U.S. patent application number 16/220387 was filed with the patent office on 2019-04-25 for nicotine-containing pharmaceutical composition.
The applicant listed for this patent is Niconovum USA, Inc.. Invention is credited to Nelly Fransen, Darrell Holton, JR., Matt Reddick.
Application Number | 20190117779 16/220387 |
Document ID | / |
Family ID | 47003242 |
Filed Date | 2019-04-25 |
United States Patent
Application |
20190117779 |
Kind Code |
A1 |
Holton, JR.; Darrell ; et
al. |
April 25, 2019 |
NICOTINE-CONTAINING PHARMACEUTICAL COMPOSITION
Abstract
A composition intended to be employed for therapeutic purposes
incorporates a nicotinic compound, a sugar substitute, and a sugar
alcohol syrup. Representative forms of nicotine include free base
(e.g., as a mixture of nicotine and microcrystalline cellulose), a
nicotine salt (e.g., as nicotine bitartrate) or nicotine
polacrilex. The composition is useful for treatment of central
nervous system conditions, diseases, and disorders, and as a
nicotine replacement therapy.
Inventors: |
Holton, JR.; Darrell;
(Clemmons, NC) ; Fransen; Nelly; (Helsingborg,
SE) ; Reddick; Matt; (Clemmons, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Niconovum USA, Inc. |
Winston-Salem |
NC |
US |
|
|
Family ID: |
47003242 |
Appl. No.: |
16/220387 |
Filed: |
December 14, 2018 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14540754 |
Nov 13, 2014 |
|
|
|
16220387 |
|
|
|
|
13240500 |
Sep 22, 2011 |
|
|
|
14540754 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/465 20130101;
A61K 9/20 20130101; A23L 27/2028 20160801; A61K 9/0056 20130101;
A61P 25/34 20180101; A61P 25/00 20180101; A61K 9/7007 20130101;
A61K 47/26 20130101; A23L 27/33 20160801; A23L 27/40 20160801; A23L
27/10 20160801 |
International
Class: |
A61K 47/26 20060101
A61K047/26; A23L 27/40 20060101 A23L027/40; A23L 27/30 20060101
A23L027/30; A23L 27/20 20060101 A23L027/20; A61K 31/465 20060101
A61K031/465; A61K 9/20 20060101 A61K009/20; A61K 9/70 20060101
A61K009/70; A61K 9/00 20060101 A61K009/00; A23L 27/10 20060101
A23L027/10 |
Claims
1. A nicotine-containing pharmaceutical composition, comprising: a.
a nicotinic compound; b. a sugar substitute in an amount of at
least about 80% by weight; and c. a sugar alcohol syrup, wherein
the sugar substitute is a non-hygroscopic sugar alcohol capable of
forming a glassy matrix and wherein the composition is in a
pharmaceutically acceptable form adapted for oral delivery of the
composition.
2. The pharmaceutical composition of claim 1, wherein at least a
portion of the nicotinic compound is in the form of a free base, a
salt, a complex, or a solvate.
3. The pharmaceutical composition of claim 2, wherein the nicotinic
compound is nicotine polacrilex.
4. The pharmaceutical composition of claim 1, wherein the nicotinic
compound is sorbed onto a porous particulate carrier.
5. The pharmaceutical composition of claim 4, wherein the porous
particulate carrier comprises microcrystalline cellulose.
6. The pharmaceutical composition of claim 1, wherein the sugar
substitute is isomalt.
7. The pharmaceutical composition of claim 1, wherein the sugar
alcohol syrup is in an amount sufficient to slow recrystallization
of the sugar substitute in melted form.
8. The pharmaceutical composition of claim 1, wherein the sugar
alcohol syrup is maltitol syrup or xylitol syrup.
9. The pharmaceutical composition of claim 1, wherein the
composition comprises at least about 85% by weight of the sugar
substitute.
10. The pharmaceutical composition of claim 1, wherein the
composition comprises at least about 4.0% by weight of sugar
alcohol syrup.
11. The pharmaceutical composition of claim 1, wherein the
composition comprises at least about 4.5% by weight of sugar
alcohol syrup.
12. The pharmaceutical composition of claim 1, wherein the
composition is in the form of a lozenge or tablet.
13. The pharmaceutical composition of claim 1, wherein the
composition is translucent.
14. The pharmaceutical composition of claim 1, wherein the
composition further comprises one or more flavorants.
15. The pharmaceutical composition of claim 14, wherein the amount
of flavorant is from about 0.1 to about 0.5 percent by weight of
the pharmaceutical composition.
16. The pharmaceutical composition of claim 14, wherein the
flavorant is vanillin and/or mint flavor.
17. The pharmaceutical composition of claim 1, further comprising
at least one sweetener.
18. The pharmaceutical composition of claim 17, wherein the at
least one sweetener comprises sucralose.
19. The pharmaceutical composition of claim 1, further comprising
NaCl.
20. The pharmaceutical composition of claim 19, wherein the amount
of NaCl is from about 0.5 to about 1 percent by weight of the
pharmaceutical composition.
21.-47. (canceled)
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. Patients, 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, U.S. patent application Ser. No. 12/769,335 and
International Application No. PCT/US2011/033928, both to Brinkley
et al., which are incorporated herein by reference.
