Hydrogel oral delivery systems and methods

Abstract

In various embodiments, novel hydrogels capable of releasing an active such as (S)-nicotine upon water absorption and swelling are described. In certain examples, hydrogels comprise (S)-nicotine, or a salt or a complex thereof, at least a polymer, at least a plasticizer and at least a disintegrant. In some embodiments, a hydrogel is utilized as the single delivery carrier for nicotine release. In other embodiments, hydrogel is composited with other carriers to form hydrogel-carrier combination fill materials usable for nicotine release. Hydrogels herein preferably comprise a polysaccharidic network or naturally occurring hydrogel-forming polymers plasticized for flexibility and including a disintegrant to accelerate decomposition of the hydrogel when used in the oral cavity of an individual for nicotine administration.

Description

HYDROGEL ORAL DELIVERY SYSTEMS AND METHODSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Patent Application No. 63 / 542,267, filed October 3, 2023, the entire contents of which is incorporated by reference herein.FIELD

[0002] The present disclosure generally relates to drug delivery systems, and in particular to novel hydrogels comprising (S)-nicotine, (S)-nicotine salts, (S)-nicotine complexes, and oral delivery forms thereof wherein the hydrogels preferably comprise a polysaccharide network or naturally occurring hydrogel-forming polymers plasticized for flexibility and including a disintegrant to accelerate decomposition when used in the oral cavity of an individual for nicotine administration.BACKGROUND

[0003] In some ways, tobacco smoking has been inconvenient at times, but more recently smoking has simply become publicly unacceptable. The increasing evidence of large amount of harmful and potentially harmful constituents other than nicotine from the tobacco combustion process, which is linked to over 20 diseases including cancer, adds to the concerns about smoking cigarettes. As such, adult smokers have demanded less-harmful alternative methods for selfadministration of nicotine. Some alternatives to traditional tobacco smoking include e-cigarettes for vaping. Additionally, there are newer smokeless nicotine products such as nicotine chewing gum, nicotine oral strips and oral nicotine pouches.

[0004] Although some of these smokeless forms to self-administer nicotine have some market success, improvements to these physical forms are still needed such that nicotine is released in the mouth of an individual at a consumer preferred rate and mouth feel. For example, most commercially available nicotine oral products cannot provide adequate nicotine delivery and satisfaction due to the slow-release rate in the oral cavity. In other examples, the amount of total nicotine released can vary significantly between different materials, brands, and manufacturers. It is desirable to provide an improved product to replace or reduce smoking cigarettes, without the aforementioned disadvantages associated with the current nicotine alternative products. The idealproduct should provide a rapid and almost complete delivery of nicotine, be devoid of other detrimental components, aptly address the stability and volatility challenges intrinsic to nicotine and / or be cost-effective and simple to manufacture. By improving nicotine release onset and reducing harshness, it holds the potential to be more readily accepted by current smokers, encouraging them to make the switch from more harmful cigarette products. This transition not only signifies individual harm reduction but, when scaled, leads to significant public health gains for the broader population.SUMMARY

[0005] In accordance with various embodiments of the present disclosure, it has now been surprisingly discovered that hydrogels prepared by certain polymers and modified with plasticizer and disintegrant are capable of releasing (S)-nicotine at faster and more acceptable rates than previous nicotine delivery forms.

[0006] Hydrogels herein have been found to be convenient and easy to use with no residue and less waste. The hydrogels retain moisture, providing fast onset of (S)-nicotine and fast release. The hydrogels are shown to have high digestibility, extended shelf life and ability to accept flavoring agent integration.

[0007] In addition to the use of hydrogels containing nicotine as a single delivery carrier as described above, it has also been surprisingly discovered that (S)-nicotine release from an oral nicotine pouch (ONP) comprising hydrogel-carrier combination composites can be significantly increased when the carrier inside the pouch is dispersed in or with a polymer network of a hydrogel and the resulting hydrogel is used as the pouch fill material.

[0008] In several embodiments, there is provided a hydrogel comprising an active, a polymer, a plasticizer, and a disintegrant. In several embodiments, there is provided a hydrogel comprising at least two of an active, a polymer, a plasticizer, and a disintegrant. In several embodiments, the active is selected from the group consisting of (S)-nicotine, an (S)-nicotine salt, an (S)-nicotine complex, caffeine, menthol, melatonin, cannabidiol (CBD), tetrahydrocannabinol (THC), quercetin, y-aminobutyric acid (GABA), theanine, L-tryptophan, 5 -hydroxy -L-tryptophan (5- HTP), and mixtures thereof.

[0009] In several embodiments, the polymer is selected from the group consisting of sodium alginate, pectin, pullulan, glucan, dextrin, maltodextrin, xanthan gum, xyloglucan, tragacanth gum, guar gum, acacia gum, Arabic gum, starch, agarose, gelatin, gellan, chitosan, carrageenan,chondroitin sulfate, collagen, silk fibroin, sericin, scleroglucan, cellulose, hyaluronic acid, hydroxypropyl methyl cellulose (HPMC), hydroxy ethyl cellulose (HEC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), ethyl cellulose (EC), hydroxypropyl ethyl cellulose (HPEC), and combinations thereof. In several embodiments, the polymer comprises gelatin, pullulan, acacia gum, sodium alginate, carboxymethylcellulose (CMC), hydroxypropyl methylcellulose (HPMC), or mixtures thereof. In several embodiments, combinations of polymers allow a multiphasic release rate of the active (or other ingredient to be released, like a flavorant) to be achieved. For example, a polymer blend may allow a rapid acute release phase of a first ingredient, followed by a longer and maintained plateau phase for that ingredient. In some, such a release profile may be accompanied by a linear release profile of a second ingredient.

[0010] In several embodiments, the active comprises (S)-nicotine, wherein the (S)-nicotine is in the form of free base nicotine without positive charge.

[0011] In several embodiments, the active comprises an (S)-nicotine salt, the (S)-nicotine salt further comprising a protonated (S)-nicotine cation in association with a negatively charged counterion comprising a conjugate base of an organic acid. In several embodiments, the organic acid is selected from the group consisting of formic acid, acetic acid, adipic acid, trifluoroacetic acid, aspartic acid, butanoic acid, butyric acid, 2-methylbutyric acid, 3- methylbutyric acid, benzoic acid, caprylic acid, citric acid, crotonic acid, butanoic acid, ethylenediaminetetraacetic acid (EDTA), C8-C26 saturated, monounsaturated, or polyunsaturated fatty acids, fumaric acid, gluconic acid, glutamic acid, glyceric acid, glycidic acid, glycolic acid, glyoxylic acid, hexanoic acid, heptanoic acid, lactic acid, lauric acid, levulinic acid, maleic acid, L-(-)-malic acid, malonic acid, mandelic acid, mesooxalic acid, methane sulfonic acid, oxalic acid, pentanoic acid, phenylacetic acid, phthalic acid, picric acid, propionic acid, 3 -oxopropan oic acid, 2,3- dioxopropanoic acid, 2, 3, -dihydroxypropanedioic acid, propiolic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tannic acid, L-(+)-tartaric acid, tartronic acid, valeric acid, vanillic acid, and mixtures thereof. In several embodiments, the (S)-nicotine salt comprises (S)-nicotine lactate, nicotine benzoate, nicotine levulinate, nicotine salicylate, nicotine malate, and / or nicotine tartrate.

