Note: Descriptions are shown in the official language in which they were submitted.
COMPOSITIONS AND METHODS FOR SUBLINGUAL DELIVERY OF NICOTINE
FIELD
Disclosed herein are compositions and methods for oral delivery of nicotine
and
nicotine derivatives. In one embodiment the nicotine is delivered in an oral
packets, pouches,
or sachets.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 is a plot of the individual plasma concentrations (ng/mL) for
Nicotine versus
time (hour) after buccal administration of the nicotine benzoate control
composition disclosed
in TABLE I in male Beagle dogs.
Figure 2 is a plot of the mean plasma concentration (ng/mL) for Nicotine
versus time
(hour) after buccal administration of nicotine benzoate control composition
disclosed in
TABLE I in male Beagle dogs.
Figure 3 is a plot of the individual plasma concentrations (ng/mL) for
Nicotine versus
time (hour) after buccal administration of the disclosed nicotine benzoate
composition
disclosed in Table II (4 mg) in male Beagle dogs.
Figure 4 is a plot of the mean plasma concentration (ng/mL) for Nicotine
versus time
(hour) after buccal administration of the disclosed compound in Table II (4
mg) in male
Beagle dogs.
Figure 5 is a plot of the individual plasma concentrations (ng/mL) for
Nicotine versus
time (hour) after buccal administration of the nicotine polacrilex control
composition disclosed
in TABLE III (4 mg) in male Beagle dogs (Group 3).
Figure 6 is a plot of the mean plasma concentration (ng/mL) for Nicotine
versus time
(hour) after buccal administration of the nicotine polacrilex control
composition disclosed in
TABLE III (4 mg) in Male Beagle dogs (Group 3)
Figure 7 is a plot of the individual plasma poncentrations (ng/mL) for
Nicotine versus
time (hour) after buccal administration of the nicotine polarcilex composition
disclosed in
TABLE VI (4 mg) in male Beagle dogs (Group 4).
Figure 8 is a plot of the mean plasma concentration (ng/mL) for Nicotine
versus time
(hour) after buccal administration of the nicotine polarcrilex composition
disclosed in TABLE
VI (4 mg) in male Beagle dogs (Group 4).
DETAILED DESCRIPTION OF THE DISCLOSURE
1
Date Recite/Date Received 2023-08-23
The materials, compounds, compositions, articles, and methods described herein
may be
understood more readily by reference to the following detailed description of
specific aspects
of the disclosed subject matter and the Examples included therein.
General Definitions
hi this specification and in the claims that follow, reference will be made to
a number of
terms, which shall be defined to have the following meanings:
All percentages, ratios and proportions herein are by weight, unless otherwise
specified.
All temperatures are in degrees Celsius (0C) unless otherwise specified.
The terms "a" and "an" are defined as one or more unless this disclosure
explicitly
requires otherwise.
Ranges may be expressed herein as from "about" one particular value, and/or to
"about"
another particular value. When such a range is expressed, another aspect
includes from the one
particular value and/or to the other particular value. Similarly, when values
are expressed as
approximations, by use of the antecedent "about," it will be understood that
the particular value
forms another aspect. It will be further understood that the endpoints of each
of the ranges are
significant both in relation to the other endpoint, and independently of the
other endpoint.
The terms "comprise" (and any form of comprise, such as "comprises" and
"comprising"), "have" (and any form of have, such as "has" and "having"),
"include" (and any
form of include, such as "includes" and "including") and "contain" (and any
form of contain,
such as "contains" and "containing") are open-ended linking verbs. As a
result, an apparatus
that "comprises," "has," "includes" or "contains" one or more elements
possesses those one or
more elements, but is not limited to possessing only those elements. Likewise,
a method that
"comprises," "has," "includes" or "contains" one or more steps possesses those
one or more
steps, but is not limited to possessing only those one or more steps.
Any embodiment of any of the disclosed methods or compositions can consist of
or
consist essentially of¨ rather than comprise/include/contain/have ¨ any of the
described steps,
elements, and/or features. Thus, in any of the claims, the term "consisting
of' or "consisting
essentially of" can be substituted for any of the open-ended linking verbs
recited above, in
order to change the scope of a given claim from what it would otherwise be
using the open-
ended linking verb.
2
Date Recue/Date Received 2023-08-23
The feature or features of one embodiment may be applied to other embodiments,
even
though not described or illustrated, unless expressly prohibited by this
disclosure or the nature
of the embodiments.
Any embodiment of any of the disclosed compounds or methods can consist of or
consist essentially of¨ rather than comprise/include/contain/have ¨ any of the
described steps,
elements, and/or features. Thus, in any of the claims, the term "consisting
of' or "consisting
essentially of' can be substituted for any of the open-ended linking verbs
recited above, in
order to change the scope of a given claim from what it would otherwise be
using the open-
ended linking verb.
For the purposes of the present disclosure the terms "sublingual" and "buccal"
are used
interchangeably. The definition of "sublingual" is administration of a drug
under the tongue to
be absorbed by the tissue therein. The definition of "buccal" is to administer
a drug by placing
it between your cheek and gum. For the purposes to the present disclosure the
user can either
place the disclosed compositions under the tongue of between the check and
gum, whichever
mode of delivery is more convenient. Therefore, the disclose compositions can
be absorbed in
any manner chosen by the user.
The feature or features of one embodiment may be applied to other embodiments,
even
though not described or illustrated, unless expressly prohibited by this
disclosure or the nature
of the embodiments.
A smokeless oral nicotine product can be provided to the user in a portioned
or a non-
portioned format. Portioned smokeless oral nicotine products can reduce or
eliminate the
handling of the tobacco by the user, which can offer significant advantages in
terms of better
hygiene, convenience and/or ease of use.
Disclosed herein are compositions for sublingual delivery of nicotine. Unlike
orally
delivered compositions, sublingual compositions are absorbed in the mucosa of
the mouth and
therefore avoid the side effect of direct contact of nicotine with the
stomach, intestines and
other digestive organs.
Disclosed herein are base compositions for sublingual or buccal delivery of
nicotine,
comprising:
a) from about 1% to about 6% by weight of nicotine, a nicotine salt,
nicotine in
combination with a resin, or mixtures thereof;
b) from about 3% to about 20% by weight of sunflower oil;
3
Date Recue/Date Received 2023-08-23
c) from about 10% to about 20% by weight of sodium bicarbonate; and
d) the balance one or more carriers.
The disclosed compositions do not comprise an organic or inorganic acid. In
addition,
the compositions are free flowing solids containing less than 0.01% by weight
moisture.
One aspect of the disclosed compositions, comprises:
a) from about 1% to about 3.5% by weight of nicotine, a nicotine salt, or
mixtures
thereof;
b) from about 3% to about 10.5% by weight of sunflower oil;
c) from about 10% to about 20% by weight of sodium bicarbonate; and
d) the balance one or more carriers.
In one non-limiting embodiment of this aspect the base compositions, comprise:
a) from about 1% to about 3.5% by weight of nicotine, a nicotine salt, or
mixtures
thereof;
b) from about 3% to about 10.5% by weight of sunflower oil;
c) from about 10% to about 20% by weight of sodium bicarbonate; and
d) the balance an admixture of microcrystalline cellulose and inulin.
The disclosed base compositions can comprise from about 1% to about 6% by
weight of
nicotine, a nicotine salt or nicotine in combination with a resin. In one
embodiment, the base
composition can comprise from about 1% to about 5% by weight of nicotine, a
nicotine salt or
nicotine in combination with a resin. In another embodiment, the base
composition can
comprise from about 2% to about 6% by weight of nicotine, a nicotine salt or
nicotine in
combination with a resin. In a further embodiment, the base composition can
comprise from
about 2% to about 5% by weight of nicotine, a nicotine salt or nicotine in
combination with a
resin. In a yet further embodiment, the base composition can comprise from
about 3% to about
5% by weight of nicotine, a nicotine salt or nicotine in combination with a
resin. For example,
the amount of nicotine, a nicotine salt or nicotine in combination with a
resin can be 1%, 2%,
3%, 4%, 5%, or 6% by weight or any fractional amounts, for example, 1.5%,
3,25%, and
5.75%.
The disclosed base compositions can comprise from about 3% to about 20% by
weight
of sunflower oil. In one embodiment the base compositions can comprise from
about 3% to
about 15% by weight of sunflower oil. In another embodiment the base
compositions can
4
Date Recue/Date Received 2023-08-23
comprise from about 5% to about 17% by weight of sunflower oil. In a further
embodiment the
base compositions can comprise from about 7.5% to about 15% by weight of
sunflower oil.
In a still further embodiment the base compositions can comprise from about 5%
to about 10%
by weight of sunflower oil. For example, the amount of sunflower oil can be
3%, 4%, 5%, 6%,
7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% by weight
of
sunflower oil or any fractional amounts, for example, 10.5%, 13.6%, and 17.5%.
According to this aspect the ratio of nicotine, a nicotine salt or nicotine in
combination
with a resin to sunflower oil is from about 1:1 to about 1:4. For example, the
ratio of nicotine,
a nicotine salt or nicotine in combination with a resin to sunflower oil can
be 1:1, 1:1.1, 1:1.2,
1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3,
1:2.4, 1:2.5, 1:2.6, 1:2.7,
1:2.8, 1:2.9, or 1:3.
