Compositions and methods for sublingual delivery of nicotine

Abstract

To provide compositions and methods for oral delivery of nicotine and nicotine derivatives.SOLUTION: In one embodiment, the nicotine is delivered in an oral packets, pouches, or sachets.SELECTED DRAWING: Figure 1

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 oral packets, pouches, or sachets. [Brief explanation 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. [Figure 2] FIG. 2 is a plot of the mean plasma concentration of nicotine (ng / mL) versus time (hr) following buccal administration of the nicotine benzoate control composition disclosed in Table I in male beagle dogs. [Figure 3] FIG. 3 is a plot of individual plasma concentrations of nicotine (ng / mL) versus time (hr) following buccal administration of the nicotine benzoate compositions (4 mg) of the present disclosure 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) from Table II in male beagle dogs. [Figure 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 (4 mg) disclosed in Table VI in male beagle dogs (Group 4). DETAILED DESCRIPTION OF THE INVENTION

[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 herein 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 herein 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 endpoint of a range is significant both in relation to the other endpoint, and independently of the other endpoint.

[0009] The terms "comprise" (and any form of "comprise," e.g., "comprises" and "comprising"), "have" (and any form of "have," e.g., "has" and "having"), "include" (and any form of "include," e.g., "includes" and "including"), and "contain" (and any form of "contain," e.g., "contains" and "containing") are open linking verbs. Consequently, an apparatus that "comprises," "has," "includes," or "contains" one or more elements includes, but is not limited to, including only, those one or more elements. Similarly, a method that "comprises," "has," "includes," or "contains" one or more steps includes, 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 modify 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, rather than comprising / comprising / containing / having. 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 modify 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. "Sublingual" is defined as administering a drug under the tongue to be absorbed by the tissues therein. "Buccal" is defined as administering a drug by placing it between a person's cheek and gums. For purposes of this disclosure, a user may place the disclosed composition either under the tongue between the cheek and gums, 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 by the mucous membranes of the mouth, thus avoiding the adverse 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 0.25% to about 6% by weight of nicotine, a nicotine salt, nicotine in combination with a resin, or a mixture thereof; b) about 1% to about 20% by weight of edible oil; c) about 5% 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. Additionally, the compositions are free-flowing solids containing less than 0.01% water by weight.

[0019] One embodiment of the composition of the present disclosure comprises: a) about 1% to about 6% by weight of nicotine, a nicotine salt, or a mixture thereof; b) about 3% to about 20% by weight of edible 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) about 3% to about 10.5% by weight of edible 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 from about 0.25% to about 6% by weight of nicotine, nicotine salt, or nicotine in combination with a resin. In one embodiment, the base composition may contain from about 1% to about 5% by weight of nicotine, nicotine salt, or nicotine in combination with a resin. In another embodiment, the base composition may contain from about 2% to about 6% by weight of nicotine, nicotine salt, or nicotine in combination with a resin. In a further embodiment, the base composition may contain from about 2% to about 5% by weight of nicotine, nicotine salt, or nicotine in combination with a resin. In yet a further embodiment, the base composition may contain from about 3% to about 5% by weight of nicotine, nicotine salt, or nicotine in combination with a resin. In yet a further embodiment, the base composition may contain from about 0.5% to about 4% by weight of nicotine, nicotine salt, or nicotine in combination with a resin. In yet another further embodiment, the base composition may include from about 0.75% to about 3% by weight of nicotine, nicotine salt, or nicotine in combination with a resin.

[0022] For example, the amount of nicotine, nicotine salt, or nicotine in combination with a resin can be 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 2%, 3%, 4%, 5%, or 6% by weight, or any fractional amount, such as 1.5%, 3.25%, and 5.75%.

[0023] The base composition of the present disclosure may comprise from about 1% to about 20% edible oil by weight. In one embodiment, the base composition may comprise from about 3% to about 15% edible oil by weight. In another embodiment, the base composition may comprise from about 5% to about 17% edible oil by weight. In a further embodiment, the base composition may comprise from about 7.5% to about 15% edible oil by weight. In a still further embodiment, the base composition may comprise from about 5% to about 10% edible oil by weight. For example, the amount of edible oil can be 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% edible oil by weight, or any fractional amount, such as 10.5%, 13.6%, and 17.5%.