[0005] It has been proposed to administer nicotine using a
transdermal patch. Representative types of nicotine-containing
transdermal patch products have been marketed under the tradenames
"Habitrol," "Nicoderm," "Nicorette," "Nicorette CQ," "Nicotinell"
and "ProStep." See also, for example, U.S. Pat. No. 4,597,961 to
Etscom; U.S. Pat. No. 5,298,257 to Bannon et al.; U.S. Pat. No.
5,603,947 to Wong et al.; U.S. Pat. No. 5,834,011 to Rose et al.;
U.S. Pat. No. 6,165,497 to Osborne et al. and U.S. Pat. No.
6,676,959 to Anderson et al., which are incorporated herein by
reference. It also has been suggested that transdermal
administration of nicotine can be accompanied by ingestion of other
types of nicotine-containing products. See, for example, U.S. Pat.
No. 5,593,684 to Baker et al.; US Pat. Pub. No. 2009/0004249 to
Gonda; and Fagerstrom, Health Values, 18:15 (1994), which are
incorporated herein by reference.
[0006] One particularly popular way to provide for oral
administration of nicotine has been through the use of
nicotine-containing gum. Nicotine-containing gum products have been
marketed under the tradenames "Nicorette," "Nicotinell" and
"Zonnic." See also, for example, U.S. Pat. No. 3,845,217 to Ferno
et al.; U.S. Pat. No. 3,877,468 to Lichtneckert et al.; U.S. Pat.
No. 3,901,248 to Lichtneckert et al.; U.S. Pat. No. 6,344,222 to
Cherukuri et al.; U.S. Pat. No. 6,358,060 to Pinney et al.; U.S.
Pat. No. 6,773,716 to Ream et al. and U.S. Pat. No. 6,893,654 to
Pinney et al.; and US Pat. Pub. No. 2004/0191322 to Hansson, which
are incorporated herein by reference.
[0007] Another way that has been employed to provide oral
administration of nicotine has been through the use of
nicotine-containing lozenge or tablet types of products.
Nicotine-containing lozenge, mini lozenge, tablet, and microtab
types of products have been marketed under the tradenames "Commit,"
"Nicorette," "Nicotinell" and "NiQuitin." 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; US Pat.
Pub. Nos. 2001/0016593 to Wilhelmsen and 2010/0004294 to Axelsson
et al., which are incorporated herein by reference.
[0008] Nicotine also has been administered in the form of nasal or
oral sprays. Various exemplary ways to administer nicotine in the
form of a nasal spray are set forth in U.S. Pat. No. 4,579,858 to
Ferno et al.; U.S. Pat. No. 5,656,255 to Jones and U.S. Pat. No.
6,596,740 to Jones, which are incorporated herein by reference.
Various exemplary ways to administer nicotine in the form of an
oral spray, such as for buccal administration, are set forth in
U.S. Pat. No. 6,024,097 to Von Wielligh; US Pat. Pub. Nos.
2003/0159702 to Lindell et al.; 2007/0163610 to Lindell et al. and
2009/0023819 to Axelsson; EP 1458388 to Lindell et al.; and PCT WO
2008/037470 to Axelsson et al., which are incorporated herein by
reference. Nicotine-containing sprays have been marketed under the
tradenames "Nicotrol NS," "Quit" and "Zonnic."
[0009] Various other ways to administer nicotine for the purpose of
providing a therapeutic effect have been proposed. For example, it
has been suggested that nicotine can be incorporated into orally
dissolving films (e.g., U.S. Pat. No. 6,709,671 to Zerbe et al.;
U.S. Pat. No. 7,025,983 to Leung et al.; and U.S. Pat. No.
7,491,406 to Leung et al.; and US Pat. Pub. Nos. 2006/0198873 to
Chan et al. and 2006/0204559 to Bess et al.); oral osmotic devices
(e.g., U.S. Pat. No. 5,147,654 to Place et al.); gum pads (e.g.,
U.S. Pat. No. 6,319,510 to Yates); oral patches (e.g., US Pat. Pub.
No. 2006/0240087 to Houze et al.); snuff-type forms in pouches or
sachets (e.g., U.S. Pat. No. 4,907,605 to Ray et al. and US Pat.
Pub. No. 2009/0293895 to Axelsson et al.); lip balm (e.g., U.S.
Pat. No. 7,105,173 to Rolling) and beverages (e.g., U.S. Pat. No.
6,268,386 to Thompson; U.S. Pat. No. 7,115,297 to Stillman and U.S.
Pat. No. 7,435,749 to Knight). It also has been suggested that
nicotine can be delivered using various types of inhalation devices
and vapor delivery systems (e.g., U.S. Pat. No. 4,284,809 to Ray;
U.S. Pat. No. 4,800,903 to Ray et al.; U.S. Pat. No. 6,234,169 to
Bulbrook et al. and U.S. Pat. No. 6,874,507 to Farr; and US Pat.
Pub. Nos. 2006/0018840 to Lechuga-Ballesteros and 2009/0005423 to
Gonda; and EP 1,618,803 to Hon).
[0010] 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
[0011] In one aspect, the present invention relates to a
nicotine-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 incorporates at least one nicotinic
compound, a sugar substitute, and a sugar alcohol syrup. In certain
embodiments, the composition exhibits some level of
translucency.