The disclosed base compositions can comprise from about 10% to about 20% by
weight
of sodium bicarbonate. In one embodiment the base compositions can comprise
from about
10% to about 15% by weight of sodium bicarbonate. In another embodiment the
base
compositions can comprise from about 15% to about 20% by weight of sodium
bicarbonate. In
a further embodiment the base compositions can comprise from about 12.5% to
about 17.5% by
weight of sodium bicarbonate. In a still further embodiment the base
compositions can
comprise from about 14% to about 17% by weight of sodium bicarbonate. For
example, the
amount of sodium bicarbonate can be 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%,
18%, 19%,
or 20% by weight of sodium bicarbonate or any fractional amounts, for example,
10.5%,
13.6%, and 17.5%.
In another aspect the base compositions can comprise:
a) from about 5 mg to about 50 mg by weight of nicotine, a nicotine salt,
nicotine
in combination with a resin, or mixtures thereof;
b) from about 15 mg to about 160 mg by weight of sunflower oil; and
c) from about 50 mg to about 300 mg by weight of sodium bicarbonate.
The disclosed base compositions can comprise from 5 mg to about 50 mg by
weight of
nicotine, a nicotine salt, nicotine in combination with a resin, or mixtures
thereof.
In one embodiment the base compositions can comprise from 10 mg to about 50 mg
by
weight of nicotine, a nicotine salt, nicotine in combination with a resin, or
mixtures thereof. In
another embodiment the base compositions can comprise from 15 mg to about 40
mg by weight
of nicotine, a nicotine salt, nicotine in combination with a resin, or
mixtures thereof. In a
Date Recue/Date Received 2023-08-23
further embodiment the base compositions can comprise from 10 mg to about 30
mg by weight
of nicotine, a nicotine salt, nicotine in combination with a resin, or
mixtures thereof. In a still
further embodiment the base compositions can comprise from 15 mg to about 30
mg by weight
of nicotine, a nicotine salt, nicotine in combination with a resin, or
mixtures thereof. In a yet
further embodiment the base compositions can comprise from 10 mg to about 25
mg by weight
of nicotine, a nicotine salt, nicotine in combination with a resin, or
mixtures thereof. The base
compositions can comprise, for example, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg,
11 mg, 12 mg,
13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg,
24 mg, 25
mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36
mg, 37 mg,
38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg,
49 mg, or
50 mg by weight of nicotine, a nicotine salt, nicotine in combination with a
resin, or mixtures
thereof or any fractional amount, for example, 7.5 mg, 22.5 mg, and 34.6 mg.
The disclosed base compositions can comprise from about 15 mg to about 160 mg
by
weight of sunflower oil. In one embodiment the base compositions can comprise
from about
15 mg to about 160 mg by weight of sunflower oil. In another embodiment the
base
compositions can comprise from about 25 mg to about 120 mg by weight of
sunflower oil. In a
further embodiment the base compositions can comprise from about 40 mg to
about 100 mg by
weight of sunflower oil. In a still further embodiment the base compositions
can comprise
from about 50 mg to about 150 mg by weight of sunflower oil. In a yet further
embodiment the
base compositions can comprise from about 75 mg to about 120 mg by weight of
sunflower oil.
The disclosed base compositions can comprise, for example, 15 mg, 16 mg, 17
mg, 18 mg, 19
mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30
mg, 31 mg,
32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg,
43 mg, 44
mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55
mg, 56 mg,
57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg,
68 mg, 69
mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80
mg, 81 mg,
82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 90 mg, 91 mg,
92 mg, 93
mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102, mg, 103,
mg, 104 mg,
105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114
mg, 115
mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg,
125 mg,
126 mg, 127 mg, 128 mg, 129 mg, 130 mg 31 mg, 132 mg, 133 mg, 134 mg, 135 mg,
136 mg,
137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146
mg, 147
6
Date Recue/Date Received 2023-08-23
mg, 148 mg, 149 mg, 150 mg, 151 mg, 152 mg, 153 mg, 154 mg, 155 mg, 156 mg,
157 mg,
158 mg, 159 mg, or 160 mg by weight of sunflower oil or any fractional amount,
for example,
27.5 mg, 82.5 mg, and 134.6 mg.
The disclosed base compositions can comprise from about 50 mg to about 300 mg
by
weight of sodium bicarbonate. In one embodiment the base compositions comprise
from about
50 mg to about 100 mg by weight of sodium bicarbonate. In another embodiment
the base
compositions comprise from about 75 mg to about 100 mg by weight of sodium
bicarbonate.
In a further embodiment the base compositions comprise from about 100 mg to
about 200 mg
by weight of sodium bicarbonate. In still further embodiment the base
compositions comprise
from about 150 mg to about 200 mg by weight of sodium bicarbonate. In a yet
further
embodiment the base compositions comprise from about 150 mg to about 300 mg by
weight of
sodium bicarbonate. In a yet another embodiment the base compositions comprise
from about
225 mg to about 300 mg by weight of sodium bicarbonate. The disclosed base
composition can
comprise, for example, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg,
58 mg, 59
mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70
mg, 71 mg,
72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg,
83 mg, 84
mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94
mg, 95 mg,
96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103, mg, 104 mg, 105 mg,
106 mg,
107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116
mg, 117
mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg,
127 mg,
128 mg, 129 mg, 130 mg 31 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg,
138 mg,
139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148
mg, 149
mg, 150 mg, 151 mg, 152 mg, 153 mg, 154 mg, 155 mg, 156 mg, 157 mg, 158 mg,
159 mg,
160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169
mg, 170
mg, 171 mg, 172 mg, 173 mg, 174 mg, 175 mg, 167 mg, 177 mg, 178 mg, 179 mg,
180 mg,
181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190
mg, 191
mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, 200 mg,
201 mg,
202 mg, 203 mg, 204 mg, 205 mg, 206 mg, 207 mg, 208 mg, 209 mg, 210 mg, 211
mg, 212
mg, 213 mg, 214 mg, 215 mg, 216 mg, 217 mg, 218 mg, 219 mg, 220 mg, 221 mg,
222 mg,
223 mg, 224 mg, 225 mg, 226 mg, 227 mg, 228 mg, 229 mg, 230 mg, 231 mg, 232
mg, 233
mg, 234 mg, 235 mg, 236 mg, 237 mg, 238 mg, 239 mg, 240 mg, 241 mg, 242 mg,
243 mg,
244 mg, 245 mg, 246 mg, 247 mg, 248 mg, 249 mg, 250 mg, 251 mg, 252 mg, 253
mg, 254
7
Date Recue/Date Received 2023-08-23
mg, 255 mg, 256 mg, 257 mg, 258 mg, 259 mg, 260 mg, 261 mg, 2 62 mg, 263 mg,
264 mg,
265 mg, 266 mg, 267 mg, 268 mg, 269 mg, 270 mg, 271 mg, 272 mg, 273 mg, 274
mg, 275
mg, 276 mg, 277 mg, 278 mg, 279 mg, 280 mg, 281 mg, 282 mg, 283 mg, 284 mg,
285 mg,
286 mg, 287 mg, 288 mg, 289 mg, 290 mg, 290 mg, 291 mg, 292 mg, 293 mg, 294
mg, 295
mg, 296 mg, 297 mg, 298 mg, 299 mg, or 300 mg by weight of sodium bicarbonate,
or any
fractional amount, for example, 110.5, 220.7 and 250.8.
Nicotine Compounds
The disclosed nicotine compounds are chosen from nicotine, pharmacologically
acceptable salts of nicotine, a nicotine complexes, and polymer resins of
containing nicotine.
Non-limiting examples of nicotine salts includes nicotine benzoate, nicotine
lactate, nicotine
malate, nicotine ditartrate, nicotine salicylate, nicotine citrate and
nicotine levulinate. Non-
limiting examples of nicotine in combination with a resin includes nicotine
polacrilex and
nicotine resinate.
In one non-limiting example the nicotine salt is nicotine benzoate. In another
non-
limiting example the nicotine salt is nicotine lactate. In a further non-
limiting example the
nicotine salt is nicotine malate. In a yet further non-limiting example the
nicotine salt is
nicotine ditartrate. In a still yet further non-limiting example the nicotine
salt is nicotine
salicylate. In a yet another non-limiting example the nicotine salt is
nicotine citrate. In a still
yet another non-limiting example the nicotine salt is nicotine levulinate.
Carriers
In one aspect the disclosed carriers are polysaccharides. Non-limiting
examples of poly
saccharide carriers include inulin, galactogen, cellulose, chitin, pectin,
psyllium, guar,
hemicellulose, potato starch, and partially hydrolyzed polysaccharides. In
another aspect the
carriers are sugar alcohols, for example, sorbitol, erythritol, xylitol,
lactitol, maltitol, mannitol,
hydrogenated starch hydrolysates, isomaltose, or any combination thereof. In a
further aspect
carrier component is based on a native or chemically modified agar, alginates,
carrageenan
gum, cellulose, chitosan, chitin, cyclodextrin, dextran, gellan gum, glycogen,
glycosaminoglycan, gum karaya, inulin, pectin, polydextrose, xanthan gum, or
any other
starches, gums or other polysaccharide, including functionalized derivatives,
dextrinized,
hydrolyzed, oxidized, alkylated, hydroxyalkylated, acetylated, fractionated,
and physically
modified starches and mixtures thereof. In some embodiments glycerin and/or
propylene
glycol can be added as a carrier.