[0012] In several embodiments, the active comprises and (S)-nicotine complex comprising (S)-nicotine in association with a saturated fatty acid, a monounsaturated fatty acid, a polyunsaturated fatty acid, or mixtures thereof.

[0013] In several embodiments, the active comprises an (S)-ni cotine complex, wherein the (S)- nicotine complex is an (S)-nicotine inclusion complex comprising (S)-nicotine in association with a cyclodextrin. In several embodiments, the cyclodextrin is selected from the group consisting of P- cyclodextrin, hydroxypropyl-P-cyclodextrin, methyl-P-cyclodextrin, dimethyl-P-cyclodextrin, heptakis(2,6-di-O-)ethyl-P-cyclodextrin, 6-O-a-maltosyl-P-cyclodextrin, randomly methylated P- 15 cyclodextrin (RAMEB), sulfobutylether-P-cyclodextrin, sulfolipo-P-cyclodextrin, y- cyclodextrin, hydroxypropyl-y-cyclodextrin, octakis-(6-bromo-6-deoxy)-y-cyclodextrin, octakis- (6-amino-6- deoxy)-y-cyclodextrin, octakis-(6-chloro-6-deoxy)-y-cyclodextrin, octakis-(6-deoxy- 6-iodo)-y- cyclodextrin, octakis-(6-deoxy-6-mercapto)-y-cyclodextrin, octakis-(2,3,6-tri-O- m ethyl )-y- cyclodextrin, octakis-(2,3-diacetyl-6-sulfato)-y-cyclodextrin, octakis-(3-O-butyryl- 2,6-di-O-pentyl)-y-cyclodextrin, octakis-6-sulfato-y-cyclodextrin, and mixtures thereof.

[0014] In several embodiments, the plasticizer is selected from the group consisting of tris-2- ethylhexyltrimellitate, dioctyl terephthalate, di-isobutyl terephthalate, N-butylbenzene sulfonamide, di-isodecylsebacate, di-2-ethylhexylsebacate, dibutylsebacate, dimethylsebacate, 25 tri s(2 -ethyl hexyl) phosphate, 2-ethylhexyl diphenyl phosphate, triphenyl phosphate, 2,2,4- trimethyl-1,3 pentanediol di-isobutyrate, di-C16-18 alkyl phthalate, benzyl C7-9-branched and linear alkyl phthalate, di-isotridecyl phthalate, di-isoundecyl phthalate, di(2-propyl heptyl) phthalate, di- isodecyl phthalate, di-isononyl phthalate, bis(2-ethylhexyl) phthalate, di-isooctyl phthalate, di-n- octyl phthalate, di-isoheptyl phthalate, di-cyclohexyl phthalate, di-isohexyl phthalate, di-n-hexylphthalate, di-n-pentyl phthalate, benzyl butyl phthalate, di-isobutyl phthalate, di-n-butyl phthalate, di-n-propyl phthalate, diethyl phthalate, dimethyl phthalate, triglyceride vegetable oils from soybean oil, linseed oil, castor oil, or sunflower oil, di-isononyl cyclohexane di carb oxy late, citric acid, acetyl tributyl citrate, tributyl citrate, triethyl citrate, triethylene glycol dibenzoate, isodecyl benzoate, isononyl benzoate, dipropylene glycol dibenzoate, diethylene glycol dibenzoate, neopentylglycol dibenzoate, diisodecyl azelate, bis[2-(2-butoxyethoxy)ethyl] adipate, di(butoxyethyl) adipate, di-n-butyl adipate, ditridecyl adipate, diisodecyl adipate, diisononyl adipate, di-2 -ethylhexyl adipate, benzyl 2-ethylhexyl adipate, diisobutyl adipate, glyceryl triacetate, diethyl succinate, dibutyl succinate, dihexyl succinate, diethylhexyl succinate, didecyl succinate, didodecyl succinate, poly(hexylene succinate), poly(butylene succinate), polypropylene glycol succinate), poly(ethylene glycol succinate), 1,2-propylene glycol, diethylene glycol, various fatty acid esters (FAEs), glycerin, ethylene glycol, diethylene glycol,triethylene glycol, tetraethylene glycol, polyethylene glycol (PEGs), propylene glycol, sorbitol, mannitol, xylitol, glucose, mannose, fructose, sucrose, urea, fatty acid glyceride comprises medium-chain length triglyceride (MCT) oil, sunflower oil, canola oil, palm oil, coconut oil, safflower oil, olive oil, sesame oil, peanut oil, avocado oil, and soybean oil, and mixtures thereof. In several embodiments, the plasticizer comprises at least one of an triglyceride vegetable oil from soybean oil, linseed oil, castor oil, or sunflower oil, citric acid, glycerin, 1,2-propylene glycol, diethylene glycol, sorbitol, and poly(ethylene glycol succinate).

[0015] In several embodiments, the disintegrant is selected from the group consisting of starch, sodium starch glycolate Type A, sodium starch glycolate Type B, powdered microcrystalline cellulose (MCC), guar gum, xanthan gum, locust bean gum, chitosan hydrochloride, alginic acid, calcium alginate, sodium alginate, docusate sodium, dicalcium phosphate, tricalcium phosphate, magnesium aluminum silicate, bentonite, guargalactomannan, crosslinked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, methylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, calcium cellulose glycolate, crospovidone, and mixtures thereof. In several embodiments, the comprises microcrystalline cellulose (MCC). In several embodiments, the MCC is in a powdered form. In several embodiments, the disintegrant comprises a surfactant selected from the group consisting of lecithin, phosphatidylcholine, EO / PO block copolymers, EO / PO / EO triblock copolymers, polyethylene glycol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, span 20, span 40, span 60, span 80, and mixtures thereof.

[0016] In several embodiments, the hydrogels provided for herein further comprise a solvent / co-solvent selected from water, or a fatty acid glyceride selected from the group consisting of sunflower oil, canola oil, palm oil, coconut oil, safflower oil, olive oil, sesame oil, peanut oil, avocado oil, soybean oil, and combinations thereof.

[0017] In several embodiments, the hydrogels provided for herein further comprise a flavoring agent.

[0018] In several embodiments, the hydrogels provided for herein further comprise a sugar alcohol from the group consisting of sorbitol, xylitol, erythritol, lactitol, maltitol, mannitol, isomalt, hydrogenated starch hydrolysates, and combinations thereof.

[0019] Additionally provided for herein is a hydrogel-based oral strip comprising an active, a polymer, a plasticizer, and a disintegrant. In several embodiments, there is provided a hydrogel-based oral strip comprising at least two of an active, a polymer, a plasticizer, and a disintegrant. In several embodiments, the active is selected from the group consisting of (S)-nicotine, an (S)- nicotine salt, an (S)-nicotine complex, caffeine, menthol, melatonin, cannabidiol (CBD), tetrahydrocannabinol (THC), quercetin, y-aminobutyric acid (GABA), theanine, L-tryptophan, 5- hydroxy-L-tryptophan (5-HTP), and mixtures thereof.

[0020] In several embodiments, the active is an (S)-nicotine salt comprising (S)-nicotine lactate, nicotine benzoate, nicotine levulinate, nicotine salicylate, nicotine malate, and / or nicotine tartrate.

