Compositions and methods for sublingual delivery of nicotine

Abstract

Disclosed herein are compositions and methods for the oral delivery of nicotine and nicotine derivatives. In one embodiment, nicotine is delivered via an oral packet, pouch, or sachet.

Description

[Technical field]

[0001] Disclosed herein are compositions and methods for the oral delivery of nicotine and nicotine derivatives. In one embodiment, nicotine is delivered via an oral packet, pouch, or sachet. [Brief description of the drawings]

[0002] [Figure 1] FIG. 1 is a plot of individual plasma concentrations of nicotine (ng / mL) versus time (hr) following buccal administration of the nicotine benzoate control compositions disclosed in Table I in male beagle dogs. [Diagram 2] FIG. 2 is a plot of mean plasma concentration of nicotine (ng / mL) versus time (hr) following buccal administration of the nicotine benzoate control compositions disclosed in Table I in male beagle dogs. [Diagram 3] FIG. 3 is a plot of individual plasma concentrations of nicotine (ng / mL) versus time (hr) following buccal administration of the disclosed nicotine benzoate composition (4 mg) disclosed in Table II in male beagle dogs. [Figure 4] FIG. 4 is a plot of the mean plasma concentration of nicotine (ng / mL) versus time (hr) following buccal administration of a compound of the present disclosure (4 mg) of Table II in male beagle dogs. [Diagram 5] FIG. 5 is a plot of individual plasma concentrations of nicotine (ng / mL) versus time (hr) following buccal administration of the nicotine polacrilex control composition (4 mg) disclosed in Table III in male beagle dogs (Group 3). [Figure 6] FIG. 6 is a plot of the mean plasma concentration of nicotine (ng / mL) versus time (hr) following buccal administration of the nicotine polacrilex control composition (4 mg) disclosed in Table III in male beagle dogs (Group 3). [Figure 7]FIG. 7 is a plot of individual plasma concentrations of nicotine (ng / mL) versus time (hr) following buccal administration of the nicotine polarcilex composition (4 mg) disclosed in Table VI in male beagle dogs (Group 4). [Figure 8] FIG. 8 is a plot of the mean plasma concentration of nicotine (ng / mL) versus time (hr) following buccal administration of the nicotine polarcrilex composition disclosed in Table VI (4 mg) in male beagle dogs (Group 4). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0003] The materials, compounds, compositions, articles, and methods described herein may be more readily understood by reference to the following detailed description of specific embodiments of the presently disclosed subject matter and the examples included therein.

[0004] Also, various publications are referenced throughout this specification. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which the subject matter of this disclosure pertains. The references in this disclosure are also individually and specifically incorporated by reference into this application for the material contained in them that is discussed in the sentence in which the reference is relied upon.

[0005] General definition In 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.

[0006] All percentages, ratios and proportions in this application are by weight unless otherwise specified. All temperatures are in degrees Celsius (° C.) unless otherwise specified.

[0007] Unless this disclosure expressly requires otherwise, the terms "a" and "an" are defined as one or more.

[0008] 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 embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, by use of "about," the particular value will be understood to form another embodiment. Further, it will be understood that each of the endpoints of the ranges is significant both in relation to the other endpoint, and independently of the other endpoint.

[0009] The terms "comprise" (and any form of comprising, e.g., "comprises" and "comprising"), "have" (and any form of comprising, e.g., "has" and "having"), "include" (and any form of comprising, e.g., "includes" and "including"), and "contain" (and any form of containing, e.g., "contains" and "containing") are open linking verbs. As a result, an apparatus that "comprises," "has," "contains," or "contains" one or more elements includes those one or more elements, but is not limited to including only those elements. Similarly, a method that "comprises," "has," "contains," or "contains" one or more steps includes those one or more steps, but is not limited to including only those one or more steps.

[0010] Any embodiment of any of the methods or compositions of the present disclosure may consist of or consist essentially of any of the recited steps, elements, and / or features. Thus, in any of the claims, the terms "consisting of" or "consisting essentially of" may be used in place of any of the open linking verbs set forth above to change the scope of a given claim from what it would otherwise be with the open linking verb.

[0011] Unless expressly prohibited by the nature of the disclosure or the embodiments, feature(s) of one embodiment may be applied to other embodiments without being described or illustrated.

[0012] Any embodiment of any of the compounds or methods of the present disclosure may consist of or consist essentially of any of the recited steps, elements, and / or features. Thus, in any of the claims, the terms "consisting of" or "consisting essentially of" may be used in place of any of the open linking verbs set forth above to change the scope of a given claim from what it would otherwise be with the open linking verb.

[0013] For purposes of this disclosure, the terms "sublingual" and "buccal" are used interchangeably. The definition of "sublingual" is the administration of a drug under the tongue to be absorbed by the tissues therein. The definition of "buccal" is the administration of a drug by placing it between a person's cheek and gums. For purposes of this disclosure, a user may place the composition of the present disclosure either under the tongue between the gums and tongue, whichever mode of delivery is more convenient. Thus, the disclosed composition may be absorbed in any manner selected by the user.

[0014] Unless expressly prohibited by the nature of the disclosure or the embodiments, feature(s) of one embodiment may be applied to other embodiments without being described or illustrated.

[0015] Smokeless oral nicotine products may be provided to users in portioned or non-portioned formats. Portioned smokeless oral nicotine products may reduce or eliminate handling of cigarettes by users, which may provide significant advantages in terms of better hygiene, convenience, and / or ease of use.

[0016] Disclosed herein are compositions for the sublingual delivery of nicotine. Unlike orally delivered compositions, sublingual compositions are absorbed through the mucous membranes of the mouth, thus avoiding the side effects of direct contact of nicotine with the stomach, intestines, and other digestive tracts.

[0017] Disclosed herein is a base composition for sublingual or buccal delivery of nicotine comprising: a) about 1% to about 6% by weight of nicotine, a nicotine salt, nicotine in combination with a resin, or a mixture thereof; b) about 3% to about 20% sunflower oil by weight; c) about 10% to about 20% by weight sodium bicarbonate; and d) The remainder is one or more carriers.

[0018] The compositions of the present disclosure are free of organic or inorganic acids. In addition, the compositions are free-flowing solids that contain less than 0.01% moisture by weight.

[0019] One embodiment of the composition of the present disclosure comprises: a) about 1% to about 3.5% by weight of nicotine, a nicotine salt, or a mixture thereof; b) from about 3% to about 10.5% by weight sunflower oil; c) about 10% to about 20% by weight sodium bicarbonate; and d) The remainder is one or more carriers.