[0024] According to this embodiment, the ratio of nicotine to edible 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 edible 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, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, or 1:4.

[0025] The base composition of the present disclosure may contain about 5% to about 20% sodium bicarbonate by weight. In one embodiment, the base composition may contain about 5% to about 15% sodium bicarbonate by weight. In another embodiment, the base composition may contain about 10% to about 20% sodium bicarbonate by weight. In a further embodiment, the base composition may contain about 12.5% ​​to about 17.5% sodium bicarbonate by weight. In a still further embodiment, the base composition may contain about 7% to about 15% sodium bicarbonate by weight. For example, the amount of sodium bicarbonate may be 5%, 6%, 7%, 8%, 9%, 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%.

[0026] In another embodiment, the base composition comprises: a) about 0.5 mg to about 50 mg by weight of nicotine, a nicotine salt, nicotine in combination with a resin, or a mixture thereof; b) about 10 mg to about 160 mg by weight of edible oil; and c) about 25 mg to about 300 mg by weight of sodium bicarbonate.

[0027] The base composition of the present disclosure may contain from 0.5 mg to about 50 mg by weight of nicotine, nicotine salt, nicotine in combination with a resin, or a mixture thereof.

[0028] In one embodiment, the base composition may contain 1 mg to about 50 mg by weight of nicotine, nicotine salt, nicotine in combination with a resin, or a mixture thereof. In another embodiment, the base composition may contain 10 mg to about 40 mg by weight of nicotine, nicotine salt, nicotine in combination with a resin, or a mixture thereof. In a further embodiment, the base composition may contain 10 mg to about 30 mg by weight of nicotine, nicotine salt, nicotine in combination with a resin, or a mixture thereof. In a still further embodiment, the base composition may contain 15 mg to about 30 mg by weight of nicotine, nicotine salt, nicotine in combination with a resin, or a mixture thereof. In a still further embodiment, the base composition may contain 10 mg to about 25 mg by weight of nicotine, nicotine salt, nicotine in combination with a resin, or a mixture thereof. The base composition may be, for example, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 2 mg, 3 mg, 4 mg, 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, 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, It may contain 7mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, or 50mg of nicotine, nicotine salt, nicotine in combination with a resin, or mixtures thereof, or any fractional amounts, for example 7.5mg, 22.5mg, and 34.6mg.

[0029] The base composition of the present disclosure may contain from about 10 mg to about 160 mg of edible oil by weight. In one embodiment, the base composition may contain from about 15 mg to about 160 mg of edible oil by weight. In another embodiment, the base composition may contain from about 25 mg to about 120 mg of edible oil by weight. In a further embodiment, the base composition may contain from about 40 mg to about 100 mg of edible oil by weight. In a still further embodiment, the base composition may contain from about 50 mg to about 150 mg of edible oil by weight. In a still further embodiment, the base composition may contain from about 75 mg to about 120 mg of edible oil by weight.The base composition of the present disclosure may be, for example, 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, 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, mg, 40mg, 41mg, 42mg, 43mg, 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, 72 mg, 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, 104mg, 105mg, 106mg, 107mg, 108mg, 109mg, 110mg, 111mg, 112mg, 113mg, 114mg, 115mg, 116mg, 117mg, 118mg, 119mg, 120mg, 121mg, 122mg, 123mg, 124mg, 125mg, 126mg, 127mg, 128mg, 129mg, 130mg It 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 edible oil, or any fractional amount, for example, 27.5 mg, 82.5 mg, and 134.6 mg.

