about 10-200
microns. In further embodiments, the formulations can include a
flavor component (such as menthol or mint) having particles in the
size range of about 10-1000 microns.
[0075] As contemplated herein, the particles of the present
invention can be produced in relatively narrow size ranges via the
use of at least one sieving step. In such an embodiment, the
sieving step includes using a sieve corresponding to the minimum or
maximum of the desired particle size range to eliminate particles
from the mixture that are smaller or bigger than the desired range.
For example, to obtain nicotine particles in the range of about 1-5
microns, a mixture of nicotine particles produced using the milling
process described herein can be provided. The mixture of nicotine
particles will have a size distribution that is dependent on the
milling conditions used and/or the characteristics of the input
mixture to the mill. The mixture of nicotine particles can first be
passed through a 5 micron sieve, wherein substantially all of the
particles smaller than 5 microns pass through the sieve and are
collected. The particles passing through the sieve can then
transferred to a 1 micron sieve, wherein substantially all of the
particles greater than 1 micron do not pass through the sieve. The
particles greater than 1 micron can be collected from the sieve,
wherein the collected particles will be substantially sized in the
range of 1-5 microns. Accordingly, such a process can be used to
narrow the range of any mixture of particles to any of the desired
particle size ranges as described hereinthroughout.
[0076] In another embodiment, a mixture of particles can be
provided that substantially meets either the minimum or maximum
criteria of the desired particle size range. For example, if a
nicotine particle size range of about 2-5 microns is desired, a
mixture of nicotine particles can be provided wherein substantially
all of the particles are less than 5 microns. Such a mixture can be
produced by modifying the milling conditions, or when the particles
are spray dried, by milling the spray dried material to result in a
mixture of particles that are generally less than 5 microns. The
mixture can then be transferred through a 2 micron sieve, wherein
the particles not passing through the sieve are collected, and
wherein the collected particles are substantially within the
desired 2-3 micron range.
[0077] It is contemplated that the percentage of particles falling
within the desired particle size range for any of the components of
the formulation of the present invention can be dependent on the
technique used to produce that component. For example, if the
targeted size of the nicotine component is in the range of 2-5
micron, it is understood that greater than 90% of that component
will fall within the desired range when using a spray drying
production technique on a relatively small scale. However, using a
relatively large scale milling production technique may only yield
greater than 70% of the nicotine component within such a targeted
range.
[0078] As mentioned previously, the formulation may optionally
include a cough suppressant component, wherein the particles of the
cough suppressant component are sized between about 5 and 10
micron. By selectively including menthol or mint particles sized
between about 5-10 microns, these non-respirable menthol or mint
particles can reduce cough by soothing irritation in the subject's
larger airways as well as the oro-pharynx. In another example, the
formulation of the present invention may optionally include a cough
suppressant component having particles sized substantially between
about 10-200 microns. This cough suppressant component may reduce a
cough caused by irritation of the oro-pharynx, the glottis vocal
cords and other anatomic regions more proximal or closer to the
mouth that contain receptors that can trigger cough or trigger
other unwanted sensations. As contemplated herein, these larger
particles do not enter the sub-glottic airways because of their
momentum.
[0079] In one embodiment, the cough suppressant component of either
the 5-10 or 10-200 micron ranges comprises menthol or mint.
Further, it should be appreciated that any other cough suppressant
compounds may be used instead of or in addition to menthol or mint,
without limitation.
[0080] As contemplated herein, any form of menthol or mint, such as
a solid form of menthol or mint can be used for processing into
menthol or mint particles useful within the present invention.
Non-limiting examples of solid forms of menthol or mint include
powders, crystals, solidified distillate, flakes, and pressed
articles. In one embodiment, menthol or mint is in the form of
crystals. Menthol or mint can be processed into particles of a size
ranging from about 5 .mu.m to about 10 .mu.m using any method known
in the art. In some embodiments, menthol or mint is admixed with
further liquid or solid additives for processing. Particulate
additives can furthermore also be used. In one embodiment, menthol
or mint is admixed with silicon dioxide. In another embodiment,
menthol or mint is admixed with a sugar, such as lactose. In some
embodiments of the wet process, the menthol or mint is processed in
a liquid carrier.
[0081] As contemplated herein, any liquid carrier may be used in
the process of producing the menthol or mint particles. In one
embodiment, the liquid carrier is water. Preferably, the liquid
carrier is one in which the menthol or mint is soluble.
Accordingly, the liquid carrier may be any liquid or liquids with
which menthol or mint, either alone or in combination with an
additional component, forms a flowable mixture which is preferably
of a generally uniform composition.
[0082] The menthol or mint flowable mixture may be dried, such as
via a spray drier, to produce composite particles of menthol or
mint, alone or in combination with an additional component, that
are suitable for delivery to the alveoli and lower airways of a
person. It should be appreciated that there is no limitation to the
method of drying the flowable mixture. Examples of methods for
drying the flowable mixture include, but are not limited to, spray
drying, vacuum drying, and freeze drying. Further still, any rate
of drying may be used (e.g., slow or rapid rate drying), provided
such rate of drying results in the formation of dry particles of
the desired size range.
[0083] As mentioned previously, the formulation may optionally
include a flavor component, wherein the particles of the flavor
component are sized between about 10 and about 1000 micron. In one
embodiment, the flavor component comprises menthol or mint and may
be produced as previously described herein. When other flavoring
compounds are used, any known processing steps suitable for such
compounds may be used to produce the flavoring component within the
desired particle size range of about 10-1000 micron.
[0084] In various embodiments, the relative weight percentage of
each component in the formulation of the present invention can be
varied to achieve different characteristics. Thus, as one skilled
in the art would understand, the relative weight percentages of the
components can be modified for various reasons, for example, but
not limited to: achieving a certain level of blood nicotine
concentration while modulating the level of harshness on the
airways of the subject, achieving a certain level of harshness
while modulating the level of satisfaction perceived by the subject
of the therapy, achieving better uptake of nicotine in the lungs of
the patient, achieving faster blood nicotine kinetics, optimizing
the cough suppressant performance of the formulation, varying or
improving the taste of the formulation, and adjusting the relative
dose of nicotine. In certain embodiments, the formulation can be
about 1-20% by weight flavor component, with a preferred weight of
1-5% flavor component. In certain embodiments, the formulation can
be about 1-10 % by weight cough suppressant, with a preferred
weight of 1-2.5% cough suppressant. In various embodiments, the
remaining portion of the formulation, aside from any flavor
components, cough suppressant components, carriers, or other
components, is the nicotine component.
[0085] The disclosures of each and every patent, patent
application, and publication cited herein are hereby incorporated
herein by reference in their entirety. While this invention has
been disclosed with reference to specific embodiments, it is
apparent that other embodiments and variations of this invention
may be devised by others skilled in the art without departing from
the true spirit and scope of the invention. The appended claims are
intended to be construed to include all such embodiments and
equivalent variations.
* * * * *