[0020] In one non-limiting embodiment of this aspect, the base composition comprises: a) about 1% to about 3.5% by weight of nicotine, a nicotine salt, or a mixture thereof; b) from about 3% to about 10.5% by weight sunflower oil; c) about 10% to about 20% by weight sodium bicarbonate; and d) The remainder is a blend of microcrystalline cellulose and inulin.

[0021] The base composition of the present disclosure may contain about 1% to about 6% by weight of nicotine, nicotine salt, or nicotine in combination with resin. In one embodiment, the base composition may contain about 1% to about 5% by weight of nicotine, nicotine salt, or nicotine in combination with resin. In another embodiment, the base composition may contain about 2% to about 6% by weight of nicotine, nicotine salt, or nicotine in combination with resin. In a further embodiment, the base composition may contain about 2% to about 5% by weight of nicotine, nicotine salt, or nicotine in combination with resin. In yet a further embodiment, the base composition may contain about 3% to about 5% by weight of nicotine, nicotine salt, or nicotine in combination with resin. For example, the amount of nicotine, nicotine salt, or nicotine in combination with the resin can be 1%, 2%, 3%, 4%, 5%, or 6% by weight, or any fractional amount, such as 1.5%, 3.25%, and 5.75%.

[0022] The base composition of the present disclosure may comprise about 3% to about 20% sunflower oil by weight. In one embodiment, the base composition may comprise about 3% to about 15% sunflower oil by weight. In another embodiment, the base composition may comprise about 5% to about 17% sunflower oil by weight. In a further embodiment, the base composition may comprise about 7.5% to about 15% sunflower oil by weight. In a still further embodiment, the base composition may comprise about 5% to about 10% sunflower oil by weight. 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% sunflower oil by weight, or any fractional amount, such as 10.5%, 13.6%, and 17.5%.

[0023] According to this embodiment, the ratio of nicotine to sunflower oil in combination with the nicotine, nicotine salt, or resin is from about 1:1 to about 1:4. For example, the ratio of nicotine to sunflower oil in combination with the nicotine, nicotine salt, or resin 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.

[0024] The base composition of the present disclosure may include about 10% to about 20% sodium bicarbonate by weight. In one embodiment, the base composition may include about 10% to about 15% sodium bicarbonate by weight. In another embodiment, the base composition may include about 15% to about 20% sodium bicarbonate by weight. In a further embodiment, the base composition may include about 12.5% ​​to about 17.5% sodium bicarbonate by weight. In yet a further embodiment, the base composition may include about 14% to about 17% sodium bicarbonate by weight. For example, the amount of sodium bicarbonate may be 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% sodium bicarbonate by weight, or any fractional amount, such as 10.5%, 13.6%, and 17.5%.

[0025] In another embodiment, the base composition comprises: a) from about 5 mg to about 50 mg by weight of nicotine, a nicotine salt, nicotine in combination with a resin, or a mixture thereof; b) about 15 mg to about 160 mg sunflower oil by weight; and c) About 50 mg to about 300 mg of sodium bicarbonate by weight.

[0026] The base composition of the present disclosure may contain from 5 mg to about 50 mg by weight of nicotine, a nicotine salt, nicotine in combination with a resin, or a mixture thereof.

[0027] In one embodiment, the base composition may contain 10 mg to about 50 mg by weight of nicotine, nicotine salts, nicotine in combination with resins, or mixtures thereof. In another embodiment, the base composition may contain 15 mg to about 40 mg by weight of nicotine, nicotine salts, nicotine in combination with resins, or mixtures thereof. In a further embodiment, the base composition may contain 10 mg to about 30 mg by weight of nicotine, nicotine salts, nicotine in combination with resins, or mixtures thereof. In a still further embodiment, the base composition may contain 15 mg to about 30 mg by weight of nicotine, nicotine salts, nicotine in combination with resins, or mixtures thereof. In a still further embodiment, the base composition may contain 10 mg to about 25 mg by weight of nicotine, nicotine salts, nicotine in combination with resins, or mixtures thereof. The base composition may contain, 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, nicotine salt, nicotine in combination with a resin, or mixtures thereof, or any fractional amounts, for example 7.5 mg, 22.5 mg, and 34.6 mg.

[0028] The base composition of the present disclosure may contain about 15 mg to about 160 mg of sunflower oil by weight. In one embodiment, the base composition may contain about 15 mg to about 160 mg of sunflower oil by weight. In another embodiment, the base composition may contain about 25 mg to about 120 mg of sunflower oil by weight. In a further embodiment, the base composition may contain about 40 mg to about 100 mg of sunflower oil by weight. In a still further embodiment, the base composition may contain about 50 mg to about 150 mg of sunflower oil by weight. In a still further embodiment, the base composition may contain about 75 mg to about 120 mg of sunflower oil by weight.The base composition of the present disclosure may, for example, be 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, 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, 109 mg, 108 mg, 3mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg , 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg, 101mg, 102,mg, 103,mg, 10 4mg, 105mg, 106mg, 107mg, 108mg, 109mg, 110mg, 111mg, 112mg, 113mg, 114mg, 115mg, 116mg, 117 mg, 118mg, 119mg, 120mg, 121mg, 122mg, 123mg, 124mg, 125mg, 126mg, 127mg, 128mg, 129mg, 130mg The composition may contain 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, or 160 mg of sunflower oil, or any fractional amount such as 27.5 mg, 82.5 mg, and 134.6 mg.

