U.S. patent application number 15/692579 was filed with the patent office on 2017-12-21 for multi-layer nicotine-containing pharmaceutical composition.
The applicant listed for this patent is Niconovum USA, Inc.. Invention is credited to Daniel Verdin Cantrell, Donna Walker Duggins, Darrell Eugene Holton, Jr., John-Paul Mua.
Application Number | 20170360767 15/692579 |
Document ID | / |
Family ID | 47722567 |
Filed Date | 2017-12-21 |
United States Patent
Application |
20170360767 |
Kind Code |
A1 |
Duggins; Donna Walker ; et
al. |
December 21, 2017 |
MULTI-LAYER NICOTINE-CONTAINING PHARMACEUTICAL COMPOSITION
Abstract
The invention provides a multi-layered pharmaceutical
composition comprising two or more formulations with varying
properties. In some embodiments, the pharmaceutical compositions
provide combinations of different organoleptic properties within
the same product. In certain embodiment, these combinations allow
for a modified release profile of active ingredients as the user
enjoys the pharmaceutical composition. The invention further
provides methods for making and using the pharmaceutical
composition.
Inventors: |
Duggins; Donna Walker;
(Winston-Salem, NC) ; Mua; John-Paul; (Advance,
NC) ; Holton, Jr.; Darrell Eugene; (Clemmons, NC)
; Cantrell; Daniel Verdin; (Lewisville, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Niconovum USA, Inc. |
Winston-Salem |
NC |
US |
|
|
Family ID: |
47722567 |
Appl. No.: |
15/692579 |
Filed: |
August 31, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13370505 |
Feb 10, 2012 |
9763928 |
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15692579 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/34 20180101;
A61P 43/00 20180101; A61K 9/2886 20130101; A61K 31/465 20130101;
A61K 9/209 20130101; A61K 9/0056 20130101; A61P 25/00 20180101 |
International
Class: |
A61K 31/465 20060101
A61K031/465; A61K 9/00 20060101 A61K009/00; A61K 9/24 20060101
A61K009/24; A61K 9/28 20060101 A61K009/28 |
Claims
1. A multi-layered pharmaceutical composition comprising two or
more formulations having different organoleptic properties, wherein
the formulations are selected from the group consisting of: i) a
dissolvable formulation comprising a sugar substitute in an amount
of at least about 80% by weight and a sugar alcohol syrup; ii) a
meltable formulation comprising a lipid having a melting point of
about 36.degree. C. to about 45.degree. C.; iii) a pastille
formulation comprising a polysaccharide filler; iv) a pastille
formulation comprising a sugar alcohol and a natural gum binder
component; v) a chewable formulation comprising a binder, an
emulsifier, and a lipid having a melting point of about 36.degree.
C. to about 45.degree. C.; and vi) a hard coating formulation
comprising a binder, a sugar substitute, and a sugar alcohol syrup;
wherein at least one fat nulation further comprises one or more
nicotinic compounds.
2. The multi-layered pharmaceutical composition of claim 1, wherein
all formulations of the multi-layered pharmaceutical composition
comprise one or more nicotinic compounds.
3. The multi-layered pharmaceutical composition of claim 1, wherein
the one or more nicotinic compounds are independently in the form
of a free base, a salt, a complex, or a solvate.
4. The multi-layered pharmaceutical composition of claim 3, wherein
the one or more nicotinic compounds comprise nicotine
polacrilex.
5. The multi-layered pharmaceutical composition of claim 1, wherein
the one or more nicotinic compounds comprise a nicotinic compound
sorbed onto a porous particulate carrier.
6. The multi-layered pharmaceutical composition of claim 5, wherein
the porous particulate carrier comprises microcrystalline
cellulose.
7. The multi-layered pharmaceutical composition of claim 1, wherein
the multi-layered pharmaceutical composition comprises between two
and ten layers.
8. The multi-layered pharmaceutical composition of claim 7, wherein
the multi-layered pharmaceutical composition comprises between two
and five layers.
9. The multi-layered pharmaceutical composition of claim 1, wherein
the form of the pharmaceutical composition is a core formulation
surrounded by one or more continuous layers or a core formulation
coated by one or more discontinuous layers so as to form a layered
or side-by-side configuration of the two or more formulations.
10. The multi-layered pharmaceutical composition of claim 1,
wherein the sugar substitute of the dissolvable formulation
comprises isomalt and wherein the sugar alcohol syrup of the
dissolvable follnulation comprises maltitol syrup.
11.-25 (canceled)
26. The multi-layered pharmaceutical composition of claim 1,
wherein the product comprises a combination of formulations
selected from the group consisting of: formulations i) and ii);
formulations i) and iii); formulations i) and iv); formulations i)
and v); formulations i) and vi); formulations ii) and iii);
formulations ii) and iv); formulations ii) and v); formulations ii)
and vi).; formulations iii) and iv); formulations iii) and v);
formulations iii) and vi); fon mlations iv) and v); formulations
iv) and vi); formulations i), ii), and iii); formulations i), ii),
and iv); formulations i), ii), and v); formulations i), ii), and
vi); formulations i), iii), and iv); formulations i), iii), and v);
formulations i), iii), and vi); formulations i), iv), and v);
formulations i), iv), and vi); formulations i), v), and vi);
formulations ii), iii), and iv); formulations ii), iii), and v);
formulations ii), iii), and vi); formulations ii), iv), and v);
formulations ii), iv), and vi); formulations ii), v), and vi);
formulations iii), iv), and v); formulations iii), iv), and vi);
and formulations iii), v), and vi).
27. A process for preparing a multi-layered pharmaceutical
composition, comprising: preparing a first formulation by combining
one or more nicotinic compounds with one or more components
selected from the group consisting of binders, lipid components,
polysaccharide fillers, sugar substitutes, sugar alcohol syrups,
flavorants, sweeteners, emulsifiers, disintegration aids,
humectants, buffering agents, and mixtures thereof to form a first
nicotinic compound-containing mixture and forming the first
nicotinic compound-containing mixture into a desired form;
preparing a second formulation by combining one or more nicotinic
compounds with one or more components selected from the group
consisting of binders, lipid components, polysaccharide fillers,
sugar substitutes, sugar alcohol syrups, flavorants, sweeteners,
emulsifiers, disintegration aids, humectants, buffering agents, and
mixtures thereof to form a second nicotinic compound-containing
mixture and forming the second nicotinic compound-containing
mixture into a desired form; and applying the second formulation to
the first formulation, wherein the formulations are selected from
the group consisting of: i) a dissolvable formulation comprising a
sugar substitute in an amount of at least about 80% by weight and a
sugar alcohol syrup; ii) a meltable formulation comprising a lipid
having a melting point of about 36.degree. C. to about 45.degree.
C.; iii) a pastille formulation comprising a polysaccharide filler;
iv) a pastille formulation comprising a sugar alcohol and a natural
gum binder component; v) a chewable formulation comprising a
binder, an emulsifier, and a lipid having a melting point of about
36.degree. C. to about 45.degree. C.; and vi) a hard coating
formulation comprising a binder, a sugar substitute, and a sugar
alcohol syrup.
28. The process of claim 27, wherein the first formulation is
formed into a desired form by pouring the first nicotinic
compound-containing mixture into a mold or injection molding the
first nicotinic compound-containing mixture.
29. The process of claim 27, wherein the second formulation is
applied by spray coating, dip coating, or by forming the second
formulation into a sheet that is applied to the first formulation
as a sandwiched coating.
30. The process of claim 29, wherein the spray coating or dip
coating is conducted at a temperature such that the first
formulation is maintained in substantially intact form.
31. The process of claim 27, further comprising applying a third
formulation as a coating on the second formulation.
32. The process of claim 31, wherein the third formulation is
applied by spray coating, dip coating, or by fanning the third
formulation into a sheet that is applied to the second formulation
as a sandwiched coating.
33. A method for treating a human subject having a condition,
disease, or disorder responsive to stimulation of nicotinic
acetylcholinergic receptors, comprising orally administering an
effective amount of a pharmaceutical composition according to claim
1 to said human subject.
34. The method of claim 33, wherein said administering step
comprises administering the pharmaceutical composition to a human
subject as a smoking cessation aid.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to compositions that contain
nicotine, and in particular, to nicotine-containing pharmaceutical
compositions intended to be administered to provide a
pharmacological effect, or otherwise used for therapeutic
purposes.
BACKGROUND OF THE INVENTION
[0002] Central nervous system (CNS) conditions, diseases, or
disorders can be drug induced; can be attributed to genetic
predisposition, infection or trauma; or can be of unknown etiology.
They comprise neuropsychiatric disorders, neurological diseases and
mental illnesses; and include neurodegenerative diseases,
behavioral disorders, cognitive disorders and cognitive affective
disorders. The clinical manifestations of several CNS conditions,
diseases or disorders have been attributed to CNS dysfunction
(i.e., disorders resulting from inappropriate levels of
neurotransmitter release, inappropriate properties of
neurotransmitter receptors, and/or inappropriate interaction
between neurotransmitters and neurotransmitter receptors).
[0003] Nicotinic compounds, such as nicotine, are capable of
affecting nicotinic acetylcholinergic receptors (nAChRs). Subtypes
of nAChRs exist in both the CNS and the peripheral nervous system
(PNS), but the distribution of subtypes is heterogeneous. For
instance, certain subtypes which are predominant in vertebrate
brain, others predominate at the autonomic ganglia, and others
predominate at neuromuscular junction. Activation of nAChRs by
nicotinic compounds results in neurotransmitter release. See, for
example, Dwoskin et al., Exp. Opin. Ther. Patents, 10: 1561-1581
(2000); Schmitt et al., Annual Reports in Med. Chem. 35: 41-51
(2000); Huang et al., J. Am. Chem. Soc., 127: 14401-14414 (2006);
Arneric et al., Biochem. Pharmacol., 74: 1092-1101 (2007) and
Millar, Biochem. Pharmacol., 78: 766-776 (2009); which are
incorporated herein by reference.
[0004] It has been suggested that administration of nicotine, and
other nicotinic compounds, can result in various pharmacological
effects. See, for example, U.S. Pat. No. 5,583,140 to Bencherif et
al.; U.S. Pat. No. 5,723,477 to McDonald et al.; U.S. Pat. No.
7,001,900 to Jacobsen et al.; U.S. Pat. No. 7,135,484 to Dart et
al. and U.S. Pat. No. 7,214,686 to Bencherif et al.; and US Pat.
Pub. No. 2010/0004451 to Ahmad et al.; which are incorporated
herein by reference. As a result, it has been suggested that
nicotine, and other nicotinic compounds, can exhibit utility in the
treatment of a wide variety of conditions, diseases, and disorders,
including those that affect the CNS. Additionally, administration
of nicotine and nicotinic compounds has been proposed for treatment
of certain other conditions, diseases, and disorders. See, for
example, U.S. Pat. No. 5,604,231 to Smith et al.; U.S. Pat. No.
5,811,442 to Bencherif et al.; U.S. Pat. No. 6,238,689 to Rhodes et
al.; and U.S. Pat. No. 6,489,349 to Bencherif et al.; which are
incorporated herein by reference. Furthermore, administration of
nicotine has been employed in an effort to help cigarette smokers
quit smoking (i.e., as a smoking cessation aid). For example,
nicotine has been an active ingredient of various types of
so-called "nicotine replacement therapy" or "NRT" products. See,
for example, background art discussed in U.S. patent application
Ser. No. 13/278,877 to Borschke et al, filed Oct. 21, 2011, which
are incorporated by reference herein.
[0005] One particular method that has been employed to provide oral
administration of nicotine is through the use of
nicotine-containing lozenge or tablet types of products.
Nicotine-containing lozenge, tablet, and microtab types of products
have been marketed, for example, under the tradenames
"Commit.RTM.," "Nicorette.RTM.," "Nicotinell.RTM." and
"NiQuitin.RTM.." See also, for example, U.S. Pat. No. 5,110,605 to
Acharya; U.S. Pat. No. 5,733,574 to Dam; U.S. Pat. No. 6,280,761 to
Santus; U.S. Pat. No. 6,676,959 to Andersson et al.; and U.S. Pat.
No. 6,248,760 to Wilhelmsen; and US Pat. Pub. No. 2001/0016593 to
Wilhelmsen, which are incorporated herein by reference.
[0006] It would be desirable to provide alternative compositions
capable of delivering or administering nicotine via an oral route
for therapeutic purposes.
SUMMARY OF THE INVENTION
[0007] In one aspect, the present invention relates to a nicotinic
compound-containing composition intended to be employed for
therapeutic purposes. The composition is typically in a
pharmaceutically acceptable form adapted for oral delivery of the
composition. The composition generally comprises a series of two or
more different formulations having different properties that may be
arranged in various ways. The different formulations comprising the
product can be provided, for example, in a multi-layered form. For
example, the nicotinic compound-containing composition can comprise
an inner core of one formulation and one or more coatings of
another formulation, which may be full or partial coatings. In this
way, it is possible to combine formulations having different
organoleptic properties within the same product to provide a unique
composition. In certain embodiments, such multi-layered
compositions afford a modified delivery profile during use. For
example, certain formulations may provide for fast release of the
nicotinic compound contained therein, whereas other formulations
may provide for extended release of the nicotinic compound
contained therein.
[0008] In one aspect of the invention is provided a multi-layered
pharmaceutical composition comprising two or more formulations
having different organoleptic properties, wherein the formulations
are selected from the group consisting of: i) a dissolvable
formulation comprising a sugar substitute in an amount of at least
about 80% by weight and a sugar alcohol syrup; ii) a meltable
formulation comprising a lipid having a melting point of about
36.degree. C. to about 45.degree. C.; iii) a pastille formulation
comprising a polysaccharide filler; iv) a pastille formulation
comprising a sugar alcohol and a natural gum binder component; v) a
chewable formulation comprising a binder, an emulsifier, and a
lipid having a melting point of about 36.degree. C. to about
45.degree. C.; and vi) a hard coating formulation comprising a
binder, a sugar substitute, and a sugar alcohol syrup; wherein at
least one formulation further comprises one or more nicotinic
compounds. In certain embodiments, all formulations of the
multi-layered pharmaceutical composition can comprise one or more
nicotinic compounds, which may be the same or different.
[0009] In some embodiments, the one or more nicotinic compounds in
the pharmaceutical compositions of the invention can be
independently in the form of a free base, a salt, a complex, or a
solvate. The one or more nicotinic compounds can comprise, for
example, nicotine polacrilex. In certain embodiments, the one or
more nicotinic compounds comprise a nicotinic compound sorbed onto
a porous particulate carrier, which can comprise, for example,
microcrystalline cellulose.
[0010] The form of the nicotinic compound-containing pharmaceutical
composition can vary. For example, in some embodiments, the form of
the pharmaceutical composition is a core formulation surrounded by
one or more continuous layers or a core formulation coated by one
or more discontinuous (e.g., partial) layers so as to form a
layered or side-by-side configuration of the two or more
formulations. The number of layers can vary; for example, the
multi-layered pharmaceutical composition can in some embodiments
comprise between two and ten layers, such as between two and five
layers.
[0011] The components of the various formulations can vary. In some
embodiments, the sugar substitute of the dissolvable formulation
can comprise isomalt and/or the sugar alcohol syrup of the
dissolvable formulation can comprise maltitol syrup. In one
exemplary embodiment, the dissolvable formulation comprises a
nicotinic compound; a sugar substitute in an amount of about 80% by
weight or greater; and a sugar alcohol syrup.
[0012] The meltable formulation, where present, may in certain
embodiments comprise a lipid having a melting point of about
38.degree. C. to about 41.degree. C. The lipid can be, for example,
an animal or plant derived fat, wax, or oil. In one exemplary
embodiment, the meltable formulation comprises a nicotinic
compound, a lipid having a melting point of about 36.degree. C. to
about 45.degree. C. in an amount of from about 10% to about 50% by
weight; and a filler in an amount of from about 20% to about 40% by
weight. In another exemplary embodiment, the meltable formulation
comprises a nicotinic compound; a lipid having a melting point of
about 36.degree. C. to about 45.degree. C. in an amount of about
30% by weight or greater; and a filler in an amount of about 30% by
weight or greater.
[0013] The pastille formulation iii), where present, may in certain
embodiments comprise polydextrose as the polysaccharide filler
component. The polysaccharide filler component in some embodiments
can be present in an amount of from about 10 weight percent to
about 25 weight percent of the pastille formulation on a dry weight
basis. In one exemplary embodiment, the pastille formation iii)
comprises a nicotinic compound; a polysaccharide filler in an
amount of about 10% by weight or greater, a humectant in an amount
of about 20% by weight or greater; a binder in an amount of about
10% by weight or greater; and an emulsifier in an amount of about
1% by weight or greater.
