U.S. patent application number 12/775910 was filed with the patent office on 2011-11-10 for nicotine-containing pharmaceutical compositions.
Invention is credited to August J. Borschke.
Application Number | 20110274628 12/775910 |
Document ID | / |
Family ID | 44902065 |
Filed Date | 2011-11-10 |
United States Patent
Application |
20110274628 |
Kind Code |
A1 |
Borschke; August J. |
November 10, 2011 |
NICOTINE-CONTAINING PHARMACEUTICAL COMPOSITIONS
Abstract
A composition intended to be employed for therapeutic purposes
incorporates nicotine and at least one other nicotinic compound.
Representative forms of nicotine can be as a free base (e.g., as a
mixture of nicotine and microcrystalline cellulose), as a form of
nicotine salt (e.g., as nicotine bitartrate) or as nicotine
polacrilex. The other nicotinic compound is a compound that can be
considered to bind selectively to certain nicotinic receptor
subtypes, and particularly those of the central nervous system. For
example, the other nicotinic compound can be a compound that binds
selectively to the nicotinic receptor subtypes .alpha..sub.7 or
.alpha..sub.4.beta..sub.2. The composition is useful for treatment
of central nervous system conditions, diseases and disorders, and
as a nicotine replacement therapy.
Inventors: |
Borschke; August J.;
(Winston-Salem, NC) |
Family ID: |
44902065 |
Appl. No.: |
12/775910 |
Filed: |
May 7, 2010 |
Current U.S.
Class: |
424/48 ; 514/250;
514/305 |
Current CPC
Class: |
A61P 25/00 20180101;
A61K 9/12 20130101; A61K 31/455 20130101; A61P 25/34 20180101; A61K
9/0053 20130101; A61K 9/009 20130101; A61P 43/00 20180101; A61K
9/1652 20130101; A61K 9/20 20130101; A61K 31/465 20130101; A61K
31/498 20130101; A61K 9/0058 20130101; A61K 31/455 20130101; A61K
2300/00 20130101; A61K 31/498 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/48 ; 514/250;
514/305 |
International
Class: |
A61K 9/68 20060101
A61K009/68; A61P 25/34 20060101 A61P025/34; A61P 25/00 20060101
A61P025/00; A61K 31/4995 20060101 A61K031/4995; A61K 31/465
20060101 A61K031/465 |
Claims
1. A nicotine-containing composition comprising: a source of
nicotine; and an agonist or pharmaceutically acceptable salt
thereof, having selectivity to a receptor selected from the group
consisting of an .alpha..sub.7 nicotinic receptor subtype and an
.alpha..sub.4.beta..sub.2 nicotinic receptor subtype; wherein the
composition is in a pharmaceutically acceptable form.
2. The composition of claim 1, wherein the receptor is an
.alpha..sub.7 nicotinic receptor subtype.
3. The composition of claim 2, wherein the agonist is selected from
the group consisting of
N-[(2S,3S)-2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofur-
an-2-carboxamide,
(5aS,8S,10aR)-5a,6,9,10-Tetrahydro,7H,11H-8,10a-methanopyrido[2',3':5,6]p-
yrano[2,3-d]azepine, 1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic
acid, 4-bromophenyl ester,
3-[(3E)-3-[(2,4-dimethoxyphenyl)methylidene]-5,6-dihydro-4H-pyridin-2-yl]-
pyridine,
2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyr-
role,
(5S)-spiro[1,3-oxazolidine-5,8'-1-azabicyclo[2.2.2]octane]-2-one,
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide,
5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide,
EVP-6124, EVP-4473, TC-6987, and MEM3454.
4. The composition of claim 3, wherein the agonist is
N-[(2S,3S)-2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofur-
an-2-carboxamide.
5. The composition of claim 1, wherein the receptor is an
.alpha..sub.4.beta..sub.2 nicotinic receptor subtype.
6. The composition of claim 5, wherein the agonist is selected from
the group consisting of
7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino(2,3-h)(3) benzazepine,
(2S,4E)-5-(5-isopropoxypyridin-3-yl)-N-methylpent-4-en-2-amine,
[3-(2(S))-azetidinylmethoxy)pyridine]dihydrochloride,
(5aS,8S,10aR)-5a,6,9,10-Tetrahydro,7H,11H-8,10a-methanopyrido[2',3':5,6]p-
yrano[2,3-d]azepine, A-969933, S35836-1, S35678-1,
3-(5,6-Dichloro-pyridin-3-yl)-1S,5S-3,6-diazabicyclo[3.2.0]heptanes,
AZD1446, and TC-6499.
7. The composition of claim 6, wherein the agonist is selected from
the group consisting of 7,8,9,10-tetrahydro-
6,10-methano-6H-pyrazino(2,3-h)(3) benzazepine and
(2S,4E)-5-(5-isopropoxypyridin-3-yl)-N-methylpent-4-en-2-amine.
8. The composition of claim 1, wherein the source of nicotine is in
the form of a free base, a salt, a complex, or a solvate.
9. The composition of claim 8, wherein the source of nicotine is
nicotine polacrilex, nicotine free base, nicotine tartrate or
nicotine bitartrate.
10. The composition of claim 1, wherein the composition is in a
form adapted for oral ingestion.
11. The composition of claim 10, wherein the pharmaceutically
acceptable form is selected from the group consisting of a pill,
tablet, lozenge, mini lozenge, capsule, caplet, pouch, gum and
spray.
12. The composition of claim 1, wherein the source of nicotine is
nicotine polacrilex, nicotine free base, nicotine tartrate or
nicotine bitartrate; wherein the receptor is an .alpha..sub.7
nicotinic receptor subtype; and wherein the pharmaceutically
acceptable form is a gum, lozenge, pouch or spray.
13. The composition of claim 1, wherein the source of nicotine is
nicotine polacrilex, nicotine free base, nicotine tartrate or
nicotine bitartrate; wherein the receptor is an
.alpha..sub.4.beta..sub.2 nicotinic receptor subtype; and wherein
the pharmaceutically acceptable form is a gum, lozenge, pouch or
spray.
14. A method for treating a condition, disease or disorder
responsive to stimulation of nicotinic acetylcholinergic receptors,
comprising orally or nasally administering an effective amount of a
pharmaceutical composition according to claim 1 to a human
subject.
15. The method of claim 14, wherein said administering step
comprises administering the pharmaceutical composition to a human
subject as a smoking cessation aid.
16. The method of claim 14, wherein the receptor is an
.alpha..sub.7 nicotinic receptor subtype.
17. The method of claim 14, wherein the receptor is an
.alpha..sub.4.beta..sub.2 nicotinic receptor subtype.
18. The method of claim 14, wherein the source of nicotine is
nicotine polacrilex, nicotine tartrate, or nicotine bitartrate.
19. The method of claim 14, wherein one or both of the source of
nicotine and the agonist are sorbed onto a porous particulate
carrier.
20. The method of claim 19, wherein the porous particulate carrier
comprises microcrystalline cellulose.
21. The method of claim 14, wherein the composition is in a form
adapted for oral ingestion.
22. The method of claim 21, wherein the composition is in the form
of a gum, lozenge, tablet, spray or a pouch product.