[0012] In certain embodiments, the present invention provides a
nicotine-containing pharmaceutical composition, comprising: a
nicotinic compound; at least about 80% by weight of a sugar
substitute; and a sugar alcohol syrup, wherein the sugar substitute
is a non-hygroscopic sugar alcohol capable of forming a glassy
matrix and wherein the composition is in a pharmaceutically
acceptable form adapted for oral delivery of the composition. At
least a portion of the nicotinic compound can, in certain
embodiments, be in the form of a free base, a salt, a complex, or a
solvate. For example, the nicotinic compound may comprise nicotine
polacrilex. In some embodiments, the nicotinic compound is sorbed
onto a porous particulate carrier. For example, the porous
particulate carrier can comprise microcrystalline cellulose.
[0013] In some embodiments, the sugar substitute is isomalt. In
certain embodiments, the sugar alcohol syrup is maltitol syrup or
xylitol syrup. The amount of the components can vary. For example,
in some embodiments, the composition comprises at least about 85%
by weight of the sugar substitute. In some embodiments, the amount
of sugar alcohol syrup is that amount sufficient to slow
recrystallization of the sugar substitute in melted form. For
example, in some embodiments, the composition comprises at least
about 4.0% by weight or at least about 4.5% by weight of the sugar
alcohol syrup.
[0014] Various components can be included within the pharmaceutical
composition. For example, in some embodiments, the composition
further comprises one or more of flavorants, sweeteners, and NaCl.
The amount and type of these components can vary. For example, in
some embodiments, the amount of flavorant is from about 0.1 to
about 0.5 percent by weight of the pharmaceutical composition. In
some embodiments, the flavorant is vanillin and/or mint flavor. In
some embodiments, the sweetener comprises sucralose. The amount of
NaCl, where included, may be from about 0.5 to about 1 percent by
weight of the composition in certain embodiments.
[0015] The pharmaceutical composition may take any form. For
example, in some embodiments, the composition is in the form of a
lozenge or tablet. In certain embodiments, the composition is
translucent. In certain embodiments, the composition is
transparent.
[0016] In another aspect of the invention is provided 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 any of the embodiments
noted herein to a human subject (e.g., administering a
nicotine-containing pharmaceutical composition, comprising: a
nicotinic compound; at least about 80% by weight of a sugar
substitute; and a sugar alcohol syrup, wherein the sugar substitute
is a non-hygroscopic sugar alcohol capable of forming a glassy
matrix and wherein the composition is in a pharmaceutically
acceptable form adapted for oral delivery of the composition). For
example, the method may involve administering a composition that
incorporates a nicotinic compound, a sugar substitute, and a sugar
alcohol syrup. The administering step can, in certain embodiments,
comprise administering the pharmaceutical composition to a human
subject having a condition, disease, or disorder of the central
nervous system. The administering step can, in certain embodiments,
comprise administering the pharmaceutical composition to a human
subject as a smoking cessation aid.
[0017] In a further aspect, the invention provides a method of
preparing a nicotine-containing pharmaceutical composition,
comprising mixing a non-hygroscopic sugar substitute capable of
forming a glassy matrix in an amount of at least about 80% by
weight and a sugar alcohol syrup, in a melted state to form a
mixture; cooling the mixture and incorporating a nicotinic compound
into the cooled mixture; and further cooling the mixture to room
temperature to form a solid nicotine-containing pharmaceutical
composition. Various other steps can be included within this
method. For example, the method may, in certain embodiments,
further comprise adding one or more components selected from the
group consisting of flavorants, sweeteners, and NaCl.
[0018] In some embodiments, the mixing step comprises heating the
sugar substitute and the sugar alcohol syrup to a temperature above
the hard crack stage of the sugar substitute and the incorporating
step comprises adding a nicotinic compound to the mixture at a
temperature below the hard crack stage of the sugar substitute. For
example, in certain specific embodiments, the hard crack stage is
about 145.degree. C. to about 155.degree. C. and the sugar
substitute and the sugar alcohol syrup are heated at a temperature
between the hard crack stage and about 171.degree. C.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0019] The present inventions now will be described more fully
hereinafter. The invention may 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 satisfy applicable legal requirements. As used in
this specification and the claims, the singular forms "a," "an,"
and "the" include plural referents unless the context clearly
dictates otherwise.
[0020] The present invention involves the use of nicotinic
compounds for therapeutic purposes and provides compositions
adapted for oral delivery of nicotinic compounds. As used herein,
"nicotinic compound" refers to 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. 13/095,277 to Byrd et al., which is incorporated herein by
reference.
[0021] 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.
[0022] 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 U.S. Pat. No. 5,301,694 to Raymond et al.,
which are all incorporated herein by reference.
[0023] 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.
[0024] 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. The membrane
can be of any type, such as plate-and-frame (having a stack of
membranes and support plates), spiral-wound (having consecutive
layers of membrane and support material rolled up around a tube),
tubular (having a membrane-defined core through which the feed
flows and an outer, tubular housing where permeate is collected),
or hollow fiber (having several small diameter tubes or fibers
wherein the permeate is collected in the cartridge area surrounding
the fibers). The membrane can be constructed of any material. For
example, polysulfone, polyethersulfone, polypropylene,
polyvinylidenefluoride, and cellulose acetate membranes are
commonly used, although other materials can be used without
departing from the invention described herein.