[0030] The base composition of the present disclosure may contain from about 10 mg to about 300 mg of sodium bicarbonate by weight. In one embodiment, the base composition contains from about 25 mg to about 100 mg of sodium bicarbonate by weight. In another embodiment, the base composition contains from about 50 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 further embodiment, the base composition contains from about 75 mg to about 100 mg of sodium bicarbonate. 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 have a weight percentage of, for example, 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, 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, 1 8mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83m g, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg, 101mg, 102mg, 103,mg, 104mg, 105mg, 106mg, 107mg, 108mg, 109mg, 110mg, 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、138mg、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、202mg、203mg、204mg、205mg、206mg、207mg、208mg、209mg、210mg、211mg、212mg、213mg、214mg、215mg、216mg、217mg、218mg、219mg、220mg、221mg、222mg、223mg、224mg、225mg、226mg、227mg、228mg、229mg、230mg、231mg、232mg、233mg、234mg、235mg、236mg、237mg、238mg、239mg、240mg、241mg、242mg、243mg、244mg、245mg、246mg、247mg、248mg、249mg、250mg、251mg、252mg、253mg、254mg、255mg、256mg、257mg、258mg、259mg、260mg、261mg、262mg、263mg、264mg、265mg、266mg、267mg、268mg、269mg、270mg、271mg、272mg、273mg、274mg、275mg、276mg、277mg、278mg、279mg、280mg、281mg、282mg、283mg、284mg、285mg、286mg、287mg、288mg、289mg、290mg、It may contain 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.

[0031] Nicotine compounds Disclosed herein are two types of nicotine sources: natural and synthetic. In the compositions disclosed herein, the two forms of nicotine are not combined or mixed with each other. The disclosed salts can be formed from either natural or synthetic nicotine. In this specification, the term "nicotine" is used to refer to both natural and synthetic nicotine, unless otherwise specified as natural or synthetic nicotine.

[0032] 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.

[0033] 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 still 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.

[0034] Nicotine can be synthesized by the procedure outlined herein in Scheme I below. Details of the synthesis are described in Del Castillo E et al., "Enantioselective Synthesis of Nicotine via an Iodine-Mediated Hoffmann-Loffler Reaction," Org. Lett. 2019, 21, 705-708.

[0035] Scheme I [ka] [ka] [ka] [ka] [ka] [ka]

[0036] cooking oil The disclosed edible oils include oils that are primarily triglyceride-containing oils. Non-limiting examples of these oils are selected from sunflower oil, coconut oil, canola oil, palm oil, soybean oil, corn oil, safflower oil, and peanut oil. In one non-limiting example, the edible oil is sunflower oil. In a further non-limiting example, the edible oil is coconut oil. In a further non-limiting example, the edible oil is canola oil. In a further non-limiting example, the edible oil is palm oil. In yet another non-limiting example, the edible oil is soybean oil. In another non-limiting example, the edible oil is corn oil. In another non-limiting example, the edible oil is safflower oil. In yet another non-limiting example, the edible oil is peanut oil.

[0037] Blended oil In addition to the disclosed edible oils, blended oils can also be used to provide the disclosed base compositions. Blended oils are monoglycerides and diglycerides of edible oils, or synthetic blended oils prepared by reacting glycerin with stoichiometric amounts of fatty acids to provide blended oils that are not full triglycerides. Non-limiting examples of blended oils are selected from glyceryl monocaprylate, glyceryl dibehenate, glyceryl monooleate, glyceryl dioleate, glyceryl monocaprylate, glyceryl dicaprylate, glyceryl monomyristate, and glyceryl dimyristate.

[0038] 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. In some embodiments, glycerin and / or propylene glycol may be added as a carrier.

[0039] In one aspect, the carrier can function as a bulking agent. In one embodiment, microcrystalline cellulose is used as a carrier in the base composition and as a bulking agent in the pouches disclosed herein below. In another embodiment, two or more carriers, such as microcrystalline cellulose and inulin, can be combined. This combination can be used in both the base composition and the pouches. When it comes to the pouches of this disclosure, dextrin is added as a bulking agent. However, dextrin can also function as a carrier for any flavoring that the formulator desires to add. For example, ethyl vanillin is a compound that provides a vanilla flavor. Ethyl vanillin can be blended with dextrin, microcrystalline cellulose, or inulin and then kneaded with a bulking agent or other carrier.

[0040] 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.

[0041] The compositions of the present disclosure may comprise about 80% to about 95% by weight of one or more carriers. In one embodiment, the compositions of the present disclosure may comprise about 80% to about 90% by weight of one or more carriers. In another embodiment, the compositions of the present disclosure may comprise about 85% to about 95% by weight of one or more carriers. In a further embodiment, the compositions of the present disclosure may comprise about 85% to about 90% by weight of one or more carriers.