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
[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. Nos. 5,583,140 to Bencherif et
al.; 5,723,477 to McDonald et al.; 7,001,900 to Jacobsen et al.;
7,135,484 to Dart et al. and 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. Nos. 5,604,231 to Smith et al.; 5,811,442 to
Bencherif et al.; 6,238,689 to Rhodes et al.; and 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.
[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. Nos. 4,597,961 to
Etscom; 5,298,257 to Bannon et al.; 5,603,947 to Wong et al.;
5,834,011 to Rose et al.; 6,165,497 to Osborne et al.; and
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. Nos. 3,845,217 to Ferno
et al.; 3,877,468 to Lichtneckert et al.; 3,901,248 to Lichtneckert
et al.; 6,344,222 to Cherukuri et al.; 6,358,060 to Pinney et al.;
6,773,716 to Ream et al.; and 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. Nos. 5,110,605 to Acharya; 5,733,574 to Dam; 6,280,761 to
Santus; 6,676,959 to Andersson et al.; and 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. Nos. 4,579,858 to
Ferno et al.; 5,656,255 to Jones; and 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. Nos. 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. Nos. 6,709,671 to Zerbe et al.;
7,025,983 to Leung et al.; and 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. Nos. 6,268,386 to Thompson;
7,115,297 to Stillman; and 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. Nos.
4,284,809 to Ray; 4,800,903 to Ray et al.; 6,234,169 to Bulbrook et
al.; 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 a composition capable of
delivering or administering nicotine for therapeutic purposes.
BRIEF SUMMARY
[0011] In one aspect, the present invention relates to a
composition intended to be employed for therapeutic purposes. The
composition includes a form that is pharmaceutically effective or
pharmaceutically acceptable. The composition incorporates a
nicotinic compound that is considered to be non-selective (i.e., is
not considered to discriminate) among the various nAChRs in the CNS
and PNS. An example of such a compound is nicotine. The composition
incorporates at least one other nicotinic compound. The other
nicotinic compound is a compound that exhibits selectivity to
nicotinic receptor subtypes within the CNS. Other nicotinic
compounds that are highly preferred act as agonists, and
representative agonists are selective to nAChRs such as
.alpha..sub.7 and .alpha..sub.4.beta..sub.2. The nicotine can be as
a free base (e.g., as a mixture of nicotine and microcrystalline
cellulose), as another form of nicotine salt (e.g., as nicotine
bitartrate) or as nicotine polacrilex. In a highly preferred
embodiment, the composition that incorporates at least two
nicotinic active ingredients is provided in a single dosage form or
unit, which is intended to be administered by oral means.
[0012] In another aspect, the present invention relates to a method
for providing treatment for a condition, disease or disorder. The
method involves administering to a human subject, such as a subject
in need thereof, an effective amount of a composition incorporating
a nicotinic compound that is considered to be non-selective among
the various nAChRs in the CNS and PNS (e.g., nicotine) and at least
one other nicotinic compound. The other nicotinic compound is a
compound that exhibits selectivity to nAChRs within the CNS. Other
nicotinic compounds that are highly preferred act as agonists, and
are selective to nAChRs such as .alpha..sub.7 and
.alpha..sub.4.beta..sub.2. In a highly preferred embodiment, the
composition is administered by oral means.
[0013] Compositions of the present invention, including
compositions incorporating other pharmaceutically acceptable
excipient ingredients, can be provided in forms suitable for
administration to human subjects. Exemplary formats and
configurations for oral administration of nicotine-containing
compositions for therapeutic purposes include gum, tablet, lozenge,
pouch and mouth-spray types of products.
[0014] Compositions of the present invention can be used to treat a
wide variety of diseases, conditions and disorders, particularly
those of the CNS. Additionally, those compositions can be used as
smoking cessation aids (e.g., as components of NRT).
DETAILED DESCRIPTION OF THE DRAWINGS AND THE PRESENTLY PREFERRED
EMBODIMENTS
[0015] 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.
[0016] Embodiments of the present invention include the use of
nicotinic compounds for therapeutic purposes and provide
compositions adapted for oral or nasal delivery of nicotinic
compounds. As used herein, "nicotinic compound" refers to a
compound capable of affecting a nicotinic acetylcholinergic
receptor (nAChR). Preferably, a nicotinic compound is an agonist of
a nicotinic acetylcholinergic receptor. As used herein, "agonist"
refers to a compound that binds to a receptor and triggers a
response. The term "agonist" includes full agonists, partial
agonists and superagonists. Full agonists bind to the receptor and
mimic the response produced by binding of the natural ligand for
the receptor. Partial agonists bind the receptor and produce a
response, but are less efficacious in producing the response as
compared to the natural ligand for the receptor. Superagonists bind
the receptor and produce a response, but are more efficacious in
producing the response as compared to the natural ligand for the
receptor. As used herein, a "source of nicotine" 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). The nicotine may
include 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 an enantiomerically enriched
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) are virtually or essentially absent of other
components obtained from or derived from tobacco.
[0017] The source of nicotine of the nicotine-containing
compositions of the invention can include nicotine in free base
form, salt form, as a complex, as a solvate, or other suitable
form. 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), which are incorporated herein by reference. Additionally,
salts of nicotine have been available from sources such as Pfaltz
and Bauer, Inc. and K&K Laboratories, Division of ICN
Biochemicals, Inc. Furthermore, combinations of forms of nicotine,
or combinations of nicotine salts, can be employed. See, for
example, U.S. patent application Ser. No. 12/769,335, filed Apr.
28, 2010, to Brinkley et al.; which is incorporated herein by
reference.
[0018] "Pharmaceutically-acceptable salt" refers to a salt which is
acceptable for administration to a patient, such as a mammal (e.g.,
salts having acceptable mammalian safety for a given dosage
regime). Such salts can be derived from pharmaceutically-acceptable
inorganic or organic bases and from pharmaceutically-acceptable
inorganic or organic acids, depending on the particular
substituents found on the compounds described herein.
[0019] When nicotinic compounds of the present invention contain
relatively basic functionalities, as in nicotine, for example, acid
addition salts can be obtained by contacting the neutral form of
such compounds with a sufficient amount of the desired acid, either
neat or in a suitable inert solvent. Exemplary pharmaceutically
acceptable nicotine salts include 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. One
skilled in the art will appreciate that analogous salts can be
formed for agonist compounds comprising relatively basic
functionalities. Additional acids that can form salts include
formic, acetic, propionic, isobutyric, butyric,
alpha-methylbutyric, isovaleric, levulinic, beta-methylvaleric,
caproic, 2-furoic, benzoic, phenylacetic, heptanoic, octanoic,
nonanoic, oxalic, malonic, glycolic acid, benzenesulfonic,
camphosulfonic, ethanesulfonic, gluconic, glucoronic, glutamic,
hippuric, hydrobromic, isethionic, lactobionic, maleic, mandelic,
methanesulfonic, mucic, naphthalenesulfonic, nicotinic, nitric,
pamoic, pantothenic, phosphoric, sulfuric and the like as well as
other fatty acids having carbon chains of up to about 20 carbon
atoms.
[0020] Although nicotinic compounds of the present invention may
include relatively acidic functionalities less frequently, base
addition salts may be obtained by contacting the neutral form of
such compounds with a sufficient amount of the desired base, either
neat or in a suitable inert solvent. Salts derived from
pharmaceutically-acceptable inorganic bases include aluminum,
ammonium, calcium, copper, ferric, ferrous, lithium, magnesium,
manganic, manganous, potassium, sodium, zinc and the like. Salts
may also be derived from pharmaceutically-acceptable organic bases
including salts of primary, secondary, tertiary and quaternary
amines.