[0029] The base composition of the present disclosure may contain from about 50 mg to about 300 mg of sodium bicarbonate by weight. In one embodiment, the base composition contains from about 50 mg to about 100 mg of sodium bicarbonate by weight. In another embodiment, the base composition contains from about 75 mg to about 100 mg of sodium bicarbonate by weight. In a further embodiment, the base composition contains from about 100 mg to about 200 mg of sodium bicarbonate by weight. In a still further embodiment, the base composition contains from about 150 mg to about 200 mg of sodium bicarbonate by weight. In a still further embodiment, the base composition contains from about 150 mg to about 300 mg of sodium bicarbonate by weight. In yet another embodiment, the base composition contains from about 225 mg to about 300 mg of sodium bicarbonate by weight. The base composition of the present disclosure may be, 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, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95m g, 96mg, 97mg, 98mg, 99mg, 100mg, 101mg, 102mg, 103,mg, 104mg, 105mg, 106mg, 107mg, 108mg, 109mg, 1 10mg, 111mg, 112mg, 113mg, 114mg, 115mg, 116mg, 117mg, 118mg, 119mg, 120mg, 121mg, 122mg, 123mg, 124mg, 125mg, 126mg, 127mg, 128mg, 129mg, 130mg, 31mg, 132mg, 133mg, 134mg, 135mg, 136mg, 137mg, 1 38mg, 139mg, 140mg, 141mg, 142mg, 143mg, 144mg, 145mg, 146mg, 147mg, 148mg, 149mg, 150mg, 151mg, 152mg, 153mg, 154mg, 155mg, 156mg, 157mg, 158mg, 159mg, 160mg, 161mg, 162mg, 163mg, 164mg, 165mg,166mg, 167mg, 168mg, 169mg, 170mg, 171mg, 172mg, 173mg, 174mg, 175mg, 167mg, 177mg, 178mg, 179mg, 180mg, 181mg, 182mg, 183mg, 184mg, 185mg, 186mg, 187mg, 188mg, 189mg, 190mg, 191mg, 192mg, 193mg, 194mg, 195mg, 196mg, 197mg, 198mg, 199mg, 200mg, 201mg, 2 02mg, 203mg, 204mg, 205mg, 206mg, 207mg, 208mg, 209mg, 210mg, 211mg, 212mg, 213mg, 214mg, 215mg, 216mg, 217mg, 218mg, 219mg, 2 20mg, 221mg, 222mg, 223mg, 224mg, 225mg, 226mg, 227mg, 228mg, 229mg, 230mg, 231mg, 232mg, 233mg, 234mg, 235mg, 236mg, 237mg, 23 8mg, 239mg, 240mg, 241mg, 242mg, 243mg, 244mg, 245mg, 246mg, 247mg, 248mg, 249mg, 250mg, 251mg, 252mg, 253mg, 254mg, 255mg, 25 6mg, 257mg, 258mg, 259mg, 260mg, 261mg, 262mg, 263mg, 264mg, 265mg, 266mg, 267mg, 268mg, 269mg, 270mg, 271mg, 272mg, 273mg, 274 The composition may contain 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 of sodium bicarbonate, or any fractional amount, for example, 110.5, 220.7, and 250.8.

[0030] Nicotine Compounds The nicotine compounds of the present disclosure are selected from nicotine, pharmacologically acceptable salts of nicotine, nicotine complexes, and polymeric resins containing nicotine.Non-limiting examples of nicotine salts include nicotine benzoate, nicotine lactate, nicotine malate, nicotine bitartrate, nicotine salicylate, nicotine citrate, and nicotine levulinate.Non-limiting examples of nicotine in combination with a resin include nicotine polacrilex and nicotine resinate.

[0031] 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 yet a further non-limiting example, the nicotine salt is nicotine bitartrate. In a still further non-limiting example, the nicotine salt is nicotine salicylate. In yet another non-limiting example, the nicotine salt is nicotine citrate. In yet another non-limiting example, the nicotine salt is nicotine levulinate.

[0032] Carrier In one embodiment, the carrier of the present disclosure is a polysaccharide. Non-limiting examples of polysaccharide carriers include inulin, galactogen, cellulose, chitin, pectin, psyllium, guar, hemicellulose, potato starch, and partially hydrolyzed polysaccharides. In another embodiment, the carrier is a sugar alcohol, such as sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, hydrogenated starch hydrolysates, isomaltose, or any combination thereof. In further aspects, the carrier component is based on natural or modified agar, alginate, carrageenan gum, cellulose, chitosan, chitin, cyclodextrin, dextran, gellan gum, glycogen, glycosaminoglycans, karaya gum, inulin, pectin, polydextrose, xanthan gum, or any other starch, gum, or other polysaccharide, including functionalized derivatives, dextrinized, hydrolyzed, oxidized, alkylated, hydroxyalkylated, acetylated, classified, and physically modified starches, and mixtures thereof, etc. In some embodiments, glycerin and / or propylene glycol may be added as a carrier.

[0033] In one aspect, the carrier can act as a bulking agent. In one embodiment, microcrystalline cellulose is used in the base composition as a carrier and in the pouch disclosed herein below as a bulking agent. In another embodiment, two or more carriers can be combined, such as microcrystalline cellulose and inulin. This combination can be used in both the base composition and the pouch. When it comes to the pouch of this disclosure, dextrin is added as a bulking agent. However, dextrin can also act as a carrier for any flavoring that the formulator wants to add. For example, ethyl vanillin is a compound that provides vanilla flavor. Ethyl vanillin can be blended with dextrin, microcrystalline cellulose, or inulin, and then kneaded with a bulking agent or other carrier.

[0034] In one embodiment of the one or more carriers, one of the carriers is water soluble and the other is not. This allows the formulator to control the release of the active agent when it is delivered via a water insoluble but water permeable pouch as described herein below. This combination of carriers allows for the delivery of nicotine either via a nicotine salt or via a polymer-loaded nicotine, such as polacrilex.

[0035] The compositions of the present disclosure may comprise from about 80% to about 95% by weight of one or more carriers. In one embodiment, the compositions of the present disclosure may comprise from about 80% to about 90% by weight of one or more carriers. In another embodiment, the compositions of the present disclosure may comprise from about 85% to about 95% by weight of one or more carriers. In a further embodiment, the compositions of the present disclosure may comprise from about 85% to about 90% by weight of one or more carriers.

[0036] Antioxidants The compositions of the present disclosure may include up to about 0.05% of an antioxidant. Non-limiting examples of antioxidants include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate (PG), tert-butylhydroquinone (TBHQ), and mixtures thereof.

[0037] The following table discloses non-limiting examples of base nicotine delivery compositions.

[0038] [Table 1]

[0039] [Table 2]

[0040] [Table 3]

[0041] [Table 4]

[0042] [Table 5]

[0043] [Table 6]

[0044] [Table 7]

[0045] [Table 8]

[0046] [Table 9]

[0047] [Table 10]

[0048] [Table 11]

[0049] [Table 12]

[0050] kit Disclosed herein is a kit for sublingual delivery of nicotine. The kit contains a base nicotine delivery system including an active ingredient and a water-insoluble liquid-permeable pouch containing the active ingredient and any necessary auxiliary ingredients useful for delivery of nicotine, nicotine salts, or of nicotine resin compositions. In one embodiment, the kit includes a pouch containing the disclosed composition comprising: A) a liquid permeable pouch containing a non-nicotine composition comprising: a) one or more delivery agents; and b) bulking agents; and B) A base nicotine delivery composition comprising: a) nicotine, nicotine salts, nicotine in combination with a resin, or mixtures thereof; b) Sunflower oil; c) sodium bicarbonate; and d) The remainder is one or more carriers.