[0042] antioxidants The compositions of the present disclosure may contain up to about 0.05% of an antioxidant. Non-limiting examples of antioxidants include butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), propyl gallate (PG), tert-butylhydroquinone (TBHQ), and mixtures thereof.

[0043] The following table discloses non-limiting examples of base nicotine delivery compositions.

[0044] [Table 1]

[0045] [Table 2]

[0046] [Table 3]

[0047] [Table 4]

[0048] [Table 5]

[0049] [Table 6]

[0050] [Table 7]

[0051] [Table 8]

[0052] [Table 9]

[0053] [Table 10]

[0054] Table 11

[0055] Table 12

[0056] Table 13

[0057] Table 14

[0058] Table 15

[0059] Table 16

[0060] Table 17

[0061] Table 18

[0062] Table 19

[0063] Table 20

[0064] Table 21

[0065] Table 22

[0066] Table 23

[0067] Table 24

[0068] Table 25

[0069] Table 26

[0070] Table 27

[0071] Table 28

[0072] Table 29

[0073] Table 30

[0074] Table 31

[0075] Table 32

[0076] Table 33

[0077] Table 34

[0078] Table 35

[0079] Table 36

[0080] Table 37

[0081] Table 38

[0082] Table 39

[0083] Table 40

[0084] Table 41

[0085] Table 42

[0086] Table 43

[0087] Table 44

[0088] Table 45

[0089] Table 46

[0090] Table 47

[0091] Table 48

[0092] Table 49

[0093] Table 50

[0094] Table 51

[0095] Table 52

[0096] [Table 53]

[0097] [Table 54]

[0098] [Table 55]

[0099] [Table 56]

[0100] 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 nicotine resin compositions. In one embodiment, the kit includes a pouch containing the disclosed composition, including: 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 resins, or mixtures thereof; b) Sunflower oil; c) sodium bicarbonate; and d) The remainder is one or more carriers.

[0101] Controlled Delivery 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 for use. These agents are typically formulated after assembly of the base nicotine delivery composition; however, formulators may add the delivery-controlling agent as part of the carrier system.

[0102] In one embodiment, the delivery agent is a solubilizing agent, such as lecithin, polyoxyethylene stearate, polyoxyethylene sorbitan fatty acid esters, fatty acid salts, mono- and diacetyltartaric 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.

[0103] 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).

[0104] Non-limiting examples of solubilizing agents include glycerol, propylene glycol, b-cyclodextrin, and propylene glycol 400 (PEG 400).

[0105] 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 resins, or mixtures thereof; b) Sunflower oil; c) sodium bicarbonate; and d) The remainder is one or more carriers.

[0106] 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.

[0107] 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.

[0108] In further embodiments of the disclosed kits, the kit comprises: A) A liquid-permeable pouch containing a non-nicotine composition comprising: a) one or more delivery agents; and b) bulking agents; c) optionally one or more formulated oils; and B) A base nicotine delivery composition comprising: a) nicotine, nicotine salts, nicotine in combination with resins, or mixtures thereof; b) Sunflower oil; c) sodium bicarbonate; d) one or more formulated oils; and e) The remainder is one or more carriers.

[0109] 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; 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; d) about 0.5% to about 1% by weight of one or more blending oils; and d) The remainder is one or more carriers.

[0110] Non-limiting examples of flavoring agents include apple, banana, cherry, cinnamon, grape, orange, pear, pineapple, raspberry, blueberry, strawberry, spearmint, peppermint, wintergreen, and vanilla.

[0111] 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 resins, or mixtures thereof; b) Sunflower oil; c) sodium bicarbonate; and d) The remainder is one or more carriers.

[0112] 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 0.5 mg to about 50 mg by weight of nicotine, a nicotine salt, nicotine in combination with a resin, or a mixture thereof; b) about 10 mg to about 160 mg by weight of sunflower oil; and c) about 25 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 is one or more delivery-controlling agents.

[0113] In another 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 0.5 mg to about 50 mg by weight of nicotine, a nicotine salt, nicotine in combination with a resin, or a mixture thereof; b) about 10 mg to about 160 mg by weight of sunflower oil; and c) about 25 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 is one or more delivery-controlling agents.