[0021] In several embodiments, the strip is configured as a rectangular shape measuring from about 3 cm2(0.5 in2) to about 13 cm2(2.0 in2) in surface area. In several embodiments, the strip measures from about 20pm (0.8 mil) to about 3,000pm (118 mil) in thickness. In several embodiments, each strip includes from about 1 mg to about 10 mg of free base nicotine as the active.

[0022] In several embodiments, the polymer is selected from the group consisting of gelatin, pullulan, acacia gum, sodium alginate, carboxymethylcellulose (CMC), hydroxypropyl methylcellulose (HPMC), and mixtures thereof.

[0023] Provided for herein in several embodiments is an oral nicotine pouch (ONP) comprising a saliva-permeable nonwoven fabric defining an enclosure containing a hydrogel therein, wherein said hydrogel comprises (S)-nicotine, or a salt or a complex thereof, a polymer, a surfactant, a flavoring agent, a polysaccharide, and a solvent / co-solvent. Also provided for herein is an ONP comprising a saliva-permeable nonwoven fabric defining an enclosure containing a hydrogel therein, wherein said hydrogel comprises at least three of (S)-nicotine, or a salt or a complex thereof, a polymer, a surfactant, a flavoring agent, a polysaccharide, and a solvent / co- solvent.

[0024] In several embodiments, the hydrogel further comprises a carrier. In several embodiments, the carrier is selected from the group consisting of agar, agarose, albumin, alginate, casein, chitin, chondroitin, dextrin, fibroin, fucoidans, galactans, gellan, guar, scleroglucan, pullulan, xyloglucan, pectin, xanthan, psyllium, silica gel, fumed silica, magnesium aluminum silicates, clay, bentonite, hectorite, mesoporous silica, cellulose, cellulose acetate, hyaluronan, various elastin-like polypeptides, P-cyclodextrin, collagen, gelatin, chitosan, carrageenan, polylactic acid, polyglycolic acid, poly(lactic-glycolicacid) (PLGA), poly(2-hydroxyethylmethacrylate), poly(2-hydroxypropyl methacrylate), poly(acrylic acid), carboxymethyl cellulose, carboxyethyl cellulose, hydroxy ethyl cellulose, hydrophobically-modified hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose (MCC), nitrocellulose, polyvinyl alcohol, polyvinylpyrrolidone, poly(vinyl methacrylate), carboxy vinyl polymers, poly(vinyl acetate), polyvinyl co-polymers, starch, modified starch, and mixtures thereof.

[0025] In several embodiments, the hydrogel is mixed with a carrier. In several embodiments, the carrier comprises water insoluble fibers, microcrystalline cellulose, bamboo fibers, lignin, wheat fibers, pea fibers, maize fibers, rice fiber, oat fibers, barley fibers, buckwheat fibers, cellulose fibers, bran fibers, powdered cellulose, or combinations thereof. In several embodiments, the carrier is microcrystalline cellulose (MCC).

[0026] In several embodiments, the amount of nicotine is from 0.1% to 4% by weight of the ONP composition, including about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1.0%, about 1.25%, about 1.5%, about 1.75%, about 2%, about 2.25%, about 2.5%, about 2.75%, about 3%, about 3.25%, about 3.5%, about 3.75%, about 4.0%, or any amount between those values listed.

[0027] In several embodiments, the amount of polymer is from 0.1% to 20% by weight of the pouch composition, including about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, or any amount between those listed.

[0028] In several embodiments, the amount of surfactant is from 0.01% to 10% by weight of the pouch composition, including about 0.01%, about 0.025%, about 0.05%, about 0.075%, about 0.1%, about 0.25%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, or any amount between those listed.

[0029] In several embodiments, the amount of polysaccharide is from 0.1% to 5% by weight of the pouch composition, including about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1.0%, about 1.25%, about 1.5%, about 1.75%, about 2%, about 2.25%, about 2.5%, about 2.75%, about 3%, about 3.25%, about 3.5%, about 3.75%, about 4.0%, about 4.25%, about 4.5%, about 4.75%, about 5%, or any amount between those values listed.

[0030] In several embodiments, the amount of solvent / co-solvent or the combination of solvent / co-solvent is from 0.1% to 60% by weight of the pouch composition, including about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, or any amount between those listed.

[0031] In several embodiments, there is provided a method of manufacturing an oral nicotine pouch (ONP), the method comprising providing a saliva-permeable nonwoven fabric defining an enclosure, preparing an aqueous mixture comprising (S)-nicotine, a salt or a complex thereof, at least a polysaccharide or other naturally occurring hydrogel -forming polymer, at least a solvent, and at least a surfactant, absorbing the aqueous mixture onto a carrier to form a free-flowing mixture, and disposing a portion of the free-flowing mixture in the enclosure.

[0032] In several embodiments, the (S)-nicotine, a salt or a complex thereof is free base nicotine. In several embodiments, the carrier is microcrystalline cellulose (MCC). In several embodiments, the portion of free-flowing mixture disposed in said enclosure weighs from about 5 mg to about 2000 mg, including about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 400 mg, about 600 mg, about 800 mg, about 1000 mg, about 1250 mg, about 1500 mg, about 1750 mg, about 2000 mg, or any amount between those listed.

[0033] In several embodiments, there is provided a method of increasing a rate of (S)-nicotine delivery from an oral nicotine pouch comprising a fdl material consisting of (S)-nicotine, or a salt or a complex thereof, admixed with or adsorbed onto a carrier, the fill material disposed inside a saliva-permeable nonwoven fabric pouch, said method comprising (1) preparing an aqueous solution or suspension comprising the (S)-nicotine, salt, or complex thereof, a polysaccharide or other naturally occurring hydrogel -forming polymer, a plasticizer, and a disintegrant; adsorbing the aqueous solution or suspension onto the carrier to form the fill material; and disposing the fill material inside the saliva-permeable nonwoven fabric pouch; or (2) dispersing the carrier in an aqueous solution or suspension comprising the (S)-nicotine, salt, or complex thereof, a polysaccharide or other naturally occurring hydrogel-forming polymer, a plasticizer, and a disintegrant; solidifying the dispersion into a hydrogel; and disposing the hydrogel as the fill material inside the saliva-permeable nonwoven fabric pouch; or (3) preparing an aqueous solution or suspension comprising the (S)-nicotine, salt, or complex thereof, a polysaccharide or other naturally occurring hydrogel -forming polymer, a plasticizer, and a disintegrant; solidifying thedispersion into a hydrogel; admixing the hydrogel with the carrier to form the fill material; and disposing the fill material inside the saliva-permeable nonwoven fabric pouch.

[0034] In several embodiments, the carrier is selected from the group consisting of agar, agarose, albumin, alginate, casein, chitin, chondroitin, dextrin, fibroin, fucoidans, galactans, gellan, guar, scleroglucan, pullulan, xyloglucan, pectin, xanthan, psyllium, silica gel, fumed silica, magnesium aluminum silicates, clay, bentonite, hectorite, mesoporous silica, cellulose, cellulose acetate, hyaluronan, various elastin-like polypeptides, P-cyclodextrin, collagen, gelatin, chitosan, carrageenan, polylactic acid, polyglycolic acid, poly(lactic-glycolic acid) (PLGA), poly(2- hydroxyethyl methacrylate), poly(2-hydroxypropyl methacrylate), poly(acrylic acid), carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, hydrophobically- modified hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose (MCC), nitrocellulose, polyvinyl alcohol, polyvinylpyrrolidone, poly(vinyl methacrylate), carboxy vinyl polymers, poly(vinyl acetate), polyvinyl co-polymers, starch, modified starch, and mixtures thereof. In one embodiment, the carrier is microcrystalline cellulose (MCC).