[0021] Also included are salts of amino acids such as arginate and
the like, and salts of organic acids like glucuronic or
galactunoric acids and the like (see, for example, Berge, S. M. et
al, "Pharmaceutical Salts", J. Pharmaceutical Science, 1977,
66:1-19). Certain compounds may contain both basic and acidic
functionalities that allow the compounds to be converted into
either base or acid addition salts.
[0022] In addition to salt forms, also included are compounds which
are in a pro-drug form. Pro-drugs of the compounds described herein
are those compounds that readily undergo chemical changes under
physiological conditions to provide the compounds of the present
invention. Additionally, pro-drugs can be converted to the
compounds of the present invention by chemical or biochemical
methods in an ex vivo environment. For example, pro-drugs can be
slowly converted to the compounds of the present invention when
placed in a transdermal patch reservoir with a suitable enzyme or
chemical reagent.
[0023] Certain compounds of the present invention can exist in
unsolvated forms as well as solvated forms, including hydrated
forms. In general, both solvated forms and unsolvated forms are
intended to be encompassed within the scope of the present
invention. Certain compounds of the present invention may exist in
multiple crystalline or amorphous forms (i.e., as polymorphs). In
general, all physical forms are equivalent for the uses
contemplated by the present invention and may be used within the
scope of the present invention.
[0024] The composition preferably includes another nicotinic
compound other than nicotine, and most preferably, that nicotinic
compound can be characterized as a selective agonist to nicotinic
receptor subtypes that are present in the brain, or that can
otherwise be characterized as a compound that modulates nicotinic
receptor subtypes of the CNS. Various nicotinic receptor subtypes
are described in Dwoskin et al., Exp. Opin. Ther. Patents, 10:
1561-1581 (2000); Huang et al., J. Am. Chem. Soc., 127: 14401-14414
(2006) and Millar, Biochem. Pharmacol., 78: 766-776 (2009); which
are incorporated herein by reference. Representative compounds that
can be characterized as other nicotinic compounds for purposes of
this invention are set forth in Schmitt et al., Annual Reports in
Med. Chem. 35: 41-51 (2000) and Arneric et al., Biochem.
Pharmacol., 74: 1092-1101 (2007); which are incorporated herein by
reference.
[0025] In one aspect, the other nicotinic compound can be a
compound has selectivity to the .alpha..sub.7 (alpha 7) nicotinic
receptor subtype, and preferably is an agonist of the .alpha..sub.7
nicotinic receptor subtype. Several compounds having such
.alpha..sub.7 receptor subtype selectivity have been reported in
the literature. For example, various compounds purported to have
selectivity to the .alpha..sub.7 nicotinic receptor subtype are set
forth in Malysz et al., Assay Drug Dev. Tech., August: 374-390
(2009). An example of one such nicotinic compound is
N-[(2S,3S)-2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofur-
an-2-carboxamide (also known as TC-5619). See, for example, Hauser
et al., Biochem. Pharmacol., 78: 803-812 (2009). Another
representative is compound is
(5aS,8S,10aR)-5a,6,9,10-Tetrahydro,7H,11H-8,10a-methanopyrido[2',3':5,6]p-
yrano[2,3-d]azepine (also known as dianicline or SSR591813 or
SSR-591,813). See, for example, Hajos et al., J. Pharmacol. Exp.
Ther., 312: 1213-1222 (2005). Another representative compound is
1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl
ester (also known as SSR180711). See, for example, Biton et al.,
Neuropsychopharmacol., 32: 1-16 (2007). Another representative
compound is
3-[(3E)-3-[(2,4-dimethoxyphenyl)methylidene]-5,6-dihydro-4H-pyridin-2--
yl]pyridine (also known as GTS-21). See, for example, U.S. Pat.
Nos. 5,516,802 to Zoltewicz et al. and 5,741,802 to Kem et al.
Another representative compound is
2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole
(also known as A-582941). See, for example, Thomsen et al.,
Neuroscience, 154: 741-753 (2008). Another representative compound
is (5S)-spiro[1,3-oxazolidine-5,8'-1-azabicyclo[2.2.2]octane]-2-one
(also known as AR-R-17779 or AR-R-17779). See, for example, Li et
al., Neuropsycopharmacol., 33: 2820-2830 (2008). Another
representative compound is
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide (also known
as PNU-282,987). See, for example, Siok et al., Eur. J. Neurosci.,
23: 570-574 (2006). Another representative compound is
5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide (also
known as WAY-317,538 or SEN-12333). See, for example, Roncarati et
al., J. Pharmacol. Exp. Ther., 329: 459-468 (2009). Yet other
examples are compounds are those designated as EVP-6124 and
EVP-4473 by Envivo Pharmaceuticals, Inc., TC-6987 by Targacept,
Inc. and MEM3454 by Memory Pharmaceuticals Corp. The foregoing
cited references are incorporated herein by reference.
[0026] In one aspect, the nicotinic compound other than nicotine
can be a compound that has selectivity to the
.alpha..sub.4.beta..sub.2 (alpha 4 beta 2) nicotinic receptor
subtype, and preferably is an agonist of the
.alpha..sub.4.beta..sub.2 nicotinic receptor subtype. Several
compounds having such .alpha..sub.4.beta..sub.2 receptor subtype
selectivity have been reported in the literature. An example of one
such nicotinic compound is known as
7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino(2,3-h)(3) benzazepine
(also known as varenicline and in the form of varenicline tartrate
which is the active ingredient of a product commercially marketed
under the tradename Chantix or Champix by Pfizer). See, for
example, Jorenby et al., JAMA, 296: 56-63 (2006) and US Pat. Pub.
No. 2010/0004451 to Ahmed et al. Another representative compound is
(2S,4E)-5-(5-isopropoxypyridin-3-yl)-N-methylpent-4-en-2-amine
(also known as ispronicline or AZD-3480 of AstraZeneca or TC-1734
of Targacept, Inc. (Winston-Salem N.C., USA)). See, for example,
Dunbar et al., Psychopharmacol. (Berlin), 191: 919-929 (2007).
Another representative compound is
[3-(2(S))-azetidinylmethoxy)pyridine]dihydrochloride, (also known
as A-85380). See, for example, Schreiber, Psychopharmacol.,
159:248-257 (2002). Another representative compound is
(5aS,8S,10aR)-5a,6,9,10-Tetrahydro,7H,11H-8,10a-methanopyrido[2',3':5,6]p-
yrano[2,3-d]azepine (also known as SSR591813). See, for example,
Cohen et al., Neuroscience, Pres. No. 811.5 (2002) and Cohen et
al., J. Pharmacol. Exp. Ther., 306: 407-420 (2003). Another
representative compound is known as A-969933. See, for example, Zhu
et al., Biochem. Pharmacol., 78: 920 (2009). Other representative
compounds are known as S35836-1 and S35678-1. See, for example,
Lockhart et al., Neuroscience, Pres. No. 684.9 (2002). Yet other
examples are compounds are those designated as
3-(5,6-Dichloro-pyridin-3-yl)-1S,5S-3,6-diazabicyclo[3.2.0]heptane
(also known as Sofinicline or ABT-894) by Abbott Laboratories;
AZD1446 by AstraZeneca and TC-6499 by Targacept, Inc. The foregoing
cited references are incorporated herein by reference.