[0025] Ultrafiltration membranes are available in a wide range of
pore sizes (typically ranging from about 0.1 to about 0.001
microns). Membranes are more typically described by their number
average molecular weight cutoffs. Ultrafiltration membranes are
commonly classified as membranes with molecular weight cutoffs of
from about 10.sup.3 Da to about 10.sup.5 Da. In practice, compounds
with molecular weights above the molecular weight cutoff are
retained in the retentate, and the compounds with molecular weights
below the cutoff pass through the filter into the permeate.
Ultrafiltration methods typically are not capable of removing low
molecular weight organic compounds and ions.
[0026] Ultrafiltration is typically a cross-flow separation
process. The liquid stream to be treated (feed) flows tangentially
along the membrane surface, separating into one stream that passes
through the membrane (permeate) and another that does not
(retentate or concentrate). The operating parameters of the
ultrafiltration system can be varied to achieve the desired result.
For example, the feed mixture to be filtered can be brought into
contact with the membrane by way of applied pressure. The rate of
permeation across the membrane is directly proportional to the
applied pressure; however, the maximum pressure may be limited. The
flow velocity of the mixture across the membrane surface can be
adjusted. Temperature can also be varied. Typically, permeation
rates increase with increasing temperature.
[0027] Commercial ultrafiltration systems are readily available and
may be used for the ultrafiltration methods of the present
invention. 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.
[0028] 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.
Accordingly, the ultrafiltered extract can 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.
[0029] The ultrafiltered extract exhibits a level of improvement in
clarity over the non-ultrafiltered extract. Clarity of the extract
(and pharmaceutical 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
certain embodiments, certain materials of the invention (e.g.,
certain tobacco extracts or pharmaceutical compositions made
therefrom) can have such a high degree of clarity that the material
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).
[0030] The improvement in clarity of the ultrafiltered extract over
the non-ultrafiltered extract can be quantified by any known
method. For example, optical methods such as turbidimetry (or
nephelometry) and colorimetry may be used to quantify the
cloudiness (light scattering) and the color (light absorption),
respectively, of the ultrafiltered extract or products made
therefrom. Translucency can also be confirmed by visual inspection
by simply holding the material (e.g., extract) or product up to a
light source and determining if light travels through the material
or product in a diffuse manner.
[0031] In certain embodiments, the ultrafiltered extract 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%. Acceptable levels of
translucency/transparency at a given wavelength in the
ultrafiltered extract can vary. Typically, the ultrafiltered
extract has 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 further processing to isolate the nicotine therefrom
for use in pharmaceutical compositions according to the present
invention.
[0032] 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 U.S. patent application
Ser. No. 12/769,335 and International Application No.
PCT/US2011/033928, both to Brinkley et al., which are incorporated
herein by reference.
[0033] 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.
[0034] 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.
[0035] 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).
[0036] 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.
[0037] 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.
[0038] Although sucrose can be used in the preparation of the
nicotine-containing products of the present invention, the products
are typically sugar-free products, 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.
[0039] In certain embodiments, the base of the nicotine products
described herein is a sugar substitute. By "base" is meant a
substance that makes up a relatively high percentage of the
nicotine product. The amount of sugar substitute in the
nicotine-containing product mixture can vary, but is typically at
least about 60%, at least about 75%, at least about 80%, at least
about 85%, or at least about 90% by weight of the mixture.
[0040] The sugar substitute is typically 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.
[0041] The sugar substitute can be any sugarless material (i.e.,
sucrose-free material) and can be natural or synthetically
produced. The sugar substitute used in the invention can be
nutritive or non-nutritive. For example, the sugar substitute is
commonly a sugar alcohol. Sugar alcohols that may be useful
according to the present invention include, but are not limited to,
erythritol, threitol, arabitol, xylitol, ribotol, mannitol,
sorbitol, dulcitol, iditol, isomalt, maltitol, lactitol,
polyglycitol, and mixtures thereof. For example, in certain
embodiments, the sugar alcohol is selected from the group
consisting of erythritol, sorbitol, and isomalt.
[0042] In certain embodiments, the sugar substitute is capable of
forming a glassy matrix. The formation of a glassy matrix is
commonly characterized by a translucent/transparent appearance.
Typically, the sugar substitute is substantially non-hygroscopic.
Non-hygroscopic materials typically do not absorb, adsorb, and/or
retain a significant quantity of moisture from the air. For
example, in some embodiments, the sugar substitute exhibits a
weight gain of water of less than about 50% upon exposure to
conditions of 25.degree. C., 80% relative humidity for two weeks.
Typically, the sugar substitute exhibits a weight gain of less than
about 30%, less than about 20%, less than about 10%, less than
about 5%, less than about 2%, or less than about 1% upon exposure
to conditions of 25.degree. C., 80% relative humidity for two
weeks. Non-hygroscopic materials can provide the benefit of
reducing the tendency of the nicotine-containing product to tackify
upon exposure to humidity.