8
Date Recue/Date Received 2023-08-23
In one aspect the carrier can serve as a bulking agent. In one embodiment,
microcrystalline cellulose is utilized as a carrier in the base compositions
and as a bulking
agent in the pouches disclosed herein below. In another embodiment, two or
more carriers can
be combined, for example, microcrystalline cellulose and inulin. This
combination can be
utilized in both the base composition, as well as in the pouches. As it
relates to the disclosed
pouches, dextrin is added as a bulking agent, however, dextrin can also serve
as carrier for any
flavors that the formulator wishes to add. For example, ethylvanillin is a
compound which
provides vanilla flavoring. Ethylvanillin can be compounded with dextrin,
microcrystalline
cellulose or inulin and then admixed with the bulking agents or other
carriers.
In one aspect of the one or more carriers, one of the carriers is water
soluble while
others are not. This allows the formulator to control the release of the
active base when the
active base is delivered by way of a non-water soluble, but water permeable
pouch as described
herein below. This combining of carriers allows the delivery of nicotine
either via a nicotine
salt or by way of a polymer supported nicotine, for example, polacrilex.
The disclosed compositions can comprise from about 80% to about 95% by weight
of
one or more carriers. In one embodiment the disclosed compositions can
comprise from about
80% to about 90% by weight of one or more carriers. In another embodiment the
disclosed
compositions can comprise from about 85% to about 95% by weight of one or more
carriers.
In a further embodiment the disclosed compositions can comprise from about 85%
to about
90% by weight of one or more carriers.
Antioxidants
The disclosed compositions can comprise about 0.05% or less of an antioxidant.
Non-
limiting examples of an antioxidant includes butylated hydroxytoluene (BHT),
butylated
hydroxyanisole (BHA), propyl gallate (PG), tert-butyl hydroquinone (1BHQ), and
mixtures
thereof.
The following tables disclose non-limiting examples of the base nicotine
delivery
compositions.
TABLE 1
9
Date Recue/Date Received 2023-08-23
Ingredients (mg) 1 2 3 4 5
Nicotine benzoate 5 17.5 7.5 15 17.5
Sunflower oil 15 52.5 22.5 45 35
Sodium bicarbonate 50 100 100 100 100
Inulin LV 110 430 660 370 340 347.5
Total 500 500 500 500 500
TABLE 2
Ingredients (mg) 6 7 8 9 10
Nicotine benzoate 12.5 17.5 5 10 7.5
Sunflower oil - 25 52.5 15 30 22.5
Sodium bicarbonate 75 75 100 100 100
Inulin LV 110 387.5 355 380 360 340
Total 500 500 500 500 500
TABLE 3
Ingredients (mg) 11 12 13 14 15
Nicotine benzoate 10 35 15 30 35
Sunflower oil 30 105 45 90 70
Sodium bicarbonate 100 200 200 200 200
Inulin LV 110 860 660 740 680 695
Total 1000 1000 1000 1000 1000
TABLE 4
Ingredients (mg) 16 17 18 19 20
Nicotine benzoate 25 35 10 20 15
Sunflower oil 50 105 30 60 45
Sodium bicarbonate 150 150 200 200 200
Inulin LV 110 775 710 760 720 740
Total 1000 1000 1000 1000 1000
Date Recite/Date Received 2023-08-23
TABLE 5
Ingredients (mg) 21 22 23 24 25
Nicotine benzoate 15 52.5 22.5 45 52.5
Sunflower oil 45 157.5 67.5 135 105
Sodium bicarbonate 150 300 300 300 300
Inulin LV 110 1290 990 1110 1020 1042.5
Total 1500 1500 1500 1500 1500
TABLE 6
Ingredients (mg) 26 27 28 29 30
Nicotine benzoate - 37.5 52.5 15 30 22.5
Sunflower oil 75 157.5 45 90 67.5
Sodium bicarbonate 225 225 300 300 300
Inulin LV 110 1162.5 1065 1140 1080 1110
Total 1500 1500 1500 1500 1500
TABLE 7
Ingredients (mg) 31 32 33 34 35
Nicotine polacrilex 5 17.5 7.5 15 17.5
Sunflower oil 15 52.5 22.5 45 35
Sodium bicarbonate 50 100 100 100 100
Inulin LV 110 430 660 370 340 347.5
Total 500 500 500 500 500
TABLE 8
Ingredients (mg) 36 37 38 39 40
Nicotine polacrilex 12.5 17.5 5 10 7.5
Sunflower oil 25 52.5 15 30 22.5
Sodium bicarbonate 75 75 100 100 100
Inulin LV 110 387.5 355 380 360 340
Total 500 500 500 500 500
11
Date Recite/Date Received 2023-08-23
TABLE 9
Ingredients (mg) 41 42 43 44 45
Nicotine polacrilex 10 35 15 30 35
Sunflower oil 30 105 45 90 70
Sodium bicarbonate 100 200 200 200 200
Inulin LV 110 860 660 740 680 695
Total 1000 1000 1000 1000 1000
TABLE 10
Ingredients (mg) 46 47 48 49 50
Nicotine polacrilex 25 35 10 20 15
Sunflower oil 50 105 30 60 45
Sodium bicarbonate 150 150 200 200 200
Inulin LV 110 775 710 760 720 740
Total 1000 1000 1000 1000 1000
TABLE 11
Ingredients (mg) 51 52 53 54 55
Nicotine polacrilex 15 52.5 22.5 45 52.5
Sunflower oil 45 157.5 67.5 135 105
Sodium bicarbonate 150 300 300 300 300
Inulin LV 110 1290 990 1110 1020 1042.5
Total 1500 1500 1500 1500 1500
TABLE 12
12
Date Recite/Date Received 2023-08-23
Ingredients (mg) 56 57 58 59 50
Nicotine polacrilex 37.5 52.5 15 30 22.5
Sunflower oil 75 157.5 45 90 67.5
Sodium bicarbonate 225 225 300 300 300
Inulin LV 110 1162.5 1065 1140 1080 1110
Total 1500 1500 1500 1500 1500
KITS
Disclosed herein are kits for sublingual delivery of nicotine. The kits
contain a base
nicotine delivery system which comprises the active ingredients and a non-
water soluble liquid
permeable pouch into which the active ingredients and any necessary adjunct
ingredients useful
for delivery of the nicotine, nicotine salt of nicotine resin compositions. In
one aspect the kit
comprises a pouch containing a disclosed composition, comprising:
A) a liquid permeable pouch comprising a non-nicotine composition
comprising:
a) one or more delivery agents; and
b) a bulking agent; and
B) a base nicotine delivery composition comprising:
a) nicotine, a nicotine salt, nicotine in combination with a resin, or
mixtures
thereof;
b) sunflower oil;
c) sodium bicarbonate; and
d) the balance one or more carriers.
Delivery Control Agents
In order to control sublingual delivery of the disclosed nicotine-containing
compositions
the kits contain one or more agents that control the release of nicotine into
the mouth of the use.
These agents are typically formulated after assembly of the base nicotine
delivery
compositions; however, the formulator can add a delivery control agent as part
of a carrier
system.
In one embodiment the delivery agents are solubilizers, for example,
lecithins,
polyoxyethylene stearate, polyoxyethylene sorbitan fatty acid esters, fatty
acid salts, mono and
diacetyl tartaric acid esters of mono and diglycerides of edible fatty acids,
citric acid esters of
mono and diglycerides of edible fatty acids, saccharose esters of fatty acids,
polyglycerol esters
13
Date Recite/Date Received 2023-08-23
of fatty acids, polyglycerol esters of interesterified castor oil acid (E476),
sodium stearoyl
lactylate, sodium lauryl sulfate and sorbitan esters of fatty acids and
polyoxyethylated
hydrogenated castor oil (for example, CREMOPHORTm), block copolymers of
ethylene oxide
and propylene oxide (for example, one or more PLURONICSTM or POLOXAMERSTm),
polyoxyethylene fatty alcohol ethers, polyoxyethylene sorbitan fatty acid
esters, sorbitan esters
of fatty acids and polyoxyethylene stearic acid esters.
In one embodiment the delivery agent is chosen from sodium stearoyl lactylate,
sodium
lauryl sulfate, glycerol, propylene glycol, b-cyclodextrin and propylene
glycol 400 (PEG 400).
Non-limiting examples of solubilizers includes glycerol, propylene glycol, b-
cyclodextrin and propylene glycol 400 (PEG 400).
In one aspect of the disclosed kits, the kits comprise:
A) a liquid permeable pouch comprising a non-nicotine composition
comprising:
a) one or more delivery agents; and
b) a bulking agent; and
B) a base nicotine delivery composition comprising:
a) nicotine, a nicotine salt, nicotine in combination with a resin, or
mixtures
thereof;
b) sunflower oil;
c) sodium bicarbonate; and
d) the balance one or more carriers.
In one embodiment of this aspect, the kits comprise:
A) a liquid permeable pouch comprising a non-nicotine composition
comprising:
a) one or more delivery agents; and
b) a bulking agent; and
B) a base nicotine delivery composition comprising:
a) from about 1% to about 6% by weight of nicotine, a nicotine salt,
nicotine in combination with a resin, or mixtures thereof;
b) from about 3% to about 20% by weight of sunflower oil;
c) from about 10% to about 20% by weight of sodium bicarbonate; and
d) the balance one or more carriers.
In one iteration of this embodiment, the kits comprise:
A) a liquid permeable pouch comprising a non-nicotine composition
comprising:
14
Date Recue/Date Received 2023-08-23
a) maltitol; and
b) an admixture of microcrystalline cellulose and inulin; and
B) a base nicotine delivery composition comprising:
a) from about 1% to about 6% by weight of nicotine, a nicotine salt,
nicotine in combination with a resin, or mixtures thereof;
b) from about 3% to about 20% by weight of sunflower oil;
c) from about 10% to about 20% by weight of sodium bicarbonate; and
d) the balance:
i) dextrose; and
ii) a flavorant.