[0027] The compositions of the invention preferably include 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 that are derived by
extracting naturally-occurring nicotine from tobacco 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, based on the total weight of the composition.
[0028] 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. 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).
[0029] 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) are preferably
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., J. Parent. Drug Assn.,
34(6): 452-462 (1980), which is incorporated herein by reference.
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.
[0030] The identity and quantity used of different 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. Nos. 5,512,306 to Carlsson et al.;
5,525,351 to Dam; 5,549,906 to Santus; 5,711,961 to Reiner et al.;
5,811,126 to Krishnamurthy; 5,939,100 to Albrechtsen et al.;
6,024,981 to Khankari et al.; 6,083,531 to Humbert-Droz et al.;
6,090,401 to Gowan, Jr. et al.; 6,110,495 to Dam; 6,248,760 to
Wilhelmsen; 6,280,761 to Santus; 6,426,090 to Ream et al.;
6,569,463 to Patel et al.; 6,583,160 to Smith et al.; 6,585,997 to
Moro et al.; 6,676,959 to Andersson et al.; 6,893,654 to Pinney et
al.; 7,025,983 to Leung et al. and 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.
[0031] Representative types of excipients that are particularly
useful for the manufacture of nicotine-containing products include
fillers or carriers for active ingredients (e.g., calcium
polycarbophil, microcrystalline cellulose, cornstarch, silicon
dioxide or calcium carbonate), thickeners, film formers and binders
(e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose,
acacia, sodium alginate, xanthan gum and gelatin), buffers and pH
control agents (e.g., magnesium oxide, magnesium hydroxide,
potassium carbonate, sodium carbonate, potassium bicarbonate,
sodium bicarbonate, or mixtures thereof), antiadherents (e.g.,
talc), glidants (e.g., colloidal silica), natural or artificial
sweeteners (e.g., saccharin, acesulfame K, aspartame, sucralose,
isomalt, lactose, mannitol, sorbitol, xylitol and sucrose),
humectants (e.g., glycerin), preservatives and antioxidants (e.g.,
sodium benzoate and ascorbyl palmitate), surfactants (e.g.,
polysorbate 80), natural or artificial flavors (e.g., mint,
cinnamon, cherry or other fruit flavors), 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).
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).
[0032] Representative compositions incorporating a source of
nicotine and another nicotinic compound as active ingredients 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
from 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, mini 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. Nos. 4,655,231 to Ray et al.;
5,147,654 to Place et al.; 5,543,424 to Carlsson et al.; 6,268,386
to Thompson; 6,319,510 to Yates; 6,488,953 Halliday et al.;
6,709,671 to Zerbe et al.; 7,025,983 to Leung et al.; 7,105,173 to
Rolling; 7,115,297 to Stillman; 7,435,749 to Knight and 7,491,406
to Leung et al.; and US Pat. Pub. Nos. 2004/0191322 to Hansson;
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.
[0033] Compositions 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.
[0034] Solid dosage forms may be formulated so as to provide a
delayed release of the active agent (i.e., the nicotinic
compounds), 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
involve application of a delayed release coating composition after
preparation of the solid dosage form (e.g., a tablet or caplet).
Application of the coating may be be implemented using methods such
as airless spraying, fluidized bed coating, use of a coating pan,
or the like. Materials for use as a delayed release 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.
[0035] Solid dosage forms according to the present invention may
also provide sustained release (i.e., releasing the active agent
over a prolonged period of time), and may or may not also provide
delayed release. Sustained release formulations are known in the
art and are generally prepared by dispersing the active ingredient
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.
[0036] The manners and methods used to formulate and manufacture
the 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,
airflow experienced by the various ingredient 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, 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.
[0037] The manners and methods for incorporating the nicotinic
compounds (i.e., the source of nicotine and the other nicotinic
compound) into the nicotine-containing composition can vary. The
location of each of the active ingredients within the composition
can vary. The nicotinic compounds can be located throughout the
composition or in selected regions of the composition (e.g.,
homogeneously throughout the composition, in an outer coating of
the composition or in the region of the composition occupied by
nicotine or in selected layer(s) of a laminated composition). As
such, certain regions of the composition can be essentially devoid
of any or all nicotinic compounds, there can exist a concentration
gradient of various nicotinic compounds within or throughout the
composition, or a certain region of the composition can have a
relatively high concentration of some or all of the nicotinic
compounds relative to other regions of that composition.
Compositions can be co-extruded, laminated or formed so as to have
sandwich-type forms; and hence the location of nicotine, other
nicotinic compound 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., gum or 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, any or all of the
other nicotinic compounds can have relatively high concentrations
towards the inner region of the product, or relatively high
concentrations towards the outer region of the product.
[0038] The other nicotinic compound can be mixed with the source of
nicotine (e.g., with nicotine salts), and incorporated into the
composition as a mixture. Various forms of nicotine and the other
nicotinic compound also can be introduced into the composition at
different times or stages of the manufacturing process, or in
combination with different ingredients employed in the
manufacturing process. Alternatively, the other nicotine compound
can be segregated from the nicotine within the composition (e.g.,
by physically locating the other nicotinic compound and nicotine at
separate locations within the composition, or by segregating the
nicotinic compound and nicotine using encapsulation or other types
of chemical means to separate those components).
[0039] In one embodiment, at least one of nicotine and the
nicotinic compound can be sorbed onto a porous particulate carrier
material, such as microcrystalline cellulose (MCC). In one
embodiment, the MCC materials so employed 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 herein by reference. Thus, in
certain embodiments, multiple forms of nicotinic compounds can be
sorbed onto the particulate carrier including any of the various
nicotinic compound combinations discussed herein, such as nicotine
free base combined with a nicotinic compound salt, two nicotinic
salts (e.g., a nicotine levulinate/nicotine tartrate mixture or a
nicotine levulinate/nicotine bitartrate mixture), and the like. The
nicotine compound can be sorbed onto the particulate carrier by,
for example, dissolving the nicotinic compound in a hydrophilic
solvent (e.g., 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 sorbed
nicotinic compound can be combined with other carriers or
excipients in order to provide a composition adapted for oral or
nasal delivery of the active ingredients.
[0040] In use, the compositions of the present invention most
preferably are administered by 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 gums, lozenges, pouch
product and sprays.
[0041] One particularly preferred type of a representative
composition incorporating a source of nicotine and another
nicotinic compound as active ingredients, and that provides
nicotine delivery in a non-inhalable form, has the form of a gum or
other type of similarly chewable product. Gum forms of product
include gum base (e.g., typically the types of pharmaceutically
acceptable gum bases available from sources such as Gum Base Co.
S.p.a., Wm. J. Wrigley Jr. Company or Gumlink A/S). See, for
example, the types of nicotine-containing gums, gum formulations,
gum formats and configurations, gum characteristics and techniques
for formulating or manufacturing gums are set forth in U.S. Pat.