[0114] preparation The base compositions of the present disclosure 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 sufficient agitation. The amount of each component varies depending on the formulator's choice of ratio of nicotine-containing component to sunflower oil. That is, the ratio of nicotine-containing component to sunflower oil, as disclosed above in this application, can be from about 1:1 to about 1:3. The selection of the ratio will also determine the relative amounts of additional supplemental components. Then, with agitation, the nicotine-containing component-sunflower oil blend is slowly heated to about 50°C to about 75°C, again based on the ratio of components and the selection of excipients.

[0115] At this point, antioxidants and other adjunct ingredients can optionally be added to the nicotine-containing compound / sunflower oil blend during heating. The amount and ratio of any antioxidants added to the blend can vary depending on the formulator's preference. In one non-limiting embodiment, the amount of antioxidant is about 0.01% to about 0.10% by weight of the blend.

[0116] The resulting blend, after optional addition of antioxidants and / or other adjunct 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 many factors, including the type of adjunct ingredients and the ratio of nicotine-containing compound to sunflower oil.

[0117] 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 base. In one non-limiting embodiment, the composition can contain from about 1% to about 25% alkalizing agent by weight.

[0118] After homogenizing the alkalizing agent into the now-formed uniform blend, other auxiliary ingredients can be added. Non-limiting examples include bulking agents that provide a mouthfeel that is compatible with the pouch, thereby providing the user with a sense of "substance" within the pouch. Bulking agents include microcrystalline cellulose and inulin. Additionally, sweeteners, such as maltitol, and / or flavoring compounds can be added to provide different mouthfeels.

[0119] The resulting composition 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, can be administered in a variety of different oral or buccal form factors.

[0120] 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 uniformly heated to 50°C. The nicotine benzoate-sunflower oil blend is then slowly metered into inulin (500 g) as a dry microparticle base 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 dehydration chamber for 90 minutes to remove residual moisture and create a molecular bond between the nicotine and sunflower oil-impregnated dry microparticles. The resulting composition is then combined with microcrystalline cellulose (200 g), maltitol (175 g), and spearmint flavor (100 g) and packaged into unit-dose oral pouches.

[0121] Pouch The properties of the pouch can affect the release of nicotine, nicotine salts, or nicotine in combination with a resin from the pouch composition, and thereby potentially affect 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.

[0122] Disclosed herein are water-insoluble pouches that 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.

[0123] In one embodiment, the pouches of the present disclosure comprise alpha cellulose obtained as a pulp from a variety of fibrous plant material, such as cellulose prepared by processing wood pulp. In a further embodiment, the pouches may comprise wheat fiber, oat fiber, or a combination thereof.

[0124] 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.

[0125] It is one 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 mouthfeel during use. It is important that the pouch material does not swell during use, as this can adversely affect the dissolution of the water-soluble components, thereby preventing the user from experiencing any loss of pouch contents during use.

[0126] Additionally, the pouch composition may also provide a desirable mouthfeel, such as a soft and / or sticky texture. The desired texture and mouthfeel may be achieved while still allowing the manufactured pouches to be stored side-by-side, e.g., in cans and the like, without sticking or clumping together and causing the pouches to burst when dispensed. 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 with it, such as tissue discoloration.

[0127] 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.

[0128] The kit comprises a water-permeable pouch into which the active agent composition and 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 controlled delivery system containing one or more delivery-controlling agents, carriers, solubilizers, or mixtures thereof.

[0129] 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 by weight of sodium bicarbonate; B) about 350 mg to about 1500 mg of one or more carriers; and C) The remainder is one or more delivery-controlling agents.

[0130] 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.

[0131] 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.

[0132] 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 inulin by weight.

[0133] 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.

[0134] 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) A blend of about 300 mg to about 1300 mg by weight of inulin and microcrystalline cellulose.

[0135] 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 by weight of nicotine polacrilex; 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; B) about 350 mg to about 1500 mg of one or more carriers; and C) The remainder is one or more delivery-controlling agents.

[0136] 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 polacrilex; 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.

[0137] In another iteration of this embodiment, a pouch comprising: a) about 5 mg to about 50 mg by weight of nicotine polacrilex; 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.

[0138] In yet a further iteration of this embodiment, a pouch comprising: a) about 5 mg to about 50 mg by weight of nicotine polacrilex; 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 inulin by weight.