[0035] In several embodiments, hydrogels provided for herein are configured for use in manufacturing one or more of an oral spray, a transdermal patch, a nasal spray, an inhaler, and a sublingual tablet.

[0036] In several embodiments, there is provided for herein a fill material for an oral nicotine pouch, the fill material comprising, nicotine, wherein the nicotine is present in amount between 0.1% and 4%; one, or both, of lactic acid and citric acid, wherein the lactic acid and / or citric acid is present in an amount between 0.1% and 2%; cellulose, wherein the cellulose is present in an amount between 40% and 70%; glycerin, wherein the glycerin is present in amount between 0.1% and 4%; a hydrogel, wherein the hydrogel is present in an amount between 1% and 15%; an emulsion, wherein the emulsion is present in an amount between 0.01% and 30%, and water, wherein the water is present in an amount between 15% and 40%; wherein the amounts are by weight of the fill material.

[0037] In several embodiments, there is provided for herein a fill material for an oral nicotine pouch, the fill material comprising, nicotine, wherein the nicotine is present in amount up to 4%; one, or both, of lactic acid and citric acid, wherein the lactic acid and / or citric acid is present in an amount up to 2%; cellulose, wherein the cellulose is present in an amount up to 70%; glycerin,wherein the glycerin is present in amount up to 4%; a hydrogel, wherein the hydrogel is present in an amount up to 15%; an emulsion, wherein the emulsion is present in an amount up to 30%, and water, wherein the water is present in an amount up to 40%; wherein the amounts are by weight of the fill material.

[0038] In several embodiments, there is provided for herein a fill material for an oral nicotine pouch, the fill material comprising at least three of the following: nicotine, wherein the nicotine is present in amount up to 4%; one, or both, of lactic acid and citric acid, wherein the lactic acid and / or citric acid is present in an amount up to 2%; cellulose, wherein the cellulose is present in an amount up to 70%; glycerin, wherein the glycerin is present in amount up to 4%; a hydrogel, wherein the hydrogel is present in an amount up to 15%; an emulsion, wherein the emulsion is present in an amount up to 30%, and water, wherein the water is present in an amount up to 40%; wherein the amounts are by weight of the fill material.

[0039] In several embodiments, the nicotine is present in an amount between 0.5% and 2%. In several embodiments, the nicotine is present in an amount of at least 0.1%. In several embodiments, the nicotine is present in an amount up to 3%. In several embodiments, the fill material comprises both lactic acid and citric acid, wherein each of the lactic acid and citric acid are present in an amount between 0.1% and 1.8%. In several embodiments, the cellulose comprises microcrystalline cellulose and is present in an amount between 40% and 70%. In several embodiments, the glycerin is present in an amount between 0.1% and 3.0%. In several embodiments, the hydrogel comprises one or more of acacia gum, sodium alginate, carboxymethyl cellulose, guar gum, tapioca maltodextrin, tara gum, Hypromellose, pullulan, maltodextrin, and gelatin, and wherein the hydrogel is present in an amount between 3% and 12%. In several embodiments, the emulsion comprises an oil and a surfactant, wherein the oil is present in an amount between 0.01% and 20% and wherein the surfactant is present in an amount between 0.01% and 20%. In several embodiments, the oil is selected from the group consisting of sunflower oil, canola oil, palm oil, coconut oil, safflower oil, olive oil, sesame oil, peanut oil, avocado oil, soybean oil, and combinations thereof. In several embodiments, the surfactant is selected from the group consisting of lecithin, phosphatidylcholine, EO / PO block copolymers, EO / PO / EO triblock copolymers, polyethylene glycol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, span 20, span 40, span 60, span 80, and mixtures thereof. In several embodiments, the surfactant comprises polysorbate 80. In several embodiments, the water comprises deionizedwater and is present in an amount between 115% and 45%. In several embodiments, the fill material further comprises one or both of a flavorant and a sweetener.

[0040] In several embodiments, there is provided a fill material for an oral delivery pouch, the fill material comprising an active agent, wherein the active agent is present in amount between 0.1% and 4%, one, or both, of lactic acid and citric acid, wherein the lactic acid and / or citric acid is present in an amount between 0.1% and 2%, cellulose, wherein the cellulose is present in an amount between 40% and 70%, glycerin, wherein the glycerin is present in amount between 0.1% and 4%, a hydrogel, wherein the hydrogel is present in an amount between 1% and 15%, an emulsion, wherein the emulsion is present in an amount between 0.01% and 30%, and water, wherein the water is present in an amount between 15% and 40%, wherein the amounts are by weight of the fill material.

[0041] In several embodiments, there is provided a fill material for an oral delivery pouch, the fill material comprising an active agent, wherein the active agent is present in amount up to 4%, one, or both, of lactic acid and citric acid, wherein the lactic acid and / or citric acid is present in an amount between up to 2%, cellulose, wherein the cellulose is present in an amount up to 70%, glycerin, wherein the glycerin is present in amount up to 4%, a hydrogel, wherein the hydrogel is present in an amount up to 15%, an emulsion, wherein the emulsion is present in an amount up to 30%, and water, wherein the water is present in an amount up to 50%, wherein the amounts are by weight of the fill material.

[0042] In several embodiments, there is provided a nicotine complex or product comprising (S)-nicotine primarily (greater than 50%) in the form of a free base alkaloid (e.g., non-salt) with less than 50% monoprotonated nicotine (e.g., salt) and one or more ingredients suitable for forming a complex with the (S)-ni cotine.

[0043] In several embodiments, there is provided a nicotine complex or product comprising (S)-nicotine in the form of a free base alkaloid or without a positive formal charge one or more ingredients suitable for forming a complex with the (S)-ni cotine. In several embodiments, the (S)- nicotine in the nicotine complexes or products provided for herein comprises, consists of, or consists essentially of (S)-nicotine in the form of a free base alkaloid or (S)-nicotine without a positive formal charge. In several embodiments, the nicotine complexes or products provided herein are substantially free or free of monoprotonated or diprotonated nicotine.

[0044] In several embodiments, the complex is in a form selected from: a charge transfer complex, a hydrogen bonded complex, a Van der Waals complex, a complex stabilized by nonionic interactions, a solubilized complex, a micellular complex, and an inclusion complex.

[0045] In several embodiments, the one or more ingredients for forming a complex with the (S)-ni cotine is selected from the group consisting of: a fatty acid having a polar and / or hydrophilic functional group, a surfactant, a solubilizer (such as an oil), and / or a polysaccharide. In several embodiments, the one or more ingredients for forming a complex with the (S)-ni cotine is selected from the group consisting of: a fatty acid having a polar and / or hydrophilic functional group, a surfactant, a solubilizer (such as an oil), and a polysaccharide.

[0046] In several embodiments, the acid having a polar and / or hydrophilic functional group comprises at least one carboxyl group. In several embodiments, the acid having a polar and / or hydrophilic functional group comprises a C8-C24 saturated fatty acid. In several embodiments, the acid having a polar and / or hydrophilic functional group comprises a C8-C24 monounsaturated fatty acid. In several embodiments, the acid having a polar and / or hydrophilic functional group comprises a C8-C24 polyunsaturated fatty acid.