Nos. 3,845,217 to Ferno et al.; 3,877,468 to Lichtneckert et al.;
3,901,248 to Lichtneckert et al.; 5,154,927 to Song et al.;
6,322,806 to Ream et al.; 6,344,222 to Cherukuri et al.; 6,355,265
to Ream et al.; 6,358,060 to Pinney et al.; 6,773,716 to Ream et
al.; 6,893,654 to Pinney et al.; 7,101,579 Athanikar et al.;
7,163,705 to Johnson et al. and 7,208,186 to Norman et al.; US Pat.
Pub. Nos. 2004/0194793 to Lindell et al.; 2006/0099300 to Andersen
et al.; 2006/0121156 to Andersen et al.; 2006/0165842 to Andersen
et al.; 2006/0204451 to Salini; 2006/0246174 to Andersen et al.;
2006/0275344 to Mody et al.; 2007/0014887 to Cherukuri et al.;
2007/0269386 to Steen et al. and 2009/0092573 to Andersen and PCT
WO 2007/104574 to Axelsson et al.; which are incorporated herein by
reference. The amount of composition contained within each piece of
unit of gum type of product can vary. For example, representative
unit or gum types of products generally weigh at least about 0.5 g,
often at least about 1 g, and frequently at least about 1.5 g, of
composition; while the weight of such types of products generally
does not exceed about 3 g, often does not exceed about 2.5 g, and
frequently does not exceed about 2 g. The time period over which
the gum piece can be chewed can vary; and typically, each piece of
gum is chewed for at least about 5 minutes, often at least about 10
minutes, while each piece of gum typically is chewed for up to
about 40 minutes, often up to about 30 minutes.
[0042] Another particularly preferred type of a representative
composition incorporating a source of nicotine and another
nicotinic compound as active ingredients, and that provides
nicotine delivery in a non-inhalable form, has the form of a
lozenge, tablet, microtab, or other type 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. Nos. 4,967,773 to Shaw; 5,110,605
to Acharya; 5,733,574 to Dam; 6,280,761 to Santus; 6,676,959 to
Andersson et al.; 6,248,760 to Wilhelmsen and 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. and
2009/0081291 to Gin et al.; PCT WO 91/09599 to Carlsson et al. and
PCT WO 2007/104575 to Axelsson; which are incorporated herein by
reference. The amount of composition contained within each piece or
unit of lozenge type of product can vary. For example,
representative units of lozenge types of products generally weigh
at least about 100 mg, often at least about 200 mg, and frequently
at least about 300 mg, of composition; while the weight of such
types of 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.
[0043] Another particularly preferred type of a representative
composition incorporating a source of nicotine and another
nicotinic compound as active ingredients, and that provides
nicotine delivery in a non-inhalable form, has the form of a pouch
or sachet type of product. See, for example, the types of pouch
materials and nicotine-containing formulations set forth in PCT WO
2007/104575 to Axelsson et al.; which is incorporated herein by
reference. See also, for example, the types of pouch materials and
pouch manufacturing techniques(e.g., filling and sealing
techniques) set forth in US Pat. Pub. No. 2010/0018539 to Brinkley
et al.; which is incorporated herein by reference. The amount of
composition contained within each pouch can vary. For example,
representative pouch products generally contain at least about 75
mg, often at least about 100 mg, and frequently at least about 150
mg, of composition; while the amount of composition contained in
representative pouch products generally does not exceed about 500
mg, often does not exceed about 400 mg, and frequently does not
exceed about 300 mg.
[0044] The amount of nicotine 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.,
chewable piece of gum product, a lozenge, a pouch product, 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. Exemplary types of such products incorporate about 2 mg, about
2.5 mg, about 3.5 mg and about 4 mg of nicotine per piece or unit
(calculated as nicotine free base).
[0045] The amount of the other nicotinic compound 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., chewable piece of gum product, a lozenge, a pouch product,
or the like), the amount of other nicotinic compound within each
dosage piece or unit typically does not exceed about 100 mg,
generally does not exceed about 75 mg, often does not exceed about
50 mg. The amount of other nicotinic compound within each dosage
piece or unit generally is at least about 0.1 mg, typically is at
least about 0.5 mg and often is at least 1 mg. Depending upon the
pharmacological effect provided by the other nicotinic compound,
the amount of that compound within each dosage piece or unit
typically can be at least about 2 mg and often can be at least
about 5 mg. Exemplary types of such products incorporate about 0.5
mg, about 1 mg, about 25 mg and about 50 mg of other nicotinic
compound per piece or unit.
[0046] Another particularly preferred type of a representative
composition incorporating a source of nicotine and another
nicotinic compound active ingredient has the form of a spray. See,
for example, the types of spray materials and nicotine-containing
spray formulations set forth in U.S. Pat. Nos. 4,579,858 to Ferno
et al.; 5,656,255 to Jones; 6,024,097 to Von Wielligh and 6,596,740
to Jones; US Pat. Pub. Nos. 2003/0159702 to Lindell et al. and
2007/0163610 to Lindell et al.; EP 1458388 to Lindell et al.; PCT
WO 2006/100075 to Axelsson and PCT WO 2008/037470 to Axelsson et
al.; which are incorporated herein by reference. Preferred spray
form products produce sprays or mists using nebulizers or other
types of devices for producing aerosols by mechanical means.
Preferred spray types of products employ liquid solvents or
carriers (e.g., water or water/ethanol mixtures) that contain
nicotine and the other nicotinic compound. The concentration of the
nicotine within the liquid spray formulation can vary, but
typically is in the range of about 0.5 percent to about 5 percent,
often about 1percent to about 3 percent, based on the total weight
of the liquid formulation. Depending upon the identity of the other
nicotinic compound incorporated within the spray formulation, the
concentration of the other nicotinic compound within the liquid
spray formulation typically is in the range of about 0.1 percent to
about 15 percent, often about 0.2 percent to about 10 percent,
based on the total weight of the liquid formulation.
[0047] Although the compositions of the invention are preferably
non-inhalable, it is possible to formulate the above-noted
combinations of nicotinic compounds in a form capable of pulmonary
delivery using various types of inhalation devices and vapor
delivery systems designed to deliver an active agent to the lungs
as opposed to buccal, sublingual, or nasal delivery. See, for
example, the types of inhalable formulations and vapor delivery
devices and systems set forth in U.S. Pat. Nos. 4,284,809 to Ray;
4,800,903 to Ray et al.; 5,167,242 to Turner et al.; 6,098,632 to
Turner et al.; 6,234,169 to Bulbrook et al. and 6,874,507 to Farr;
US Pat. Pub. Nos. 2004/0034068 to Warchol et al; 2006/0018840 to
Lechuga-Ballesteros; 2008/0302375 to Andersson et al. and
2009/0005423 to Gonda; and EP 1,618,803 to Hon, which are
incorporated herein by reference.
[0048] Though not preferred, compositions of the present invention
can be administered in a transdermal manner. See, for example, the
types of transdermal delivery technologies set forth in U.S. Pat.
Nos. 4,597,961 to Etscom; 5,298,257 to Bannon et al.; 5,603,947 to
Wong et al.; 5,834,011 to Rose et al.; 6,165,497 to Osborne et al.
and 6,676,959 to Anderson et al and PCT WO 2007/012963 to Johnson
et al.; which are incorporated herein by reference.