Non-limiting examples of flavorants include apple, banana, cherry, cinnamon,
grape,
orange, pear, pineapple, raspberry, blueberry, strawberry, spearmint,
peppermint, wintergreen,
and vanilla.
Disclosed herein is a kit, comprising:
A) a liquid permeable pouch comprising a non-nicotine composition
comprising:
a) one or more delivery control agents; and
b) a bulking agent; and
B) a base nicotine delivery composition comprising:
a) nicotine, a nicotine salt, nicotine in combination with a resin, or
mixtures
thereof;
b) sunflower oil;
c) sodium bicarbonate; and
d) the balance one or more carriers.
In one non-limiting example, the kit comprises:
A) a liquid permeable pouch comprising a non-nicotine composition
comprising:
a) one or more delivery control agents; and
b) a bulking agent; and
B) from about 70 mg to about 510 mg of an active base delivery
system,
comprising:
a) from about 5 mg to about 50 mg by weight of nicotine benzoate;
b) from about 15 mg to about 160 mg by weight of sunflower oil;
c) from about 50 mg to about 300 mg by weight of sodium bicarbonate;
Date Recue/Date Received 2023-08-23
d) from about 350 mg to about 1500 mg of one or more carriers; and
e) the balance one or more delivery control agents.
In another non-limiting example, the kit comprises:
A) a liquid permeable pouch comprising a non-nicotine composition
comprising:
a) one or more delivery control agents; and
b) a bulking agent; and
B) from about 70 mg to about 510 mg of an active base delivery
system,
comprising:
a) from about 5 mg to about 50 mg by weight of nicotine polacrilex;
b) from about 15 mg to about 160 mg by weight of sunflower oil;
c) from about 50 mg to about 300 mg by weight of sodium bicarbonate;
d) from about 350 mg to about 1500 mg of one or more carriers; and
e) the balance one or more delivery control agents.
PREPARATION
The disclosed base compositions can be prepared by the following general
procedure.
Nicotine, a nicotine salt, or nicotine in combination with a resin, is
combined with sunflower
oil in a vessel with adequate stirring. The amount of each ingredient varies
depending upon the
formulator's choice of the ratio of the nicotine-containing ingredient and
sunflower oil, i.e., the
ratio of nicotine-containing ingredient to sunflower oil can be, as disclosed
herein above, from
about 1:1 to about 1:3. The choice of ratio will also dictate the relative
amounts of adjunct
ingredients that are added. With stirring, the nicotine-containing ingredient
sunflower oil
admixture is then slowly heated to from about 50 C to about 75 C, again
predicated on the
ratio of ingredients and the choice of excipients.
At this point antioxidants, as well as other adjunct ingredients can be
optionally added
to the nicotine-containing compound/sunflower oil admixture during heating.
The amount and
ratio of any antioxidants added to the admixture varies depending upon the
formulator's choice.
In one non-limiting embodiment, the amount of antioxidant is from about 0.01%
to about
0.10% by weight of the admixture.
Following the optional addition of an antioxidant and/or other adjunct
ingredients, the
resulting admixture is then slowly added to a dry particulate substrate with
sufficient mixing to
form a homogenous dispersion. The quantity of the admixture that is added to
the substrate is
from about 5% to about 60% by weight. The final dispersion is then dehydrated
by which ever
16
Date Recue/Date Received 2023-08-23
means chosen by the formulator, for example, oven drying, lyophilization,
convection drying,
microwave radiation, etc. In one non-limiting embodiment, the dispersion is
dried from about
45 to about 135 minutes. Depending upon many factors including the type of
adjunct
ingredients and the ratio of the nicotine-containing compound to sunflower
oil, the time can be
shortened or lengthened.
At this point an alkalizing agent is incorporated. In one non-limiting
example, sodium
bicarbonate is used as the alkalizing agent. The amount of alkalizing agent is
predicated on the
amounts of other ingredients and the choice of substrate. In one non-limiting
embodiment the
composition can comprise from about 1% to about 25% by weight of the
alkalizing agent.
After homogenizing the alkalizing agent into the homogeneous admixture now
formed,
other adjunct ingredients can be added. Non-limiting examples include bulking
agents which
provide a mouthfeel that is compatible with the pouches, thereby providing the
user with a
feeling of "substance" inside the pouch. Bulking agents include
microcrystalline cellulose and
inulin. In addition, sweeteners, for example, maltitol, and/or flavoring
compounds are added to
provide different oral sensations.
The resulting composition can then be further compounded with other adjunct
ingredients, at levels that vary depending upon the formulator's choice, such
as bulking agents
(e.g., microcrystalline cellulose), high potency sweeteners (e.g., maltitol)
and/or flavoring
compounds, and ultimately rendered in various different oral or intraoral form
factors.
In one non-limiting example, nicotine benzoate (15 g) and sunflower oil (45 g)
are
combined in a stainless-steel reaction vessel with efficient stirring and
heated to 50 C until
homogeneous. The nicotine benzoate sunflower oil admixture is then slowly
metered into
inulin (500 g) as a dry particulate substrate compound while mixing until
homogeneously
dispersed. Sodium bicarbonate (20 g) is added while mixing until homogenously
dispersed.
The admixture is then placed in a convection airflow dehydration chamber for
90 minutes to
remove remaining moisture and effect a molecular association between the
nicotine and the
sunflower oil infused dry particulate. The resulting composition is then
combined with
microcrystalline cellulose (200 g), maltitol (175 g) and spearmint flavoring
(100 g) and then
charged to unit dose oral pouches.
Pouches
The properties of the pouch can influence the release of the nicotine,
nicotine salt, or
nicotine in combination with a resin from the pouch composition and thereby
possibly
17
Date Recue/Date Received 2023-08-23
influence the rate of uptake by the user. The disclosed pouches comprise water
insoluble fiber
which allows moisture, typically the user's saliva, to enter the pouch and
solubilize the water-
soluble components.
Disclosed herein are water-insoluble pouches which can comprise insoluble
fiber, for
example, wheat fibers, oat fibers, pea fibers, rice fiber, maize fibers, oat
fibers, tomato fibers,
barley fibers, rye fibers, sugar beet fibers, buckwheat fibers, potato fibers,
cellulose fibers,
apple fibers, cocoa fibers, cellulose fiber, powdered cellulose, bamboo
fibers, bran fibers or
combinations thereof.
In one embodiment the disclosed pouches comprise cellulose prepared by
processing
alpha-cellulose obtained as a pulp from strains of fibrous plant materials,
such as wood pulp.
In a further embodiment the pouches can comprise wheat fibers, oat fibers, or
combinations
thereof.
The following are non-limiting examples of plant fibers Vitacel WF 600,
Vitacel HF
600, Vitacel P95Tm, Vitacel WF 2001M, Vitacel LOO', Vitacel Erbsenfaser EF 150
Tm,
Vitacel bamboo fiberbaf 90, Vitacel HF 600, Vitacel Cellulose L700GTm, Vitacel
PF200, Vitacel potatofiber KF200", Vitacel bamboo fiberhaf BAF40', Vitacel
Haferfaser/oat fiber HF-401-30, Vitacel L 00w, Vitacel Cellulose L700G",
Vitacel
LC l000, Vitacel L600-20, Vitacel L600Tm or combination thereof.
In formulating pouches containing various amounts of the base nicotine
delivery
composition it is one embodiment of the present disclosure that the amount of
water-insoluble
fiber can be reduced without compromising the mouthfeel during use. It is
important that the
pouch material does not cause swelling in use because this fact can counteract
the dissolution
of the water-soluble component, thereby preventing the user from experiencing
any decrease in
pouch content during use.
In addition, the pouch composition can also provide for a desirable mouthfeel
such as a
soft and/or sticky texture. The desirable texture and mouthfeel can be
obtained while still being
able to store manufactured pouches together in abutment, for example, in cans
and the like
without sticking or clumping together to result in ruptures of the pouches
when being removed.
The desirable mouthfeel can in some embodiments also comprise a tingling
sensation
reminiscent of tobacco pouches, but without many of the undesirable effects
associated
therewith, for example, discoloring of tissue.
18
Date Recue/Date Received 2023-08-23
In one aspect of the disclosed kits, the kits comprise an active base
composition and a
pouch for delivery of nicotine sublingually to the user.
The kits comprise a water-permeable pouch, into which an active base
composition and
a delivery system is added. The disclosed pouches comprise:
A) from about 5% to about 20% by weight of an active base
composition,
comprising"
a) from about 1% to about 6% by weight of nicotine, a nicotine salt,
nicotine in combination with a resin, or mixtures thereof;
b) from about 3% to about 20% by weight of sunflower oil;
c) from about 10% to about 20% by weight of sodium bicarbonate; and
B) from about 80% to about 95% by weight of a delivery system
wherein the
delivery control system contains one or more delivery control agents,
carriers,
solubilizers or mixtures thereof.
In one embodiment of this aspect, the pouches comprise:
A) from about 70 mg to about 510 mg of an active base composition,
comprising:
a) from about 5 mg to about 50 mg by weight of nicotine benzoate;
b) from about 15 mg to about 160 mg by weight of sunflower oil;
c) from about 50 mg to about 300 mg by weight of sodium bicarbonate;
B) from about 350 mg to about 1500 mg of one or more carriers; and
C) the balance one or more delivery control agents.