[0014] In one exemplary embodiment, the pastille formation iv)
comprises a nicotinic compound; humectant in an amount of about
0.5% by weight or greater; sugar alcohol filler in an amount of
about 20% by weight or greater; and a natural gum binder in an
amount of about 10% or greater.
[0015] The chewable formulation, where present, may in certain
embodiments comprise gum arabic as the binder material. In one
exemplary embodiment, the chewable formulation comprises a
nicotinic compound, a binder material in an amount of about 30% by
weight or greater, and a lipid having a melting point of about
36.degree. C. to about 45.degree. C. in an amount of about 15% by
weight or greater.
[0016] The hard coating formulation, where present, may in certain
embodiments comprise carboxymethylcellulose as the binder
component. The hard coating formulation, where present, may in
certain embodiments comprise isomalt as the sugar substitute. In
one exemplary embodiment, the hard coating formulation comprises a
nicotinic compound; a binder; a sugar substitute in an amount of
about 20% by weight or greater; and a sugar alcohol syrup in an
amount of about 5% by weight or greater.
[0017] Any combination of two or more formulations as described
herein can be used within the multi-layered pharmaceutical
compositions of the invention. For example, the product may, in
certain embodiments, comprise two different formulations, wherein
the formulations comprise: formulations i) and ii), formulations i)
and iii), formulations i) and iv), formulations i) and v),
formulations i) and vi), formulations ii) and iii), formulations
ii) and iv), formulations ii) and v), formulations ii) and vi),
formulations iii) and iv), formulations iii) and v), formulations
iii) and vi), formulations iv) and v), or formulations iv) and vi),
wherein the formulations can be arranged in any manner. For the
foregoing, the listed formulations are meant to include
permutations thereof and the formulations can be structured in
various ways with respect to each other. For example, "formulation
i) and ii)" can also include formulation ii) and formulation i),
and "formulations iv) and vi)" can also include formulation vi) and
formulation iv). In other words, "formulations i) and ii)" is
intended to cover embodiments wherein formulation i) is the core
and formulation ii) is a partial or complete layer thereon as well
as embodiments wherein formulation ii) is the core and formulation
i) is a partial or complete layer thereon.
[0018] In certain embodiments, combinations of three or more
formulations as described herein can be used within the
multi-layered pharmaceutical compositions of the invention. In
certain embodiments, the product may comprise formulations i), ii),
and iii); formulations i), ii), and iv); formulations i), ii), and
v); formulations i), ii), and vi); formulations i), iii), and iv);
formulations i), iii), and v); formulations i), iii), and vi);
formulations i), iv), and v); formulations i), iv), and vi);
formulations i), v), and vi); formulations ii), iii), and iv);
formulations ii), iii), and v); formulations ii), iii), and vi);
formulations ii), iv), and v); formulations ii), iv), and vi);
formulations ii), v), and vi); formulations iii), iv), and v);
formulations iii), iv), and vi); or formulations iii), v), and vi),
wherein the formulations can be arranged in any manner. For the
foregoing, the listed formulations are meant to include
permutations thereof and the formulations can be structured in
various ways with respect to each other. For example, "formulations
i), ii), and iii)" can also include formulation i), iii), and ii);
formulation ii), iii), and i); formulation ii), i), and iii);
formulation iii), i), and ii), and formulation iii), ii), and i).
In other words, "formulations i), ii), and iii)" is intended to
cover embodiments wherein formulation i) is the core, formulation
ii) is a partial or complete layer on formulation i), and
formulation iii) is a partial or complete layer on formulation ii),
as well as embodiments wherein formulation i) is the core,
formulation iii) is a partial or complete layer on formulation i),
and formulation ii) is a partial or complete layer on formulation
iii), as well as embodiments wherein formulation ii) is the core,
formulation iii) is a partial or complete layer on formulation ii),
and formulation i) is a partial or complete layer on formulation
iii), as well as embodiments wherein formulation ii) is the core,
formulation i) is a partial or complete layer on formulation ii),
and formulation iii) is a partial or complete layer on formulation
ii), as well as embodiments wherein formulation iii) is the core,
formulation i) is a partial or complete layer on formulation iii),
and formulation ii) is a partial or complete layer on formulation
i), as well as embodiments wherein formulation iii) is the core,
formulation ii) is a partial or complete layer on formulation iii),
and formulation i) is a partial or complete layer on formulation
ii).
[0019] In another aspect of the invention is provided a process for
preparing a multi-layered pharmaceutical composition, comprising:
preparing a first formulation by combining a nicotinic compound
with one or more components selected from the group consisting of
binders, lipid components, polysaccharide fillers, sugar
substitutes, sugar alcohol syrups, flavorants, sweeteners,
emulsifiers, disintegration aids, humectants, buffering agents, and
mixtures thereof to form a first nicotinic compound-containing
mixture and forming the first nicotinic compound-containing mixture
into a desired form; preparing a second formulation by combining a
nicotinic compound with one or more components selected from the
group consisting of binders, lipid components, polysaccharide
fillers, sugar substitutes, sugar alcohol syrups, flavorants,
sweeteners, emulsifiers, disintegration aids, humectants, buffering
agents, and mixtures thereof to form a second nicotinic
compound-containing mixture and forming the second nicotinic
compound-containing mixture into a desired form; and applying the
second formulation to the first formulation, wherein the
formulations are selected from formulations i), ii), iii), iv), v),
and iv), as described herein.
[0020] In certain embodiments, the first formulation can be formed
into a desired form by pouring or otherwise introducing the first
nicotinic compound-containing mixture into a mold, injection
molding the first nicotinic compound-containing mixture, or other
suitable means for providing a formulation. In certain embodiments,
the second formulation can be applied by spray coating, dip
coating, or by forming the second formulation into a sheet that is
applied to the first formulation as a sandwiched coating. Spray
coating or dip coating can be conducted at a temperature such that
the first formulation is maintained in substantially intact form.
In some embodiments, the method further comprises applying a third
formulation as a coating on the second formulation. The third
nicotinic compound-containing formulation can be applied, for
example, by spray coating, dip coating, or by forming the third
nicotinic compound-containing formulation into a sheet that is
applied to the second formulation as a sandwiched coating.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0021] The present invention now will be described more fully
hereinafter. This invention may, however, be embodied in many
different forms and should not be construed as limited to the
embodiments set forth herein; rather, these embodiments are
provided so that this disclosure will be thorough and complete, and
will fully convey the scope of the invention to those skilled in
the art. As used in this specification and the claims, the singular
forms "a," "an," and "the" include plural referents unless the
context clearly dictates otherwise. Reference to "dry weight
percent" or "dry weight basis" refers to weight on the basis of dry
ingredients (i.e., all ingredients except water).
[0022] According to the invention, a nicotinic compound
pharmaceutical composition is provided which comprises at least two
different formulations. Specifically, such compositions generally
comprise formulations with different organoleptic properties, such
as multi-layered pharmaceutical compositions, wherein two or more
formulations are provided as layers of the pharmaceutical
compositions. Each formulation within the nicotinic
compound-containing composition can comprise one or more nicotinic
compounds. Although at least one formulation within the nicotinic
compound-containing composition comprises a nicotinic compound, in
certain embodiments, one or more other formulations (e.g., one or
more layers) within the composition can be essentially (including
completely) free of nicotinic compounds. The invention further
provides processes for preparing multi-layered nicotinic
compound-containing pharmaceutical compositions.
[0023] By "layered" is meant that the structure of the
multi-layered pharmaceutical composition is generally that of a
core, surrounded by one or more coating layers, which may be
partial or complete layers. In other words, each coating layer may
completely coat the core or previous layer or may only cover
portions thereof. The core can be any shape, such as a flattened
sheet or structure of a given shape (e.g., square, round, oval,
oblong, or rectangular) or a shape that can be described generally
as spherical, cylindrical (e.g., ranging form the general shape of
a flattened disc to the general shape of a relatively long, slender
stick), helical, obloid, or the like). In some embodiments, the
core and/or multi-layered pharmaceutical composition can have the
form of a bead, granular powder, capsule, film, strip, gel, or the
like. The shape of the composition can, in certain embodiments,
resemble a wide variety of pill, tablet, lozenge, capsule, and
caplet types of products. It is noted that side-by-side type
configurations are also intended to be encompassed within the
present invention, e.g., wherein the composition comprises two
layers adhered together along one surface and, optionally,
additional layers adhered to one or both of those two layers. The
number of layers comprising the pharmaceutical composition can vary
but typically is about 2 to about 10, such as 2, 3, 4, 5, 6, 7, 8,
9, or 10 layers. It is noted that although the pharmaceutical
composition is described herein as "layered" or "multi-layered,"
the layers may not be discrete layers of different formulations,
with clear demarcation between the layers. For example, there may
be some degree of mingling between the formulations comprising
adjacent layers of the product. However, in preferred embodiments,
the pharmaceutical composition retains properties and behaviors of
the individual formulations.
[0024] The organoleptic properties of the one or more formulations
that make up the multi-layered pharmaceutical compositions
generally vary. By "organoleptic" as used herein is meant any
aspects that may be associated with the pharmaceutical composition
formulations as experienced by the senses of the user. Organoleptic
properties include, but are not limited to, taste, smell, mouthfeel
(e.g., texture, dissolvability/meltability, firmness, resilience,
crunchiness, chewiness) and the like. For example, the formulations
within a given multi-layered pharmaceutical composition can, in
certain embodiments, have organoleptic properties independently
selected from hard, dissolvable, chewable, chewy, meltable, crisp,
and combinations thereof. Certain formulations useful as components
of a pharmaceutical composition according to the invention can be
described as lozenge-like or pastille-like. The resulting
multi-layered pharmaceutical composition can, in certain
embodiments, comprise a unique mixture of organoleptic properties
as a result of the combination of formulations having varying
organoleptic properties. For example, in one specific embodiment,
the pharmaceutical composition may have a hard, lozenge-like outer
formulation and a meltable core formulation such that, when placed
into the mouth of the user, the user initially experiences a
dissolving effect and later in use, experiences a melting effect.
It is noted that numerous other combinations of formulations
providing varying combinations of organoleptic properties are
encompassed herein.
[0025] As used herein, the terms "dissolve," "dissolving," and
"dissolvable" refer to formulations having aqueous-soluble
components that interact with moisture in the oral cavity and enter
into solution, thereby causing gradual consumption of the
product.
[0026] As used herein, "melt," "melting," and "meltable" refer to
the ability of the formulation to change from a solid state to a
liquid state. That is, melting occurs when a substance (e.g., the
formulation within a pharmaceutical composition) changes from solid
to liquid, usually by the application of heat. The application of
heat in regard to the pharmaceutical composition of the present
invention is provided by the internal temperature of a user's
mouth. Thus, the term "meltable" refers to a formulation that is
capable of liquefying in the mouth of the user as the product
changes phase from solid to liquid, and is intended to distinguish
formulations and/or products that merely disintegrate in the oral
cavity through loss of cohesiveness within the formulation or
formulations that merely dissolve in the oral cavity as
aqueous-soluble components of the formulation interact with
moisture.
[0027] As used herein, the term "pastille" refers to a dissolvable
oral formulation made by solidifying a liquid or gel composition,
such as a composition that includes a gelling or binding agent, so
that the final product is a hardened solid gel. In certain
embodiments, such formulations are characterized by sufficient
cohesiveness to withstand light chewing action in the oral cavity
without rapidly disintegrating. Pastille-like formulations of the
disclosure typically do not exhibit a highly deformable chewing
quality as found in conventional chewing gum.
[0028] As used herein, "chewable" means deformable in the mouth
with a cohesiveness greater than that of a pastille, but generally
less than that of a gum. Such formulations may be characterized by
sufficient cohesiveness to withstand a greater extent of chewing
than a pastille; however, such compositions generally disintegrate
in the oral cavity (unlike gum formulations).
[0029] As used herein, "hard coating-like" means a layer that
exhibits some degree of hardness and/or crunchiness. It is
generally a somewhat thin layer, allowing it to be easily broken by
teeth of the user and/or readily dissolved in the mouth of the
user. Although it is referred to herein as a "coating," it is noted
that this layer need not comprise an exterior layer of the
pharmaceutical composition, and may comprise an interior layer of
the product.
[0030] The one or more "nicotinic compounds" within the
pharmaceutical formulations of the present invention are naturally
occurring or synthetic nicotine unbound from a plant material,
meaning the compound is at least partially purified and not
contained within a plant structure such as a tobacco leaf. Most
preferably, nicotine is naturally-occurring and obtained as an
extract from a Nicotiana species (e.g., tobacco). Exemplary types
of tobacco and manners of processing the tobacco are set forth in
U.S. patent application Ser. No. 13/240,500 to Holton, Jr. et al.,
filed Sep. 22, 2011, and which is incorporated herein by reference.
See also the nicotine-containing compositions set forth in U.S.
Pat. Pub. Nos. 2011/0268809 to Brinkley et al. and 2011/0274628 to
Borschke, as well as U.S. patent application Ser. No. 13/278,877 to
Borschke et al, filed Oct. 21, 2011, all of which are incorporated
by reference herein.
[0031] The nicotine can have the enantiomeric form S(-)-nicotine,
R(+)-nicotine, or a mixture of S(-)-nicotine and R(+)-nicotine.
Most preferably, the nicotine is in the form of S(-)-nicotine
(e.g., in a form that is virtually all S(-)-nicotine) or a racemic
mixture composed primarily or predominantly of S(-)-nicotine (e.g.,
a mixture composed of about 95 weight parts S(-)-nicotine and about
5 weight parts R(+)-nicotine). Most preferably, the nicotine is
employed in virtually pure form or in an essentially pure form.
Highly preferred nicotine that is employed has a purity of greater
than about 95 percent, more preferably greater than about 98
percent, and most preferably greater than about 99 percent, on a
weight basis. Despite the fact that nicotine can be extracted from
Nicotiana species, it is highly preferred that the nicotine (and
the composition and products produced in accordance with the
present invention) is virtually or essentially absent of other
components of tobacco.
[0032] In embodiments wherein nicotine is derived from a plant of
the Nicotiana species, the plant or portions thereof can be
subjected to various types of processing conditions to provide the
nicotine. For example, components can be separated from one
another, or otherwise fractionated into chemical classes or
mixtures of individual compounds. Typical separation processes can
include one or more process steps (e.g., solvent extraction using
polar solvents, organic solvents, or supercritical fluids),
chromatography, distillation, filtration, recrystallization, and/or
solvent-solvent partitioning. Exemplary extraction and separation
solvents or carriers include water, alcohols (e.g., methanol or
ethanol), hydrocarbons (e.g., heptane and hexane), diethyl ether
methylene chloride and supercritical carbon dioxide. Exemplary
techniques useful for extracting components from Nicotiana species
are described in U.S. Pat. No. 4,144,895 to Fiore; U.S. Pat. No.
4,150,677 to Osborne, Jr. et al.; U.S. Pat. No. 4,267,847 to Reid;
U.S. Pat. No. 4,289,147 to Wildman et al.; U.S. Pat. No. 4,351,346
to Brummer et al.; U.S. Pat. No. 4,359,059 to Brummer et al.; U.S.
Pat. No. 4,506,682 to Muller; U.S. Pat. No. 4,589,428 to Keritsis;
U.S. Pat. No. 4,605,016 to Soga et al.; U.S. Pat. No. 4,716,911 to
Poulose et al.; U.S. Pat. No. 4,727,889 to Niven, Jr. et al.; U.S.
Pat. No. 4,887,618 to Bernasek et al.; U.S. Pat. No. 4,941,484 to
Clapp et al.; U.S. Pat. No. 4,967,771 to Fagg et al.; U.S. Pat. No.
4,986,286 to Roberts et al.; U.S. Pat. No. 5,005,593 to Fagg et
al.; U.S. Pat. No. 5,018,540 to Grubbs et al.; U.S. Pat. No.
5,060,669 to White et al.; U.S. Pat. No. 5,065,775 to Fagg; U.S.
Pat. No. 5,074,319 to White et al.; U.S. Pat. No. 5,099,862 to
White et al.; U.S. Pat. No. 5,121,757 to White et al.; U.S. Pat.