[0051] Delivery Control Agents To control the sublingual delivery of the nicotine-containing compositions of the present disclosure, the kits contain one or more agents that control the release of nicotine into the mouth to be used. These agents are typically formulated after assembly of the base nicotine delivery composition; however, formulators may add delivery-controlling agents as part of the carrier system.

[0052] In one embodiment, the delivery agent is a solubilizing agent, such as lecithin, polyoxyethylene stearates, 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, sucrose esters of fatty acids, polyglycerol esters 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 (e.g., CREMOPHOR™), block copolymers of ethylene oxide and propylene oxide (e.g., one or more of Pluronic™ or Poloxamer™), polyoxyethylene fatty alcohol ethers, polyoxyethylene sorbitan fatty acid esters, sorbitan esters of fatty acids, and polyoxyethylene stearic acid esters.

[0053] In one embodiment, the delivery agent is selected from sodium stearoyl lactylate, sodium lauryl sulfate, glycerol, propylene glycol, b-cyclodextrin, and propylene glycol 400 (PEG400).

[0054] Non-limiting examples of solubilizing agents include glycerol, propylene glycol, b-cyclodextrin, and propylene glycol 400 (PEG 400).

[0055] In one embodiment of the kit of the present disclosure, the kit comprises: A) a liquid permeable pouch containing a non-nicotine composition comprising: a) one or more delivery agents; and b) bulking agents; and B) A base nicotine delivery composition comprising: a) nicotine, nicotine salts, nicotine in combination with a resin, or mixtures thereof; b) Sunflower oil; c) sodium bicarbonate; and d) The remainder is one or more carriers.

[0056] In one embodiment of this aspect, the kit comprises: A) a liquid permeable pouch containing a non-nicotine composition comprising: a) one or more delivery agents; and b) bulking agents; and B) A base nicotine delivery composition comprising: a) about 1% to about 6% by weight of nicotine, a nicotine salt, nicotine in combination with a resin, or a mixture thereof; b) about 3% to about 20% sunflower oil by weight; c) about 10% to about 20% by weight sodium bicarbonate; and d) The remainder is one or more carriers.

[0057] In one iteration of this embodiment, the kit includes: A) a liquid permeable pouch containing a non-nicotine composition comprising: a) maltitol; and b) a blend of microcrystalline cellulose and inulin; and B) A base nicotine delivery composition comprising: a) about 1% to about 6% by weight of nicotine, a nicotine salt, nicotine in combination with a resin, or a mixture thereof; b) about 3% to about 20% sunflower oil by weight; c) about 10% to about 20% by weight sodium bicarbonate; and d) Remainder: i) dextrose; and ii) Flavoring agents.

[0058] Non-limiting examples of flavorings include apple, banana, cherry, cinnamon, grape, orange, pear, pineapple, raspberry, blueberry, strawberry, spearmint, peppermint, wintergreen, and vanilla.

[0059] Disclosed herein is a kit comprising: A) a liquid permeable pouch containing a non-nicotine composition comprising: a) one or more delivery controlling agents; and b) bulking agents; and B) A base nicotine delivery composition comprising: a) nicotine, nicotine salts, nicotine in combination with a resin, or mixtures thereof; b) Sunflower oil; c) sodium bicarbonate; and d) The remainder is one or more carriers.

[0060] In one non-limiting example, the kit includes: A) a liquid permeable pouch containing a non-nicotine composition comprising: a) one or more delivery controlling agents; and b) bulking agents; and B) about 70 mg to about 510 mg of an active ingredient delivery system comprising: a) about 5 mg to about 50 mg by weight of nicotine benzoate; b) about 15 mg to about 160 mg of sunflower oil by weight; c) about 50 mg to about 300 mg sodium bicarbonate by weight; d) about 350 mg to about 1500 mg of one or more carriers; and e) the remainder being one or more delivery controlling agents.

[0061] In another non-limiting example, the kit comprises: A) a liquid permeable pouch containing a non-nicotine composition comprising: a) one or more delivery controlling agents; and b) bulking agents; and B) about 70 mg to about 510 mg of an active ingredient delivery system comprising: a) about 5 mg to about 50 mg of nicotine polacrilex by weight; b) about 15 mg to about 160 mg of sunflower oil by weight; c) about 50 mg to about 300 mg sodium bicarbonate by weight; d) about 350 mg to about 1500 mg of one or more carriers; and e) the remainder being one or more delivery controlling agents.

[0062] preparation The base compositions of the present disclosure may be prepared by the following general procedure: Nicotine, nicotine salt, or nicotine in combination with a resin is combined with sunflower oil in a vessel with sufficient agitation. The amount of each component may vary depending on the formulator's choice of ratio of nicotine-containing component and sunflower oil. That is, the ratio of nicotine-containing component to sunflower oil may be from about 1:1 to about 1:3, as disclosed hereinabove. The choice of ratio will also determine the relative amount of additional supplemental components added. Then, the nicotine-containing component sunflower oil mixture is slowly heated to about 50° C. to about 75° C., again with agitation, based on the ratio of components and the choice of excipients.

[0063] At this point, antioxidants and other auxiliary ingredients may be optionally added to the nicotine-containing compound / sunflower oil blend during heating. The amount and ratio of any antioxidants added to the blend may vary depending on the formulator's choice. In one non-limiting embodiment, the amount of antioxidant is about 0.01% to about 0.10% by weight of the blend.

[0064] The resulting blend, after optional addition of antioxidants and / or other auxiliary ingredients, is then slowly added to the dry particulate substrate with sufficient mixing to form a uniform dispersion. The amount of blend added to the substrate is about 5% to about 60% by weight. The final dispersion is then dehydrated by any means selected by the formulator, such as oven drying, freeze drying, convection drying, microwave irradiation, etc. In one non-limiting embodiment, the dispersion is dried for about 45 to about 135 minutes. The time can be shortened or extended depending on a number of factors, including the type of auxiliary ingredients and the ratio of nicotine-containing compound to sunflower oil.