In one iteration of this embodiment, the one or more carriers serves as the
delivery
control agent. For example, a pouch comprising:
a) from about 5 mg to about 50 mg by weight of nicotine benzoate;
b) from about 15 mg to about 160 mg by weight of sunflower oil;
c) from about 50 mg to about 300 mg by weight of sodium bicarbonate; and
d) from about 300 mg to about 1300 mg by weight of a carrier chosen from
inulin,
galactogen, cellulose, chitin, pectin, psyllium, guar, hemicellulose, potato
starch,
or partially hydrolyzed polysaccharides.
In another iteration of this embodiment, a pouch comprising:
a) from about 5 mg to about 50 mg by weight of nicotine benzoate;
b) from about 15 mg to about 160 mg by weight of sunflower oil;
c) from about 50 mg to about 300 mg by weight of sodium bicarbonate; and
19
Date Recue/Date Received 2023-08-23
d) from about 300 mg to about 1300 mg by weight of a carrier chosen from,
sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, hydrogenated
starch
hydrolysates, isomaltose, or any combination thereof.
In a still further iteration of this embodiment, a pouch comprising:
a) from about 5 mg to about 50 mg by weight of nicotine benzoate;
b) from about 15 mg to about 160 mg by weight of sunflower oil;
c) from about 50 mg to about 300 mg by weight of sodium bicarbonate; and
d) from about 300 mg to about 1300 mg by weight of inulin.
In a yet still further iteration of this embodiment, a pouch comprising:
a) from about 5 mg to about 50 mg by weight of nicotine benzoate;
b) from about 15 mg to about 160 mg by weight of sunflower oil;
c) from about 50 mg to about 300 mg by weight of sodium bicarbonate; and
d) from about 300 mg to about 1300 mg by weight of microcrystalline
cellulose.
In a yet still further iteration of this embodiment, a pouch comprising:
a) from about 5 mg to about 50 mg by weight of nicotine benzoat;
b) from about 15 mg to about 160 mg by weight of sunflower oil;
c) from about 50 mg to about 300 mg by weight of sodium bicarbonate; and
d) from about 300 mg to about 1300 mg by weight of an admixture of inulin
and
microcrystalline cellulose.
In another embodiment of this aspect, the pouches comprise:
A) from about 70 mg to about 510 mg of an active base composition,
comprising:
a) from about 5 mg to about 50 mg by weight of nicotine polacrilex;
b) from about 15 mg to about 160 mg by weight of sunflower oil;
c) from about 50 mg to about 300 mg by weight of sodium bicarbonate;
B) from about 350 mg to about 1500 mg of one or more carriers; and
C) the balance one or more delivery control agents.
In one iteration of this embodiment, the one or more carriers serves as the
delivery
control agent. For example, a pouch comprising:
a) from about 5 mg to about 50 mg by weight of nicotine polacrilex;
b) from about 15 mg to about 160 mg by weight of sunflower oil;
c) from about 50 mg to about 300 mg by weight of sodium bicarbonate; and
Date Recue/Date Received 2023-08-23
d) from about 300 mg to about 1300 mg by weight of a carrier
chosen from inulin,
galactogen, cellulose, chitin, pectin, psyllium, guar, hemicellulose, potato
starch,
or partially hydrolyzed polysaccharides.
In another iteration of this embodiment, a pouch comprising:
a) from about 5 mg to about 50 mg by weight of nicotine polacrilex;
b) from about 15 mg to about 160 mg by weight of sunflower oil;
c) from about 50 mg to about 300 mg by weight of sodium bicarbonate; and
d) from about 300 mg to about 1300 mg by weight of a carrier chosen from,
sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, hydrogenated
starch
hydrolysates, isomaltose, or any combination thereof.
In a still further iteration of this embodiment, a pouch comprising:
a) from about 5 mg to about 50 mg by weight of nicotine polacrilex;
b) from about 15 mg to about 160 mg by weight of sunflower oil;
c) from about 50 mg to about 300 mg by weight of sodium bicarbonate; and
d) from about 300 mg to about 1300 mg by weight of inulin.
In a yet still further iteration of this embodiment, a pouch comprising:
a) from about 5 mg to about 50 mg by weight of nicotine polacrilex;
b) from about 15 mg to about 160 mg by weight of sunflower oil;
c) from about 50 mg to about 300 mg by weight of sodium bicarbonate; and
d) from about 300 mg to about 1300 mg by weight of microcrystalline
cellulose.
In a yet still further iteration of this embodiment, a pouch comprising:
a) from about 5 mg to about 50 mg by weight of nicotine polacrilex;
b) from about 15 mg to about 160 mg by weight of sunflower oil;
c) from about 50 mg to about 300 mg by weight of sodium bicarbonate; and
d) from about 300 mg to about 1300 mg by weight of an admixture of inulin
and
microcrystalline cellulose.
The disclosed compositions can comprise from about 80% to about 95% by weight
of
one or more delivery control agents, carriers, solubilizers or mixtures
thereof. In one
embodiment the disclosed compositions can comprise from about 80% to about 90%
by weight
of one or more delivery control agents, carriers, solubilizers or mixtures
thereof. In another
embodiment the disclosed compositions can comprise from about 85% to about 95%
by weight
of one or more delivery control agents, carriers, solubilizers or mixtures
thereof. In a further
21
Date Recue/Date Received 2023-08-23
embodiment the disclosed compositions can comprise from about 85% to about 90%
by weight
of one or more delivery control agents, carriers, solubilizers or mixtures
thereof.
PROCESS
The disclosed base compositions can be prepared by the following general
procedure.
Nicotine, a nicotine salt, or nicotine in combination with a resin, is
combined with sunflower
oil in a vessel with adequate stirring. The amount of each ingredient varies
depending upon the
formulator's choice of the ratio of the nicotine-containing ingredient and
sunflower oil, i.e., the
ratio of nicotine-containing ingredient to sunflower oil is from about 1:1 to
about 1:3. The
choice of ratio will also dictate the relative amounts of adjunct ingredients
that are added. With
stifling, the nicotine-containing ingredient sunflower oil admixture is then
slowly heated to
from about 50 C to about 75 C, again predicated on the ratio of ingredients
and the choice of
excipients.
In one non-limiting example, nicotine benzoate (15 g) and sunflower oil (45 g)
are
combined in a stainless-steel reaction vessel with efficient stirring and
heated to 50 C until
homogeneous. Inulin (500 g) is slowly metered in and stirring continued until
all the inulin is
dispersed. Sodium bicarbonate (150 g) is slowly added while raising the
temperature to 60 C.
Once the admixture is homogeneous, inulin (790 g) is added at a rate to
maintain a
homogeneous admixture. The admixture is then slowly cooled to 30 C and placed
in a
vacuum oven for 5 hours to remove all of the remaining moisture. The resulting
composition
can then be combined with additional inulin or microcrystalline cellulose then
charged to one
or more pouches.
The following are non-limiting examples of compositions delivered by way of an
insoluble plant or synthetic pouch.
EXAMPLE 1
Ingredients (mg) A
Nicotine benzoate 5 17.5 7.5 15 17.5
Sunflower oil 15 52.5 22.5 45 35
Sodium bicarbonate 50 100 100 100 100
Inulin LV 110 300 460 170 240 147.5
P-cyclodextrin 130 200 200 100 200
Total 500 500 500 500 500
22
Date Recite/Date Received 2023-08-23
EXAMPLE 2
Ingredients (mg) F G H I J
Nicotine benzoate 5 17.5 7.5 15 17.5
Sunflower oil 15 52.5 22.5 45 35
Sodium bicarbonate 50 100 100 100 100
Inulin LV 110 330 510 210 240 247.5
propylene glycol 100 150 80 100 100
Total 500 500 500 500 500
EXAMPLE 3
Ingredients (mg) K L M N 0
Nicotine benzoate 5 17.5 7.5 15 17.5
Sunflower oil 15 52.5 22.5 45 35
Sodium bicarbonate 50 100 100 100 100
Inulin LV 110 320 510 270 240 197.5
glycerol 110 150 100 100 150
Total 500 500 500 500 500
EXAMPLE 4
Ingredients (mg) P Q R S T
Nicotine benzoate 5 17.5 7.5 15 17.5
Sunflower oil 15 52.5 22.5 45 35
Sodium bicarbonate 50 100 100 100 100
Inulin LV 110 330 560 190 240 247.5
PEG 400 100 100 100 100 100
Total 500 500 500 500 500
EXAMPLE 5
23
Date Recite/Date Received 2023-08-23
Ingredients (mg) U V W X Y
Nicotine polacrilex 5 17.5 7.5 15 17.5
Sunflower oil 15 52.5 22.5 45 35
Sodium bicarbonate 50 100 100 100 100
Inulin LV 110 300 460 170 240 147.5
13-cyclodextrin 130 200 200 100 200
Total 500 500 500 500 500
EXAMPLE 6
Ingredients (mg) Z AA BB CC DD
Nicotine polacrilex 5 17.5 7.5 15 17.5
Sunflower oil 15 52.5 22.5 45 35
Sodium bicarbonate 50 100 100 100 100
Inulin LV 110 330 510 210 240 247.5
propylene glycol 100 150 80 100 100
Total 500 500 500 500 500
EXAMPLE 7
Ingredients (mg) EE FF GG HH II
Nicotine polacrilex 5 17.5 7.5 15 17.5
Sunflower oil 15 52.5 22.5 45 35
Sodium bicarbonate 50 100 100 100 100
Inulin LV 110 320 510 270 240 197.5
glycerol 110 150 100 100 150
Total 500 500 500 500 500
EXAMPLE 8
24
Date Recite/Date Received 2023-08-23
Ingredients (mg) JJ KK LL MM NN
Nicotine polacrilex 5 17.5 7.5 15 17.5
Sunflower oil 15 52.5 22.5 45 35
Sodium bicarbonate 50 100 100 100 100
Inulin LV 110 330 560 190 240 247.5
PEG 400 100 100 100 100 100
Total 500 500 500 500 500
As demonstrated by the following data and Figures 1 to 8, the disclosed
compositions
are more effective in increasing the plasma level of nicotine via oral
delivery than providing
nicotine alone in a carrier. The following animal study provides conclusive
proof of this fact.