[0139] In yet a further iteration of this embodiment, a pouch comprising: a) about 5 mg to about 50 mg by weight of nicotine polacrilex; 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.

[0140] In yet a further iteration of this embodiment, a pouch comprising: a) about 5 mg to about 50 mg by weight of nicotine polacrilex; 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.

[0141] 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.

[0142] process The base compositions of the present disclosure 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 sufficient agitation. The amount of each component varies depending on the formulator's choice of ratio of nicotine-containing component to sunflower oil, i.e., a ratio of nicotine-containing component to sunflower oil of about 1:1 to about 1:3. The ratio selection will also determine the relative amounts of additional supplemental components. The nicotine-containing component-sunflower oil blend is then slowly heated to about 50°C to about 75°C with agitation, again based on the ratio of components and the choice of excipients.

[0143] 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 uniformly heated to 50°C. Inulin (500 g) is slowly measured in and stirring is continued until all the inulin is dispersed. Sodium bicarbonate (150 g) is slowly added while the temperature is raised to 60°C. Once the blend is uniform, inulin (790 g) is added at a rate sufficient 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. [Example]

[0144] The following are non-limiting examples of compositions that may be delivered by insoluble botanical or synthetic pouches.

[0145] [Table 57]

[0146] [Table 58]

[0147] [Table 59]

[0148] [Table 60]

[0149] [Table 61]

[0150] [Table 62]

[0151] [Table 63]

[0152] [Table 64]

[0153] 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.

[0154] 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 point throughout the conduct of the study.

[0155] dosage Four mg of nicotine per pouch was administered bucally. Animals were anesthetized with propofol at a dose of 6 mg / kg. The animals were then intubated and maintained under anesthesia using 1-5% isoflurane and 2 L of oxygen. The pouch containing the test substance was placed in the buccal space and rinsed with a small volume of water (0.5-1 mL). Every 5 minutes after placing the test substance in the buccal space, the isoflurane mask was removed and the pouch was gently compressed. Special care was taken to ensure that saliva did not escape from the mouth. After 30 minutes, the test substance pouch 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 bearing the animal's ID and pouch identification.

[0156] Test Composition

[0157] [Table 65]

[0158] [Table 66]

[0159] [Table 67]

[0160] [Table 68]

[0161] As shown in the table below, Group 1 received the nicotine benzoate control group. Group 2 received a composition of the present disclosure containing nicotine benzoate. Group 3 received the nicotine polacrilex control. Group 4 received a composition of the present disclosure 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.

[0162] [Table 69]

[0163] 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 minutes 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.

[0164] 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 the resulting pharmacokinetic parameters are shown in Tables 4-7. All data are expressed as ng / mL of nicotine. Samples below the limit of quantitation (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.

[0165] 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. The maximum plasma concentration (Cmax) and time to 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 method by calculation up to the last quantifiable data point (AUC0-last) and, when applicable, by extrapolation to infinity (AUC∞). The plasma half-life (t1 / 2) was calculated from 0.693 / slope of the terminal elimination phase. The mean residence time (MRT) was calculated by dividing the area under the moment curve (AUMC) by the AUC. Any samples below the limit of quantification (1.0 ng / mL plasma) were not used in calculating the mean values.

[0166] 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)

[0167] [Table 70]

[0168] [Table 71]

[0169] Table VIII provides the means and standard deviations of the results for animals 1-10.

[0170] [Table 72]

[0171] Figure 1 is a plot of individual plasma concentrations of nicotine (ng / mL) versus time (hr) in male beagle dogs after 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 after buccal administration of a nicotine benzoate control composition disclosed in Table I.

[0172] 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).

[0173] [Table 73]

[0174] [Table 74]

[0175] Table XI provides the means and standard deviations of the results for animals 11-21.

[0176] [Table 75]

[0177] Figure 3 illustrates the individual plasma concentrations of nicotine (ng / mL) versus time (hr) following buccal administration of 4 mg of a nicotine benzoate composition of the present disclosure disclosed in Table II in male beagle dogs. Figure 4 illustrates the mean plasma concentrations of nicotine (ng / mL) versus time (hr) following buccal administration of 4 mg of a compound of the present disclosure in Table II in male beagle dogs.