No. 5,131,414 to Fagg; U.S. Pat. No. 5,131,415 to Munoz et al.;
U.S. Pat. No. 5,148,819 to Fagg; U.S. Pat. No. 5,197,494 to Kramer;
U.S. Pat. No. 5,230,354 to Smith et al.; U.S. Pat. No. 5,234,008 to
Fagg; U.S. Pat. No. 5,243,999 to Smith; U.S. Pat. No. 5,301,694 to
Raymond et al.; U.S. Pat. No. 5,318,050 to Gonzalez-Parra et al.;
U.S. Pat. No. 5,343,879 to Teague; U.S. Pat. No. 5,360,022 to
Newton; U.S. Pat. No. 5,435,325 to Clapp et al.; U.S. Pat. No.
5,445,169 to Brinkley et al.; U.S. Pat. No. 6,131,584 to
Lauterbach; U.S. Pat. No. 6,298,859 to Kierulff et al.; U.S. Pat.
No. 6,772,767 to Mua et al.; and U.S. Pat. No. 7,337,782 to
Thompson, all of which are incorporated herein by reference. See
also, the types of separation techniques set forth in Brandt et
al., LC-GC Europe, p. 2-5 (March, 2002) and Wellings, A Practical
Handbook of Preparative HPLC (2006), which are incorporated herein
by reference. In addition, the plant or portions thereof can be
subjected to the types of treatments set forth in Ishikawa et al.,
Chem. Pharm. Bull., 50, 501-507 (2002); Tienpont et al., Anal.
Bioanal. Chem., 373, 46-55 (2002); Ochiai, Gerstel Solutions
Worldwide, 6, 17-19 (2006); Coleman, III, et al., J. Sci. Food and
Agric., 84, 1223-1228 (2004); Coleman, III et al., J. Sci. Food and
Agric., 85, 2645-2654 (2005); Pawliszyn, ed., Applications of Solid
Phase Microextraction, RSC Chromatography Monographs, (Royal
Society of Chemistry, UK) (1999); Sahraoui et al., J. Chrom., 1210,
229-233 (2008); and 5,301,694 to Raymond et al., which are all
incorporated herein by reference.
[0033] In certain embodiments, isolation of nicotine from a plant
of the Nicotiana species comprises a step of removing high
molecular weight components from a tobacco extract. In certain
embodiments, high molecular weight components that are beneficially
removed according to the present invention include, but are not
limited to, high molecular weight Maillard browning polymers,
proteins, polysaccharides, certain pigments, and bacteria. Various
methods can be used for this purpose, including size exclusion
chromatography, microfiltration, ultrafiltration, nanofiltration,
reverse osmosis, and combinations thereof.
[0034] In one embodiment, ultrafiltration is used to remove high
molecular weight components from tobacco material. The
ultrafiltration method is typically applied to a tobacco material
in the form of a tobacco extract (e.g., an aqueous tobacco
extract). In ultrafiltration, the material to be filtered is
brought into contact with a semipermeable membrane as described in
more detail in 13/240,500 to Holton, Jr. et al., filed Sep. 22,
2011, which is incorporated herein by reference. In such
embodiments, the ultrafiltration step is designed to achieve a
tobacco extract having a decreased level of suspended solids, and
thus an increased level of clarity.
[0035] Commercial ultrafiltration systems are readily available and
may be used in some embodiments for ultrafiltration of tobacco
extracts. For example, commercial suppliers such as Millipore,
Spectrum.RTM. Labs, Pall Corporation, Whatman.RTM., Porex
Corporation, and Snyder Filtration manufacture various filter
membranes and cartridges, and/or filtration systems (e.g.,
tangential flow filtration systems). Exemplary membranes include,
but are not limited to, Biomax.RTM. and Ultracel.RTM. membranes and
Pellicon.RTM. XL cassettes (from Millipore), Microkros.RTM.,
Minikros.RTM., and KrosFlo.RTM. Hollow Fiber Modules (from
Spectrum.RTM. Labs), and Microza filters and Centramate,.TM.
Centrasette,.TM. Maximate.TM., and Maxisette.TM. Tangential Flow
Filtration Membrane Cassettes. Commercially available filtration
systems include, but are not limited to, Millipore's Labscale.TM.
Tangential Flow Filtration (TFF) system and Spectrum.RTM. Labs'
KrosFlo.RTM. and MiniKros.RTM. Tangential Flow Filtration
Systems.
[0036] Filters and/or membranes that may be useful according to the
present invention include those with molecular weight cutoffs of
less than about 100,000 Da, less than about 75,000 Da, less than
about 50,000, less than about 25,000 Da, less than about 20,000 Da,
less than about 15,000 Da, less than about 10,000 Da, and less than
about 5,000 Da. In certain embodiments, a multistage filtration
process is used to provide an extract with improved clarity. Such
embodiments employ multiple filters and/or membranes of different
(typically decreasing) molecular weight cutoffs. Any number of
filters and/or membranes can be used in succession according to the
invention. For example, a first filtration may be conducted using a
50,000 Da molecular weight cutoff filter and a second filtration
may be conducted using a 5,000 Da molecular weight cutoff filter.
Thus, depending on the molecular weight cutoff of the filters, the
ultrafiltered extract may comprise only compounds with molecular
weights below about 50,000, below about 25,000, below about 10,000
Da, below about 7,500 Da, below about 5,000 Da, below about 2,500
Da, or below about 1,000 Da. The ultrafiltered extract typically
comprises primarily sugars, nicotine, and amino acids.
Ultrafiltration can be used in combination with other separation
and purification methods to provide nicotine having an acceptable
purity level.
[0037] The ultrafiltered extract may exhibit a level of improvement
in clarity over the non-ultrafiltered extract. Clarity of the
extract, and compositions according to the invention made
therefrom, is typically defined in terms of translucency. As used
herein, "translucent" or "translucency" refers to materials
allowing some level of light to travel therethrough diffusely. In
various embodiments, certain materials of the invention (e.g.,
certain tobacco extracts or nicotine obtained therefrom can have
such a high degree of clarity that the material or a portion
thereof can be classified as "transparent" or exhibiting
"transparency," which is defined as a material allowing light to
pass freely through without significant diffusion. The clarity of
the ultrafiltered extract is such that there is some level of
translucency as opposed to opacity (which refers to materials that
are impenetrable by light). In certain embodiments, the
ultrafiltered extract is visually analyzed or is analyzed by
contacting the extract with light and measuring the percent of
light that has not been absorbed and/or dispersed by the extract.
The measurement can be done, for example, using a standard
spectrophotometer at a given wavelength. The spectrophotometer is
typically calibrated with deionized water, which is assigned a
transparency value of 100%. Ultrafiltered extract may, in some
embodiments, exhibit a translucency of greater than about 5%,
greater than about 10%, greater than about 15%, greater than about
20%, greater than about 25%, greater than about 30%, greater than
about 40%, greater than about 50%, greater than about 60%, greater
than about 60%, greater than about 70%, greater than about 80%, or
greater than about 90%. Typically, the ultrafiltered extract will
not be colorless, and will have some discernible brown/black
coloring. Following ultrafiltration, the extract can be stored in
the refrigerator or freezer or the extract can be freeze dried or
spray dried prior to use in the compositions of the invention. In
certain embodiments, it is provided in syrup form. The
ultrafiltered extract in some embodiments can be further treated to
provide a nicotinic compound in a sufficient level of purity.
[0038] Nicotinic compounds of the invention can include nicotine in
free base form, salt form, as a complex, or as a solvate. See, for
example, the discussion of nicotine in free base form in US Pat.
Pub. No. 2004/0191322 to Hansson, which is incorporated herein by
reference. At least a portion of the nicotinic compound can be
employed in the form of a resin complex of nicotine where nicotine
is bound in an ion exchange resin such as nicotine polacrilex. See,
for example, U.S. Pat. No. 3,901,248 to Lichtneckert et al.; which
is incorporated herein by reference. At least a portion of the
nicotine can be employed in the form of a salt. Salts of nicotine
can be provided using the types of ingredients and techniques set
forth in U.S. Pat. No. 2,033,909 to Cox et al. and Perfetti,
Beitrage Tabakforschung Int., 12, 43-54 (1983). Additionally, salts
of nicotine have been available from sources such as Pfaltz and
Bauer, Inc. and K&K Laboratories, Division of ICN Biochemicals,
Inc. Exemplary pharmaceutically acceptable nicotine salts include
nicotine salts of tartrate (e.g., nicotine tartrate and nicotine
bitartrate) chloride (e.g., nicotine hydrochloride and nicotine
dihydrochloride), sulfate, perchlorate, ascorbate, fumarate,
citrate, malate, lactate, aspartate, salicylate, tosylate,
succinate, pyruvate, and the like; nicotine salt hydrates (e.g.,
nicotine zinc chloride monohydrate), and the like. In certain
embodiments, at least a portion of the nicotinic compound is in the
form of a salt with an organic acid moiety, including, but not
limited to, levulinic acid as discussed in US Pat. Pub. No.
2011/0268809 to Brinkley et al., which is incorporated herein by
reference.
[0039] In one embodiment, the nicotinic compound is sorbed onto a
porous particulate carrier material, such as microcrystalline
cellulose (MCC) prior to incorporation within the compositions of
the invention. In one embodiment, the MCC materials used in the
invention have an average particle size range of about 15 to about
250 microns. Exemplary MCC materials include various grades of
AVICEL.RTM. and VIVACEL.RTM. materials. See, for example, US Pat.
Pub. No. 2004/0191322 to Hansson, which is incorporated by
reference herein. In certain embodiments, multiple forms of
nicotinic compounds could be sorbed onto the particulate carrier,
including any of the various nicotinic compound combinations
discussed herein. In some embodiments, the nicotinic compound and,
optionally, an organic acid moiety can be sorbed onto the
particulate carrier by, for example, dissolving the nicotinic
compound (and, optionally, an organic acid moiety) in a hydrophilic
solvent (such as water, alcohol, or mixtures thereof) and combining
the solution with the particulate carrier, followed by drying to
remove the solvent. The particulate carrier material with the
sorbed nicotine and, optionally, organic acid moiety, can be
combined with other carriers or excipients in order to provide a
composition adapted for oral delivery of the active ingredient.
[0040] The compositions of the invention possess a form that is
pharmaceutically effective and pharmaceutically acceptable. That
is, the composition most preferably does not incorporate to any
appreciable degree, or does not purposefully incorporate,
components of tobacco, other than nicotine. As such,
pharmaceutically effective and pharmaceutically acceptable
compositions do not include tobacco, processed tobacco components,
or many of the components of tobacco traditionally present within
tobacco-containing cigarettes, cigars, pipes, or smokeless forms of
tobacco products. Highly preferred compositions include less than
0.5 weight percent of tobacco components other than nicotine, more
often less than about 0.25 weight percent, and typically are
entirely absent or devoid of components of tobacco, processed
tobacco components, or components derived from tobacco, other than
nicotine.
[0041] According to the invention, nicotinic compounds in one or
more of the various forms as described herein are used in the
production of pharmaceutical compositions. Specifically, a
nicotinic compound can be combined with one or more additional
components to give a formulation that is used in combination with
other nicotinic compound-containing or non-nicotinic
compound-containing formulations to provide the multi-layered
pharmaceutical compositions of the present invention. The types of
formulations included within a pharmaceutical composition according
to the invention can vary, and can include, but are not limited to,
lozenge-type formulations, meltable-type formulations,
chewable-type formulations, hard coating-type formulations, and
starch-molded and injection molded formulations. Each formulation
can contain one or more nicotinic compounds or can be free of
nicotinic compounds. However, at least one component of the
multi-layered pharmaceutical composition typically comprises a
nicotinic compound.
[0042] The components of each formulation in the multi-layered
pharmaceutical composition can vary and are independently selected
such that the two or more formulations generally comprise different
combinations of other components. The individual components
(including, optionally, one or more nicotinic compounds) can be
processed, blended, formulated, combined and/or mixed to produce
the desired formulation.
[0043] The other components of the formulations can be artificial
or can be obtained or derived from herbal or biological sources.
Exemplary types of components that can be incorporated within one
or more formulations according to the invention include salts
(e.g., sodium chloride, potassium chloride, sodium citrate,
potassium citrate, sodium acetate, potassium acetate, and the
like), natural sweeteners (e.g., fructose, sucrose, glucose,
maltose, vanillin, ethylvanillin glucoside, mannose, galactose,
lactose, and the like), artificial sweeteners (e.g., sucralose,
saccharin, aspartame, acesulfame K, neotame and the like), organic
and inorganic fillers (e.g., grains, processed grains, puffed
grains, maltodextrin, dextrose, calcium carbonate, calcium
phosphate, calcium polycarbofil, corn starch, lactose, sugar
alcohols such as isomalt, mannitol, xylitol, or sorbitol, finely
divided cellulose, hydroxypropylcellulose, vegetable protein,
silicon dioxide, and the like), film formers and binders (e.g.,
povidone, sodium carboxymethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, and other modified cellulosic types
of binders, sodium alginate, acacia, xanthan gum, starch-based
binders (e.g., potato starch, maize starch, etc.), gum arabic,
gellan gum, lecithin, and the like), gelling agents (e.g., fish
gelatin), pH adjusters or buffering agents (e.g., metal hydroxides,
preferably alkali metal hydroxides such as sodium hydroxide and
potassium hydroxide, and other alkali metal buffers such as metal
carbonates, preferably potassium carbonate or sodium carbonate, or
metal bicarbonates such as sodium bicarbonate, and the like),
emulsifiers, colorants (e.g., dyes and pigments, including caramel
coloring, titanium dioxide, D&C Yellow No. 10, and the like),
humectants (e.g., glycerin, propylene glycol, and the like), oral
care additives (e.g., thyme oil, eucalyptus oil, and zinc),
preservatives and antioxidants (e.g., potassium sorbate, sodium
benzoate, ascorbyl palmitate, and the like), syrups (e.g., honey,
high fructose corn syrup, and the like), thickeners, disintegration
or compressibility aids (e.g., microcrystalline cellulose,
croscarmellose sodium, crospovidone, sodium starch glycolate,
pregelatinized corn starch, and the like), lubricants or processing
aids (e.g., magnesium stearate or calcium stearate), antiadherents
(e.g., talc), glidants (e.g., colloidal silica), surfactants (e.g.,
polysorbate 80), flavorant and flavoring mixtures, and mixtures
thereof. Exemplary types of components may include those described
in, for example, U.S. Pat. Pub. No. 2010/0291245 to Gao et al.,
which is incorporated herein by reference.
[0044] The pharmaceutical compositions of the invention may be
conveniently made available in a unit dosage form, whereby such
formulations may be prepared by any of the methods generally known
in the pharmaceutical arts. Generally speaking, such methods of
preparation comprise combining (by various methods) an active agent
with a suitable carrier or other adjuvant, which may consist of one
or more ingredients. The combination of the active ingredient with
the one or more adjuvants is then physically treated to present the
formulation in a suitable form for delivery (e.g., shaping into a
tablet or forming an aqueous suspension).
[0045] The nicotine-containing pharmaceutical compositions of the
invention can incorporate various pharmaceutically acceptable
excipients. By "pharmaceutically acceptable carrier" or
"pharmaceutically acceptable excipient" is intended a carrier or
excipient that is conventionally used in the art to facilitate the
storage, administration, and/or the healing effect of an active
agent (e.g., a nicotinic compound). The carrier(s) must be
pharmaceutically acceptable in the sense of being compatible with
the other ingredients of the formulation and not unduly deleterious
to the recipient thereof. A carrier may also reduce any undesirable
side effects of the agent. See, Wang et al. (1980) J. Parent. Drug
Assn. 34(6):452-462, herein incorporated by reference in its
entirety. Other exemplary pharmaceutical excipients and/or
additives suitable for use in the compositions according to the
invention are listed in Remington: The Science & Practice of
Pharmacy, 21.sup.st ed., Lippincott Williams & Wilkins (2006);
in the Physician's Desk Reference, 64.sup.th ed., Thomson PDR
(2010); and in Handbook of Pharmaceutical Excipients, 6.sup.th ed.,
Eds. Raymond C. Rowe et al., Pharmaceutical Press (2009), which are
incorporated herein by reference.
[0046] The various excipients can vary, and the selection and
amount of each excipient can depend upon factors such as the
ultimate form and function of product that is desired. See, for
example, the types of ingredients, relative amounts and
combinations of ingredients, nicotine-containing formulations and
preparation processes for nicotine-containing products set forth in
U.S. Pat. No. 5,512,306 to Carlsson et al.; U.S. Pat. No. 5,525,351
to Dam; U.S. Pat. No. 5,549,906 to Santus; U.S. Pat. No. 5,711,961
to Reiner et al.; U.S. Pat. No. 5,811,126 to Krishnamurthy; U.S.