[0065] 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 based on the amounts of other ingredients and the selection of the base. In one non-limiting embodiment, the composition can include about 1% to about 25% alkalizing agent by weight.

[0066] After homogenizing the alkalizing agent into the now formed uniform blend, other auxiliary ingredients may be added. Non-limiting examples include bulking agents that provide a mouthfeel that is compatible with the pouch, thereby providing the user with a feeling of "substance" within the pouch. Bulking agents include microcrystalline cellulose and inulin. Additionally, sweeteners, such as maltitol, and / or flavoring compounds are added to provide different mouth sensations.

[0067] The resulting compositions can then be further formulated with varying levels of other adjunct ingredients, such as bulking agents (e.g., microcrystalline cellulose), high potency sweeteners (e.g., maltitol), and / or flavoring compounds, depending on the formulator's choice, and finally presented in a variety of different oral or buccal form factors.

[0068] 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 uniformly dispersed. The nicotine benzoate sunflower oil blend is then slowly metered into inulin (500 g) as a dry particulate matrix compound while mixing until uniformly dispersed. Sodium bicarbonate (20 g) is added while mixing until uniformly dispersed. The blend is then placed in a convection airflow dehydration chamber for 90 minutes to remove residual moisture and provide molecular bonding between the nicotine and sunflower oil impregnated dry particulates. The resulting composition is then combined with microcrystalline cellulose (200 g), maltitol (175 g), and spearmint flavoring (100 g) and then packaged into unit dose oral pouches.

[0069] Pouch The characteristics of the pouch can affect the release of nicotine, nicotine salt, or nicotine in combination with a resin from the pouch composition, and potentially, the rate of uptake by the user. The pouches of the present disclosure contain water-insoluble fibers, which allow moisture, typically the user's saliva, to enter the pouch and solubilize the water-soluble components.

[0070] Disclosed herein are water insoluble pouches, which may contain insoluble fiber such as wheat fiber, oat fiber, pea fiber, rice fiber, corn fiber, oat fiber, tomato fiber, barley fiber, rye fiber, sugar beet fiber, buckwheat fiber, potato fiber, cellulose fiber, apple fiber, cocoa fiber, cellulose fiber, powdered cellulose, bamboo fiber, bran fiber, or combinations thereof.

[0071] In one embodiment, the pouch of the present disclosure comprises alpha cellulose obtained as a pulp from a variety of fibrous plant material, such as cellulose prepared by processing wood pulp, hi further embodiments, the pouch may comprise wheat fiber, oat fiber, or a combination thereof.

[0072] The following are non-limiting examples of plant fibers: Vitacel-WF600™, Vitacel-HF600™, Vitacel-P95™, Vitacel-WF200™, Vitacel-LOO™, Vitacel-Erbsenfaser-EF150™, Vitacel Bamboo Fiber baf90™, Vitacel-HF600™, Vitacel Cellulose L700G™, Vitacel-PF200™ ), Vitacel Potato Fiber KF200™, Vitacel Bamboo Fiber haf-BAF40™, Vitacel-Haferfaser / Oat Fiber HF-401-30™, Vitacel-L00™, Vitacel Cellulose L700G™, Vitacel-LC1000™, Vitacel-L600-20™, Vitacel-L600™, or combinations thereof.

[0073] It is an embodiment of the present disclosure that in formulating pouches containing various amounts of the base nicotine delivery composition, 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 during use, as this fact may counteract the dissolution of the water-soluble components, thereby preventing the user from experiencing any reduction in the contents of the pouch during use.

[0074] In addition, the pouch composition may also enable a desirable mouthfeel, such as a soft and / or sticky texture. The desirable texture and mouthfeel may be obtained while still allowing the manufactured pouches to be stored side by side, such as in cans and the like, without sticking or clumping together and causing the pouch to burst when removed. Also, in some embodiments, the desirable mouthfeel may include a numbing sensation reminiscent of a tobacco pouch, but without many of the undesirable effects associated therewith, such as tissue discoloration.

[0075] In one embodiment of the kit of the present disclosure, the kit includes an active agent composition and a pouch for sublingual delivery of nicotine to a user.

[0076] The kit comprises a water-permeable pouch into which the active agent composition and the delivery system are added. The pouch of the present disclosure comprises: A) about 5% to about 20% by weight of an active base composition comprising: a) about 1% to about 6% by weight of nicotine, a nicotine salt, nicotine in combination with a resin, or a mixture thereof; b) about 3% to about 20% sunflower oil by weight; c) about 10% to about 20% by weight sodium bicarbonate; and B) About 80% to about 95% by weight of a delivery system, the delivery controlled system containing one or more delivery controlling agents, carriers, solubilizers, or mixtures thereof.

[0077] In one embodiment of this aspect, the pouch comprises: A) about 70 mg to about 510 mg of an active ingredient composition comprising: a) about 5 mg to about 50 mg by weight of nicotine benzoate; b) about 15 mg to about 160 mg of sunflower oil by weight; c) about 50 mg to about 300 mg sodium bicarbonate by weight; B) about 350 mg to about 1500 mg of one or more carriers; and C) the remainder being one or more delivery control agents.

[0078] In one iteration of this embodiment, one or more carriers act as delivery control agents, for example a pouch comprising: a) about 5 mg to about 50 mg by weight of nicotine benzoate; b) about 15 mg to about 160 mg of sunflower oil by weight; c) about 50 mg to about 300 mg by weight of sodium bicarbonate; and d) about 300 mg to about 1300 mg by weight of a carrier selected from inulin, galactogen, cellulose, chitin, pectin, psyllium, guar, hemicellulose, potato starch, or partially hydrolyzed polysaccharides.

[0079] In another iteration of this embodiment, a pouch comprising: a) about 5 mg to about 50 mg by weight of nicotine benzoate; b) about 15 mg to about 160 mg of sunflower oil by weight; c) about 50 mg to about 300 mg by weight of sodium bicarbonate; and d) about 300 mg to about 1300 mg by weight of a carrier selected from sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, hydrogenated starch hydrolysates, isomaltose, or any combination thereof.

[0080] In yet a further iteration of this embodiment, a pouch comprising: a) about 5 mg to about 50 mg by weight of nicotine benzoate; b) about 15 mg to about 160 mg of sunflower oil by weight; c) about 50 mg to about 300 mg by weight of sodium bicarbonate; and d) From about 300 mg to about 1300 mg of inulin by weight.