[0043] In certain embodiments, the sugar substitute comprises one
or more sugar alcohols. For example, in one embodiment, the sugar
substitute is isomalt. Isomalt is a disaccharide that is typically
made by enzymatic rearrangement of sucrose into isomaltulose,
followed by hydrogenation to give an equimolar composition of
6-O-.alpha.-D-glucopyranosido-D-sorbitol (1,6-GPS) and
1-O-.alpha.-D-glucopyranosido-D-mannitol-dihydrate
(1,1-GPM-dihydrate).
[0044] In addition to the nicotinic compound and sugar substitute,
the nicotine-containing product of the present invention typically
contains a syrup, e.g., a sugar syrup or a sugar alcohol syrup.
"Sugar alcohol syrup" as used herein is intended to refer to a
thick solution of sugar alcohol in water, e.g., having greater than
about 40% solids, preferably having greater than about 50% solids,
greater than about 60% solids, greater than about 70% solids, or
greater than about 80% solids, by weight. Typically, the solid
content of the sugar alcohol syrup primarily comprises the named
sugar alcohol (i.e., maltitol syrup typically comprises greater
than about 80%, greater than about 85%, or greater than about 90%
by weight maltitol on a dry basis). Sugar alcohol syrups are
generally prepared by heating a solution of the sugar alcohol in
water and cooling the mixture to give a viscous composition. The
resulting syrup is typically characterized by a relatively high
concentration of sugar alcohol and relatively high stability (i.e.,
the sugar alcohol typically does not crystallize from solution,
e.g., at room temperature).
[0045] The syrup, e.g., sugar alcohol syrup, desirably is capable
of affecting the re-crystallization of a melted sugar substitute.
One exemplary sugar alcohol syrup that is particularly useful
according to the present invention is maltitol syrup. Other sugar
alcohol syrups can be used, including, but not limited to, syrups
containing xylitol, mannitol, glycerol, erythritol, threitol,
arabitol, ribitol, mannitol, sorbitol, dulcitol, iditol, isomalt,
lactitol, or polyglycitol. Such sugar alcohol syrups can be
prepared or can be obtained from commercial sources. For example,
maltitol syrups are commercially available from such suppliers as
Corn Products Specialty Ingredients of Newark, Delaware. Although
sugar alcohol syrups may be preferred, sugar syrups can, in certain
embodiments, be used in place of or in combination with the sugar
alcohol syrup. For example, in some embodiments, corn syrup, golden
syrup, and/or molasses can be used.
[0046] The amount of sugar alcohol syrup added to the product
mixture is typically that amount required to slow recrystallization
of the sugar substitute in melted form. One of skill in the art
would understand the need to vary the amount of sugar alcohol syrup
depending on the composition of the remaining ingredients to ensure
that the recrystallization is sufficiently slow to provide a
material with the desired characteristics (e.g., a desired level of
translucency/transparency). Accordingly, 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 nicotine-containing product 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.
[0047] Other pharmaceutically acceptable components may be added to
the products of the invention. For example, in certain embodiments,
the nicotine-containing pharmaceutical composition further
comprises a salt. The presence of a salt in the composition may act
to suppress bitterness and/or enhance sweetness. Any type of salt
can be used. Common table salt (NaCl) is typically used according
to the present invention, but other types of salts are intended to
be encompassed as well. The amount of salt added may vary, but
typically ranges from 0% to about 8%, for example from about 1% to
about 4% or from about 0% to about 2%, often around 1% by weight of
the pharmaceutical composition mixture. In some embodiments, a
somewhat salty taste is a desirable feature of the pharmaceutical
composition.
[0048] In some embodiments, the composition according to the
invention further comprises one or more buffering agents and/or pH
adjusters (e.g., acids or bases). Certain exemplary buffering
agents and/or pH adjusters include, but are not limited to,
magnesium oxide, magnesium hydroxide, potassium carbonate, sodium
carbonate, potassium bicarbonate, sodium bicarbonate, or mixtures
thereof. In some embodiments, one or more buffering agents and/or
pH adjusters are added to the mixture to ensure that the final
pharmaceutical composition has a pH within a desirable range.
Exemplary pH ranges in such compositions are generally from about
6-11, and often about 7-10 (e.g., about 7 or about 8). In such
embodiments, the amount of buffering agent and/or pH adjuster added
to the composition mixture is simply that amount required to bring
the formulation to, or keep the formulation at, the desired pH. The
amount of buffering agent and/or pH adjuster added to any given
formulation can be readily calculated by one skilled in the art and
may comprise, for example, about 0.5% to about 1% by weight of the
mixture. It is noted that in certain embodiments, a basic pH is not
necessary in the products of the present invention. Accordingly,
certain products of the present invention have a pH of less than
about 6 or less than about 5 (e.g., from about 4 to about 6).
[0049] 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. W02008/040371 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.