Pat. No. 5,939,100 to Albrechtsen et al.; U.S. Pat. No. 6,024,981
to Khankari et al.; U.S. Pat. No. 6,083,531 to Humbert-Droz et al.;
U.S. Pat. No. 6,090,401 to Gowan, Jr. et al.; U.S. Pat. No.
6,110,495 to Dam; U.S. Pat. No. 6,248,760 to Wilhelmsen; U.S. Pat.
No. 6,280,761 to Santus; U.S. Pat. No. 6,426,090 to Ream et al.;
U.S. Pat. No. 6,569,463 to Patel et al.; U.S. Pat. No. 6,583,160 to
Smith et al.; U.S. Pat. No. 6,585,997 to Moro et al.; U.S. Pat. No.
6,676,959 to Andersson et al.; U.S. Pat. No. 6,893,654 to Pinney et
al.; U.S. Pat. No. 7,025,983 to Leung et al.; and U.S. Pat. No.
7,163,705 Johnson et al.; US Pat. Pub. Nos. 2003/0176467 to
Andersson et al.; 2003/0235617 to Martino et al.; 2004/0096501 to
Vaya et al.; 2004/0101543 to Liu et al.; 2004/0191322 to Hansson;
2005/0053665 to Ek et al.; 2005/0123502 to Chan et al.;
2008/0038209 to Andersen et al.; 2008/0286341 to Andersson et al.;
2009/0023819 to Axelsson; 2009/0092573 to Andersen; 2010/0004294 to
Axelsson et al.; and 2010/0061940 to Axelsson et al.; which are
incorporated herein by reference.
[0047] The foregoing components can be provided in a powder or
granulated form for mixing with the one or more nicotinic
compounds, or otherwise may be provided in liquid form. Most
preferably, the components when provided in a powder or granulated
form are employed in the form of parts or pieces that have an
average particle size less than about 50 microns. According to some
aspects, the average particle size of the components may be about
25 microns or less. The moisture content of the components provided
in a powder or granulated form may vary. Most preferably, the
moisture content of the components provided in a powder or
granulated form is less than about 10 weight percent, and may be
less than about 5 percent, and is often less than about 2.5 weight
percent. The components may be admixed with the nicotine in, for
example, a Hobart mixer with a paddle prior to adding any liquid
components. In the event liquid components are provided, the
resultant mixture may still have a relatively low moisture content
of less than about 10 weight percent, and may be less than about 5
percent, and is often less than about 2.5 weight percent. The
relative amounts of the various additive components within the
pharmaceutical composition may vary.
[0048] The aforementioned types of components can be employed
together (e.g., as component formulations) or separately (e.g.,
individual components can be added at different stages involved in
the preparation of the nicotinic compound-containing formulation
and the final pharmaceutical product). The relative amounts of the
various components within the nicotinic compound-containing
formulation may vary, and typically are selected so as to provide
the desired sensory and performance characteristics to the
pharmaceutical composition. Furthermore, the aforementioned types
of components may be encapsulated as provided in the final product
or composition. Exemplary encapsulated components are described,
for example, in WO 2010/132444 A2 to Atchley, which has been
incorporated by reference herein.
[0049] As used herein, a "flavorant" or "flavoring agent" is any
flavorful or aromatic substance capable of altering the sensory
characteristics associated with the pharmaceutical composition.
Exemplary sensory characteristics that can be modified by the
flavorant include, taste, mouthfeel, moistness, coolness/heat,
and/or fragrance/aroma. The flavorants can be natural or synthetic,
and the character of these flavors can be described as, without
limitation, fresh, sweet, herbal, confectionary, floral, fruity or
spice. Specific types of flavors include, but are not limited to,
vanilla, coffee, chocolate, cream, mint, spearmint, menthol,
peppermint, wintergreen, lavender, cardamon, nutmeg, cinnamon,
clove, cascarilla, sandalwood, honey, jasmine, ginger, anise, sage,
licorice, lemon, orange, apple, peach, lime, cherry, and
strawberry. Flavorants utilized in the invention also can include
components that are considered moistening, cooling or smoothening
agents, such as eucalyptus. These flavors may be provided neat
(i.e., alone) or in a composite (e.g., spearmint and menthol or
orange and cinnamon). In some instances, the flavorant may be
provided in a spray-dried form. Flavorants are typically present in
an amount of about 0.5 to about 10 dry weight percent, often about
1 to about 6 dry weight percent, and most often about 2 to about 5
dry weight percent.
[0050] Sweeteners can be used in natural or artificial form or as a
combination of artificial and natural sweeteners. In one
embodiment, sucralose, sucrose, or a combination thereof is the
primary sweetener ingredient. When present, a representative amount
of sweetener, whether an artificial sweetener and/or natural sugar,
may make up at least about 0.2 percent , at least about 1 percent,
or at least about 5 percent, of the total dry weight of the
composition. Preferably, the amount of sweetener within the
composition will not exceed about 40 percent, often will not exceed
about 35 percent, and frequently will not exceed about 30 percent,
of the total dry weight of the composition.
[0051] Sucrose can be a particularly advantageous sweetener in
certain embodiments (e.g., as a component of a starch-molded type
formulation) as it is believed to contribute to the chewing
resistance or "bounce" of the final product. In addition, while
granulated sucrose provides far less sweetening effect as compared
to sucralose, the presence of sucrose can be advantageous as an
additional filler component. When these two sweeteners are present
together, the sucralose is typically present in an amount of at
least about 0.25 dry weight percent, often at least about 0.5 dry
weight percent, and most often at least about 1.0 dry weight
percent (e.g., about 0.25 to about 2.0 dry weight percent), and the
sucrose is typically present in an amount of at least about 2.0 dry
weight percent, often at least about 3.0 dry weight percent, and
most often at least about 4.0 dry weight percent (e.g., about 1.0
to about 6.0 dry weight percent).
[0052] In certain embodiments, some formulations (or the entire
pharmaceutical composition) are sugar-free, comprising one or more
sugar substitutes. "Sugar-free" as used herein is intended to
include products having less than about 1/15th sugar by weight, or
less than about 1/10th sugar by weight. A sugar substitute, where
used, may be provided in pure, solid form (e.g., granular or
powdered form). In certain embodiments, the sugar substitute is
dry, comprising a very low water content. For example, the sugar
substitute can comprise less than about 5% water by weight, less
than about 3% water by weight, less than about 2% water by weight,
or less than about 1% water by weight.
[0053] In some embodiments, a syrup (e.g., corn syrup) preferably
may be employed in an amount sufficient to provide desired flavor
attributes to the pharmaceutical composition.
[0054] In some embodiments (e.g., in starch molded type
formulations), syrup may be employed in amounts sufficient to
provide chewiness and retard solubilization. A representative
amount of syrup (e.g., high fructose corn syrup) may make up less
than about 10 percent or less than about 5 percent of the total dry
weight of the composition.
[0055] In certain embodiments, a sugar syrup or sugar alcohol syrup
is added to a lozenge-type formulation to affect the
re-crystallization of another component of the formulation during
preparation (e.g., a melted sugar substitute). Exemplary sugar
alcohol syrups for such purposes include maltitol syrup, xylitol,
mannitol, glycerol, erythritol, threitol, arabitol, ribitol,
mannitol, sorbitol, dulcitol, iditol, isomalt, lactitol, and
polyglycitol syrups. Other syrups, such as corn syrup, golden
syrup, or molasses can be used. The amount of sugar alcohol syrup
can vary, but typically ranges from about 0.1% to about 2%, often
from about 0.5% to about 1.5%, and more often about 1% by weight of
the pharmaceutical composition mixture. In certain embodiments, the
amount of sugar alcohol syrup is higher, for example, up to about
2% by weight of the mixture, up to about 5% by weight of the
mixture, up to about 10% by weight of the mixture, or up to about
20% by weight of the mixture
[0056] The pharmaceutical composition of the present disclosure may
typically include at least one filler ingredient. When a
polysaccharide filler component is present, the optional filler
ingredient may be provided in addition to the polysaccharide filler
component. Such filler components of the composition often fulfill
multiple functions, such as enhancing certain organoleptic
properties such as texture and mouthfeel, enhancing cohesiveness or
compressibility of the product, and the like. In certain
embodiments (e.g., in starch molded-type formulations), sugar
alcohols are particularly advantageous as filler components as they
contribute some sweetness and do not disrupt the desired chewable
characteristics of the final product. Sugar alcohols (e.g.,
isomalt) are polyols derived from monosaccharides or disaccharides
that have a partially or fully hydrogenated form. Exemplary sugar
alcohols have between about 4 and about 20 carbon atoms and include
erythritol, arabitol, ribitol, isomalt, maltitol, dulcitol, iditol,
mannitol, xylitol, lactitol, sorbitol, and combinations thereof
(e.g., hydrogenated starch hydrolysates). A sugar alcohol can be
added in the form of an aqueous solution or suspension, such as a
solution or suspension with a solids content of about 50 to about
90 weight percent. Combinations of a sugar alcohol with a further
filler component can also be used. When present, a representative
amount of filler, whether an organic and/or inorganic filler, may
make up at least about 10 percent, at least about 20 percent, or at
least about 25 percent, based on the total dry weight of the
composition. Preferably, the amount of additional filler within the
composition will not exceed about 50 percent, and frequently will
not exceed about 40 percent, of the total dry weight of the
composition. In one embodiment, a sugar alcohol such as sorbitol is
provided as an additional filler.
[0057] A salt (e.g., sodium chloride, flour salt) may be employed
in amounts sufficient to provide desired sensory attributes to the
pharmaceutical composition. When present, a representative amount
of salt is at least about 0.5 dry weight percent or at least about
1.0 dry weight percent or at least about 1.5 dry weight percent,
but will typically make up less than about 5 percent of the total
dry weight of the composition (e.g., about 0.5 to about 4 dry
weight percent). In some embodiments, the salt, when present, will
make up less than about 2 percent or less than about 1 percent of
the total dry weight of the composition.
[0058] A humectant (e.g., glycerin) may be employed in amounts
sufficient to provide desired moisture attributes to the
pharmaceutical composition. Further, in some instances, the
humectant may impart desirable flow characteristics to the
pharmaceutical composition (e.g., for depositing in a starch
mould). When present, a representative amount of humectant will
typically make up at least about 1 percent of the total dry weight
of the composition, at least about 1.5 dry weight percent, or at
least about 2 dry weight percent. In certain embodiments, the
amount of humectant is at least about 10 dry weight percent or at
least about 20 dry weight percent. An exemplary dry weight range is
about 1 to about 40 weight percent, more often about 3 to about 35
dry weight percent. In some embodiments, the humectant is provided
in am amount of less than about 5 percent of the total dry weight
of the composition (e.g., about 0.5 to about 4 dry weight
percent).
[0059] A binder (or combination of binders) may be employed in
amounts sufficient to provide the desired physical attributes and
physical integrity to the pharmaceutical composition. When present,
a representative amount of binder may make up at least about 5
percent, at least about 10 percent, at least about 15 percent, at
least about 20 percent, or at least about 25 percent of the total
dry weight of the composition. Preferably, the amount of binder
within the composition will not exceed about 35 percent, about 40
percent, or about 45 percent of the total dry weight of the
composition. Often, the amount of binder within a desirable
composition will not exceed about 20 percent, and frequently will
not exceed about 15 percent, of the total dry weight of the
composition. In certain embodiments, the binder material includes a
natural gum. As used herein, a natural gum refers to polysaccharide
materials of natural origin that are useful as thickening or
gelling agents. Representative natural gums derived from plants,
which are typically water soluble to some degree, include xanthan
gum, guar gum, gum arabic, ghatti gum, gum tragacanth, karaya gum,
locust bean gum, gellan gum, and combinations thereof.
[0060] An emulsifier may be employed in amounts sufficient to
provide desired stabilization attributes to the pharmaceutical
composition. When present, a representative amount of emulsifier
will typically make up less than about 5 percent of the total dry
weight of the composition.
[0061] Certain buffering agents buffer within a pH range of about 6
to about 10, and exemplary buffering agents include metal
hydroxides, metal carbonates, metal bicarbonates, or mixtures
thereof. The buffering agent, where present, is typically present
in an amount less than about 1 percent based on the dry weight of
the formulation. Various food-grade buffering agents are known and
can be used to adjust the pH of the products of the present
invention. Suitable buffering agents include those selected from
the group consisting of acetates, glycinates, phosphates,
glycerophosphates, citrates such as citrates of alkaline metals,
carbonates, hydrogen carbonates, and borates, and mixtures thereof.
In certain embodiments, the buffering agent is an amino acid, as
taught for example, in US Pat. Pub. No. 2008/0286341 to Andersson
et al. and PCT Appl. No. WO2008/040371 to Andersson et al., which
are both incorporated herein by reference. As noted therein,
various amino acids and salts thereof are useful for this purpose,
including, but not limited to, arginine, asparigine, glutamic acid,
glutamine, glycine, histidine, isoleucine, leucine, lysine,
methionine, phenylalanine, serine, threonine, valine, cysteic acid,
N-glycylglycine, and ornithine. In certain embodiments,
N-glycylglycine or L-lysine is added as a buffering agent. In some
embodiments, an amino acid buffering agent is used in combination
with another amino acid buffering agent and/or in combination with
one or more non-amino acid buffering agents. In certain
embodiments, the optional pH adjusting agent is a base (e.g.,
NaOH). In certain embodiments, L-lysine and NaOH are added to the
compositions of the present invention.
[0062] It is well-known that nicotine is subject to oxidation and
accordingly, it may be advantageous to incorporate one or more
anti-oxidants, such as, e.g., ascorbyl palmitate and/or sodium
ascorbate, in a composition according to the invention. The one or
more anti-oxidants may be present in a concentration of from about
0.05% to about 0.3% by weight, such as, e.g., from about 0.1% to
about 0.25% or from about 0.15% to about 0.2% in the pharmaceutical
composition mixture.
[0063] Formulations of the present invention may include
short-term, rapid-onset, rapid-offset, controlled release,
sustained release, delayed release, and pulsatile release
formulations, providing the formulations achieve administration of
a nicotinic compound as described herein. See Remington's
Pharmaceutical Sciences (18.sup.th ed.; Mack Publishing Company,
Eaton, Pa., 1990), which is incorporated herein by reference in its
entirety.
[0064] Compositions of the present invention incorporate a
pharmaceutically effective amount of nicotine. The dose of active
ingredient (i.e., all the various nicotine forms) is preferably
that amount effective to treat some symptoms of, or prevent
occurrence of the symptoms of, the condition, disease, or disorder
from which the subject or patient suffers. By "effective amount",
"therapeutic amount" or "effective dose" is meant that amount
sufficient to elicit the desired pharmacological or therapeutic
effects, thus resulting in effective prevention or treatment of the
condition, disease, or disorder. Thus, an effective amount of
active ingredient is an amount sufficient to enter relevant regions
of the body (e.g., to pass across the blood-brain barrier of the
subject), to bind to relevant receptor sites in the CNS and PNS of
the subject, and/or to elicit neuropharmacological effects (e.g.,
elicit neurotransmitter secretion, thus resulting in effective
prevention or treatment of the condition, disease, or disorder).
Prevention of the disorder is manifested, for example, by delaying
the onset of the symptoms of the condition, disease, or disorder.
Treatment of the disorder is manifested by, for example, a decrease
in the symptoms associated with the condition, disease, or disorder
or an amelioration of the reoccurrence of the symptoms thereof.
[0065] The amount of active ingredient within the overall
composition can vary. For a composition intended for oral
consumption by insertion into the mouth of the subject (e.g., a
lozenge or the like), the amount of nicotine within each dosage
piece or unit typically is at least about 0.5 mg, generally is at
least 1 mg, often is at least about 1.5 mg, and frequently is at
least about 2 mg; while the amount of nicotine within each piece
typically does not exceed about 10 mg, generally does not exceed
about 8 mg, often does not exceed about 6 mg, and frequently does
not exceed about 5 mg, calculated as nicotine base. Exemplary types
of such products can incorporate about 2 mg, about 2.5 mg, about 3
mg, about 3.5 mg, about 4 mg, and about 4.5 mg of nicotine per
piece or unit, calculated as nicotine base. The amount of nicotine
incorporated into any given formulation layer within a multi-layer
composition can vary, and typically will be selected so as to
provide an overall nicotine content within each product unit in the
ranges noted above.