[0081] In yet a further iteration of this embodiment, a pouch comprising: a) about 5 mg to about 50 mg by weight of nicotine benzoate; b) about 15 mg to about 160 mg of sunflower oil by weight; c) about 50 mg to about 300 mg by weight of sodium bicarbonate; and d) about 300 mg to about 1300 mg by weight of microcrystalline cellulose.

[0082] In yet a further iteration of this embodiment, a pouch comprising: a) about 5 mg to about 50 mg by weight of nicotine benzoat; b) about 15 mg to about 160 mg of sunflower oil by weight; c) about 50 mg to about 300 mg by weight of sodium bicarbonate; and d) A blend of about 300 mg to about 1300 mg by weight of inulin and microcrystalline cellulose.

[0083] In another embodiment of this aspect, the pouch comprises: A) about 70 mg to about 510 mg of an active ingredient composition comprising: a) about 5 mg to about 50 mg of nicotine polacrilex by weight; b) about 15 mg to about 160 mg of sunflower oil by weight; c) about 50 mg to about 300 mg sodium bicarbonate by weight; B) about 350 mg to about 1500 mg of one or more carriers; and C) the remainder being one or more delivery control agents.

[0084] In one iteration of this embodiment, one or more carriers act as delivery control agents, for example a pouch comprising: a) about 5 mg to about 50 mg of nicotine polacrilex by weight; b) about 15 mg to about 160 mg of sunflower oil by weight; c) about 50 mg to about 300 mg by weight of sodium bicarbonate; and d) about 300 mg to about 1300 mg by weight of a carrier selected from inulin, galactogen, cellulose, chitin, pectin, psyllium, guar, hemicellulose, potato starch, or partially hydrolyzed polysaccharides.

[0085] In another iteration of this embodiment, a pouch comprising: a) about 5 mg to about 50 mg of nicotine polacrilex by weight; b) about 15 mg to about 160 mg of sunflower oil by weight; c) about 50 mg to about 300 mg by weight of sodium bicarbonate; and d) about 300 mg to about 1300 mg by weight of a carrier selected from sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, hydrogenated starch hydrolysates, isomaltose, or any combination thereof.

[0086] In yet a further iteration of this embodiment, a pouch comprising: a) about 5 mg to about 50 mg of nicotine polacrilex by weight; b) about 15 mg to about 160 mg of sunflower oil by weight; c) about 50 mg to about 300 mg by weight of sodium bicarbonate; and d) From about 300 mg to about 1300 mg of inulin by weight.

[0087] In yet a further iteration of this embodiment, a pouch comprising: a) about 5 mg to about 50 mg of nicotine polacrilex by weight; b) about 15 mg to about 160 mg of sunflower oil by weight; c) about 50 mg to about 300 mg by weight of sodium bicarbonate; and d) about 300 mg to about 1300 mg by weight of microcrystalline cellulose.

[0088] In yet a further iteration of this embodiment, a pouch comprising: a) about 5 mg to about 50 mg of nicotine polacrilex by weight; b) about 15 mg to about 160 mg of sunflower oil by weight; c) about 50 mg to about 300 mg by weight of sodium bicarbonate; and d) A blend of about 300 mg to about 1300 mg by weight of inulin and microcrystalline cellulose.

[0089] The compositions of the present disclosure may comprise about 80% to about 95% by weight of one or more delivery control agents, carriers, solubilizers, or mixtures thereof. In one embodiment, the compositions of the present disclosure may comprise about 80% to about 90% by weight of one or more delivery control agents, carriers, solubilizers, or mixtures thereof. In another embodiment, the compositions of the present disclosure may comprise about 85% to about 95% by weight of one or more delivery control agents, carriers, solubilizers, or mixtures thereof. In a further embodiment, the compositions of the present disclosure may comprise about 85% to about 90% by weight of one or more delivery control agents, carriers, solubilizers, or mixtures thereof.

[0090] process The base compositions of the present disclosure may be prepared by the following general procedure: Nicotine, nicotine salt, or nicotine in combination with a resin is combined with sunflower oil in a vessel with sufficient agitation. The amount of each component will vary depending on the formulator's choice of ratio of nicotine-containing component and sunflower oil, i.e., the ratio of nicotine-containing component to sunflower oil is from about 1:1 to about 1:3. The choice of ratio will also determine the relative amounts of additional components added. The nicotine-containing component sunflower oil blend is then slowly heated to about 50° C. to about 75° C., again based on the ratio of components and the choice of excipients, with agitation.

[0091] 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 uniformly to 50° C. Inulin (500 g) is slowly weighed in and stirring is continued until all the inulin is dispersed. Sodium bicarbonate (150 g) is slowly added while the temperature is increased to 60° C. Once the blend is uniform, inulin (790 g) is added at a rate to maintain a uniform blend. The blend is then slowly cooled to 30° C. and placed in a vacuum oven for 5 hours to remove any remaining moisture. The resulting composition can then be combined with additional inulin or microcrystalline cellulose and then packaged into one or more pouches. EXAMPLES

[0092] The following are non-limiting examples of compositions that may be delivered by the insoluble vegetable or synthetic pouch.

[0093] [Table 13]

[0094] [Table 14]

[0095] [Table 15]

[0096] [Table 16]

[0097] [Table 17]

[0098] [Table 18]

[0099] [Table 19]

[0100] [Table 20]

[0101] As demonstrated by the following data and Figures 1 through 8, the compositions of the present disclosure are more effective at increasing plasma levels of nicotine via oral delivery than providing nicotine alone via a carrier. The following animal studies provide conclusive evidence of this fact.

[0102] An animal study of the present disclosure was conducted utilizing the compositions of the present disclosure. Table I summarizes the study design. Male beagle dogs from Marshall Bioresources were utilized in this study. Animals were identified by ear tattoos and cage labels. The study was unblinded. 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 points throughout the conduct of the study.

[0103] dosage Nicotine was administered at 4 mg per pouch via buccal administration. Animals were anesthetized with propofol at a dose of 6 mg / kg. Animals were then intubated and maintained under anesthesia using 1-5% isoflurane and 2 L of oxygen flow. The pouch with the test article was placed in the buccal space. Rinsing was performed with a small volume of water (0.5-1 mL). Every 5 minutes after placing the pouch test article in the buccal space, the isoflurane mask was removed and the pouch was gently compressed. Special care was taken to ensure that no saliva escaped from the mouth. After 30 minutes, the pouch test article was removed from the buccal space and the animals were allowed to recover from anesthesia. All pouches were retained after dosing. Each pouch was placed in an individual conical tube with the animal's ID and pouch identification.