[0049] For compositions of the present invention, the intended dose
of the nicotine active ingredient can vary. The overall dose of
that active ingredient can depend upon factors such as the weight
of the subject ingesting the composition, the condition, disease or
disorder being treated, the state or severity of the condition,
disease or disorder being treated, the desired pharmacological
effect, or other such factors. Typically, the amount of nicotine
active ingredient 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. The dose of nicotine, whether on a per dose or
on an overall daily basis, is such that the subject does not
experience untoward side effects resulting from overexposure of
that subject to nicotine. See also, for example, the types of
dosing regimens and administration techniques set forth in U.S.
Pat. Nos. 6,660,754 to Kyle et al. and US Pat. Pub. Nos.
2004/0006113 to Sachs; 2005/0214229 to Pinney et al. and
2008/0124283 to Andersen and PCT WO 2007/104573 to Axelsson et al.;
which are incorporated herein by reference.
[0050] For compositions of the present invention, the intended dose
of the other nicotinic compound active ingredient can vary. The
overall dose of that 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, the
potency of that active ingredient, the amount of nicotine present
in the composition in combination with that active ingredient, or
other such factors. Typically, the amount of other nicotinic
compound active ingredient administered to a subject per day does
not exceed about 75 mg, and often does not exceed about 50 mg. For
certain other nicotinic compound active ingredients, the amount
administered to a subject per day typically does not exceed 10 mg,
and often does not exceed about 5 mg. A highly preferred dose of
the other nicotinic compound is such that sufficient compound is
administered to provide the desired CNS effect (e.g., due to the
effect of that compound at nAChRs within the CNS), while not
sufficiently high so as to cause provide side effects associated
with toxicity or unwanted side effects resulting from significant
interaction of that compound at nAChRs within the PNS.
[0051] For compositions of the present invention, the amount
nicotine active ingredient relative the amount of other nicotinic
compound active ingredient in each dosage source or unit can vary.
In one regard, the amount of nicotine active ingredient can be less
than, approximately equal to or exceed the amount of the other
nicotinic compound active ingredient, on a weight basis. For
example, a piece gum or lozenge can incorporate about 1 to about 5
mg of nicotine, and about 0.1 mg to about 2 mg of either a compound
known as varenicline or an agonist of an .alpha..sub.7 nicotinic
receptor subtype or an .alpha..sub.4.beta..sub.2 nicotinic receptor
subtype. In one regard, the amount of the other nicotinic compound
active ingredient can exceed the amount of the nicotine active
ingredient, on a weight basis. For example, a piece gum or lozenge
can incorporate about 1 to about 5 mg of nicotine, and about 10 mg
to about 75 mg of either a compound known as AZD-3480 or a compound
known as TC-5619.
[0052] The dose of the combination of active ingredients is 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
ingredients 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 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 by delaying the onset of
the symptoms of the condition, disease or disorder. Treatment of
the disorder is manifested by a decrease in the symptoms associated
with the condition, disease or disorder or an amelioration of the
reoccurrence of the symptoms thereof.
[0053] In use, the sources of nicotine and the other nicotinic
compound active ingredients are administered in combination with
one another. For example, pharmaceutically effective amounts of
each active ingredient preferably are incorporated into a single
dosage source or unit (e.g., an individual piece of gum, a single
lozenge, or the like, and preferably by ingestion by oral means).
The nicotine active ingredient is an example of an ingredient that,
at the dose administered, binds to and activates various nicotinic
receptor subtypes located in both the CNS and the PNS. Hence, at
the dose administered, the nicotine active ingredient does not
discriminate (from the standpoint of its ability to undergo binding
and elicit activation) among the various nAChRs expressed in the
CNS and PNS. As such, administration of nicotine introduces CNS
effects as well as PNS effects at peripheral sites (e.g.,
neuromuscular, cardiovascular and gastrointestinal sites).
Conversely, the other nicotinic compound active ingredient is
selective to certain nAChRs expressed in the CNS. That is, the
other nicotinic compound active ingredient, at the dose
administered, exhibits an affinity to bind to and activate
nicotinic receptor subtypes located in the CNS. Thus,
administration of the combination of nicotinic compound active
ingredients provides CNS effects (e.g., as a result of the
administration of the combination of nicotine and the other
nicotinic compound) and PNS effects (e.g., principally or virtually
entirely as a result of the administration of nicotine). As such,
it is highly preferred that the other nicotinic compound be
administered within the relevant "therapeutic window" or within the
"therapeutic index" of that compound, and that the dose of that
other nicotinic compound be within a dosage range sufficient that
the compound elicits a desirable response within the CNS while
effects of that compound upon the PNS are avoided to any
significant extent. See, for example, Bencherif et al., J.
Pharmacol. Exp. Ther., 279: 1413-1421 (1996) and U.S. Pat. No.
5,583,140 to Bencherif et al.; which are incorporated herein by
reference.
[0054] The compositions of the present invention can be used for
treatment of a wide variety of conditions, diseases and disorders.
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 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).
[0055] 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.
EXAMPLE 1
[0056] A lozenge generally similar in shape and form to a lozenge
incorporating 0.5 mg varenicline in the form of the tartrate salt
of the active ingredient of a product commercially marketed under
the tradename Chantix by Pfizer Incorporated is produced using
generally similar excipient ingredients and processing conditions
used for the manufacture of the commercial lozenge, except that the
varenicline active ingredient replaced by a mixture of nicotine
polacrilex and varenicline. The amount of nicotine polacrilex
incorporated into each lozenge is such that the amount of nicotine
active ingredient within each lozenge from that source is 2 mg; and
the amount of varenicline incorporated into each lozenge is such
that the amount of that active ingredient within each lozenge is
0.5 mg. As such, each lozenge (i.e., each dosing unit) incorporates
both nicotine and a nicotinic compound purported to have
selectivity to the .alpha..sub.4.beta..sub.2 nicotinic receptor
subtype.
EXAMPLE 2
[0057] A lozenge generally similar in shape and form to a lozenge
incorporating 0.5 mg varenicline and commercially available as
Chantix is produced using generally similar excipient ingredients
and processing conditions used for the manufacture of the
commercial lozenge, except that the varenicline active ingredient
replaced by a mixture of nicotine polacrilex and varenicline. The
amount of nicotine polacrilex incorporated into each dosage unit
(i.e., each lozenge) is such that the amount of nicotine active
ingredient within each lozenge from that source is 3 mg; and the
amount of varenicline incorporated into each lozenge is such that
the amount of that active ingredient within each lozenge is 0.1 mg.
As such, each lozenge (i.e., each dosing unit) incorporates both
nicotine and a nicotinic compound purported to have selectivity to
the .alpha..sub.4.beta..sub.2 nicotinic receptor subtype.
EXAMPLE 3
[0058] A gum generally similar in shape and form to a
nicotine-containing gum incorporating 4 mg of nicotine and
commercially available as Nicorette Original Gum (distributed by
GlaxoSmithKline Consumer Healthcare, L.P.) is produced using
generally similar excipient ingredients and processing conditions
used for the manufacture of the commercial gum, except that the
nicotine polacrilex thereof is replaced by a mixture of nicotine
polacrilex and a compound known as varenicline (e.g., in the form
of the tartrate salt found in Chantix). The amount of nicotine
polacrilex incorporated into each chewing piece of gum is such that
the amount of nicotine active ingredient within each chewing piece
from that source is 3 mg; and the amount of varenicline active
ingredient incorporated into each chewing piece of gum is such that
the amount of active ingredient within each chewing piece from that
source is 1 mg. As such, each chewing piece of the gum product
(i.e., each dosing unit) incorporates both nicotine and a nicotinic
compound purported to have selectivity to the
.alpha..sub.4.beta..sub.2 nicotinic receptor subtype.