The disclosed animal studies were conducted utilizing the disclosed
compositions.
Table I summarizes the Study design. Male Beagle dogs from Marshall
Bioresources were
utilized for this study. Animals were identified by ear tattoo and cage label.
The study was not
blinded. The animals were healthy at the start of the study. Body weights were
recorded at
each dosing time point. General health observations were recorded at each
dosing and sample
collection time point for the duration of the study.
Dosing
Nicotine, 4 mg per pouch, was administered via buccal administration. Animals
were
anesthetized with propofol at a dose of 6 mg/kg, animals were then intubated
and maintained in
an anesthetic state using isoflurane at 1-5% and 2 L of oxygen flow. The pouch
with test
article was placed in the buccal space, rinsed with a small volume of water
(0.5 - lmL). Every
minutes after placing the pouch the test article test article in the buccal
space, the isoflurane
mask was removed and the pouch gently squeezed. Special attention was taken to
ensure saliva
did not leak from the mouth. Following 30 minutes, the pouch test article was
removed from
the buccal space and the animal allowed to recover from anesthesia. All
pouches were retained
following dosing. Each pouch was placed in individual conical tube with the
animal ID and
pouch identification.
TEST COMPOSITIONS
Nicotine Benzoate Control
TABLE I
Date Recite/Date Received 2023-08-23
Ingredients mg
Nicotine benzoate 1.11 7
Inulin LV 110 (pre-tested) 98.89 624
Total 100 631
Nicotine Benzoate Disclosed Composition
TABLE II
Ingredients mg
Nicotine benzoate 1.37 8.6
Sunflower oil 4.09 25.8
Sodium bicarbonate 13.72 86.6
Inulin LV 110 (pre-tested) 80.82 510
Total 100 631
Nicotine Polacrilex Control
TABLE III
Ingredients mg
Nicotine polacrilex 3.6 20
Glycerin 0.4 2.2
Inulin LV 110 (pre-tested) 96.0 632.8
Total 100 555
Nicotine Polacrilex Disclosed Composition
TABLE IV
Ingredients mg
Nicotine polacrilex 3.91 21.7
Sunflower oil 13.04 72.6
Sodium bicarbonate 13.69 76.1
Glycerin 0.44 2.4
Inulin LV 110 (pre-tested) 68.92 383.2
Total 100 556
26
Date Recite/Date Received 2023-08-23
As shown in the table below, Group 1 was administered the nicotine benzoate
control
group. Group 2 was administered the disclosed composition comprising nicotine
benzoate.
Group 3 was administered the nicotine polacrilex control. Group 4 was
administered the
disclose composition comprising nicotine polacrilex. The actual amounts based
on results of
potency testing was 3.12, 3.31, 3.48, and 3.79 mg per pouch, in Groups 1, 2,3,
and 4,
respectively
TABLE V
Group # Test Dosing N= Dose Dose Blood
Article Route (mg/pouch) Volume Sampling
Time Points
1 Nicotine benzoate Buccal 10 631 N/A
(Control)
2 Nicotine benzoate Buccal 10 631 N/A Pre-dose, 2,
4, 6,
8,10, 15, 30, 45,
3 Nicotine polacrilex Buccal 10 555 N/A
60, and 120
(Control)
minutespost
dose*
4 Nicotine polacrilex Buccal 10 556 N/A
Sample Collection, Preparation and Storage
Each blood sample (approx. 2000 L) was collected from the jugular vein in a
K2ETDA
collection tube and gently inverted several time to mix. The samples were kept
on ice until
centrifugation at 4 C for 5 minutes at 3,000 x g. Approximately 1000 jiL
plasma was separated
by centrifugation. The resulting plasma samples were stored at -80 C until
bioanalysis was
conducted.
Quantitative Plasma Sample Analysis
Plasma samples were extracted by protein precipitation and analyzed using LC-
MS/MS.
Individual and Mean plasma concentrations and resulting pharmacokinetic
parameters for
nicotine are shown in Tables 4 - 7. All data are expressed as ng/mL of
nicotine. Samples that
were below the limit of quantification (1.0 ng/mL in plasma) were excluded
from the
calculation of mean values. Mean concentrations versus time data are plotted
in Figures 1 - 8.
27
Date Recite/Date Received 2023-08-23
Pharmacokinetic parameters were calculated from the time course of the plasma
concentration. Pharmacokinetic parameters were determined with Phoenix
WinNonlin (v8.0)
software using a noncompaitmental model. The maximum plasma concentration
(Cmax) and
the time to reach maximum plasma concentration (tmax) after dosing were
observed from the
data. The area under the time concentration curve (AUC) was calculated using
the linear
trapezoidal rule with calculation to the last quantifiable data point (AUCO-
last), and with
extrapolation to infinity (AUCco) if applicable. Plasma half-life (t1/2) was
calculated from
0.693/slope of the terminal elimination phase. Mean residence time, MRT, was
calculated by
dividing the area under the moment curve (AUMC) by the AUC. Any samples below
the limit
of quantitation (1.0 ng/mL plasma) were not used in the calculation of mean
values
DATA
Pharmacokinetic Parameters and Plasma Concentrations (ng/mL) for Nicotine
after
Buccal Administration of the Nicotine Benzoate Control composition disclosed
in
TABLES VI and VII in Male Beagle dogs (Group 1)
TABLE VI
Animal number
Sample time (hr) 1 2 3 4 5
0.0333 15.1 7.43 4.83 5.09 2.39
0.0666 18.7 24.9 46.4 9.37 9.00
0.1 19.3 27.0 50.0 9.5 13.7
0.122 21.5 30.7 301 20.5 19.6
0.167 94.1 32.1 54.3 50.3 20.0
0.25 50.6 34.0 55.4 192.4 25.4
0.5 50.9 42.6 55.9 88.9 62.8
0.75 49.1 121 94.2 47.4 46.9
1 73.3 49.8 33.9 41.1 38.6
2 12.8 7.05 5.4 12.1 9.17
Dose (mg/kg) 0.354 0.62 0.362 0.385 0.3
Cmax (ng/mL) 94.1 121 94.2 192.4 62.8
tmax (hr) 0.167 0.75 0.75 0.250 0.5
t1/2 0.547 ND2 ND2 0.614 0.516
28
Date Recite/Date Received 2023-08-23
Animal number
Sample time (hr) 1 2 3 4 5
MRTEast (hr) 0.827 0.792 0.691 0.65
0.815
AUCiast (hr.ng/mL) 93.6 - 86.1 78.9 102.3 63.0
AUC.(hr.ng/mL) 104 ND2 ND2 113 69.9
AUCiast/D
264 238 218 266 210
(hr.kg.ng/mL/mg)
AUC./D
293 ND2 ND2 294 233
(hr.kg.ng/mL/mg)
1. AUCIast/D (hr.kg.ng/mL/mg) and AUGID (hr.kg.ng/mL/mg) are dose normalized
values.
2. Not determined because the line defining the terminal elimination phase had
an r2 of
<0.85.
TABLE VII
Animal number
Sample time (hr) 6 7 8 9 10
0.0333 15.4 4.45 11.2 BLOQ3 9.41
0.0666 17.0 10.0 181 2.32 38.5
0.1 21.3 21.3 33.2 6.8 40.6
0.122 31.4 28.4 34.0 16.4 ND2
0.167 33.4 29.0 34.9 35.3 53.7
0.25 34.1 43.1 38.6 49.2 50.1
0.5 53.4 - 67.0 73.2 116.5 55.6
0.75 90.5 44.1 99.4 126.7 57.8
1 57.2 36.2 39.5 37.8 62.8
2 10.5 3.46 5.53 9.6 12.4
Dose (mg/kg) 0.376 0.30 0.416 0.243
0.223
Cm= (ng/mL) 90.5 67.0 99.4 127 62.8
tmax (hr) 0.75 0.50 0.75 0.75 1.0
t1/2 ND2 0.326 ND2 ND2 ND2
29
Date Recite/Date Received 2023-08-23
Animal number
Sample time (hr) 6 7 8 9 10
MRTEast (hr) 0.822 0.712 0.732 0.738
0.507
AUCiast (hr.ng/mL) 87.4 63.1 82.5 100 89.9
AUC.(hr.ng/mL) ND2 64.7 ND2 ND2 ND2
AUCiast/D
233 211 198 412 403
(hr.kg.ng/mL/mg)
AUC./D
ND2 216 ND2 ND2 ND2
(hr.kg.ng/mL/mg)
1. AUCIast/D (hr.kg.ng/mL/mg) and AUC./D (hr.kg.ng/mL/mg) are dose normalized
values .9.
2. Not determined because the line defining the terminal elimination phase had
an r2 of
<0.85.