[0104] Test Composition

[0105] [Table 21]

[0106] [Table 22]

[0107] [Table 23]

[0108] [Table 24]

[0109] As shown in the table below, Group 1 received the nicotine benzoate control group. Group 2 received the disclosed composition containing nicotine benzoate. Group 3 received the nicotine polacrilex control. Group 4 received the disclosed composition containing nicotine polacrilex. The actual amounts based on the results of the potency test were 3.12, 3.31, 3.48, and 3.79 mg per pouch for Groups 1, 2, 3, and 4, respectively.

[0110] [Table 25]

[0111] Sample collection, preparation, and storage Each blood sample (approximately 2000 μL) was collected from the jugular vein into a K2ETDA collection tube and mixed by gentle inversion several times. Samples were kept on ice until centrifugation at 3,000 × g for 5 min at 4°C. Approximately 1000 μL of plasma was isolated by centrifugation. The resulting plasma samples were stored at -80°C until bioanalysis was performed.

[0112] Quantitative Plasma Sample Analysis Plasma samples were extracted by protein precipitation and analyzed using LC-MS / MS. Individual and mean plasma concentrations of nicotine and resulting pharmacokinetic parameters are shown in Tables 4-7. All data are expressed as ng / mL of nicotine. Samples below the limit of quantification (1.0 ng / mL in plasma) were excluded from the calculation of mean values. Mean concentration versus time data are plotted in Figures 1-8.

[0113] Pharmacokinetic parameters were calculated from the time course of plasma concentrations. Pharmacokinetic parameters were determined using a noncompartmental model with Phoenix WinNonlin (v8.0) software. Maximum plasma concentration (Cmax) and time to maximum plasma concentration (tmax) after dosing were observed from the data. Area under the time-concentration curve (AUC) was calculated using the linear trapezoidal method by calculation to the last quantifiable data point (AUC0-last) and by extrapolation to infinity (AUC∞) when 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 AUC. Any samples below the limit of quantification (1.0 ng / mL plasma) were not used in calculating the mean values.

[0114] data Pharmacokinetic parameters and plasma concentrations (ng / mL) of nicotine following buccal administration of the nicotine benzoate control compositions disclosed in Tables VI and VII in male beagle dogs (Group 1).

[0115] [Table 26]

[0116] [Table 27]

[0117] Table VIII provides the means and standard deviations of the results for animals 1-10.

[0118] [Table 28]

[0119] Figure 1 is a plot of individual plasma concentrations of nicotine (ng / mL) versus time (hr) in male beagle dogs following buccal administration of a nicotine benzoate control composition disclosed in Table I. Figure 2 is a plot of mean plasma concentrations of nicotine (ng / mL) versus time (hr) in male beagle dogs following buccal administration of a nicotine benzoate control composition disclosed in Table I.

[0120] Pharmacokinetic parameters and plasma concentrations (ng / mL) of nicotine following buccal administration of pouches containing the disclosed compositions (4 mg) of nicotine benzoate of Tables IX and X in male beagle dogs (Group 2).

[0121] [Table 29]

[0122] [Table 30]

[0123] Table XI provides the means and standard deviations of the results for animals 11-21.

[0124] [Table 31]

[0125] Figure 3 illustrates the individual plasma concentrations of nicotine (ng / mL) versus time (hr) following buccal administration of a nicotine benzoate composition of the present disclosure disclosed in Table II (4 mg) in male beagle dogs. Figure 4 illustrates the average plasma concentrations of nicotine (ng / mL) versus time (hr) following buccal administration of a compound of the present disclosure in Table II (4 mg) in male beagle dogs.

[0126] Pharmacokinetics of Nicotine and Individual Plasma Concentrations (ng / mL) vs. Time (hr) Following Buccal Administration of Nicotine Polacrilex Control Compositions (4 mg) Disclosed in Tables XII and XIII in Male Beagle Dogs (Group 3)

[0127] [Table 32]

[0128] [Table 33]

[0129] Table XIV provides the means and standard deviations of the results for animals 21-30.

[0130] [Table 34]

[0131] Figure 5 shows the individual plasma concentrations of nicotine (ng / mL) versus time (hr) following buccal administration of a nicotine polacrilex control composition (4 mg) disclosed in Table III in male beagle dogs (Group 3). Figure 6 shows the mean plasma concentrations of nicotine (ng / mL) versus time (hr) following buccal administration of a nicotine polacrilex control composition (4 mg) disclosed in Table III in male beagle dogs (Group 3).

[0132] Pharmacokinetic parameters and plasma concentrations (ng / mL) of nicotine following buccal administration of pouches containing the disclosed compositions (4 mg) of nicotine polacrilex of Tables XV and XVI in male beagle dogs (Group 4).

[0133] [Table 35]

[0134] [Table 36]

[0135] Table XVII provides the means and standard deviations of the results for animals 31-40.

[0136] [Table 37]

[0137] Figure 7 shows the individual plasma concentrations of nicotine (ng / mL) versus time (hr) following buccal administration of a nicotine polacrilex composition (4 mg) disclosed in Table VI in male beagle dogs (Group 4). Figure 8 discloses the mean plasma concentrations of nicotine (ng / mL) versus time (hr) following buccal administration of a nicotine polacrilex composition (4 mg) disclosed in Table VI in male beagle dogs (Group 4).

[0138] procedure Preparation of analytical stock solutions Analytical stock solutions (1.00 mg / mL free drug) were prepared in water.

[0139] Preparation of standards Standards were prepared with blank male beagle plasma. A working solution was prepared with 50:50 acetonitrile:water. Working solution was then added to plasma to make calibration standards at final concentrations of 2000, 1000, 500, 250, 100, 50, 10, 5, 2, and 1 ng / mL. Standards were treated identically to the study samples.

[0140] Sample extraction Plasma samples were manually extracted on 96-well plates by precipitation with acetonitrile.