EXAMPLE 4
[0059] A gum generally similar in shape and form to a
nicotine-containing gum incorporating 4 mg of nicotine and
commercially available as Nicorette Original Gum (distributed by
GlaxoSmithKline Consumer Healthcare, L.P.) is produced using
generally similar excipient ingredients and processing conditions
used for the manufacture of the commercial gum, except that the
nicotine polacrilex thereof is replaced by a mixture of nicotine
polacrilex and a compound known as varenicline (e.g., in the form
of the tartrate salt found in Chantix). The amount of nicotine
polacrilex incorporated into each dosage unit (i.e., into each
chewing piece of gum) is such that the amount of nicotine active
ingredient within each chewing piece from that source is 3 mg; and
the amount of varenicline active ingredient incorporated into each
chewing piece of gum is such that the amount of active ingredient
within each chewing piece from that source is 0.2 mg. As such, each
chewing piece of the gum product (i.e., each dosing unit)
incorporates both nicotine and a nicotinic compound purported to
have selectivity to the .alpha..sub.4.beta..sub.2 nicotinic
receptor subtype.
EXAMPLE 5
[0060] A gum generally similar in shape and form to a
nicotine-containing gum incorporating 4 mg of nicotine and
commercially available as Nicorette Original Gum (distributed by
GlaxoSmithKline Consumer Healthcare, L.P.) is produced using
generally similar excipient ingredients and processing conditions
used for the manufacture of the commercial gum, except that the
nicotine polacrilex thereof is replaced by a mixture of nicotine
polacrilex and a compound of Targacept, Inc, (Winston-Salem, N.C.,
USA), known as TC-5619. In one aspect, the amount of nicotine
polacrilex incorporated into each chewing piece of gum is such that
the amount of nicotine active ingredient within each chewing piece
from that source is 3 mg; and the amount of TC-5619 (active
ingredient in free base form) incorporated into each chewing piece
of gum is such that the amount of active ingredient within each
chewing piece from that source is 1 mg. In a second aspect, the
amount of nicotine polacrilex incorporated into each chewing piece
of gum is such that the amount of nicotine active ingredient within
each chewing piece from that source is 3 mg; and the amount of
TC-5619 (active ingredient in free base form) incorporated into
each chewing piece of gum is such that the amount of active
ingredient within each chewing piece from that source is 5 mg. In a
third aspect, the amount of nicotine polacrilex incorporated into
each chewing piece of gum is such that the amount of nicotine
active ingredient within each chewing piece from that source is 3
mg; and the amount of TC-5619 (active ingredient in free base form)
incorporated into each chewing piece of gum is such that the amount
of active ingredient within each chewing piece from that source is
25 mg. As such, each chewing piece of the gum product (i.e., each
dosing unit) incorporates nicotine and a nicotinic compound
purported to have selectivity to the .alpha..sub.7 nicotinic
receptor subtype.
EXAMPLE 6
[0061] A gum generally similar in shape and form to a
nicotine-containing gum incorporating 4 mg of nicotine and
commercially available as Nicorette Original Gum (distributed by
GlaxoSmithKline Consumer Healthcare, L.P.) is produced using
generally similar excipient ingredients and processing conditions
used for the manufacture of the commercial gum, except that the
nicotine polacrilex thereof is replaced by a mixture of nicotine
polacrilex and a compound of AstraZeneca known as AZD-3480
((2S,4E)-5-(5-isopropoxypyridin-3-yl)-N-methylpent-4-en-2-amine).
In one aspect, the amount of nicotine polacrilex incorporated into
each chewing piece of gum is such that the amount of nicotine
active ingredient within each chewing piece from that source is 3
mg; and the amount of AZD-3480 incorporated into each chewing piece
of gum is such that the amount of active ingredient within each
chewing piece from that source is 25 mg. In another aspect, the
amount of nicotine polacrilex incorporated into each chewing piece
of gum is such that the amount of nicotine active ingredient within
each chewing piece from that source is 3 mg; and the amount of
AZD-3480 incorporated into each chewing piece of gum is such that
the amount of active ingredient within each chewing piece from that
source is 50 mg. As such, each chewing piece of the gum product
(i.e., each dosing unit) incorporates nicotine and a nicotinic
compound purported to have selectivity to the
.alpha..sub.4.beta..sub.2 nicotinic receptor subtype.
EXAMPLE 7
[0062] A coated gum generally similar in shape and form to a
nicotine-containing gum incorporating 4 mg of nicotine and
commercially available as Nicorette Fruit Chill Gum (distributed by
Walgreen Co.) is produced using generally similar excipient
ingredients and processing conditions used for the manufacture of
the commercial gum, except that the nicotine polacrilex thereof is
replaced by a mixture of nicotine polacrilex and a compound of
Targacept, Inc. known as TC-5619. In one aspect, the amount of
nicotine polacrilex incorporated into each chewing piece of gum is
such that the amount of nicotine active ingredient within each
chewing piece from that source is 3 mg; and the amount of TC-5619
(active ingredient in free base form) incorporated into each
chewing piece of gum is such that the amount of active ingredient
within each chewing piece from that source is 1 mg. In a second
aspect, the amount of nicotine polacrilex incorporated into each
chewing piece of gum is such that the amount of nicotine active
ingredient within each chewing piece from that source is 3 mg; and
the amount of TC-5619 (active ingredient in free base form)
incorporated into each chewing piece of gum is such that the amount
of active ingredient within each chewing piece from that source is
5 mg. In a third aspect, the amount of nicotine polacrilex
incorporated into each chewing piece of gum is such that the amount
of nicotine active ingredient within each chewing piece from that
source is 3 mg; and the amount of TC-5619 (active ingredient in
free base form) incorporated into each chewing piece of gum is such
that the amount of active ingredient within each chewing piece from
that source is 25 mg. As such, each chewing piece of the gum
product (i.e., each dosing unit) incorporates nicotine and a
nicotinic compound purported to have selectivity to the
.alpha..sub.7 nicotinic receptor subtype.
EXAMPLE 8
[0063] A coated gum generally similar in shape and form to a
nicotine-containing gum incorporating 4 mg of nicotine and
commercially available as Zonnic (distributed by Niconovum AB,
Sweden) is produced using generally similar excipient ingredients
and processing conditions used for the manufacture of the
commercial gum, except that the nicotine and microcrystalline
cellulose thereof is replaced by a mixture of
nicotine/microcrystalline cellulose and a compound of AstraZeneca
known as AZD-3480. In one aspect, the amount of
nicotine/microcrystalline cellulose incorporated into each chewing
piece of gum is such that the amount of nicotine active ingredient
within each chewing piece from that source is 3 mg; and the amount
of AZD-3480 incorporated into each chewing piece of gum is such
that the amount of active ingredient within each chewing piece from
that source is 25 mg. In another aspect, the amount of
nicotine/microcrystalline cellulose incorporated into each chewing
piece of gum is such that the amount of nicotine active ingredient
within each chewing piece from that source is 3 mg; and the amount
of AZD-3480 incorporated into each chewing piece of gum is such
that the amount of active ingredient within each chewing piece from
that source is 50 mg. As such, each chewing piece of the gum
product (i.e., each dosing unit) incorporates nicotine and a
nicotinic compound purported to have selectivity to the
.alpha..sub.4.beta..sub.2 nicotinic receptor subtype.