[0047] In several embodiments, the acid having a polar and / or hydrophilic functional group comprises at least one hydroxyl group, at least one double bond, at least one conjugated double bond, at least one carboxyl group, or combinations thereof. In several embodiments, the acid having a polar and / or hydrophilic functional group comprises at least one hydroxyl group. In several embodiments, the acid having a polar and / or hydrophilic functional group comprises at least one double bond. In several embodiments, the acid having a polar and / or hydrophilic functional group comprises at least one conjugated double bond. In several embodiments, the acid having a polar and / or hydrophilic functional group comprises at least one carboxyl group.

[0048] In several embodiments, the C8-C24 fatty acid is saturated and is selected from the group consisting of caprylic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, icosanoic acid, docosanoic acid, and tetracosanoic acid. In several embodiments, the C8-C24 fatty acid is monounsaturated and is selected from the group consisting of myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic acid, eicosenoic acid, erucic acid, and nervonic acid. In several embodiments, the C8-C24 fatty acid is polyunsaturated and is selected from the group consisting of linoleic acid, a-linolenic acid, y-linolenic acid, mead acid, stearidonic acid, arachidonic acid, eicosapentaenoic acid, and cervonicacid (docosahexaenoic acid). In several embodiments, the -C24 fatty acid is polyunsaturated and is selected from the group consisting of conjugated linoleic acid, eicosadienoic acid, docosadienoic acid, pinolenic acid, a-eleostearic acid, P-eleostearic acid, catalpic acid, dihomo-y-linolenic acid, eicosatri enoic acid, eicosatetraenoic acid, adrenic acid, bosseopentaenoic acid, ozubondo acid, sardine acid, tetracosapentaenoic acid, and herring acid. In several embodiments, the acid having a polar and / or hydrophilic functional group comprises a conjugated fatty acid and is selected from the group consisting of conjugated linoleic acid, punicic acid, jacaric acid, calendid acid, catapic acid, alpha-eleostearic acid, beta-eleostearic acid, parinaric acid, anadiplosis acid, and tung acid. In several embodiments, the acid having a polar and / or hydrophilic functional group comprises conjugated linoleic acid.

[0049] In several embodiments, the surfactant is selected from the group consisting of an anionic surfactant, a nonionic surfactant, a cationic surfactant, a zwitterionic surfactant, and mixtures thereof. In several embodiments, the surfactant is selected from the group consisting of lecithin, phosphatidylcholine, EO / PO block copolymers, EO / PO / EO triblock copolymers, polyethylene glycol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, span 20, span 40, span 60, span 80, and mixtures thereof.

[0050] In several embodiments, the solubilizer comprises a mono-, di-, or tri-fatty acid glyceride. In several embodiments, the solubilizer comprises a mono-fatty acid glyceride. In several embodiments, the solubilizer comprises a di-fatty acid glyceride. In several embodiments, the solubilizer comprises a tri-fatty acid glyceride. In several embodiments, the solubilizer comprises a mono-, di-, or tri-fatty acid glyceride. In several embodiments, the fatty acid glyceride comprises medium-chain length triglyceride (MCT) oil. In several embodiments, the fatty acid glyceride comprises one or more of sunflower oil, canola oil, palm oil, coconut oil, safflower oil, olive oil, sesame oil, peanut oil, avocado oil, or soybean oil. In several embodiments, the fatty acid glyceride comprises sunflower oil. In several embodiments, the fatty acid glyceride comprises canola oil. In several embodiments, the fatty acid glyceride comprises palm oil. In several embodiments, the fatty acid glyceride comprises coconut oil. In several embodiments, the fatty acid glyceride comprises safflower oil. In several embodiments, the fatty acid glyceride comprises olive oil. In several embodiments, the fatty acid glyceride comprises sesame oil. In several embodiments, the fatty acid glyceride comprises peanut oil. In several embodiments, the fatty acidglyceride comprises avocado oil. In several embodiments, the fatty acid glyceride comprises soybean oil.

[0051] In several embodiments, the polysaccharide comprises a cyclodextrin. In several embodiments, the cyclodextrin is selected from the group consisting of P-cyclodextrin, hydroxypropyl-P-cyclodextrin, methyl-P-cyclodextrin, dimethyl-P-cyclodextrin, heptakis(2,6-di- O-)ethyl-P-cyclodextrin, 6-O-a-maltosyl-P-cyclodextrin, randomly methylated P-cyclodextrin (RAMEB), sulfobutylether-P-cyclodextrin, sulfolipo-P-cyclodextrin, y-cyclodextrin, hydroxypropyl-y-cyclodextrin, octakis-(6-bromo-6- deoxy)-y-cyclodextrin, octakis-(6-amino-6- deoxy)-y-cyclodextrin, octakis-(6-chloro-6-deoxy)-y- cyclodextrin, octakis-(6-deoxy-6-iodo)-y- cyclodextrin, octakis-(6-deoxy-6-mercapto)-y-cyclodextrin, octakis-(2,3,6-tri-O-methyl)-y- cyclodextrin, octakis-(2,3-diacetyl-6-sulfato)-y-cyclodextrin, octakis-(3-O-butyryl-2,6-di-O- pentyl)-y-cyclodextrin, octakis-6-sulfato-y-cyclodextrin, and mixtures thereof. In several embodiments, the polysaccharide comprises an unsubstituted P-cyclodextrin. In several embodiments, the polysaccharide comprises hydroxypropyl-P-cyclodextrin.

[0092]

[0052] In several embodiments, the nicotine complexes and products provided for herein further comprise a sugar alcohol from the group consisting of sorbitol, xylitol, erythritol, lactitol, maltitol, mannitol, isomalt, hydrogenated starch hydrolyzates, and combinations thereof.

[0053] In several embodiments, the nicotine complexes and products provided for herein further comprise a flavoring agent or a plurality of flavoring agents.

[0054] In several embodiments, the nicotine complexes and products provided for herein further comprise an antioxidant selected from the group consisting of tocopherols (vitamin E), butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, tertiary butylhydroquinone (TBHQ), rosemary extracts, green tea extract, and combinations thereof. In several embodiments, the nicotine complexes and products provided for herein further comprise tocopherols (vitamin E). In several embodiments, the nicotine complexes provided for herein further comprise butylated hydroxy anisole (BHA). In several embodiments, the nicotine complexes and products provided for herein further comprise butylated hydroxytoluene (BHT). In several embodiments, the nicotine complexes and products provided for herein further comprise propyl gallate. In several embodiments, the nicotine complexes provided for herein further comprise tertiary butylhydroquinone (TBHQ). In several embodiments, the nicotine complexesand products provided for herein further comprise rosemary (or other herbal) extracts. In several embodiments, the nicotine complexes provided for herein further comprise green tea extract.

[0055] In several embodiments, the nicotine complexes and products provided for herein comprise a pH adjuster selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate, and any combination thereof. In several embodiments, the nicotine complexes and products provided for herein comprise sodium bicarbonate. In several embodiments, the nicotine complexes and products provided for herein comprise sodium carbonate. In several embodiments, the nicotine complexes and products provided for herein comprise potassium bicarbonate. In several embodiments, the nicotine complexes and products provided for herein comprise potassium carbonate. In several embodiments, the nicotine complexes and products provided for herein comprise magnesium carbonate.