[0066] The specific components and amounts thereof in a given
formulation will depend on the desired characteristics of that
formulation. For example, the components can vary depending upon
the desired flavor, texture, and other characteristics. Certain
exemplary formulations are provided in more detail below. It is to
be noted that these are only exemplary formulations and are not
intended to be limiting of the invention.
[0067] For example, a typical lozenge-type formulation may comprise
a nicotinic compound, a sugar substitute, and a sugar alcohol
syrup. The sugar substitute (e.g., isomalt) is a non-hygroscopic
sugar alcohol capable of forming a glassy matrix. In one particular
embodiment of the present invention, a lozenge-type formulation
comprises: a nicotinic compound; a sugar substitute in an amount of
at least about 80% by weight; and a sugar alcohol syrup. In certain
embodiments, the sugar substitute is present in an amount of at
least about 85% by weight or at least about 90% by weight. In a
specific embodiment, a lozenge-type formulation may comprise
isomalt, maltitol syrup, a nicotinic compound, NaCl, and sucralose.
In certain embodiments, the formulation is translucent. For more
details on representative lozenge-type formulations, see U.S.
patent application Ser. No. 13/240,525 to Holton, Jr. et al., filed
on Sep. 22, 2011, which is incorporated herein by reference.
[0068] A typical meltable-type formulation generally comprises a
nicotinic compound and a lipid. The lipid can vary and may be, for
example, a fat, oil, or wax substance (or combination thereof),
forming a portion of the formulation. The lipid components can be
derived from animal or plant material and typically comprise mostly
triglycerides along with lesser amounts of free fatty acids and
mono- or di-glycerides. In certain embodiments, the lipid is a
plant-derived fat material that is solid or semi-solid at room
temperature (i.e., at about 25.degree. C.) and which at least
partially liquefies when subjected to the temperature of the oral
cavity of the user. The melting point of the lipid can vary and in
certain embodiments may be within the range of about 36.degree. C.
to about 45.degree. C. (e.g., about 38.degree. C. to about
41.degree. C.).
[0069] Plant-derived fats are comprised primarily of saturated or
unsaturated fatty acid chains (most of which are bound within
triglyceride structures) having a carbon length of about 10 to
about 26 carbon atoms, more typically about 14 to about 20 carbon
atoms, and most often about 14 to about 18 carbon atoms. Exemplary
plant-derived fats that can be used include palm oil, palm kernel
oil, soybean oil, cottonseed oil, and mixtures thereof. According
to some aspects, the lipid substance may be hydrogenated, partially
hydrogenated, or non-hydrogenated. In some instances, the lipid
substance may include a blend of lipid components. For example, the
lipid substance may include a blend of palm oil and palm kernel
oil.
[0070] In certain specific embodiments, a meltable-type formulation
is provided, which comprises a nicotinic compound, about 10 to
about 50 percent lipid component, about 0 to about 1 percent
artificial sweetener, about 20 to about 40 percent filler, a
flavorant in an amount of up to about 10 percent, and salt in an
amount up to about 5 percent, based on the total dry weight of the
formulation. Specific lipids and greater detail regarding
meltable-type formulations comprising lipids can be found in U.S.
patent application Ser. No. 13/330,929, filed Dec. 20, 2011 to
Cantrell et al., which is incorporated herein by reference.
[0071] A typical chewable-type formulation typically comprises a
nicotinic compound, a natural gum (e.g., gum arabic), a lipid
component, and an emulsifier. In one specific embodiment, the
chewable-type formulation comprises gum arabic, an emulsifier, a
lipid component, glycerin, a nicotinic compound, sucralose, sodium
chloride, sodium hydroxide, and a flavorant.
[0072] A typical hard coating-type formulation typically comprises
a nicotinic compound, a binder, and a sugar alcohol syrup. In one
specific embodiment, the hard coating-type formulation comprises a
nicotinic compound, a binder, a sugar alcohol, isomalt, sodium
hydroxide, sucralose, and a flavorant. Although hard coating-type
formulations according to the invention typically comprise such
components, it is noted that other types of coatings can be applied
in certain embodiments and may, in some embodiments, be applied in
addition to the hard coating-type formulation. For example, the
entire multi-layered pharmaceutical composition of the invention
and/or any of the component formulations described herein may, in
certain embodiments, include an outer coating, which may comprise
ingredients such as carnauba wax and/or pharmaceutically acceptable
forms of shellacs, glazing compositions and surface polish agents.
Application of a coating can be accomplished using techniques such
as airless spraying, fluidized bed coating, use of a coating pan,
or the like. Other materials for use as a coating can be polymeric
in nature, such as cellulosic material (e.g., cellulose butyrate
phthalate, hydroxypropyl methylcellulose phthalate, and
carboxymethyl ethylcellulose), and polymers and copolymers of
acrylic acid, methacrylic acid, and esters thereof. For example,
such a coating can comprise a film-forming polymer, such as a
cellulosic polymer, and an optional plasticizer. Other optional
coating ingredients include flavorants, sweeteners, colorants, and
salts.
[0073] A typical injection molded-type formulation (i.e., pastille)
can comprise, for example, a nicotinic compound, and about 10
weight percent to about 25 weight percent of polysaccharide filler
component on a dry weight basis. The polysaccharide filler can
vary, but in certain embodiments, comprises polydextrose. Certain
embodiments comprise one or more of a sugar alcohol filler (e.g.,
sorbitol), a binder comprising a water soluble gum (e.g., gum
arabic), and/or components including flavorants, binders,
emulsifiers, disintegration aids, humectants, and mixtures thereof.
In one specific embodiment, the formulation comprises a nicotinic
compound; at least about 10 dry weight percent of polysaccharide
filler component; at least about 10 dry weight percent of at least
one binder; at least about 20 dry weight percent of at least one
humectant; and at least about 1 dry weight percent of at least one
emulsifier. For more details on representative injection
molded-type formulations, see U.S. patent application Ser. No.
12/957,838 to Cantrell et al., filed on Dec. 1, 2010, which is
incorporated herein by reference.
[0074] A typical starch molded-type formulation (i.e., pastille)
may comprise, for example, a nicotinic compound, at least one
binder or gelling agent in the form of a natural gum, and at least
one sugar alcohol as a filler component. In another embodiment, the
starch molded-type formulation comprises a nicotinic compound, at
least one binder or gelling agent in the form of a natural gum,
sucrose, and corn syrup. For example, in one embodiment, a starch
molded-type formulation comprises at least about 10 percent sugar
alcohol filler, at least about 10 percent binder, about 0.1 to
about 2 percent artificial sweetener, about 1 to about 5 percent
humectant, about 1 to about 5 percent natural sweetener, up to
about 5 percent flavorants, and up to about 3 percent salt, based
on the total dry weight of the pharmaceutical composition.
[0075] One specific starch molded-type formulation comprises: at
least about 10 dry weight percent of a sugar alcohol (e.g.,
sorbitol, isomalt, maltitol, and/or combinations thereof); at least
about 10 or 15 dry weight percent of a natural gum binder component
(e.g., gum arabic); at least about 0.5 dry weight percent of a
humectant (e.g., glycerin); at least about 0.2 dry weight percent
of a sweetener (e.g., sucralose); and at least about 0.5 dry weight
percent of a flavorant. Another exemplary composition comprises: at
least about 20 dry weight percent of a sugar alcohol; at least
about 25 dry weight percent of a natural gum binder component; at
least about 2 dry weight percent of a humectant; at least about 1
dry weight percent of a sweetener; and at least about 4 dry weight
percent of a flavorant. In a still further embodiment, the
composition comprises: at least about 30 dry weight percent of a
sugar alcohol; at least about 40 dry weight percent of a natural
gum binder component; at least about 2 dry weight percent of a
humectant; and at least about 2 dry weight percent of a salt (e.g.,
NaCl). Yet another embodiment comprises: at least about 30 dry
weight percent of sucrose; at least about 40 dry weight percent of
a natural gum binder component; at least about 2 dry weight percent
of a syrup (e.g., corn syrup); at least about 2 dry weight percent
of a humectant; and at least about 2 dry weight percent of a salt.
For more details on representative starch molded-type formulations,
see U.S. application Ser. No. 12/957,821 to Cantrell et al., filed
Dec. 1, 2010, which is incorporated herein by reference.
[0076] The formulations that make up the pharmaceutical composition
of the present invention can have various organoleptic properties.
For example, a starch molded-type formulation can, in certain
embodiments, be characterized as dissolvable and lightly chewable
and is generally in the form of a hardened solid gel (e.g., a
"pastille"). In certain embodiments, starch molded-type
formulations are characterized by sufficient cohesiveness to
withstand light chewing action in the oral cavity without rapidly
disintegrating. Such formulations of the disclosure typically do
not exhibit a highly deformable chewing quality as found in
conventional chewing gum. A meltable formulation can be, in certain
embodiments, described as capable of providing a smooth and creamy
sensation when in the mouth of the user (rather than a slick, waxy
or slimy sensation). A lozenge-type formulation generally is hard
in texture and exhibits a dissolvable quality. A chewable
formulation generally exhibits a chewiness that is between that of
a pastille as described herein and a gum. Like a pastille, a
chewable formulation typically exhibits cohesiveness to withstand
light chewing action in the oral cavity, but typically
disintegrates at a slower rate than a pastille, allowing for more
chewing action prior to complete disintegration of the composition.
A hard coating-type formulation generally provides some sense of
crunchiness or crispness.
[0077] The structure and makeup of the formulations within a given
multi-layered pharmaceutical composition can vary. In certain
embodiments, 2-component and 3-component pharmaceutical
compositions are provided as shown in Table 1, where the Core may
refer to the innermost component of a coated formulation and Layer
1 and Layer 2 are layers applied consecutively to the core
formulation. The core may alternatively refer to one component of a
side-by-side-type configuration, where Layer 1 is applied such that
it is adhered to the Core formulation on at least one surface and
Layer 2, where present, is adhered to the Layer 1 formulation on at
least one surface.
[0078] Table 1 describes various combinations of formulations that
may comprise multi-layered pharmaceutical compositions. Depending
on the specific composition of each formulation, Table 1 represents
exemplary products of the present invention having different
combinations of different formulations. Each formulation provided
in Table 1 is preferably a formulation having a specific
composition as described herein.
TABLE-US-00001 TABLE 1 Representative Pharmaceutical Compositions
Core formulation Layer 1 formulation Layer 2 formulation
Meltable-type Lozenge-type None Meltable-type Starch molded-type
None Meltable-type Injection molded-type None Meltable-type
Chewable-type None Meltable-type Hard coating-type None
Lozenge-type Meltable-type None Lozenge-type Starch molded-type
None Lozenge-type Injection molded-type None Lozenge-type
Chewable-type None Lozenge-type Hard coating-type None Starch
molded-type Meltable-type None Starch molded-type Lozenge-type None
Starch molded-type Injection molded-type None Starch molded-type
Chewable-type None Starch-molded type Hard coating-type None
Injection molded-type Meltable-type None Injection molded-type
Lozenge-type None Injection molded-type Starch molded-type None
Injection molded-type Chewable-type None Injection molded-type Hard
coating-type None Chewable-type Lozenge-type None Chewable-type
Meltable-type None Chewable-type Starch molded-type None
Chewable-type Injection molded-type None Chewable-type Hard
coating-type None Hard coating-type Lozenge-type None Hard
coating-type Meltable-type None Hard coating-type Starch
molded-type None Hard coating-type Injection molded-type None Hard
coating-type Chewable-type None Meltable-type Lozenge-type
Meltable-type Meltable-type Lozenge-type Injection molded-type
Meltable-type Lozenge-type Starch molded-type Meltable-type
Lozenge-type Chewable-type Meltable-type Lozenge-type Hard
coating-type Meltable-type Starch molded-type Meltable-type
Meltable-type Starch molded-type Lozenge-type Meltable-type Starch
molded-type Injection molded-type Meltable-type Starch molded-type
Chewable-type Meltable-type Starch molded-type Hard coating-type
Meltable-type Injection molded-type Meltable-type Meltable-type
Injection molded-type Lozenge-type Meltable-type Injection
molded-type Starch molded-type Meltable-type Injection molded-type
Chewable-type Meltable-type Injection molded-type Hard coating-type
Meltable-type Chewable-type Meltable-type Meltable-type
Chewable-type Lozenge-type Meltable-type Chewable-type Starch
molded-type Meltable-type Chewable-type Injection molded-type
Meltable-type Chewable-type Hard coating-type Meltable-type Hard
coating-type Meltable-type Meltable-type Hard coating-type
Lozenge-type Meltable-type Hard coating-type Starch molded-type
Meltable-type Hard coating-type Injection molded-type Meltable-type
Hard coating-type Chewable-type Lozenge-type Meltable-type
Lozenge-type Lozenge-type Meltable-type Starch molded-type
Lozenge-type Meltable-type Injection molded-type Lozenge-type
Meltable-type Chewable-type Lozenge-type Meltable-type Hard
coating-type Lozenge-type Starch molded-type Meltable-type
Lozenge-type Starch molded-type Lozenge-type Lozenge-type Starch
molded-type Injection molded-type Lozenge-type Starch molded-type
Chewable-type Lozenge-type Starch molded-type Hard coating-type
Lozenge-type Injection molded-type Lozenge-type Lozenge-type
Injection molded-type Meltable-type Lozenge-type Injection
molded-type Starch molded-type Lozenge-type Injection molded-type
Chewable-type Lozenge-type Injection molded-type Hard coating-type
Lozenge-type Chewable-type Lozenge-type Lozenge-type Chewable-type
Meltable-type Lozenge-type Chewable-type Injection molded-type
Lozenge-type Chewable-type Starch molded-type Lozenge-type
Chewable-type Hard coating-type Lozenge-type Hard coating-type
Lozenge-type Lozenge-type Hard coating-type Meltable-type
Lozenge-type Hard coating-type Injection molded-type Lozenge-type
Hard coating-type Starch molded-type Lozenge-type Hard coating-type
Chewable-type Starch molded-type Meltable-type Lozenge-type Starch
molded-type Meltable-type Injection molded-type Starch molded-type
Meltable-type Starch molded-type Starch molded-type Meltable-type
Chewable-type Starch molded-type Meltable-type Hard coating-type
Starch molded-type Lozenge-type Meltable-type Starch molded-type
Lozenge-type Starch molded-type Starch molded-type Lozenge-type
Injection molded-type Starch molded-type Lozenge-type Chewable-type
Starch molded-type Lozenge-type Hard coating-type Starch
molded-type Injection molded-type Meltable-type Starch molded-type
Injection molded-type Lozenge-type Starch molded-type Injection
molded-type Starch molded-type Starch molded-type Injection
molded-type Chewable-type Starch molded-type Injection molded-type
Hard coating-type Starch molded-type Chewable-type Lozenge-type
Starch molded-type Chewable-type Meltable-type Starch molded-type
Chewable-type Starch molded-type Starch molded-type Chewable-type
Injection molded-type Starch molded-type Chewable-type Hard
coating-type Starch molded-type Hard coating-type Lozenge-type
Starch molded-type Hard coating-type Meltable-type Starch
molded-type Hard coating-type Starch molded-type Starch molded-type
Hard coating-type Injection molded-type Starch molded-type Hard
coating-type Chewable-type Injection molded-type Meltable-type
Lozenge-type Injection molded-type Meltable-type Injection
molded-type Injection molded-type Meltable-type Starch molded-type
Injection molded-type Meltable-type Chewable-type Injection
molded-type Meltable-type Hard coating-type Injection molded-type
Lozenge-type Meltable-type Injection molded-type Lozenge-type
Injection molded-type Injection molded-type Lozenge-type Starch
molded-type Injection molded-type Lozenge-type Chewable-type
Injection molded-type Lozenge-type Hard coating-type Injection
molded-type Starch molded-type Lozenge-type Injection molded-type
Starch molded-type Meltable-type Injection molded-type Starch
molded-type Injection molded-type Injection molded-type Starch
molded-type Chewable-type Injection molded-type Starch molded-type
Hard coating-type Injection molded-type Chewable-type Lozenge-type
Injection molded-type Chewable-type Meltable-type Injection
molded-type Chewable-type Starch molded-type Injection molded-type
Chewable-type Injection molded-type Injection molded-type
Chewable-type Hard coating-type Injection molded-type Hard
coating-type Lozenge-type Injection molded-type Hard coating-type
Meltable-type Injection molded-type Hard coating-type Starch
molded-type Injection molded-type Hard coating-type Injection
molded-type Injection molded-type Hard coating-type Chewable-type
Chewable-type Lozenge-type Meltable-type Chewable-type Lozenge-type
Starch molded-type Chewable-type Lozenge-type Injection molded-type
Chewable-type Lozenge-type Chewable-type Chewable-type Lozenge-type
Hard coating-type Chewable-type Meltable-type Lozenge-type
Chewable-type Meltable-type Starch molded-type Chewable-type
Meltable-type Injection molded-type Chewable-type Meltable-type
Chewable-type Chewable-type Meltable-type Hard coating-type
Chewable-type Starch molded-type Lozenge-type Chewable-type Starch
molded-type Meltable-type Chewable-type Starch molded-type
Injection molded-type Chewable-type Starch molded-type
Chewable-type Chewable-type Starch molded-type Hard coating-type
Chewable-type Injection molded-type Lozenge-type Chewable-type
Injection molded-type Meltable-type Chewable-type Injection
molded-type Starch molded-type Chewable-type Injection molded-type
Chewable-type Chewable-type Injection molded-type Hard coating-type
Chewable-type Hard coating-type Lozenge-type Chewable-type Hard
coating-type Meltable-type Chewable-type Hard coating-type Starch
molded-type Chewable-type Hard coating-type Injection molded-type
Chewable-type Hard coating-type Chewable-type Hard coating-type
Lozenge-type Meltable-type Hard coating-type Lozenge-type Starch
molded-type Hard coating-type Lozenge-type Injection molded-type
Hard coating-type Lozenge-type Chewable-type Hard coating-type
Lozenge-type Hard coating-type Hard coating-type Meltable-type
Lozenge-type Hard coating-type Meltable-type Starch molded-type
Hard coating-type Meltable-type Injection molded-type Hard
coating-type Meltable-type Chewable-type Hard coating-type
Meltable-type Hard coating-type Hard coating-type Starch
molded-type Lozenge-type Hard coating-type Starch molded-type
Meltable-type Hard coating-type Starch molded-type Injection
molded-type Hard coating-type Starch molded-type Chewable-type Hard
coating-type Starch molded-type Hard coating-type Hard coating-type
Injection molded-type Lozenge-type Hard coating-type Injection
molded-type Meltable-type Hard coating-type Injection molded-type
Starch molded-type Hard coating-type Injection molded-type
Chewable-type Hard coating-type Injection molded-type Hard
coating-type Hard coating-type Chewable-type Lozenge-type Hard
coating-type Chewable-type Meltable-type Hard coating-type
Chewable-type Starch molded-type Hard coating-type Chewable-type
Injection molded-type Hard coating-type Chewable-type Hard
coating-type
[0079] Pharmaceutical compositions according to the present
invention are advantageous in that they are capable of exhibiting
various mixtures of organoleptic properties. In certain
embodiments, because such pharmaceutical compositions are
multi-layered, they can provide the user with a range of
organoleptic sensations during use of the product. For example,
pharmaceutical compositions can be tailored to exhibit a certain
range of organoleptic properties in a desired order of experience
(e.g., an initial hard, dissolvable sensation followed by a chewy
sensation).