[0178] Pharmacokinetics of Nicotine and Individual Plasma Concentrations (ng / mL) vs. Time (hr) Following Buccal Administration of the Nicotine Polacrilex Control Composition (4 mg) Disclosed in Tables XII and XIII in Male Beagle Dogs (Group 3)

[0179] [Table 76]

[0180] [Table 77]

[0181] Table XIV provides the means and standard deviations of the results for animals 21-30.

[0182] [Table 78]

[0183] Figure 5 shows the individual plasma concentrations of nicotine (ng / mL) versus time (hr) after 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) after buccal administration of a nicotine polacrilex control composition (4 mg) disclosed in Table III in male beagle dogs (Group 3).

[0184] 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).

[0185] [Table 79]

[0186] [Table 80]

[0187] Table XVII provides the means and standard deviations of the results for animals 31-40.

[0188] [Table 81]

[0189] Figure 7 shows the individual plasma concentrations of nicotine (ng / mL) versus time (hr) following buccal administration of 4 mg of a nicotine polacrilex composition disclosed in Table VI in male beagle dogs (Group 4). Figure 8 shows the mean plasma concentrations of nicotine (ng / mL) versus time (hr) following buccal administration of 4 mg of a nicotine polacrilex composition disclosed in Table VI in male beagle dogs (Group 4).

[0190] procedure Preparation of analytical stock solutions Analytical stock solutions (1.00 mg / mL free drug) were prepared in water.

[0191] Preparation of standards Standards were prepared using blank male beagle dog plasma. A working solution was prepared using 50:50 acetonitrile:water. The working solution was then added to plasma to create calibration standards at final concentrations of 2000, 1000, 500, 250, 100, 50, 10, 5, 2, and 1 ng / mL. The standards were treated identically to the study samples.

[0192] Sample extraction Plasma samples were manually extracted on 96-well plates by precipitation with acetonitrile.

[0193] [Table 82]

[0194] HPLC conditions Apparatus: 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

[0195] [Table 83]

[0196] Flow rate: 600μL / min Injection volume: 3 μL Runtime: 2.0 min 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

[0197] Mass spectrometer conditions Apparatus: 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: 2.5 kV

[0198] 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 0.25% to about 6% by weight of nicotine, nicotine salt, nicotine in combination with a resin, or a mixture thereof; b) about 1% to about 20% by weight of an edible oil; c) about 5% to about 20% by weight sodium bicarbonate; and d) The remainder is one or more carriers.

2. The composition of claim 1 comprising nicotine.

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

4. 4. The composition of claim 3, wherein the nicotine salt is selected from nicotine-containing polymer resins, non-limiting examples of nicotine salts include nicotine benzoate, nicotine lactate, nicotine malate, nicotine bitartrate, nicotine salicylate, nicotine citrate, and nicotine levulinate.

5. 10. The composition of claim 1, comprising nicotine in combination with a resin.

6. 6. The composition of claim 5, wherein the nicotine in combination with the resin is nicotine polacrilex or nicotine resinate.

7. 10. The composition of claim 1, wherein the edible oil is selected from sunflower oil, coconut oil, canola oil, palm oil, soybean oil, corn oil, safflower oil, or peanut oil.

8. 10. 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.

9. 2. The composition of claim 1, wherein the carrier is selected from sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, hydrogenated starch hydrolysates, or isomaltose.

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

11. 10. The composition of claim 1, wherein the ratio of nicotine to edible oil in the combination of nicotine, nicotine salt, and resin is from about 1:1 to about 1:

4.

12. A composition comprising: a) about 0.5 mg to about 50 mg by weight of nicotine, a nicotine salt, nicotine in combination with a resin, or a mixture thereof; b) about 10 mg to about 160 mg by weight of edible oil; and c) about 25 mg to about 300 mg by weight of sodium bicarbonate.

13. 13. The composition of claim 12, comprising from 15 mg to about 40 mg by weight of nicotine, nicotine salt, nicotine in combination with a resin, or a mixture thereof.

14. 13. The composition of claim 12, wherein the edible oil is selected from sunflower oil, coconut oil, canola oil, palm oil, soybean oil, corn oil, safflower oil, or peanut oil.