EXAMPLE 9
[0064] A gum product generally similar in shape and form, and
produced using generally similar excipient ingredients and
processing conditions, to the nicotine-containing gum designated as
Composition A as set forth in Example 6 of PCT WO 2007/104574 to
Axelsson et al. is provided, except that, in addition to the
nicotine ingredient of each gum piece, sufficient compound of
AstraZeneca known as AZD-3480 is incorporated into each gum piece
such that the amount of active ingredient within each dosage unit
from that source is 25 mg. As such, each chewing piece of the gum
product (i.e., each dosing unit) incorporates nicotine and a
nicotinic compound purported to have selectivity to the
.alpha..sub.4.beta..sub.2 nicotinic receptor subtype.
EXAMPLE 10
[0065] A gum product generally similar in shape and form, and
produced using generally similar excipient ingredients and
processing conditions, to the nicotine-containing gum designated as
Composition B, as set forth in Example 6 of PCT WO 2007/104574 to
Axelsson et al. is provided, except that, in addition to the
nicotine ingredient of each gum piece, sufficient compound of
Targacept, Inc. known as TC-5619 is incorporated into each gum
piece such that the amount of TC-5619 active ingredient within each
gum piece is 25 mg. As such, each chewing piece of the gum product
(i.e., each dosing unit) incorporates nicotine and a nicotinic
compound purported to have selectivity to the .alpha..sub.7
nicotinic receptor subtype.
EXAMPLE 11
[0066] A lozenge generally similar in shape and form to a
nicotine-containing lozenge incorporating 2.5 mg of nicotine is
produced using generally similar excipient ingredients and
processing conditions used for the manufacture of that lozenge set
forth in Table 1 of Example 3 of PCT WO 2007/104575 to Axelsson,
except that, in addition to the nicotine bitartrate dihydrate
ingredient of that lozenge, sufficient compound of Targacept, Inc.
known as TC-5619 is incorporated into each lozenge such that the
amount of nicotine active ingredient within each lozenge is 2.5 mg
and the amount of TC-5619 active is 25 mg. As such, each lozenge
(i.e., each dosing unit) incorporates nicotine and a nicotinic
compound purported to have selectivity to the .alpha..sub.7
nicotinic receptor subtype.
EXAMPLE 12
[0067] A lozenge generally similar in shape and form to a
nicotine-containing lozenge incorporating 2 mg of nicotine and
commercially available as NiQuitin (distributed by GSK Consumer
Healthcare NS) is produced using generally similar excipient
ingredients and processing conditions used for the manufacture of
the commercial lozenge, except that the nicotine bitartrate active
ingredient replaced by a mixture of nicotine bitartrate and a
compound of Targacept, Inc. known as TC-5619. The amount of
nicotine bitartrate incorporated into each lozenge is such that the
amount of nicotine active ingredient within each lozenge from that
source is 2 mg; and the amount of TC-5619 incorporated into each
lozenge is such that the lozenge product incorporates 25 mg of
TC-5619. As such, each lozenge (i.e., each dosing unit)
incorporates nicotine and a nicotinic compound purported to have
selectivity to the .alpha..sub.7 nicotinic receptor subtype.
EXAMPLE 13
[0068] A pouch type of product similar in shape and form to a
nicotine-containing pouch commercially available as Zonnic
(distributed by Niconovum A.B.) is produced using generally similar
pouch material, excipient ingredients and processing conditions
used for the manufacture of the commercial pouch, except that the
nicotine/microcrystalline cellulose ingredient thereof is replaced
by a mixture of a compound known as TC-5619 and
nicotine/microcrystalline cellulose. The amount of
nicotine/microcrystalline cellulose incorporated into each pouch is
such that the amount of nicotine active ingredient within each
pouch from that source is the same as the commercially available
pouch, and the amount of TC-5619 incorporated into the pouch is
such that 25 mg of TC-5619 active ingredient is incorporated into
the pouch. As such, each pouch (i.e., each dosing unit)
incorporates nicotine and a nicotinic compound purported to have
selectivity to the .alpha..sub.7 nicotinic receptor subtype.
EXAMPLE 14
[0069] Pouch type products generally similar in shape and form to a
nicotine-containing pouches set forth as snuff bag compositions E-J
in Example 1 of PCT WO 2007/104573 to Axelsson et al. are produced
using generally similar excipient ingredients and processing
conditions used for the manufacture of those pouch type products,
except that 25 mg of a compound of AstraZeneca known as AZD-3480
also is incorporated within the formulation employed to manufacture
that pouch product. Thus, both nicotine and another nicotinic
compound are active ingredients incorporated into each dosage unit
(i.e., within each pouch or bag). As such, each pouch (i.e., each
dosing unit) incorporates nicotine and a nicotinic compound
purported to have selectivity to the .alpha..sub.4.beta..sub.2
nicotinic receptor subtype.
EXAMPLE 15
[0070] A spray formulation generally similar to a
nicotine-containing spray formulation designated as Composition A
and set forth in Example 1 of PCT WO 2006/100075 to Axelsson is
prepared, except that, in addition, 0.2 mg of varenicline active
ingredient is incorporated into that formulation. As such, the
spray incorporates both nicotine and a nicotinic compound purported
to have selectivity to the .alpha..sub.4.beta..sub.2 nicotinic
receptor subtype.
EXAMPLE 16
[0071] A spray formulation generally similar to a
nicotine-containing spray formulation commercially available as
Zonnic (distributed by Niconovum A.B.) is prepared, except that, in
addition, 10 mg of a compound of AstraZeneca known as AZD-3480 is
incorporated into that formulation. Thus, nicotine and another
nicotinic compound are the active ingredients incorporated into
each dosage unit (i.e., within the spray formulation). As such, the
spray incorporates both nicotine and a nicotinic compound purported
to have selectivity to the .alpha..sub.4.beta..sub.2 nicotinic
receptor subtype.
[0072] A spray formulation generally similar to a
nicotine-containing spray formulation commercially available as
Zonnic (distributed by Niconovum A.B.) is prepared, except that, in
addition, 10 mg of a compound of Targacept, Inc, known as TC-5619
is incorporated into that formulation. Thus, nicotine and another
nicotinic compound are the active ingredients incorporated into
each dosage unit (i.e., within the spray formulation). As such, the
spray incorporates both nicotine and a nicotinic compound purported
to have selectivity to the .alpha..sub.7 nicotinic receptor
subtype.
[0073] Those of skill in the art will appreciate that embodiments
not expressly illustrated herein may be practiced within the scope
of the present invention, including that features described herein
for different embodiments may be combined with each other and/or
with currently-known or future-developed technologies while
remaining within the scope of the claims presented here. It is
therefore intended that the foregoing detailed description be
regarded as illustrative rather than limiting. And, it should be
understood that the following claims, including all equivalents,
are intended to define the spirit and scope of this invention.
Furthermore, the advantages described above are not necessarily the
only advantages of the invention, and it is not necessarily
expected that all of the described advantages will be achieved with
every embodiment of the invention.
* * * * *