[0080] Due to the multi-layered structure of the pharmaceutical
compositions of the present invention, it is possible in certain
embodiments to tailor the flavor and/or nicotine release profile of
the product as a whole. In other words, the manner and/or rate at
which the nicotine released can vary. Certain types of formulations
typically exhibit faster or slower release of nicotine. Such
formulations can advantageously be positioned within the
multi-layered structure of the pharmaceutical composition such that
the product exhibits a desired release profile. For example, in one
specific embodiment, the exterior formulation comprises a
formulation that exhibits relatively fast release of nicotine,
whereas the one or more internal formulations exhibit a more
extended nicotine release profile, providing a product that
provides both a fast initial release of nicotine and an extended
release of nicotine. In certain embodiments, different flavorants
and/or other components (e.g., sensates) can be incorporated within
certain layers. Varying the flavors and/or organoleptic sensations
of the different layers can provide the user with a unique range of
taste and/or sensory experiences over the course of use of the
product.
[0081] Compositions of the present invention incorporate a
pharmaceutically effective amount of nicotine. The dose of active
ingredient (i.e., all the various nicotine forms) is preferably
that amount effective to treat some symptoms of, or prevent
occurrence of the symptoms of, the condition, disease, or disorder
from which the subject or patient suffers. By "effective amount",
"therapeutic amount" or "effective dose" is meant that amount
sufficient to elicit the desired pharmacological or therapeutic
effects, thus resulting in effective prevention or treatment of the
condition, disease, or disorder. Thus, an effective amount of
active ingredient is an amount sufficient to enter relevant regions
of the body (e.g., to pass across the blood-brain barrier of the
subject), to bind to relevant receptor sites in the CNS and PNS of
the subject, and/or to elicit neuropharmacological effects (e.g.,
elicit neurotransmitter secretion, thus resulting in effective
prevention or treatment of the condition, disease, or disorder).
Prevention of the disorder is manifested, for example, by delaying
the onset of the symptoms of the condition, disease, or disorder.
Treatment of the disorder is manifested by, for example, a decrease
in the symptoms associated with the condition, disease, or disorder
or an amelioration of the reoccurrence of the symptoms thereof.
[0082] For compositions of the present invention, the intended
daily dose of the active ingredient can vary. The overall dose of
active ingredient can depend upon factors such as the weight of the
subject ingesting the composition, the condition being treated, the
state or severity of the disease or disorder being treated, the
desired pharmacological effect, or other such factors. Typically,
the amount of nicotine active ingredient, calculated as nicotine
base, administered to a subject per day is at least about 2 mg,
often is at least about 4 mg, and frequently is at least about 10
mg. Typically, the amount of nicotine active ingredient
administered to a subject per day does not exceed about 60 mg,
often does not exceed about 50 mg, and frequently does not exceed
about 40 mg. See also, for example, the types of dosing regimens
and administration techniques set forth in U.S. Pat. No. 5,593,684
to Baker et al.; U.S. Pat. No. 6,660,754 to Kyle et al.; and US
Pat. Pub. Nos. 2004/0006113 to Sachs; 2005/0214229 to Pinney et
al.; 2008/0124283 to Andersen; and 2009/0293895 to Axelsson et al.;
which are incorporated herein by reference.
[0083] Representative compositions incorporating nicotine as an
active ingredient can have various types of formats and
configurations, and as a result, the character, nature, behavior,
consistency, shape, form, size and weight of the composition can
vary. The shape of a representative composition can be generally
spherical, cylindrical (e.g., ranging form the general shape of a
flattened disc to the general shape of a relatively long, slender
stick), helical, obloid, square, rectangular, or the like; or the
composition can have the form of a bead, granular powder,
crystalline powder, capsule, film, strip, gel, or the like. The
shape of the composition can resemble a wide variety of pill,
tablet, lozenge, capsule, caplet, pouch and gum types of products
that traditionally have been employed for the administration of
pharmaceutical types of products. The general nature of a
representative composition can be soft or hard to the touch, or of
intermediate softness or hardness; and as such, the composition can
be considered to be malleable, flexible, chewy, resilient, brittle,
or the like. When administered orally, various components of the
product can be considered to be readily dispersible or slow to
disperse, or those various components can dissolve at varying rates
(e.g., from relatively fast to relatively slow). As a result, for
compositions ingested by insertion in the mouth of the human
subject, the release rate of active ingredient during use of the
product can vary from relatively fast to relatively slow, depending
upon factors such as the design of the product and the use of
product by the subject using that product. See also, by way of
example, the types of products proposed in U.S. Pat. No. 4,655,231
to Ray et al.; U.S. Pat. No. 5,147,654 to Place et al.; U.S. Pat.
No. 5,543,424 to Carlsson et al.; U.S. Pat. No. 6,268,386 to
Thompson; U.S. Pat. No. 6,319,510 to Yates; U.S. Pat. No. 6,488,953
Halliday et al.; U.S. Pat. No. 6,709,671 to Zerbe et al.; U.S. Pat.
No. 7,025,983 to Leung et al.; U.S. Pat. No. 7,105,173 to Rolling;
U.S. Pat. No. 7,115,297 to Stillman; U.S. Pat. No. 7,435,749 to
Knight; and U.S. Pat. No. 7,491,406 to Leung et al.; and US Pat.
Pub. Nos. 2006/0198873 to Chan et al.; 2006/0240087 to Houze et
al.; 2006/0204559 to Bess et al.; 2007/0269492 to Steen et al.;
2008/0020050 to Chau et al.; 2008/0286340 to Andersson et al.;
2008/0292683 to Sanghvi et al.; and 2009/0004248 to Bunick et al.;
which are incorporated herein by reference.
[0084] The means by which multi-layered nicotinic
compound-containing pharmaceutical compositions can be produced can
vary. Generally, the core formulation can be provided by any means
for providing such a formulation. Exemplary means for providing
certain types of formulations are provided herein, although it is
noted that other methods can be used without departing from the
present invention. Typically, the core formulation is produced and
the one or more additional layers are applied thereto. The core can
be formed, for example, into the desired shape by pouring the
formulation mixture directly into molds, forming (e.g., rolling or
pressing) into the desired shape, or extruding. In some
embodiments, the mixture can be extruded, starch molded, or
injection molded.
[0085] In certain embodiments, the method by which the one or more
additional layers are formed may require some degree of tailoring
so as to accommodate application of the formulation onto the core
or previous layer of the pharmaceutical composition. For example,
second and subsequent layers of the pharmaceutical compositions are
often applied by means of coatings (e.g., by dip coating, spray
coating, or preparing a separate sheet of the formulation that can
be used to enwrap the core formulation or to adhere to one or more
surface of the core formulation, as in a side-by-side type
configuration).
[0086] Typical conditions associated with manufacture of food grade
products such as described herein include control of heat and
temperature (i.e., the degree of heat to which the various
ingredients are exposed during manufacture and the temperature of
the manufacturing environment), moisture content (e.g., the degree
of moisture present within individual ingredients and within the
final composition), humidity within the manufacturing environment,
atmospheric control (e.g., nitrogen atmosphere), airflow
experienced by the various ingredients during the manufacturing
process, and other similar types of factors. Additionally, various
process steps involved in product manufacture can involve selection
of certain solvents and processing aids, use of heat and radiation,
refrigeration and cryogenic conditions, ingredient mixing rates,
and the like. The manufacturing conditions also can be controlled
due to selection of the form of various ingredients (e.g., solid,
liquid, or gas), particle size or crystalline nature of ingredients
of solid form, concentration of ingredients in liquid form, or the
like. Ingredients can be processed into the desired composition by
techniques such as extrusion, compression, spraying, and the
like.
[0087] Meltable-type formulations can, in certain embodiments, be
prepared by combining the components (e.g., a nicotinic compound
and one or more additional components) with a melted lipid, and
forming a molten pharmaceutical formulation slurry, which can then
be deposited into a mold or coated onto another formulation.
[0088] Lozenge-type formulations may, in certain embodiments, be
prepared by heating a mixture of ingredients comprising a high
percentage of isomalt to about 143.degree. C. Once all components
are dissolved, the temperature is raised past the hard crack stage
(e.g., to about 166.degree. C.) and then removed from the heat to
allow the mixture to cool. Various components can be added at
certain stages (e.g., they may be added to the isomalt mixture at
room temperature, may be added when the mixture reaches 143.degree.
C. or 166.degree. C. or may be added at a given temperature during
the cooling process).
[0089] Injection molded-type formulations can, in certain
embodiments, be prepared by mixing the components (e.g., a
nicotinic compound, binder, and polysaccharide filler component) to
form a pharmaceutical formulation mixture; injection molding the
pharmaceutical formulation mixture (e.g., by compressing the
mixture using a compressive force of at least about 75,000 kPa or
at least about 100,000 kPa); and cooling the pharmaceutical
formulation mixture to form a solidified pharmaceutical formulation
(e.g., cooling to a temperature of about 20.degree. C. to about
25.degree. C.).
[0090] The means by which the formulations are prepared can vary
and certain methods of making certain formulation types may have to
be adapted, depending upon the makeup of a given pharmaceutical
composition. For example, where an outer layer comprises a
formulation that is traditionally molded, the method may require
modification such that that the formulation can be coated onto
another formulation. For example, such formulations can be capable
of being wet- or dry-sprayed onto another surface or applied to
another surface by dipping that surface into the formulation.
Depending on the nature of the formulation, the method of
application may require modification of traditional spray coating
techniques. For example, to spray coat a lozenge-type formulation
onto another formulation, it may be necessary to maintain the
formulation and the spray coating equipment at an elevated
temperature during the process. In certain embodiments, temperature
control is important to avoid altering the nature of other
formulations. For example, care must be taken to avoid melting a
meltable-type formulation in the core of a pharmaceutical
composition during the application of an additional layer.
[0091] In certain embodiments, at least a portion of the
pharmaceutical composition is transparent or translucent as defined
herein. Transparency/translucency can be determined by any means
commonly used in the art; however, it is commonly measured by
spectrophotometric light transmission over a range of wavelengths
(e.g., from about 400-700 nm). Transmission measurements for
certain pharmaceutical compositions of the present invention may be
higher than those of traditional nicotine-containing pharmaceutical
compositions. Translucency can also be confirmed by visual
inspection by simply holding the pharmaceutical composition up to a
light source and determining if light travels through the product
in a diffuse manner.
[0092] Aspects of the present invention are more fully illustrated
by the following examples, which are set forth to illustrate
certain aspects of the present invention and are not to be
construed as limiting thereof.
EXPERIMENTAL
Example 1
Preparation of Lozenge-Type Formulations
[0093] A nicotinic compound-containing formulation suitable for use
as a lozenge-type component of a pharmaceutical composition for
oral use is provided in the following manner. Isomalt, NaCl, and
vanillin are mixed in a pot and the temperature of the mixture is
brought to 143.degree. C. The mixture is held at 143.degree. C.
until the isomalt is melted and the temperature is then increased
to 166.degree. C. In a separate vessel, nicotine, maltitol syrup,
H.sub.2O, sucralose, and, optionally, L-lysine are mixed to form a
solution. Optionally, in a second separate vessel, water and sodium
hydroxide are mixed to form a solution.
[0094] The isomalt mixture is removed from the heat and allowed to
cool to 132.degree. C. The remaining components (i.e., the
nicotine-containing solution and optional sodium hydroxide
solution) are combined and, optionally, one or more flavorings are
added to the combined solution. The combined solution is poured
into the hot isomalt mixture and folded in.
[0095] The resulting mixture is poured into molds. When the mixture
becomes too viscous to pour, the mixture can be heated in a
microwave using high heat (e.g., for about 7 seconds).
Representative pharmaceutical formulation mixtures are set forth
below. Mixture 1 below contains no base, while Mixtures 2 and 3
contain sodium hydroxide at varying levels.
TABLE-US-00002 MIXTURE 1 Ingredient Percent by weight Isomalt ST-M*
93.8 Maltitol syrup 1.0 Nicotine 0.2 NaCl 1.0 Vanillin 0.3
Sucralose 0.2 H.sub.2O 3.3 Flavorant 0.1 *Isomalt in which 1,6-GPS
and 1,1-GPM are present in essentially equimolar amounts and which
has a medium grain size, the diameter of approximately 90% of all
particles being <3 mm.
TABLE-US-00003 MIXTURE 2 Ingredient Percent by weight Isomalt ST-M
93.8 Maltitol syrup 1.0 Nicotine 0.2 NaCl 1.0 Vanillin 0.3
Sucralose 0.2 H.sub.2O 3.1 Flavorant 0.1 NaOH 0.2
TABLE-US-00004 MIXTURE 3 Ingredient Percent by weight Isomalt ST-M
94.2 Maltitol syrup 1.0 Nicotine 0.2 NaCl 1.0 Vanillin 0.3
Sucralose 0.2 H.sub.2O 2.7 Flavorant 0.1 NaOH 0.3
[0096] Other acceptable excipients of lozenge-type formulations are
provided, for example, in U.S. patent application No. 13/240,500 to
Holton, Jr. filed on Sept. 22, 2011, which is incorporated herein
by reference.