15. 13. The composition of claim 12, further comprising a carrier, wherein the carrier is selected from inulin, microcrystalline cellulose, galactogen, cellulose, chitin, pectin, psyllium, guar, hemicellulose, potato starch, partially hydrolyzed polysaccharides, sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, hydrogenated starch hydrolysates, or isomaltose.

16. The composition of claim 12, further comprising glycerol, propylene glycol, β-cyclodextrin, propylene glycol 400 (PEG 400), or a mixture thereof.

17. 13. The composition of claim 12, comprising: a) about 8.6 mg to about 21.7 mg of nicotine, a nicotine salt, nicotine in combination with a resin, or a mixture thereof; b) about 25.8 mg to about 72.6 mg sunflower oil; and c) about 76.1 mg to about 86.6 mg sodium bicarbonate.

18. A composition comprising: a) about 1% to about 6% by weight of nicotine, nicotine salt, nicotine in combination with a resin, or a mixture thereof; b) about 3% to about 20% by weight of one or more edible oils c) about 10% to about 20% by weight sodium bicarbonate; and d) The remainder is one or more carriers.

19. 20. The composition of claim 18, comprising nicotine.

20. 20. The composition of claim 18, comprising a nicotine salt.

21. 20. The composition of claim 18, comprising nicotine in combination with a resin.

22. 20. The composition of claim 18, wherein the edible oil is selected from sunflower oil, coconut oil, canola oil, palm oil, soybean oil, corn oil, safflower oil, or peanut oil.

23. 19. The composition of claim 18, wherein the carrier is selected from inulin, microcrystalline cellulose, galactogen, cellulose, chitin, pectin, psyllium, guar, hemicellulose, potato starch, or partially hydrolyzed polysaccharides.

24. 19. The composition of claim 18, wherein the carrier is selected from sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, hydrogenated starch hydrolysates, or isomaltose.

25. 19. The composition of claim 18, further comprising glycerol, propylene glycol, β-cyclodextrin, propylene glycol 400 (PEG 400), or a mixture thereof.

26. A composition comprising: a) 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 by weight of one or more sunflower oils; and c) about 50 mg to about 300 mg by weight of sodium bicarbonate.

27. 27. The composition of claim 26, comprising from about 15 mg to about 40 mg by weight of nicotine, nicotine salt, nicotine in combination with a resin, or a mixture thereof.

28. 27. The composition of claim 26, further comprising a carrier.

29. 29. The composition of claim 28, wherein the carrier is selected from inulin, microcrystalline cellulose, galactogen, cellulose, chitin, pectin, psyllium, guar, hemicellulose, potato starch, or partially hydrolyzed polysaccharides.

30. 29. The composition of claim 28, wherein the carrier is selected from sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, hydrogenated starch hydrolysates, or isomaltose.

31. 27. The composition of claim 26, further comprising glycerol, propylene glycol, β-cyclodextrin, propylene glycol 400 (PEG 400), or a mixture thereof.

32. A composition comprising: a) from about 8.6 mg to about 21.7 mg by weight of nicotine, a nicotine salt, nicotine in combination with a resin, or a mixture thereof; b) about 25.8 mg to about 72.6 mg by weight of one or more sunflower oils; and c) about 76.1 mg to about 86.6 mg sodium bicarbonate by weight.

33. 33. The composition of claim 32, wherein the nicotine salt is nicotine benzoate and the nicotine in combination with the resin is nicotine polacrilex.

34. 33. The composition of claim 32, comprising about 383.2 mg to about 510 mg of inulin.

35. 33. The composition of claim 32, comprising nicotine polacrilex.

36. 33. The composition of claim 32, comprising glycerin.

37. Kit includes: 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 in combination with resins, or mixtures thereof; b) Edible oil; c) sodium bicarbonate; and d) The remainder is one or more carriers.

38. 38. The kit of claim 37, 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.

39. 38. The kit of claim 37, wherein the edible oil is selected from sunflower oil, coconut oil, canola oil, palm oil, soybean oil, corn oil, safflower oil, or peanut oil.

40. 38. The kit of claim 37, wherein the carrier is selected from inulin, microcrystalline cellulose, galactogen, cellulose, chitin, pectin, psyllium, guar, hemicellulose, potato starch, partially hydrolyzed polysaccharides, sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, hydrogenated starch hydrolysates, or isomaltose.

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