[0056] In several embodiments, the nicotine complexes and products provided for herein further comprise a substrate. In several embodiments, the substrate contributes to a physical form or a function of the nicotine product. In several embodiments, the substrate comprises a nonwoven fabric, a latex or rubber swatch, a fabric swatch, a wood splint, polymer fibers, cellulose viscose, paper, cotton, or a combination thereof. In several embodiments, substrate comprises spunbonded cotton, melt blown cotton, needle punched cotton, thermally bonded cotton, chemically bonded cotton, hydroentangled cotton, spun-laced cotton, or air-laid cotton. In several embodiments, the substrate comprises a nonwoven fabric, wherein the nonwoven fabric is saliva-permeable.

[0057] In several embodiments, the nicotine complexes and products provided for herein further comprise a carrier. In several embodiments, the carrier is selected from the group consisting of water insoluble fibers, microcrystalline cellulose, bamboo fibers, lignin, wheat fibers, pea fibers, maize fibers, rice fiber, oat fibers, barley fibers, buckwheat fibers, cellulose fibers, bran fibers, powdered cellulose, and combinations thereof. In several embodiments, the carrier comprises water insoluble fibers. In several embodiments, the carrier comprises microcrystalline cellulose. In several embodiments, the carrier comprises bamboo fibers. In several embodiments, the carrier comprises lignin. In several embodiments, the carrier wheat fibers. In several embodiments, the carrier comprises pea fibers. In several embodiments, the carrier comprises maize fibers. In several embodiments, the carrier comprises rice fibers. In several embodiments, the carrier comprises oat fibers. In several embodiments, the carrier comprises barley fibers. Inseveral embodiments, the carrier comprises buckwheat fibers. In several embodiments, the carrier comprises cellulose fibers. In several embodiments, the carrier bran fibers. In several embodiments, the carrier comprises powdered cellulose.

[0058] In several embodiments, the nicotine complexes and products provided for herein are devoid of a crystal lattice structure. In several embodiments, the nicotine complexes and products provided for herein are substantially free of nicotine salt formed by an ionic bond. In several embodiments, the nicotine complexes and products provided for herein comprise (S)-nicotine having an alkaline pH. In several embodiments, the (S)-nicotine has pH greater than pH 7. In several embodiments, the pH value of (S)-nicotine complex is between 7 and 10.

[0059] In several embodiments, there is also provided an oral nicotine pouch, comprising a saliva-permeable nonwoven fabric, wherein the saliva-permeable nonwoven fabric defines an enclosure and a fill material within the enclosure and comprising an (S)-nicotine complex to the present disclosure and a carrier. In several embodiments, the fill material is sealed within the enclosure. In several embodiments, the carrier comprises microcrystalline cellulose. In several embodiments, the (S)-nicotine complex comprises a non-salt nicotine complex emulsion. In several embodiments, the non-salt nicotine complex emulsion comprises micelles, colloidal particles, or self-assembled structures. In several embodiments, the non-salt nicotine complex emulsion comprises micelles. In several embodiments, the non-salt nicotine complex emulsion comprises colloidal particles. In several embodiments, the non-salt nicotine complex emulsion comprises self-assembled structures. In several embodiments, the non-salt nicotine complex emulsion comprises micelles, colloidal particles, or self-assembled structures have a particle size between 10 nm to 10 pm. In several embodiments the non-salt nicotine complex emulsion comprises an unsaturated fatty acid complexed with the (S)-nicotine. In several embodiments, the unsaturated fatty acid comprises a C8-C24 fatty acid. In several embodiments, the C8-C24 fatty acid comprises conjugated linoleic acid. In several embodiments, the amount of nicotine is from about 0.1 to about 4% by weight of the pouch, including about 0.1% to about 0.5%, about 0.5% to about 1.0%, about 1.0% to about 1.5%, about 1.5% to about 2.0%, about 2.0% to about 2.5%, about 2.5% to about 3.0%, about 3.0% to about 3.5%, about 3.5% to about 4.0%, and any percentage in between those listed, including endpoints. In several embodiments, the amount of C8-C24 fatty acid is from about 0.1 to about 10% by weight of the pouch, including about 0.1% to about 0.5%, about 0.%% to about 1.0%, about 1.0% to about 2.0%, about 2.0% to about 3.0%, about 3.0% toabout 4.0%, about 4.0% to about 5.0%, about 5.0% to about 6.0%, about 6.0% to about 7.0%, about 7.0% to about 8.0%, about 8.0% to about 9.0%, about 9.0% to about 10.0%, and any percentage in between those listed, including endpoints. In several embodiments, the amount of moisture is at least about 15% by weight of the pouch, including about 20%, about 25% about 30%, about 40%, about 50%, about 60%, about 70% and greater. In several embodiments, the amount of pH adjuster is from about 0.01% to about 10% by weight of the pouch, including about 0.01% to about 0.05%, about 0.05% to about 0.1%, about 0.1% to about 0.5%, about 0.5% to about 1.0%, about 1.0% to about 2.0%, about 2.0% to about 3.0%, about 3.0% to about 4.0%, about 4.0% to about 5.0%, about 5.0% to about 6.0%, about 6.0% to about 7.0%, about 7.0% to about 8.0%, about 8.0% to about 9.0%, about 9.0% to about 10.0%, and any percentage in between those listed, including endpoints.. In several embodiments, the amount of surfactant is from about 0.1 to about 10% by weight of the pouch, , including about 0.1% to about 0.5%, about 0.%% to about 1.0%, about 1.0% to about 2.0%, about 2.0% to about 3.0%, about 3.0% to about 4.0%, about 4.0% to about 5.0%, about 5.0% to about 6.0%, about 6.0% to about 7.0%, about 7.0% to about 8.0%, about 8.0% to about 9.0%, about 9.0% to about 10.0%, and any percentage in between those listed, including endpoints. In several embodiments, the amount of solubilizer is from about 0.1 to about 40% by weight of the pouch, including about 0.1% to about 0.5%, about 0.%% to about 1.0%, about 1.0% to about 2.0%, about 2.0% to about 3.0%, about 3.0% to about 4.0%, about 4.0% to about 5.0%, about 5.0% to about 6.0%, about 6.0% to about 7.0%, about 7.0% to about 8.0%, about 8.0% to about 9.0%, about 9.0% to about 10.0%, about 10.0% to about 15.0%, about 15.0% to about 20.0%, about 20.0% to about 25.0%, about 25.0% to about 30.0%, about 30.0% to about 35.0%, about 35.0% to about 40.0% and any percentage in between those listed, including endpoints.. In several embodiments, the amount of polysaccharide is from 0.1 to 5% by weight of the pouch, , including about 0.1% to about 0.5%, about 0.5% to about 1.0%, about 1.0% to about 2.0%, about 2.0% to about 3.0%, about 3.0% to about 4.0%, about 4.0% to about 5.0%, and any percentage in between those listed, including endpoints..