3. BLOQ = below the limit of quantitation (1 ng/mL)
TABLE VIII provides the mean and standard deviation for the results of Animals
1-10.
TABLE VIII
Sample time (hr) mean SD
0.0333 8.36 4.73
0.0666 19.6 14.7
0.1 24.3 13.7
0.122 25.3 6.55
0.167 43.7 21.0
0.25 57.3 48.4
0.5 66.7 24.8
0.75 77.7 32.3
1 47.0 13.3
2 8.79 3.28
Dose (mg/kg) 0.332 0.063
C. (ng/mL) 101 39.0
tmax (hr) 0.617 0.258
Date Recite/Date Received 2023-08-23
Sample time (hr) mean SD
t1/2 0.501 0123
MRliast (hr) 0.759 0.062
AUCiast (hr.ng/mL) 84.7 - 13.5
AUC.(hr.ng/mL) 87.8 24.1
AUClast/D
265 78.3
(hr.kg.ng/mL/mg)
AUC./D
259 40.3
(hr.kg.ng/mL/mg)
Figure 1 is a plot of the individual plasma concentrations (ng/mL) for
Nicotine versus
time (hour) after buccal administration of the nicotine benzoate control
composition disclosed
in TABLE I in male Beagle dogs. Figure 2 is a plot of the mean plasma
concentration
(ng/mL) for Nicotine versus time (hour) after buccal administration of
nicotine benzoate
control composition disclosed in TABLE I in male Beagle dogs.
Pharmacokinetic Parameters and Plasma Concentrations (ng/mL) for Nicotine
after
Buccal Administration of pouches containing the nicotine benzoate disclosed
composition
in TABLES IX and X (4 mg) in Male Beagle dogs (Group 2)
TABLE IX
Animal number
Sample time (hr) - 11 12 13 14 15
0.0333 132 50.0 25.6 38.8 107
0.0666 233 70.9 64.3 332 134
0.1 240 100 78.9 446 412
0.122 247 105 88.7 349 413
0.167 253 117 98.8 258 136
0.25 350 486 113 241 418
0.5 342 175 228 240 647
0.75 150 95.7 91.8 220 153
1 88.2 6104 78.1 83.3 82.4
2 33.0 30.9 21.8 37.0 32.4
31
Date Recite/Date Received 2023-08-23
Animal number
Sample time (hr) 11 12 13 14 15
Dose (mg/kg) 0.38 0.269 0.331 0.429
0.413
Cmax (ng/mL) 350 - 486 228 446 647
tmax (hr) 0.25 0.25 0.5 0.10 0.50
t1/2 0.606 0.823 0.583 0.554 0.601
MRTiast (hr) 0.603 0.597 0.710 0.632 0.55
AUCiast (hr.ng/mL) 296 220 173 280 0397
AUC00(hr.ng/mL) 325 257 191 309 425
AUCIast/D
778 819 523 652 961
(hr.kg.ng/mL/mg)
AUC./D
854 956 578 720 1029
(hr.kg.ng/mL/mg)
1. AUCIast/D (hr.kg.ng/mL/mg) and AUGID (hr.kg.ng/mL/mg) are dose normalized
values.
2. Not determined because the line defining the terminal elimination phase had
an r2 of
<0.85.
TABLE X
Animal number
Sample time (hr) - 16 17 18 19 20
0.0333 34.9 14.3 556 6.85 5.63
0.0666 18.2 48.4 368 27.2 12.8
0.1 117 - 73.5 105 384 57.9
0.122 125 88.1 124 788 73.4
0.167 133 89.3 130 703 76.3
0.25 135 156 131 231 79.0
0.5 137 225 150 227 81.4
0.75 156 108 70 204 197
1 46.4 107.6 53.4 81.0 52.7
2 17.6 23.4 11.9 21.6 16.3
32
Date Recite/Date Received 2023-08-23
Animal number
Sample time (hr) 16 17 18 19 20
Dose (mg/kg) 0.380 0.318 0.341 0.290
0.301
Cmax (ng/mL) 156 225 150 788 197
tmax (hr) 0.750 0.50 0.50 0.133 0.750
t1/2 ND2 0.530 0.481 0.418 ND2
MRTiaat (hr) 0.664 0.732 0.631 0.554
0.757
AUCiaat (hr.ng/mL) 152 201 135 289 133
AUC00(hr.ng/mL) ND2 219 143 302 ND2
AUCIast/D
400 632 395 997 443
(hr.kg.ng/mL/mg)
AUC./D
ND2 688 420 1042 ND2
(hr.kg.ng/mL/mg)
1. AUCIast/D (hr.kg.ng/mL/mg) and AUGID (hr.kg.ng/mL/mg) are dose normalized
values.
2. Not determined because the line defining the terminal elimination phase had
an r2 of
<0.85.
3. BLOQ = below the limit of quantitation (1 ng/mL)
TABLE XI provides the mean and standard deviation for the results of Animals
11-21.
TABLE XI
Sample time (hr) mean SD
0.0333 46.1 44.6
0.0666 108 108
0.1 201 156
0.122 240 226
0.167 207 198
0.25 234 140
0.5 245 158
0.75 145 52.1
1 73.4 19.3
33
Date Recite/Date Received 2023-08-23
Sample time (hr) mean SD
2 24.6 8.83
Dose (mg/kg) 0.345 0.054
(ng/mL) 367 220
tmax(hr) 0.423 0.232
t1/2 0.574 0.119
MRTiast (hr) 0.643 0.072
AUCiast (hr.ng/mL) 228 86.2
AUCoo(hr.ng/mL) 271 88.5
AUClast/D
660 223
(hr.kg.ng/mL/mg)
AUC./D
786 223
(hr.kg.ng/mL/mg)
Figure 3 depicts the individual plasma concentrations (ng/mL) for Nicotine
versus time
(hour) after buccal administration of the disclosed nicotine benzoate
composition disclosed in
Table II (4 mg) in male Beagle dogs. Figure 4 shows the mean plasma
concentration (ng/mL)
for Nicotine versus time (hour) after buccal administration of the disclosed
compound in Table
II (4 mg) in male Beagle dogs.
Pharmacokinetic and Individual Plasma Concentrations (ng/mL) for Nicotine
versus time
(hour) after Buccal administration of nicotine polacrilex control composition
disclosed in
TABLES XII and XIII (4 mg) in Male Beagle dogs (Group 3)
TABLE XII
Animal number
Sample time (hr) 21 22 23 24 25
0.0333 18.3 1.36 BLOQ BLOQ 1.146
0.0666 26.3 1.73 1.55 3.08 2.76
0.1 27.1 2.04 1.80 4.02 5.64
0.122 29.2 3.24 1.92 6.40 9.68
0.167 52.7 3.54 2.44 9.00 10.1
0.25 29.3 4.76 7.10 9.54 11.7
34
Date Recite/Date Received 2023-08-23
Animal number
Sample time (hr) 21 22 23 24 25
0.5 27.3 10.1 19.8 12.0 18.4
0.75 7.34 - 10.9 11.6 27.6
31.3
1 4.60 7.18 10.4 8.36 19.7
2 1.32 1.61 1.7 1.34 2.59
Dose (mg/kg) 0.290 0.303 0.264 0.266 0.317
C. (ng/M1) 52.7 10.9 19.8 27.6 31.3
_ tmax (hr) 0.167 0.750 0.50 0.750 0.750 _
t1/2 0.518 ND2 0.423 ND2 ND2
MRTiast (hr) 0.468 0.818 0.787 0.749 0.851
AUCiast (hr.ng/M1) 23.5 11.8 16.7 18.4 22.2
AUC.,(hr.ng/M1) 24.5 ND2 17.7 ND2 ND2
AUCiast/D
81.0 39.0 63.3 69.2 81.4
(hr.kg.ng/Ml/mg)
AUC./D
84.4 ND2 67.2 ND2 ND2
(hr.kg.ng/Ml/mg)
1. AUCiast/D (hr.kg.ng/Ml/mg) and AUC.ID (hr.kg.ng/Ml/mg) are dose normalized
values.
2. Not determined because the line defining the terminal elimination phase had
an r2 of
<0.85.
TABLE XIII
Animal number
Sample time (hr) 26 27 28 29 30
0.0333 BLOQ 1.60 BLOQ BLOQ BLOQ
0.0666 BLOQ 2.25 NS4 BLOQ 3.07
0.1 1.33 7.51 2.89 1.31 3.15
0.122 1.74 8.62 8.35 2.71 4.02
0.167 5.14 6.56 31.7 9.38 4.91
0.25 7.69 9.36 52.2 9.64 14.4
Date Recite/Date Received 2023-08-23
Animal number
Sample time (hr) 26 27 28 29 30
0.5 15.4 10.4 35.5 11.9 16.0
0.75 16.0 10.0 34.0 30.2 45.4
1 18.5 9.1 15.9 20.5 21.3
2 1.95 1.70 2.11 2.29 1.60
Dose (mg/kg) 0.272 0.363 0.400 0.290 0.484
C. (ng/mL) 18.5 10.4 52.2 30.2 45.4
tnax (hr) 1.00 0.50 0.250 0.750 0.750
t1/2 ND2 0.465 0.320 ND2 ND2
MRTiast (hr) 0.851 0.778 0.645 0.849 0.802
AUCiast (hr.ng/mL) 22.2 14.2 39.4 26.8 32.5
AUC.(hr.ng/mL) ND2 15.4 40.4 ND2 ND2
AUCiast/D
81.4 39.2 98.4 92.4 67.3
(hr.kg.ng/mL/mg)
AUC./D
ND2 42.3 100.8 ND2 ND2
(hr.kg.ng/mL/mg)
1. AUClast/D (hr.kg.ng/mL/mg) and AUC.,/D (hr.kg.ng/mL/mg) are dose normalized
values.9.