[0141] [Table 38]

[0142] HPLC conditions Equipment: Waters Acquity UPLC Column: Waters Phenyl BEH, 1.7 μm, 2.1 x 50 mm Aqueous reservoir (A): 10 mM ammonium bicarbonate in water, pH 9.5 Organic reservoir (B): acetonitrile

[0143] [Table 39]

[0144] Flow rate: 600μL / min Injection volume: 3 μL Runtime: 2.0min Column temperature: 30℃ Sample temperature: 4℃ Autosampler Strong Wash: 1:1:1:1 (v:v) acetonitrile:methanol:isopropanol:water Autosampler Weak Wash: 50:50 (v:v) methanol:water

[0145] Mass spectrometer conditions Instrument: Waters XevoTQ-MS Interface: Electrospray Mode: Multiple Reaction Monitoring (MRM) Desolvation gas: 1000L / hr Cone gas: 100L / hr Collision gas: 0.25mL / min Desolvation temperature: 500℃ Capillary voltage: 2.5kV

[0146] 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 present disclosure. It is therefore intended in the appended claims to cover all such changes and modifications that are within the scope of this disclosure.

Claims

1. A composition comprising: a) about 1% to about 6% by weight of nicotine, a nicotine salt, nicotine polacrilex, or a mixture thereof; b) about 3% to about 20% by weight of sunflower oil; c) about 10% to about 20% by weight sodium bicarbonate; and d) The remainder is one or more carriers.

2. The composition according to claim 1, characterized in that it contains nicotine.

3. 2. The composition of claim 1, comprising a nicotine salt.

4. The composition described in claim 1, characterized by containing nicotine polacrilex.

5. 2. The composition of claim 1, wherein the carrier is selected from inulin, microcrystalline cellulose, galactogen, cellulose, chitin, pectin, psyllium, guar, hemicellulose, potato starch, or partially hydrolyzed polysaccharides.

6. 2. The composition according to claim 1, wherein the carrier is selected from the group consisting of sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, hydrogenated starch hydrolysates, and isomaltose.

7. 10. The composition of claim 1, further comprising glycerol, propylene glycol, β-cyclodextrin, propylene glycol 400 (PEG 400), or a mixture thereof.

8. A composition comprising: a) about 5 mg to about 50 mg by weight of nicotine, a nicotine salt, nicotine polacrilex, or a mixture thereof; b) about 15 mg to about 160 mg by weight of sunflower oil; and c) about 50 mg to about 300 mg by weight of sodium bicarbonate.

9. 9. The composition of claim 8, comprising from 15 mg to about 40 mg by weight of nicotine, a nicotine salt, nicotine polacrilex, or a mixture thereof.

10. The composition of claim 8 further comprising a carrier.

11. 11. The composition of claim 10, wherein the carrier is selected from inulin, microcrystalline cellulose, galactogen, cellulose, chitin, pectin, psyllium, guar, hemicellulose, potato starch, or partially hydrolyzed polysaccharides.

12. 11. The composition according to claim 10, wherein the carrier is selected from the group consisting of sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, hydrogenated starch hydrolysates, and isomaltose.

13. The composition of claim 8, further comprising glycerol, propylene glycol, β-cyclodextrin, propylene glycol 400 (PEG 400), or a mixture thereof.

14. The kit features: A) A liquid permeable pouch containing a non-nicotine composition comprising: a) one or more delivery controlling agents; and b) a bulking agent; and B) A base nicotine delivery composition comprising: a) nicotine, nicotine salts, nicotine polacrilex, or mixtures thereof; b) Sunflower oil; c) sodium bicarbonate; and d) The remainder is one or more carriers.

15. 15. The kit of claim 14, wherein the liquid permeable pouch comprises wheat fiber, oat fiber, pea fiber, rice fiber, corn fiber, oat fiber, tomato fiber, barley fiber, rye fiber, sugar beet fiber, buckwheat fiber, potato fiber, cellulose fiber, apple fiber, cocoa fiber, cellulose fiber, powdered cellulose, bamboo fiber, bran fiber, or a combination thereof.

16. The kit according to claim 15, comprising: B) about 70 mg to about 510 mg of an active agent delivery system comprising: a) about 5 mg to about 50 mg by weight of nicotine benzoate; b) about 15 mg to about 160 mg by weight of sunflower oil; c) about 50 mg to about 300 mg by weight of sodium bicarbonate; d) about 350 mg to about 1500 mg of one or more carriers; and e) the remainder being one or more delivery controlling agents.

17. 17. The kit of claim 16, wherein the carrier is selected from inulin, microcrystalline cellulose, galactogen, cellulose, chitin, pectin, psyllium, guar, hemicellulose, potato starch, or partially hydrolyzed polysaccharides.

18. 17. The kit according to claim 16, wherein the carrier is selected from the group consisting of sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, hydrogenated starch hydrolysates, and isomaltose.

19. 17. The kit of claim 16, wherein the one or more carriers are bulking agents selected from dextrin, microcrystalline cellulose, inulin, and mixtures thereof.

20. 17. The kit of claim 16, wherein the delivery control agent is selected from glycerol, propylene glycol, b-cyclodextrin, and propylene glycol 400 (PEG 400).

21. The kit according to claim 14, comprising: B) about 70 mg to about 510 mg of an active ingredient composition comprising: a) about 5 mg to about 50 mg of nicotine polacrilex by weight; b) about 15 mg to about 160 mg by weight of sunflower oil; c) about 50 mg to about 300 mg by weight of sodium bicarbonate; d) about 350 mg to about 1500 mg of one or more carriers; and e) the remainder being one or more delivery controlling agents.

22. 22. The kit of claim 21, wherein the carrier is selected from inulin, microcrystalline cellulose, galactogen, cellulose, chitin, pectin, psyllium, guar, hemicellulose, potato starch, or partially hydrolyzed polysaccharides.

23. 22. The kit according to claim 21, wherein the carrier is selected from sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, hydrogenated starch hydrolysates, or isomaltose.

24. 22. The kit of claim 21, wherein the one or more carriers are bulking agents selected from dextrin, microcrystalline cellulose, inulin, and mixtures thereof.

25. 22. The kit of claim 21, wherein the delivery control agent is selected from glycerol, propylene glycol, b-cyclodextrin, and propylene glycol 400 (PEG 400).

26. A composition comprising: a) about 8.6 mg to about 21.7 mg of nicotine, a nicotine salt, nicotine polacrilex, or a mixture thereof; b) about 25.8 to about 72.6 mg sunflower oil; and c) about 76.1 mg to about 86.6 mg sodium bicarbonate.

27. 27. The composition of claim 26, wherein the nicotine salt is nicotine benzoate.

28. 27. The composition of claim 26, further comprising about 383.2 mg to about 510 mg of inulin.

29. 27. The composition of claim 26, comprising nicotine polacrilex.

30. 30. The composition of claim 29, further comprising glycerin.

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