[0060] In several embodiments, there is provided a nicotine product comprising (i) a nicotine complex, (ii) at least one unsaturated fatty acid, (iii) at least one oil, (iv) at least one surfactant, and (v) at least one of a pouch, a carrier, an antioxidant, a flavorant, or a sugar alcohol. In several embodiments, there is a provided a nicotine product comprising (i) a nicotine complex, (ii) at least one unsaturated fatty acid, (iii) at least one surfactant, and (iv) at least one of a pouch, a carrier, anantioxidant, a flavorant, or a sugar alcohol. In several embodiments, there is provided a nicotine product comprising (i) a nicotine complex, (ii) at least one polysaccharide, (iii) at least one oil, (iv) at least one surfactant, and (v) at least one of a pouch, a carrier, an antioxidant, a flavorant, or a sugar alcohol.

[0061] In several embodiments of the nicotine products provided for herein, the nicotine within the nicotine complex comprises at least 40% nicotine in the form of a free base alkaloid and having less than 40% in a monoprotonated form.

[0062] In several embodiments of the nicotine products provided for herein, the at least one unsaturated fatty acid comprises conjugated linoleic acid. In several embodiments of the nicotine products provided for herein, the at least one oil comprises on or both of MCT oil and sunflower oil. In several embodiments of the nicotine products provided for herein, the at least one polysaccharide comprises a cyclodextrin. In several embodiments, the cyclodextrin comprises hydroxypropyl-P-cyclodextrin. In several embodiments of the nicotine products provided for herein, the product comprises at least two of a pouch, a carrier, an antioxidant, a flavorant, or a sugar alcohol. In several embodiments of the nicotine products provided for herein, the product comprises at least three of a pouch, a carrier, an antioxidant, a flavorant, or a sugar alcohol. In several embodiments, the at least one surfactant comprises polysorbate 80.

[0063] In several embodiments, there is provided a method of tailoring a subject’s nicotine experience comprising administering to the subject a nicotine complex, an oral nicotine pouch, or a nicotine product according to the present disclosure.

[0064] In several embodiments there is provided the use of a nicotine complex, an oral nicotine pouch, or a nicotine product according to the present disclosure for modulation of nicotine release rate and / or quantity to a subject. In several embodiments, the nicotine release rate and / or quantity is increased as compared to free base nicotine, or an oral nicotine pouch or nicotine product not comprising a nicotine complex. In several embodiments the nicotine release rate and / or quantity is reduced as compared to free base nicotine, or an oral nicotine pouch or nicotine product not comprising a nicotine complex.

[0065] In several embodiments, there is provided a hydrogel comprising an active, a polymer, a plasticizer, and a disintegrant. In several embodiments, the active is selected from the group consisting of (S)-nicotine, an (S)-nicotine salt, an (S)-nicotine complex, caffeine, menthol,melatonin, cannabidiol (CBD), tetrahydrocannabinol (THC), quercetin, y-aminobutyric acid (GABA), theanine, L-try ptophan, 5 -hydroxy -L-tryptophan (5-HTP), and mixtures thereof.

[0066] In several embodiments, the polymer is selected from the group consisting of sodium alginate, pectin, pullulan, glucan, dextrin, maltodextrin, xanthan gum, xyloglucan, tragacanth gum, guar gum, acacia gum, Arabic gum, starch, agarose, gelatin, gellan, chitosan, carrageenan, chondroitin sulfate, collagen, silk fibroin, sericin, scleroglucan, cellulose, hyaluronic acid, hydroxypropyl methyl cellulose (HPMC), hydroxy ethyl cellulose (HEC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), ethyl cellulose (EC), hydroxypropyl ethyl cellulose (HPEC), and combinations thereof.

[0067] In several embodiments, the polymer comprises gelatin, pullulan, acacia gum, sodium alginate, carboxymethylcellulose (CMC), hydroxypropyl methylcellulose (HPMC), or mixtures thereof. In several embodiments, the polymer comprises gelatin. In several embodiments, the polymer comprises pullulan. In several embodiments, the polymer comprises acacia gum. In several embodiments, the polymer comprises sodium alginate. In several embodiments, the polymer comprises carboxymethylcellulose (CMC). In several embodiments, the polymer comprises hydroxypropyl methylcellulose (HPMC).

[0068] In several embodiments the hydrogel comprises a (S)-nicotine salt, which comprises a protonated (S)-nicotine cation in association with a negatively charged counterion comprising a conjugate base of an organic acid. Depending on the embodiment, the organic acid is selected from the group consisting of formic acid, acetic acid, adipic acid, trifluoroacetic acid, aspartic acid, butanoic acid, butyric acid, 2-methylbutyric acid, 3-methylbutyric acid, benzoic acid, caprylic acid, citric acid, crotonic acid, butanoic acid, ethylenediaminetetraacetic acid (EDTA), C8-C26 saturated, monounsaturated, or polyunsaturated fatty acids, fumaric acid, gluconic acid, glutamic acid, glyceric acid, glycidic acid, glycolic acid, glyoxylic acid, hexanoic acid, heptanoic acid, lactic acid, lauric acid, levulinic acid, maleic acid, L-(-)-malic acid, malonic acid, mandelic acid, mesooxalic acid, methane sulfonic acid, oxalic acid, pentanoic acid, phenylacetic acid, phthalic acid, picric acid, propionic acid, 3-oxopropanoic acid, 2,3-dioxopropanoic acid, 2,3,- dihydroxypropanedioic acid, propiolic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tannic acid, L-(+)-tartaric acid, tartronic acid, valeric acid, vanillic acid, and mixtures thereof. In one embodiment, the (S)-nicotine salt comprises (S)-nicotine lactate.

[0069] In several embodiments, the hydrogel comprises an (S)-nicotine inclusion complex which comprises (S)-nicotine in association with a cyclodextrin. In several embodiments, the cyclodextrin is selected from the group consisting of P-cyclodextrin, hydroxypropyl-P- cyclodextrin, methyl-P-cyclodextrin, dimethyl -P-cyclodextrin, heptakis(2,6-di-O-)ethyl-P- cyclodextrin, 6-O-a-maltosyl-P-cyclodextrin, randomly methylated P-cyclodextrin (RAMEB), sulfobutylether-P-cyclodextrin, sulfolipo-P-cyclodextrin, y-cyclodextrin, hydroxypropyl-y- cyclodextrin, octakis-(6-bromo-6-deoxy)-y-cyclodextrin, octakis-(6-amino-6-deoxy)-y- cyclodextrin, octakis-(6-chloro-6-deoxy)-y-cyclodextrin, octakis-(6-deoxy-6-iodo)-y- cyclodextrin, octakis-(6-deoxy-6-mercapto)-y-cyclodextrin, octakis-(2,3,6-tri-O-methyl)-y- cyclodextrin, octakis-(2,3-diacetyl-6-sulfato)-y-cyclodextrin, octakis-(3-O-butyryl-2,6-di-O- pentyl)-y-cyclodextrin, octakis-6-sulfato-y-cyclodextrin, and mixtures thereof.