[0050] In some embodiments, one or more additional sweeteners are
added to the compositions of the present invention. The one or more
additional sweeteners can comprise any natural or artificial
sweetener, including, but not limited to, sugar or any of the sugar
substitutes described previously. In certain embodiments, the
sweetener can include, glycyrrhizin, glycerol, inulin, lactitol,
lactose, mabinlin, maltitol, mannitol, miraculin, monatin,
monellin, osladin, pentadin, polydextrose, sorbitol, stevia,
tagatose, thaumatin, acesulfame potassium, alitame, aspartame,
cyclamate, dulcin, glucin, neotame, saccharin, sorbitol, sucralose,
xylitol, and combinations thereof. In certain embodiments, the
sweetener comprises sucralose
(1,6-Dichloro-1,6-dideoxy-.beta.-D-fructofuranosyl-4-chloro-4-deoxy-.alph-
a.-D-galactopyranoside). The amount of sweetener added can vary,
but is typically that amount required for a sufficiently "sweet"
taste. For example, sweetener can be added to make the sweetness of
the nicotine-containing pharmaceutical composition comparable to
that of sugar. In particular embodiments, sucralose is added in an
amount of about 0.5% to about 2% by weight of the product mixture,
often in an amount of about 1% by weight of the mixture.
[0051] Various natural and/or artificial flavorants can also be
added to the pharmaceutical compositions of the present invention,
and the character of these flavors can be described as, without
limitation, fresh, sweet, herbal, confectionary, floral, fruity or
spicy. Specific types of flavors include, but are not limited to,
vanilla (e.g., vanillin optionally in complexed form), coffee,
chocolate, cream, mint, spearmint, menthol, peppermint,
wintergreen, lavender, cardamon, nutmeg, cinnamon, clove,
cascarilla, sandalwood, honey, jasmine, ginger, anise, sage,
licorice, and fruit flavors such as lemon, orange, apple, peach,
lime, cherry, and strawberry. See also, Leffingwill et al., Tobacco
Flavoring for Smoking Products, R. J. Reynolds Tobacco Company
(1972), which is incorporated herein by reference. Flavorings also
can include components that are considered moistening, cooling or
smoothening agents, such as eucalyptus. Flavorings can also include
sensates, which can add a range of tactile, organoleptic properties
to the pharmaceutical compositions. For example, sensates can
provide a warming, cooling, or tingling sensation. These flavors
may be provided neat (i.e., alone) or in a composite (e.g.,
spearmint and menthol, or orange and cinnamon). Flavorants of this
type can be present in an amount of from about 0.5% to about 15%,
often between about 0.5% and about 1.5% by weight of the mixture.
In certain embodiments, the flavorant is present in any amount of
at least about 0.5% by weight or at least about 0.75% by weight of
the mixture.
[0052] 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.
[0053] Various other substances can be added to the compositions of
the present invention. For example, excipients such as fillers or
carriers for active ingredients (e.g., calcium polycarbophil,
microcrystalline cellulose, hydroxypropylcellulose, sodium
carboxymethylcellulose, cornstarch, silicon dioxide, calcium
carbonate, lactose, and starches including potato starch, maize
starch, etc.), thickeners, film formers and binders (e.g.,
hydroxypropyl cellulose, hydroxypropyl methylcellulose, acacia,
sodium alginate, xanthan gum and gelatin), antiadherents (e.g.,
talc), glidants (e.g., colloidal silica), humectants (e.g.,
glycerin), preservatives and antioxidants (e.g., sodium benzoate
and ascorbyl palmitate), surfactants (e.g., polysorbate 80), dyes
or pigments (e.g., titanium dioxide or D&C Yellow No. 10), and
lubricants or processing aids (e.g, calcium stearate or magnesium
stearate) are added to the compositions in certain embodiments.
[0054] Certain types of nicotine-containing products also can have
outer coatings composed of ingredients capable of providing
acceptable outer coatings (e.g., an outer coating can be composed
of ingredients such as carnauba wax, and 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. 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.
[0055] 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.
[0056] For example, solid dosage forms may be formulated so as to
provide a delayed release of the active agent (i.e., the nicotinic
compound), such as by application of a coating. Delayed release
coatings are known in the art, and dosage forms containing such may
be prepared by any known suitable method. Such methods generally
include that, after preparation of the solid dosage form (e.g., a
tablet or caplet), a delayed release coating composition is
applied. Solid dosage forms according to the present invention may
also be sustained release (i.e., releasing the active agent over a
prolonged period of time), and may or may not also be delayed
release. Sustained release formulations are known in the art and
are generally prepared by dispersing an active agent within a
matrix of a gradually degradable or hydrolyzable material, such as
an insoluble plastic, a hydrophilic polymer, or a fatty compound.
Alternatively, a solid dosage form may be coated with such a
material.
[0057] Compositions can be co-extruded, laminated or formed so as
to have sandwich-type forms; and hence the location of nicotine and
other ingredients can be controlled in order to provide the desired
features such as performance, behavior, interaction or
non-interaction with other ingredients, storage stability, and the
like. In addition, mixtures of component ingredients can be
formulated and manufactured into core/shell types of configurations
(e.g., lozenge types of products that have an inner region and at
least one additional overlayer), with the various regions of such
products having differing overall compositions or properties. Thus,
for example, the nicotinic compound can have a relatively high
concentration towards the inner region of the product, or a
relatively high concentration towards the outer region of the
product.
[0058] One particularly preferred type of a representative
composition incorporating nicotine as an active ingredient, and
that comprises nicotine in an orally provided form, has the form of
a lozenge, tablet, microtab, or other tablet-type product. See, for
example, the types of nicotine-containing lozenges, lozenge
formulations, lozenge formats and configurations, lozenge
characteristics and techniques for formulating or manufacturing
lozenges set forth in U.S. Pat. No. 4,967,773 to Shaw; 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.; U.S. Pat. No. 6,248,760 to Wilhelmsen; and U.S. Pat. No.