Example 2
Preparation of Meltable-Type Formulations
[0097] a) Meltable Formulation 1
[0098] A nicotinic compound-containing formulation suitable for use
as a meltable component of a pharmaceutical composition for oral
use is provided in the following manner. Various dry ingredients
are provided, which include a filler (isomalt), a salt (sodium
chloride), a sweetener (sucralose), and flavorants (vanillin,
spray-dried peppermint, spray-dried menthol). All dry ingredients,
in powder form, as well as a nicotinic compound (e.g., nicotine),
are added together and thoroughly mixed in a Hobart mixer with a
paddle for about three minutes at about 120 rpm.
[0099] A lipid substance having a melting point of about 38.degree.
C. to about 42.degree. C. is provided (available as 108-24-B from
AarhusKarlshamn USA Inc.). The lipid substance is a
non-hydrogenated lauric coating fat containing a blend of palm
kernel oil and palm oil. The lipid substance is melted in a mixing
vessel. While maintaining heat to the mixing vessel having the
melted lipid substance, the mixed dry formulation is added while
mixing occurs, thereby creating a flowable slurry of a nicotinic
compound-containing composition having a moisture content of less
than about 10 percent. The slurry is deposited in a mold to achieve
about 1 gram weight per piece of pharmaceutical composition. The
slurry is allowed to harden by ambient air drying for about 45
minutes, after which the individual pieces of meltable nicotinic
compound-containing formulation are removed from the mold. The
mixture of the nicotinic compound-containing composition is about
53.0 parts lipid substance, 39.8 parts filler, 0.2 parts nicotine,
0.8 parts salt, 0.7 parts sweetener, and 5.5 parts flavorant.
[0100] b) Meltable Formulation 2
[0101] A nicotinic compound-containing formulation suitable for use
as a meltable component of a pharmaceutical composition for oral
use is provided in the following manner. Various dry ingredients
are provided, which include a filler (isomalt), a salt (sodium
chloride), a sweetener (sucralose), and flavorants (vanillin,
spray-dried peppermint, spray-dried menthol). All dry ingredients,
in powder form, as well as a nicotinic compound (e.g., nicotine),
are added together and thoroughly mixed in a Hobart mixer with a
paddle for about three minutes at about 120 rpm.
[0102] A lipid substance having a melting point of about 38.degree.
C. to about 42.degree. C. is provided (available as 108-24-B from
AarhusKarlshamn USA Inc.). The lipid substance is a
non-hydrogenated lauric coating fat containing a blend of palm
kernel oil and palm oil. The lipid substance is melted in a mixing
vessel. While maintaining heat to the mixing vessel having the
melted lipid substance, the mixed dry formulation is added while
mixing occurs, thereby creating a flowable slurry of nicotinic
compound-containing composition having a moisture content of less
than about 10 percent. The slurry is deposited in a mold to achieve
about 1 gram weight per piece of pharmaceutical composition. The
slurry is allowed to harden by ambient air drying for about 45
minutes, after which the individual pieces of meltable nicotinic
compound-containing formulation are removed from the mold. The
mixture of the nicotinic compound-containing composition is about
53.0 parts lipid substance, 38.2 parts filler, 0.2 parts nicotine,
0.8 parts salt, 0.7 parts sweetener, and 7.1 parts flavorant.
[0103] c) Meltable Formulation 3
[0104] A nicotinic compound-containing formulation suitable for use
as a meltable component of a pharmaceutical composition for oral
use is provided in the following manner. Various dry ingredients
are provided, which include a filler (isomalt), a salt (sodium
chloride), a sweetener (sucralose), and flavorants (vanillin,
spray-dried peppermint, spray-dried menthol). All dry ingredients,
in powder form, as well as a nicotinic compound (e.g., nicotine),
are added together and thoroughly mixed in a Hobart mixer with a
paddle for about three minutes at about 120 rpm.
[0105] A lipid substance having a melting point of about 38.degree.
C. to about 42.degree. C. is provided (available as 108-24-B from
AarhusKarlshamn USA Inc.). The lipid substance is a
non-hydrogenated lauric coating fat containing a blend of palm
kernel oil and palm oil. The lipid substance is melted in a mixing
vessel. While maintaining heat to the mixing vessel having the
melted lipid substance, the mixed dry formulation is added while
mixing occurs, thereby creating a flowable slurry of nicotinic
compound-containing composition having a moisture content of less
than about 10 percent. The slurry is deposited in a mold to achieve
about 1 gram weight per piece of nicotinic compound-containing
formulation. The slurry is allowed to harden by ambient air drying
for about 45 minutes, after which the individual pieces of meltable
nicotinic compound-containing formulation are removed from the
mold. The mixture of the nicotinic compound-containing composition
is about 53.0 parts lipid substance, 36.6 parts filler, 0.2 parts
nicotine, 0.8 parts salt, 0.7 parts sweetener, and 8.7 parts
flavorant.
[0106] d) Meltable Formulation 4
[0107] A nicotinic compound-containing formulation suitable for use
as a meltable component of a pharmaceutical composition for oral
use is provided in the following manner. Various dry ingredients
are provided, which include a filler (isomalt), a sweetener
(sucralose), and a flavorant (vanillin). All dry ingredients, in
powder form, as well as a nicotinic compound (e.g., nicotine), are
added together and thoroughly mixed in a Hobart mixer with a paddle
for about three minutes at about 120 rpm.
[0108] A lipid substance having a melting point of about 38.degree.
C. to about 42.degree. C. is provided (available as 108-24-B from
AarhusKarlshamn USA Inc.). The lipid substance is a
non-hydrogenated lauric coating fat containing palm kernel oil and
palm oil. The lipid substance is melted in a mixing vessel. While
maintaining heat to the mixing vessel having the melted lipid
substance, the mixed dry formulation is added while mixing occurs,
thereby creating a flowable slurry of nicotinic compound-containing
composition having a moisture content of less than about 10
percent. The slurry is deposited in a mold to achieve about 1 gram
weight per piece of nicotinic compound-containing formulation. The
slurry is allowed to harden by ambient air drying for about 45
minutes, after which the individual pieces of nicotinic
compound-containing formulation are removed from the mold. The
mixture of the nicotinic compound-containing composition is about
52.9 parts lipid substance, 46.1 parts filler, 0.2 parts nicotine,
0.7 parts sweetener, and 0.1 parts flavorant.
[0109] e) Meltable Formulation 5
[0110] A nicotinic compound-containing formulation suitable for use
as a meltable component of a pharmaceutical composition for oral
use is provided in the following manner. Various dry ingredients
are provided, which include a filler (isomalt), additives (sodium
chloride, flour), a sweetener (sucralose), and a flavorant
(vanillin). All dry ingredients, in powder form, as well as a
nicotinic compound (e.g., nicotine), are added together and
thoroughly mixed in a Hobart mixer with a paddle for about three
minutes at about 120 rpm.
[0111] A lipid substance having a melting point of about 38.degree.
C. to about 42.degree. C. is provided (available as 108-24-B from
AarhusKarlshamn USA Inc.). The lipid substance is a
non-hydrogenated lauric coating fat containing palm kernel oil and
palm oil. The lipid substance is melted in a mixing vessel. While
maintaining heat to the mixing vessel having the melted lipid
substance, the mixed dry formulation is added while mixing occurs,
thereby creating a flowable slurry of nicotinic compound-containing
composition having a moisture content of less than about 10
percent. The slurry is deposited in a mold to achieve about 1 gram
weight per piece of nicotinic compound-containing formulation. The
slurry is allowed to harden by ambient air drying for about 45
minutes, after which the individual pieces of nicotinic
compound-containing formulation are removed from the mold. The
mixture of the nicotinic compound-containing composition is about
53.0 parts lipid substance, 45.2 parts filler, 0.2 parts nicotine,
0.8 parts additive, 0.7 parts sweetener, and 0.1 parts
flavorant.
[0112] f) Meltable Formulation 6
[0113] A nicotinic compound-containing formulation suitable for use
as a meltable component of a pharmaceutical composition for oral
use is provided in the following manner. Various dry ingredients
are provided, which include a filler (isomalt), additives (sodium
chloride, flour), a sweetener (sucralose), and a flavorant
(vanillin). All dry ingredients, in powder form, as well as a
nicotinic compound (e.g., nicotine), are added together and
thoroughly mixed in a Hobart mixer with a paddle for about three
minutes at about 120 rpm.
[0114] A lipid substance having a melting point of about 39.degree.
C. to about 41.degree. C. is provided (available as 108-48-B from
AarhusKarlshamn USA Inc.). The lipid substance is non-hydrogenated
lauric coating fat containing palm kernel oil and palm oil.
[0115] The lipid substance is melted in a mixing vessel. While
maintaining heat to the mixing vessel having the melted lipid
substance, the mixed dry formulation is added while mixing occurs,
thereby creating a flowable slurry of nicotinic compound-containing
composition having a moisture content of less than about 10
percent. The slurry is deposited in a mold to achieve about 1 gram
weight per piece of pharmaceutical composition. The slurry is
allowed to harden by ambient air drying for about 45 minutes, after
which the individual pieces of nicotinic compound-containing
composition are removed from the mold. The mixture of the nicotinic
compound-containing composition is about 53.0 parts lipid
substance, 45.2 parts filler, 0.2 parts nicotine, 0.8 parts
additive, 0.7 parts sweetener, and 0.1 parts flavorant.
[0116] g) Meltable Formulation 7
[0117] A nicotinic compound-containing formulation suitable for use
as a meltable component of a pharmaceutical composition for oral
use is provided in the following manner. Various dry ingredients
are provided, which include a filler (isomalt), a salt (sodium
chloride), a sweetener (sucralose), and two flavorants (vanillin
and mint). All dry ingredients, in powder form, as well as a
nicotinic compound (e.g., nicotine), are added together and
thoroughly mixed in a Hobart mixer with a paddle for about three
minutes at about 120 rpm.
[0118] A lipid substance having a melting point of about 38.degree.
C. to about 42.degree. C. is provided (available as 108-24-B from
AarhusKarlshamn USA Inc.). The lipid substance is a
non-hydrogenated lauric coating fat containing palm kernel oil and
palm oil. The lipid substance is melted in a mixing vessel using a
microwave. The melted lipid is slowly added to the dry blend while
stirring. While maintaining heat to the mixing vessel, addition of
the entire melted lipid component creates a flowable slurry of
nicotinic compound-containing composition. The slurry is deposited
in a mold to achieve about 1 gram weight per piece nicotinic
compound-containing composition. The slurry is allowed to harden by
ambient air drying for about 45 minutes, after which the individual
pieces of nicotinic compound-containing formulation are removed
from the mold. The mixture of the nicotinic compound-containing
composition is about 53.0 parts lipid substance, 45.2 parts filler,
0.2 parts nicotine, 0.8 parts additive, 0.7 parts sweetener, and
0.1 parts flavorant.
[0119] Other acceptable excipients of meltable-type formulations
are provided, for example, in U.S. patent application Ser. No.
13/330,929, filed Dec. 20, 2011 to Cantrell et al., which is
incorporated herein by reference.
Example 3
Preparation of Starch Molded-Type Formulations (Pastilles)
[0120] a) Starch Molded Formulation 1
[0121] A nicotinic compound-containing formulation suitable for use
as a starch molded component of a pharmaceutical composition for
oral use is provided in the following manner. An aqueous mixture is
prepared. The aqueous mixture is formed by hydrating a binder
material (gum arabic) with water and then admixing the hydrated gum
with a filler (isomalt), an additional filler (maltitol; available
as LYCASIN from Roquette Freres S.A.), and a salt using a high
shear mixer. The aqueous mixture is about 33 parts binder material,
29 parts isomalt, 4.1 parts maltitol, 2 parts salt, and 33 parts
water.
[0122] The aqueous mixture is mixed with a sweetener (sucralose)
and nicotine in a Hobart mixing bowl to form a nicotinic
compound-containing composition. The mixture of the nicotinic
compound-containing composition is about 99.3 parts aqueous
mixture, 0.2 parts nicotine, and 0.5 parts sucralose.
[0123] The nicotinic compound-containing composition is heated to
about 54.degree. C. and then deposited into a starch mould. The
nicotinic compound-containing composition remains in the starch
mould for about 19 hours at about 60.degree. C. The nicotinic
compound-containing composition is allowed to cool and then removed
from the starch mould. The nicotinic compound-containing
composition is then cured at ambient room temperature for about 24
hours.
[0124] b) Starch Molded Formulation 2
[0125] A nicotinic compound-containing formulation suitable for use
as a starch molded component of a pharmaceutical composition for
oral use is provided in the following manner. An aqueous mixture is
prepared by hydrating a binder material (gum arabic) with water and
adding sodium hydroxide to adjust the mixture to a pH of 8.0. The
mixture is heated to about 82.degree. C. Separately, isomalt and
maltitol syrup are combined and heated to about 166.degree. C.,
cooled to about 132.degree. C., and added to the aqueous mixture.
Flavorant, salt, sucralose, glycerin, and nicotine are added and
mixed. The mixture of the nicotinic compound-containing composition
is about 64.2 parts aqueous mixture (32 parts water, 32 parts
binder, 0.2 parts buffering agent), 0.2 parts nicotine, 2.4 parts
glycerin, 29.0 parts isomalt, 1.3 parts maltitol syrup, 0.3 parts
sucralose, 2 parts salt, 0.6 parts flavorant.
[0126] The nicotinic compound-containing composition deposited into
a starch mould at a temperature of about 71.degree. C. (depositing
temperature should be greater than about 66.degree. C.). The
nicotinic compound-containing composition remains in the starch
mould for about 72 hours at about 60.degree. C. The nicotinic
compound-containing composition is allowed to cool and then removed
from the starch mould. The nicotinic compound-containing
composition is then cured at ambient room temperature for about 24
hours.
[0127] Other acceptable excipients of starch molded-type
formulations are provided, for example, in U.S. appliation Ser. No.
12/957,821 to Cantrell et al., filed Dec. 1, 2010, which is
incorporated herein by reference.
Example 4
Preparation of Injection Molded-Type Formulations (Pastilles)
[0128] a) Injection Molded Formulation 1
[0129] A nicotinic compound-containing formulation suitable for use
as an injection molded component of a pharmaceutical composition
for oral use is provided in the following manner. A humectant
(available as HYSTAR 3375 from Corn Products International), an
emulsifier (available as DUR-EM 117 from Loders Croklaan), corn
syrup, glycerin and a flavorant are admixed and heated to form a
liquid blend.
[0130] Nicotine is mixed with salt, sucralose, a binder material
(gum arabic) and polydextrose powder (available as LITESSE from
Danisco A/S) in a Hobart mixing bowl. The liquid blend is added to
the Hobart mixing bowl containing the nicotine blend, binder
material, and polydextrose powder, wherein the ingredients are
admixed in Hobart mixer (Model N-50) for about 4-5 minutes at about
120 rpm to form a nicotinic compound-containing composition. The
nicotinic compound-containing composition is passed through a meat
grinder on the Hobart mixer to incorporate the liquid ingredients
into the dry ingredients. The nicotinic compound-containing
composition is extruded through a grinder apparatus. Upon
extrusion, the nicotinic compound-containing composition is placed
in a Hobart mixer to form a powder granulation. The mixture of the
nicotinic compound-containing composition is about 21.4 parts
binder material, 0.2 parts nicotine, 42.7 parts humectant, 1.5 part
emulsifier, 21.4 parts polydextrose, 5.3 parts corn syrup, 3.2
parts glycerin, 2.8 parts salt, 0.3 parts sucralose, and 1.2 parts
flavorant.
[0131] The granulated nicotinic compound-containing composition is
transferred to an injection mold and compressed at about 103,500
kPa for 1 minute. The mold is a stainless steel two-piece block
that is filled with the nicotinic compound-containing composition
and then compressed via engagement with a hydraulic press unit
(Wabach Hydraulic Press, Model 12-102T, Serial 2201). The nicotinic
compound-containing composition is removed from the injection mold
after cooling at ambient temperature for about 60 minutes.
[0132] b) Injection Molded Formulation 2
[0133] A nicotinic compound-containing composition suitable for use
as a pharmaceutical composition for oral use is provided in the
following manner. A filler (maltitol; available as LYCASIN from
Roquette Freres S.A.), an emulsifier (available as DUR-EM 117 from
Loders Croklaan), corn syrup, glycerin and a flavorant are admixed
and heated to form a liquid blend.