2. Not determined because the line defining the terminal elimination phase had
an r2 of
<0.85.
3. BLOQ = below the limit of quantitation (1 ng/mL)
TABLE XIV provides the mean and standard deviation for the results of Animals
21-
30.
TABLE XIV
Sample time (hr) mean SD
0.0333 5.58 8.48
0.0666 5.82 9.05
0.1 5.68 7.80
0.122 7.58 8.13
36
Date Recite/Date Received 2023-08-23
Sample time (hr) mean SD
0.167 13.5 16.1
0.25 15.6 14.6
0.5 17.7 8.17
0.75 22.4 12.9
1 13.6 6.27
2 1.82 0.412
Dose (mg/kg) 0.325 0.071
Cnm, (ng/mL) 29.9 15.8
tmax(hr) 0.617 0.258
t1/2 0.431 0.084
MRTiast (hr) 0.756 0.117
AUCiast (hr.ng/mL) 23.5 8.66
AUCoo(hr.ng/mL) 24.5 11.3
AUCbst/D
72.3 21.0
(hr.kg.ng/mL/mg)
AUC./D
73.7 25.0
(hr.kg.ng/mL/mg)
Figure 5 shows the individual plasma poncentrations (ng/mL) for Nicotine
versus time
(hour) after buccal administration of the nicotine polacrilex control
composition disclosed in
TABLE III (4 mg) in male Beagle dogs (Group 3). Figure 6 displays the mean
plasma
concentration (ng/mL) for Nicotine versus time (hour) after buccal
administration of the
nicotine polacrilex control composition disclosed in TABLE III (4 mg) in Male
Beagle dogs
(Group 3)
Pharmacokinetic Parameters and Plasma Concentrations (ng/mL) for Nicotine
after
Buccal Administration of pouches containing the nicotine polacrilex disclosed
composition in TABLES XV and XVI (4 mg) in male Beagle dogs (Group 4)
TABLE XV
37
Date Recite/Date Received 2023-08-23
Animal number
Sample time (hr) 31 32 33 34 35
0.0333 5.50 18.9 192 5.26 2.05
0.0666 27.5 - 19.6 374 44.3 10.7
0.1 36.1 30.9 874 51.0 44.5
0.122 51.4 44.2 893 63.2 50.5
0.167 53.6 48.8 609 66.3 74.3
0.25 68.4 77.8 207 86.2 100
0.5 120 167 175 118 176
0.75 105 144 149 74.4 92.0
1 45.1 60.8 76.2 59.2 67.2
2 9.77 18.2 18.7 20.6 20.6
Dose (mg/kg) 0.242 0.304 0.327 0.314 0.304
Gan (ng/mL) 120 167 893 118 176
tmax (hr) 0.500 0.500 0.133 0.500 0.500
_
tin 0.387 0.455 0.451 0.511 0.581
MRTiasi (hr) 0.709 0.749 0.485 0.731 0.744
AUCiasi (hr.ng/mL) 108 144 286 116 144
AUC00(hr.ng/mL) 113 156 298 126 161
AUCiast/D
446 476 874 369 475
(hr.kg.ng/mL/mg)
AUC./D
468 515 912 403 531
(hr.kg.ng/mL/mg)
1. AUCiasi/D (hr.kg.ng/mL/mg) and AUCAD (hr.kg.ng/mL/mg) are dose normalized
values.
2. Not determined because the line defining the terminal elimination phase had
an r2 of
<0.85.
TABLE XVI
38
Date Recite/Date Received 2023-08-23
Animal number
Sample time (hr) 36 37 38 39 40
0.0333 8.03 9.83 13.2 11.1 3.67
0.0666 94.4 - 16.8 320 65.8
9.77
0.1 401 37.9 72.3 255 21.2
0.122 638 53.3 81.7 238 28.6
0.167 817 56.1 418 94.5 36.5
0.25 595 73.7 184 331 70.4
0.5 225 149 172 217 139
0.75 108 267 160 74 57.7
1 59.0 73.7 85.0 39.7 43.7
2 16.4 16.5 21.1 11.0 8.69
Dose (mg/kg) 0.311 0.358 0.345 0.336 0.319
Cmax (ng/mL) 817 267 418 331 139
tmax (hr) 0.167 0.750 0.167 0.250 0.500
tin 0.481 ND2 0.473 0.475 0.449
MRTiaai (hr) 0.443 0.795 0.662 0.495 0.700
AUCiasi (hr.ng/mL) 313 183 209 193 97
AUC00(hr.ng/mL) 325 ND2 223 200 102
AUCiast/D
1008 511 605 574 303
(hr.kg.ng/mL/mg)
AUC./D
1044 ND2 647 596 321
(hr.kg.ng/mL/mg)
1. AUCiadD (hr.kg.ng/mL/mg) and AUGID (hr.kg.ng/mL/mg) are dose normalized
values.9.
2. Not determined because the line defining the terminal elimination phase had
an r2 of
<0.85.
3. BLOQ = below the limit of quantitation (1 ng/mL).
TABLE XVII provides the mean and standard deviation for the results of Animals
31-
40.
39
Date Recite/Date Received 2023-08-23
TABLE XVII
Sample time (hr) mean SD
0.0333 27.0 58.3
0.0666 73.6 116
0.1 182 273
0.122 214 302
0.167 242 297
0.25 179 169
0.5 166 36.2
0.75 123 61.3
1 60.9 15.0
2 16.5 5.66
Dose (mg/kg) 0.316 0.032
(ng/mL) 345 287
tmax(hr) 0.397 0.204
t1/2 0.474 0.052
MRTtast (hr) 0.651 0.127
AUCiast (hr.ng/mL) 1799 73.7
AUC.,(hr.ng/mL) 190 79.6
AUClast/D
564 219
(hr.kg.ng/mL/mg)
AUC./D
604 235
(hr.kg.ng/mL/mg)
Figure 7 shows the individual plasma poncentrations (ng/mL) for Nicotine
versus time
(hour) after buccal administration of the nicotine polarcilex composition
disclosed in TABLE
VI (4 mg) in male Beagle dogs (Group 4). Figure 8 discloses the mean plasma
concentration
(ng/mL) for Nicotine versus time (hour) after buccal administration of the
nicotine polarcrilex
composition disclosed in TABLE VI (4 mg) in male Beagle dogs (Group 4).
PROCEDURES
Analytical Stock Solution Preparation
Date Recite/Date Received 2023-08-23
Analytical stock solutions (1.00 mg/mL of the free drug) was prepared in
water.
Standard Preparation
Standards were prepared in blank male Beagle dog plasma. Working solutions
were
prepared in 50:50 acetonitrile:water. Working solutions were then added to
plasma to make
calibration standards to final concentrations of 2000, 1000, 500, 250, 100,
50, 10, 5,2 and 1
ng/mL. Standards were treated identically to the study samples.
Sample Extraction
Plasma samples were manually extracted via precipitation with acetonitrile in
a 96-well
plate.
Step Procedure
1 Standards: Add 10 L of appropriate working solution to 50 pt of
blank plasma.
Blanks: Add 10 L of 50:50 (v:v) acetonitrile:water to 50 I, of blank plasma.
Samples: Add 10 L of 50:50 (v:v) acetonitrile:water to 50111_, of plasma
study
sample.
2 Add 150 1_, of acetonitrile containing 20 ng/mL nicotine-d4 in
acetonitrile as an
internal standard. Cap and vortex.
3 Centrifuge samples at 4 C, at 3000 rpm for 5 minutes.
4 Transfer 125 1., supernatant and analysis by LC-MS/MS
HPLC Conditions
Instrument: Waters Acquity UPLC
Column: Waters Phenyl BEH 1.7 p.m, 2.1 x 50 mm
Aqueous Reservoir (A): lOmm Ammonium bicarbonate in water, pH 9.5
Organic Reservoir (B): Acetonitrile
Gradient Program
Gradient
Time (mm.) % A % B
Curve
0.00 6 90 10
0.20 6 90 10
41
Date Recite/Date Received 2023-08-23
1.00 6 10 90
1.50 6 10 95
1.51 6 90 10
2.00 6 90 10
Flow Rate: 600 tiL/min
Injection Volume: 3 pL
Run Time: 2.0 min
Column Temperature: 30 C
Sample Temperature: 4 C
Strong Autosampler Wash: 1:1:1:1 (v:v) acetonitrile:methanolisopropanol:water
Weak Autosampler Wash: 50:50 (v:v) methanol :water
Mass Spectrometer Conditions
Instrument: Waters Xevo TQ-MS
Interface: Electrospray
Mode: Multiple Reaction Monitoring (MRM)
Desolvation Gas: 1000 L/hr
Cone Gas: 100 L/hr
Collision Gas: 0.25 mL/min
Desolvation Temp: 500 C
Capillary Voltage: 2.5 kV
While particular embodiments of the present disclosure have been illustrated
and
described, it would be obvious to those skilled in the art that various other
changes and
modifications can be made without departing from the spirit and scope of the
disclosure. It is
therefore intended to cover in the appended claims all such changes and
modifications that are
within the scope of this disclosure.
42
Date Recite/Date Received 2023-08-23