7,374,779; US Pat. Pub. Nos. 2001/0016593 to Wilhelmsen;
2004/0101543 to Liu et al.; 2006/0120974 to Mcneight; 2008/0020050
to Chau et al.; 2009/0081291 to Gin et al.; and 2010/0004294 to
Axelsson et al.; which are incorporated herein by reference.
[0059] The amount of the composition of the invention contained
within each piece or unit of lozenge type of product can vary. For
example, a representative unit for lozenge products generally
weighs at least about 100 mg, often at least about 200 mg, and
frequently at least about 300 mg; while the weight of a
representative unit for such products generally does not exceed
about 1.5 g, often does not exceed about 1 g, and frequently does
not exceed about 0.75 g.
[0060] 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 and about 4 mg of nicotine per piece or unit,
calculated as nicotine base.
[0061] 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.
[0062] 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.
[0063] 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 feel, 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;
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.
[0064] In certain embodiments, the nicotine-containing
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 the
nicotine-containing products of the present invention are typically
comparable to or higher than those of traditional
nicotine-containing products. Translucency can also be confirmed by
visual inspection by simply holding the product up to a light
source and determining if light travels through the product in a
diffuse manner.
[0065] The manners and methods used to formulate and manufacture
the nicotine-containing composition can vary. Typical conditions
associated with manufacture of pharmaceutical types of products
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.
[0066] For example, the compositions can be prepared via any method
commonly used for the preparation of hard boiled confections.
Exemplary methods for the preparation of hard confections can be
found, for example, in LFRA Ingredients Handbook, Sweeteners, Janet
M. Dalzell, Ed., Leatherhead Food RA (Dec. 1996), pp. 21-44, which
is incorporated herein by reference.
[0067] Typically, the products of the invention are prepared by
first preparing a first mixture of ingredients. The composition of
the first mixture of ingredients can vary; however, it typically
comprises a sugar substitute and may contain various optional
additional substances (e.g., the sugar alcohol syrup, NaCl,
preservatives, further sweeteners, water, and/or flavorings). In
certain embodiments, the first mixture of ingredients comprises the
sugar substitute and sugar alcohol syrup (e.g., maltitol syrup or
xylitol syrup). Typically, the first mixture of ingredients does
not contain the nicotinic compound.
[0068] The first mixture of ingredients is heated until it melts;
subsequently, the mixture is heated to or past the hard crack
stage. In confectionary making, the hard crack stage is defined as
the temperature at which threads of the heated mixture (obtained by
pulling a sample of cooled syrup between the thumb and forefinger)
are brittle or as the temperature at which trying to mold the syrup
results in cracking. According to the present method, the
temperature at which the hard crack stage is achieved can vary,
depending on the specific makeup of the product mixture but
generally is between about 145.degree. C. and about 170.degree. C.
(e.g., about 165.degree. C.). Typically, the mixture is not heated
above about 171.degree. C., which is the temperature at which
caramelization begins to occur. In the processes of the present
invention, the mixture is typically heated to the hard crack stage
temperature or above and then allowed to cool. The heating can be
conducted at atmospheric pressure or under vacuum. Typically, the
method of the present invention is conducted at atmospheric
pressure.
[0069] In one exemplary embodiment, the first mixture of
ingredients comprises a high percentage of isomalt and the mixture
is heated past the hard crack stage (e.g., to about 165.degree.
C.). The mixture is heated to this temperature and then removed
from the heat to allow the mixture to cool. At one or more
predetermined temperatures, certain additional components are
added. For example, in certain embodiments, various components are
added when the melt has cooled to about 143.degree. C. For example,
certain components that may be added at this point include, but are
not limited to, buffers, water, and/or the nicotinic compound. In
some embodiments, various components are added when the melt has
cooled to about 120.degree. C. For example, certain components that
may be added at this point include, but are not limited to,
flavorants, the nicotinic compound, water, and/or sweeteners.
Certain flavorants are volatile and are thus preferably added after
the mixture has cooled somewhat. Further, in some embodiments, it
is desirable to add the tobacco component at a somewhat cooled
temperature. As noted above, in certain embodiments, various
components are added at different stages in the cooling process.
However, it is also possible to combine these components and add
them together at a single stage in the cooling process.
[0070] The combined mixture is then formed into the desired shape.
In certain embodiments, the mixture is poured directly into molds,
formed (e.g., rolled or pressed) into the desired shape, or
extruded. If desired, the mixture can be extruded or injection
molded. In certain embodiments, the mixture is formed or extruded
into a mold of desired shape in an enclosed system, which may
require decreased temperature and which may limit evaporation of
certain mixture components. For example, such a system may limit
the evaporation of volatile components including, but not limited
to, the nicotinic compound and/or flavorants. Other methods of
producing nicotine-containing products such as lozenges are also
intended to be encompassed herein. In use, the compositions of the
present invention are typically administered in a form adapted for
buccal or sublingual delivery. In certain embodiments, the
compositions are in a form suitable for oral ingestion. For
example, nicotine-containing compositions can be administered and
employed using the manners and methods typically used for the
administration of traditional types of nicotine-containing
lozenges.