[0134] Nicotine is mixed with salt, sucralose, a binder material
(gum arabic) and a polysaccharide (maltodextrin; available as
MALTRIN M100 from Grain Processing Corporation) in a Hobart mixing
bowl. The liquid blend is added to the Hobart mixing bowl
containing the nicotine blend, binder material, and polysaccharide,
wherein the ingredients are admixed in Hobart mixer (Model N-50)
for about 4-5 minutes at about 120 rpm to form a nicotinic
compound-containing composition. The nicotinic compound-containing
composition is passed through a meat grinder on the Hobart mixer to
incorporate the liquid ingredients into the dry ingredients. The
nicotinic compound-containing composition is extruded through a
grinder apparatus. Upon extrusion, the nicotinic
compound-containing composition is placed in a Hobart mixer to form
a powder granulation. The mixture of the nicotinic
compound-containing composition is about 21.4 parts binder
material, 0.2 parts nicotine, 21.4 parts polysaccharide, 42.7 parts
filler, 1.5 parts emulsifier, 5.3 parts corn syrup, 3.2 parts
glycerin, 2.9 parts salt, 0.3 parts sucralose, and 1.2 parts
flavorant.
[0135] The granulated nicotinic compound-containing composition is
transferred to an injection mold and compressed at about 103,500
kPa for 1 minute. The mold is a stainless steel two-piece block
that is filled with the nicotinic compound-containing composition
and then compressed via engagement with a hydraulic press unit
(Wabach Hydraulic Press, Model 12-102T, Serial 2201). The nicotinic
compound-containing composition is removed from the injection mold
after cooling at ambient temperature for about 60 minutes.
[0136] c) Injection Molded Formulation 3
[0137] A nicotinic compound-containing composition suitable for use
as a pharmaceutical composition for oral use is provided in the
following manner. A filler (maltitol; available as LYCASIN from
Roquette Frees S.A.), an emulsifier (available as DUR-EM 117 from
Loders Croklaan), corn syrup, glycerin and a flavorant are admixed
and heated to form a liquid blend.
[0138] Nicotine is mixed with salt, sucralose, a binder material
(gum arabic) and a polysaccharide (pullulan powder) in a Hobart
mixing bowl. The liquid blend is added to the Hobart mixing bowl
containing the nicotine blend, binder material, and polysaccharide,
wherein the ingredients are admixed in Hobart mixer (Model N-50)
for about 4-5 minutes at about 120 rpm to form a nicotinic
compound-containing composition. The nicotinic compound-containing
composition is passed through a meat grinder on the Hobart mixer to
incorporate the liquid ingredients into the dry ingredients. The
nicotinic compound-containing composition is extruded through a
grinder apparatus. Upon extrusion, the nicotinic
compound-containing composition is placed in a Hobart mixer to form
a powder granulation. The mixture of the nicotinic
compound-containing composition is about 21.4 parts binder
material, 0.2 parts nicotine, 21.4 parts polysaccharide, 42.6 parts
filler, 1.5 parts emulsifier, 5.3 parts corn syrup, 3.2 parts
glycerin, 2.8 parts salt, 0.3 parts sucralose, and 1.3 parts
flavorant.
[0139] The granulated nicotinic compound-containing composition is
transferred to an injection mold and compressed at about 103,500
kPa for 1 minute. The mold is a stainless steel two-piece block
that is filled with the nicotinic compound-containing composition
and then compressed via engagement with a hydraulic press unit
(Wabach Hydraulic Press, Model 12-102T, Serial 2201). The nicotinic
compound-containing composition is removed from the injection mold
after cooling at ambient temperature for about 60 minutes.
[0140] d) Injection Molded Formulation 4
[0141] A nicotinic compound-containing composition suitable for use
as a pharmaceutical composition for oral use is provided in the
following manner. A humectant (available as HYSTAR 3375 from Corn
Products International), an emulsifier (available as DUR-EM 117
from Loders Croklaan), corn syrup, glycerin and a flavorant are
admixed and heated to form a liquid blend.
[0142] Nicotine is mixed with salt, sucralose, a binder material
(gum arabic) and polydextrose powder (available as LITESSE from
Danisco A/S) in a Hobart mixing bowl. The liquid blend is added to
the Hobart mixing bowl containing the nicotine blend, binder
material, and polydextrose powder, wherein the ingredients are
admixed in Hobart mixer (Model N-50) for about 4-5 minutes at about
120 rpm to form a nicotinic compound-containing composition. The
nicotinic compound-containing composition is passed through a meat
grinder on the Hobart mixer to incorporate the liquid ingredients
into the dry ingredients. The nicotinic compound-containing
composition is extruded through a grinder apparatus. Upon
extrusion, the nicotinic compound-containing composition is placed
in a Hobart mixer to form a powder granulation. The mixture of the
nicotinic compound-containing composition is about 22.4 parts
binder material, 0.2 parts nicotine, 40 parts humectant, 1.6 parts
emulsifier, 22.4 parts polydextrose, 5.6 parts corn syrup, 3.4
parts glycerin, 2.8 parts salt, 0.3 parts sucralose, and 1.3 parts
flavorant.
[0143] The granulated nicotinic compound-containing composition is
transferred to an injection mold and compressed at about 103,500
kPa for 1 minute. The mold is a stainless steel two-piece block
that is filled with the nicotinic compound-containing composition
and then compressed via engagement with a hydraulic press unit
(Wabach Hydraulic Press, Model 12-102T, Serial 2201). The nicotinic
compound-containing composition is removed from the injection mold
after cooling at ambient temperature for about 60 minutes.
[0144] e) Injection Molded Formulation 5
[0145] A nicotinic compound-containing composition suitable for use
as a pharmaceutical composition for oral use is provided in the
following manner. A humectant (available as HYSTAR 3375 from Corn
Products International), an emulsifier (available as DUR-EM 117
from Loders Croklaan), corn syrup, glycerin and a flavorant are
admixed and heated to form a liquid blend.
[0146] Nicotine is mixed with salt, sucralose, a binder material
(gum arabic) and polydextrose powder (available as LITESSE from
Danisco A/S) in a Hobart mixing bowl. The liquid blend is added to
the Hobart mixing bowl containing the nicotine blend, binder
material, and polydextrose powder, wherein the ingredients are
admixed in Hobart mixer (Model N-50) for about 4-5 minutes at about
120 rpm to form a nicotinic compound-containing composition. The
nicotinic compound-containing composition is passed through a meat
grinder on the Hobart mixer to incorporate the liquid ingredients
into the dry ingredients. The nicotinic compound-containing
composition is extruded through a grinder apparatus. Upon
extrusion, the nicotinic compound-containing composition is placed
in a Hobart mixer to form a powder granulation. The mixture of the
nicotinic compound-containing composition is about 26 parts binder
material, 0.2 parts nicotine, 31.5 parts humectant, 1.2 parts
emulsifier, 26 parts polydextrose, 6.2 parts corn syrup, 4.1 parts
glycerin, 2 parts salt, 0.2 parts sucralose, and 0.9 parts
flavorant.
[0147] The nicotinic compound-containing composition is transferred
to an injection mold and compressed at about 103,500 kPa for 1
minute. The mold is a stainless steel two-piece block that is
filled with the nicotinic compound-containing composition and then
compressed via engagement with a hydraulic press unit (Wabach
Hydraulic Press, Model 12-102T, Serial 2201). The nicotinic
compound-containing composition is removed from the injection mold
after cooling at ambient temperature for about 60 minutes.
[0148] Other acceptable excipients of injection molded-type
formulations are provided, for example, in US Pat. Appl. No.
12/957,838 to Cantrell et al., filed December 1, 2010, which is
incorporated herein by reference.
Example 5
Preparation of Chewable-Type Formulation
[0149] A nicotinic compound-containing formulation suitable for use
as a chewable component of a pharmaceutical composition for oral
use is provided in the following manner. An aqueous mixture is
prepared. The aqueous mixture is formed by adding nicotine and
hydrating a binder material (gum arabic) with the water. The
aqueous mixture is about 49.7 parts binder, about 0.6 parts
nicotine, and about 49.7 parts water.
[0150] The aqueous mixture is mixed with a salt (NaCl), a buffering
agent (sodium hydroxide), a sweetener (sucralose), glycerin, and an
emulsifier (sunflower lecithin) and the added components are
allowed to dissolve therein. The mixture is heated to about
49.degree. C. The heated mixture is combined with a lipid substance
having a melting point of about 38.degree. C. to about 42.degree.
C. (available as 108-24-B from AarhusKarlshamn USA Inc.), which has
been heated to a melt and flavorant. The mixture of the nicotinic
compound-containing composition is about 36 parts aqueous mixture,
24 parts lipid substance, 6 parts glycerin, 0.2 parts emulsifier
component, 0.2 parts sucralose, 0.6 parts salt, 0.3 parts buffering
agent, 0.6 parts flavorant, and 32 parts water.
[0151] The nicotinic compound-containing composition is formed in
various ways. In one example, it is deposited into a mold and
remains in the mold at ambient conditions until dry and then
removed from the mold. In another example, it is poured onto a
tabletop to air dry to a semi-moist state and formed into desired
shapes using a drop roller.
Example 6
Preparation of Hard Coating-Type Formulation
[0152] An aqueous mixture is prepared by adding sodium hydroxide,
nicotine, and a binder (CMC-15) and the mixture is heated to about
57.degree. C. The aqueous mixture is about 0.3 parts sodium
hydroxide, about 2 parts nicotine, about 13 parts CMC-15, and about
84.7 parts water. A mixture of sorbitol, isomalt, maltitol syrup,
and sucralose is melted to a liquid, cooled to about 135.degree.
C., and added to the aqueous mixture. Flavorant and pigment (to
provide a pearlescent appearance) is added to give a nicotinic
compound-containing composition that is about 10 parts aqueous
mixture (about .2 parts nicotine), about 7 parts sorbitol, about
26.2 parts isomalt, about 0.2 parts sucralose, about 8.2 parts
maltitol syrup, about 0.2 parts flavorant, and about 48.2 parts
water.
[0153] The resulting formulation can be cast into sheets (e.g., by
casting into sheets on stainless steel plates) or dip- or
spray-coated onto the composition described previously in this
example. When the formulation is cast into sheets, it can be cut
(e.g., with a casting knife) and applied as a sandwiched coating
onto the composition described previously in this example. When the
formulation is dip- or spray-coated, it is maintained at a
temperature of greater than about 66.degree. C., applied as a
liquid, and then cooled to harden.
Example 7
Preparation of 2-Layered Products
[0154] a) Lozenge/Meltable
[0155] A lozenge-type formulation is prepared as described in
Example 1, poured into molds, and cooled. A meltable-type
formulation as described in Example 2 is prepared. However, rather
than pouring the flowable slurry into molds, it is applied directly
to the surface of the cooled lozenge-type formulation. For example,
the molded lozenge-type formulations are dipped into the flowable
slurry and it is allowed to dry and harden at room temperature to
provide a 2-layered product comprising a lozenge-type core and a
meltable-type coating.
[0156] b) Lozenge/Chewable
[0157] A lozenge-type formulation is prepared as described in
Example 1, poured into molds, and cooled. A chewable formulation as
described in Example 5 is prepared. The formulation is poured onto
a tabletop to air dry to a semi-moist state and formed around the
surface of the lozenge-type formulations to provide a 2-layered
product comprising a lozenge-type core and a chewable-type
coating.
[0158] c) Lozenge/Hard Coating
[0159] A lozenge-type formulation is prepared as described in
Example 1, poured into molds, and cooled. A hard coating-type
formulation as described in Example 6 is prepared. The coated
formulation is cast into sheets, cut, and applied directly to the
surface of the lozenge-type product as a sandwich coating to
provide a 2-layered product comprising a lozenge-type core and a
hard coating-type coating.
[0160] d) Meltable/Lozenge
[0161] A meltable-type formulation is prepared as described in
Example 2. A lozenge-type formulation as described in Example 1 is
prepared, except that rather than pouring the hot mixture into
molds, it is applied directly to the surface of the meltable-type
formulation. For example, the hot mixture may be introduced into
spray coating equipment adapted to maintain a temperature of about
132.degree. C. and sprayed onto the surface of the cooled
meltable-type formulation. As noted in Example 1, the mixture must
be held at an elevated temperature to maintain sufficient
flexibility and pliability to be manipulated into the desired
shape. Because the meltable-type formulation may exhibit some
degree of melting at such an elevated temperature, steps must be
taken to avoid or limit the melting of the meltable-type
formulation during the application of the lozenge-type formulation.
For example, the meltable-type formulation may be frozen prior to
applying the lozenge-type formulation to limit the degree of
melting.
[0162] e) Meltable/Hard Coating
[0163] A meltable-type formulation is prepared as described in
Example 2. A hard coating-type formulation as described in Example
6 is prepared. The coated formulation is cast into sheets, cut, and
applied directly to the surface of the meltable-type product as a
sandwich coating to provide a 2-layered product comprising a
meltable-type core and a hard coating-type coating.
[0164] f) Starch molded/Meltable
[0165] A starch molded-type formulation is prepared as described in
Example 3, poured into molds, and cooled. A meltable-type
formulation as described in Example 2 is prepared. However, rather
than pouring the flowable slurry into molds, it is applied directly
to the surface of the cooled starch molded-type formulation. For
example, the starch molded -type formulations are dipped into the
flowable slurry and it is allowed to dry and harden at room
temperature to provide a 2-layered product comprising a starch
molded-type core and a meltable-type coating.
[0166] g) Starch molded/Lozenge
[0167] A starch molded-type formulation is prepared as described in
Example 3, poured into molds, and cooled. A lozenge-type
formulation as described in Example 1 is prepared, except that
rather than pouring the hot mixture into molds, it is applied
directly to the surface of the starch molded-type formulation. For
example, the hot mixture may be introduced into spray coating
equipment adapted to maintain a temperature of about 132.degree. C.
and sprayed onto the surface of the cooled starch molded-type
formulation. As noted in Example 1, the mixture must be held at an
elevated temperature to maintain sufficient flexibility and
pliability to be manipulated into the desired shape.
[0168] h) Injection molded/Meltable
[0169] An injection molded-type formulation is prepared as
described in Example 4, injection molded into the desired size and
shape, and cooled. A meltable-type formulation as described in
Example 2 is prepared. However, rather than pouring the flowable
slurry into molds, it is applied directly to the surface of the
cooled injection molded-type formulation. For example, the
injection molded-type formulations are dipped into the flowable
slurry and it is allowed to dry and harden at room temperature to
provide a 2-layered product comprising an injection molded-type
core and a meltable-type coating.
[0170] i) Injection molded/Lozenge
[0171] An injection molded-type formulation is prepared as
described in Example 4, injection molded into the desired size and
shape, and cooled. A lozenge-type formulation as described in
Example 1 is prepared, except that rather than pouring the hot
mixture into molds, it is applied directly to the surface of the
injection molded-type formulation. For example, the hot mixture may
be introduced into spray coating equipment adapted to maintain a
temperature of about 132.degree. C. and sprayed onto the surface of
the cooled injection molded-type formulation. As noted in Example
1, the mixture must be held at an elevated temperature to maintain
sufficient flexibility and pliability to be manipulated into the
desired shape.
Example 8
Preparation of 3-Layered Products
[0172] a) Lozenge/Meltable/Hard Coating
[0173] A 2-layered product comprising a lozenge-type core and a
meltable-type coating is prepared as described above in Example 7a.
A hard coating-type formulation as described in Example 6 is
prepared. The coated formulation is cast into sheets, cut, and
applied directly to the surface of the 2-layered lozenge/meltable
composition as a sandwich coating to provide a 3-layered product
comprising a lozenge-type core, a meltable-type first coating and a
hard coating-type second coating.
[0174] b) Starch molded/Lozenge/Meltable
[0175] A 2-layered product comprising a starch molded-type core and
a lozenge-type coating is prepared as described above in Example
7g. A meltable-type formulation as described in Example 2 is
prepared. However, rather than pouring the flowable slurry into
molds, it is applied directly to the surface of the cooled
2-layered starch molded/lozenge composition. For example, the
2-layered composition is dipped into the flowable slurry and it is
allowed to dry and harden at room temperature to provide a
3-layered product comprising a starch molded-type core, a
lozenge-type first coating and a meltable-type second coating.
[0176] Many modifications and other embodiments of the invention
will come to mind to one skilled in the art to which this invention
pertains having the benefit of the teachings presented in the
foregoing description. Therefore, it is to be understood that the
invention is not to be limited to the specific embodiments
disclosed and that modifications and other embodiments are intended
to be included within the scope of the appended claims. Although
specific terms are employed herein, they are used in a generic and
descriptive sense only and not for purposes of limitation.
* * * * *