[0071] The compositions of the present invention can be used for
treatment of a wide variety of conditions, diseases, and disorders
responsive to stimulation of one or more types of nicotinic
acetylcholinergic receptors (nAChRs). The compositions can be used
to treat those types of conditions, diseases, and disorders that
have been reported to be treatable through the use or
administration of nicotine as an agonist of nAChRs. As such, the
compositions can be used to treat various CNS conditions, diseases,
and disorders, and the compositions also can be used as smoking
cessation aids (i.e., as components of NRT). Exemplary conditions,
diseases or disorders that can be treated include cognitive
disorders such as Alzheimer's disease and attention deficit
disorder, schizophrenia, Parkinson's disease, Tourette's syndrome,
ulcerative colitis, dry eye disease, hypertension, obesity, and
hemorrhoids. Compositions of the invention may also find use as a
treatment to reduce stress or pain.
[0072] 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.
[0073] 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 construed as
limiting thereof.
EXPERIMENTAL
[0074] The following examples are provided in order to further
illustrate the invention but should not be construed as limiting
the scope thereof. Unless otherwise noted, all parts and
percentages are by weight.
[0075] Hard-boiled lozenges are prepared according to the following
process. Isomalt and maltitol syrup (or xylitol syrup) are heated
to melting without stirring, to hard crack temperature (e.g.,
165.degree. C.). The melt is cooled to approximately 143.degree.
C., with very slight, discontinuous stirring. Other components
(e.g., buffer, nicotine, sweetener, and/or flavorants) are added to
the mixture and folded in carefully with a spatula without
introducing much air into the melt. The melt is further cooled to
about 120.degree. C. Further components (e.g., buffer, nicotine,
sweetener, and/or flavorants) are added to the mixture and folded
in carefully with a spatula without introducing much air into the
melt. The final mixture is poured into a glass beaker, the contents
are poured from the beaker in a chord on a metal brick, in
breakaway molds with niches of suitable dimensions, or in molds
(for individual lozenges). It may be necessary to reheat the beaker
in order to obtain a viscosity of the melt so it flows easily. The
melt is cooled for a time suitable for solidifying (e.g., at room
temperature).
[0076] Table 1 below provides six examples of product compositions
prepared according to the invention as outlined above.
TABLE-US-00001 TABLE 1 Formulations of Samples 1-6 Sample 1 Sample
2 Sample 3 Sample 4 Sample 5 Sample 6 Component (g) (g) (g) (g) (g)
(g) Isomalt 279.6 279.6 278.8 279.6 281.85 278.85 Maltitol syrup
15.0 15.0 15.0 -- 15.0 -- Sodium carbonate 2.25 2.25 2.25 2.25 --
2.25 Acesulfame K 0.15 0.15 0.15 0.15 0.15 0.15 Mint-derived 0.75
0.75 0.75 0.75 0.75 1.5 Flavorant Peppermint Flavorant 0.75 0.75 --
-- -- 0.75 Mint Flavorant -- -- 1.5 0.75 0.75 -- Water 7.75 + 10* 4
-- 4 4 4 Nicotine bitartrate 1.5 1.5 1.5 1.5 1.5 1.5 dihydrate
Xylitol syrup -- -- -- 15.0 -- 15.0 *Added in two separate process
steps as provided in Table 2, below (7.75 g added in Addition 1, 10
g added in Addition 2)
[0077] In Table 2 below, each of the six samples is described in
terms of process steps used to produce the product. The steps
including the step of forming a first mixture (e.g., Isomalt and
maltitol syrup), melting the first mixture at a temperature above
the hard crack stage, cooling the first mixture to about
143.degree. C. and then adding a second composition to the first
mixture (i.e., Addition 1 in the table), and finally cooling the
product mixture to 120.degree. C. before adding the final
ingredients (i.e., Addition 2 in the table).
TABLE-US-00002 TABLE 2 Preparation of Samples 1-6 Process step
Sample 1 Sample 2 Sample 3 Sample 4 Sample 5 Sample 6 Melt Isomalt,
Isomalt, Isomalt, Isomalt, Isomalt, Isomalt, maltitol maltitol
maltitol xylitol maltitol xylitol syrup syrup, syrup, syrup, syrup
syrup, sodium sodium sodium sodium carbonate carbonate carbonate
carbonate Cooling to yes yes yes yes yes yes 143.degree. C.
Addition 1 Sodium -- Nicotine Nicotine Nicotine Nicotine carbonate,
bitartrate bitartrate bitartrate bitartrate water dihydrate
dihydrate, dihydrate, dihydrate, water water water Cooling to yes
yes yes yes yes yes 120.degree. C. Addition 2 Nicotine Nicotine
Acesulfame Acesulfame Acesulfame Acesulfame bitartrate bitartrate
K, Cooling K, Cooling K, Cooling K, Cooling dihydrate, dihydrate,
Flavorant, Flavorant, Flavorant, Flavorant, water, water, Mint Mint
Mint Peppermint acesulfame acesulfame Flavorant Flavorant Flavorant
Flavorant K, Cooling K, Cooling Flavorant, Flavorant, Peppermint
Peppermint Flavorant Flavorant Appearance Brown Brown Brown, Brown
Slightly Brown (translucent opaque yellow unless otherwise
described)
* * * * *