[0070] In several embodiments, the plasticizer is selected from the group consisting of tris-2- ethylhexyltrimellitate, dioctyl terephthalate, di-isobutyl terephthalate, N-butylbenzene sulfonamide, di -isodecyl sebacate, di-2-ethylhexylsebacate, dibutyl sebacate, dimethylsebacate, tri s(2 -ethyl hexyl) phosphate, 2-ethylhexyl diphenyl phosphate, triphenyl phosphate, 2,2,4- trimethyl-1,3 pentanediol di-isobutyrate, di-Ci6-i8 alkyl phthalate, benzyl C?-9-branched and linear alkyl phthalate, di -isotri decyl phthalate, di-isoundecyl phthalate, di(2-propyl heptyl) phthalate, diisodecyl phthalate, di-isononyl phthalate, bis(2-ethylhexyl) phthalate, di-isooctyl phthalate, di-n- octyl phthalate, di-isoheptyl phthalate, di-cyclohexyl phthalate, di-isohexyl phthalate, di-n-hexyl phthalate, di-n-pentyl phthalate, benzyl butyl phthalate, di-isobutyl phthalate, di-n-butyl phthalate, di-n-propyl phthalate, diethyl phthalate, dimethyl phthalate, epoxidized triglyceride vegetable oils from soybean oil, linseed oil, castor oil, or sunflower oil, di-isononyl cyclohexane dicarboxylate, citric acid, acetyl tributyl citrate, tributyl citrate, triethyl citrate, triethylene glycol dibenzoate, isodecyl benzoate, isononyl benzoate, dipropylene glycol dibenzoate, diethylene glycol dibenzoate, neopentylglycol dibenzoate, diisodecyl azelate, bis[2-(2-butoxyethoxy)ethyl] adipate, di(butoxyethyl) adipate, di-n-butyl adipate, ditridecyl adipate, diisodecyl adipate, diisononyl adipate, di-2-ethylhexyl adipate, benzyl 2-ethylhexyl adipate, diisobutyl adipate, glyceryl triacetate, diethyl succinate, dibutyl succinate, dihexyl succinate, diethylhexyl succinate, didecyl succinate, didodecyl succinate, poly(hexylene succinate), poly(butylene succinate), polypropylene glycol succinate), poly(ethylene glycol succinate), 1,2-propylene glycol, diethylene glycol, various fatty acid esters (FAEs), glycerin, ethylene glycol, diethylene glycol,triethylene glycol, tetraethylene glycol, polyethylene glycol (PEGs), sorbitol, mannitol, xylitol, glucose, mannose, fructose, sucrose, urea, and mixtures thereof.

[0071] In several embodiments, the plasticizer comprises at least one of a triglyceride vegetable oil from soybean oil, linseed oil, castor oil, or sunflower oil, citric acid, glycerin, 1,2- propylene glycol, diethylene glycol, sorbitol, and poly(ethylene glycol succinate). Optionally, in some embodiments, the triglyceride vegetable oil is epoxidized. In several embodiments, the plasticizer is at least one of glycerin and citric acid. In several embodiments, the plasticizer is glycerin. In several embodiments, the plasticizer is citric acid.

[0072] In several embodiments, the disintegrant is selected from the group consisting of starch, sodium starch glycolate Type A, sodium starch glycolate Type B, powdered microcrystalline cellulose (MCC), guar gum, xanthan gum, locust bean gum, chitosan hydrochloride, alginic acid, calcium alginate, sodium alginate, docusate sodium, dicalcium phosphate, tricalcium phosphate, magnesium aluminum silicate, bentonite, guargalactomannan, crosslinked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, methylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, calcium cellulose glycolate, crospovidone, and mixtures thereof. In one embodiment, the disintegrant comprises powdered microcrystalline cellulose (MCC).

[0073] In several embodiments, the hydrogel further comprises a flavoring agent.

[0074] There is also provided herein a hydrogel-based oral strip comprising an active, a polymer, a plasticizer, and a disintegrant.

[0075] In several embodiments, the active in the oral strip is selected from the group consisting of (S)-nicotine, an (S)-nicotine salt, an (S)-nicotine complex, caffeine, menthol, melatonin, cannabidiol (CBD), tetrahydrocannabinol (THC), quercetin, y-aminobutyric acid (GABA), theanine, L-tryptophan, 5 -hydroxy -L-tryptophan (5-HTP), and mixtures thereof. In several embodiments, the active is an (S)-nicotine salt comprising (S)-nicotine lactate.

[0076] In several embodiments, the oral strip further comprises a flavoring agent. In some embodiments, the strip is configured as a thin rectangular shape measuring from about 3 cm2(0.5 in2) to about 13 cm2(2.0 in2) in surface area, and from about 20pm (0.8 mil) to about 3,000pm (118 mil) in thickness.

[0077] In several embodiments, each oral strip includes from about Img to about lOmg of (S)- ni cotine lactate as the active.

[0078] In several embodiments, the polymer is selected from the group consisting of gelatin, pullulan, acacia gum, sodium alginate, carboxymethylcellulose (CMC), hydroxypropyl methylcellulose (HPMC), and mixtures thereof.

[0079] Additionally provided for herein is an oral nicotine pouch (ONP) comprising a saliva- permeable nonwoven fabric defining an enclosure containing a hydrogel therein, said hydrogel comprising (S)-nicotine, or a salt or a complex thereof, a polymer, a plasticizer, and a disintegrant.

[0080] In several embodiments, the hydrogel of the ONP further comprises a carrier. In several embodiments, the carrier is selected from the group consisting of agar, agarose, albumin, alginate, casein, chitin, chondroitin, dextrin, fibroin, fucoidans, galactans, gellan, guar, scleroglucan, pullulan, xyloglucan, pectin, xanthan, psyllium, silica gel, fumed silica, magnesium aluminum silicates, clay, bentonite, hectorite, mesoporous silica, cellulose, cellulose acetate, hyaluronan, various elastin-like polypeptides, P-cyclodextrin, collagen, gelatin, chitosan, carrageenan, polylactic acid, polyglycolic acid, poly(lactic-glycolic acid) (PLGA), poly(2- hydroxyethyl methacrylate), poly(2-hydroxypropyl methacrylate), poly(acrylic acid), carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, hydrophobically- modified hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose (MCC), nitrocellulose, polyvinyl alcohol, polyvinylpyrrolidone, poly(vinyl methacrylate), carboxy vinyl polymers, poly(vinyl acetate), polyvinyl co-polymers, starch, modified starch, and mixtures thereof. In several embodiments, the carrier is microcrystalline cellulose (MCC).

[0081] In several embodiments, there is provided a method of manufacturing an oral nicotine pouch (ONP), the method comprising providing a saliva-permeable nonwoven fabric defining an enclosure, preparing an aqueous mixture of (S)-nicotine, a salt or a complex thereof, at least a polysaccharide or other naturally occurring hydrogel-forming polymer, at least a plasticizer, and at least a disintegrant in water, absorbing the aqueous mixture onto a carrier to form a free-flowing mixture, and disposing a portion of the free-flowing mixture in the enclosure.

[0082] In several embodiments, the (S)-nicotine, a salt or a complex thereof is (S)-nicotine lactate. In several embodiments, the carrier is microcrystalline cellulose (MCC). In several embodiments, the portion of free-flowing mixture disposed in said enclosure weighs from about 10 mg to about 500 mg, including about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg,about 400 mg, about 450 mg, about 500 mg, and any amount between those listed. In several embodiments, the portion of free-flowing mixture disposed in said enclosure weighs from about 10 mg to about 2000 mg, include about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, and any amount between those listed.

[0083] Also provided for herein is a method of increasing a rate of (S)-nicotine delivery from an oral nicotine pouch comprising a fill material consisting of (S)-nicotine, or a salt or a complex thereof, admixed with or adsorbed onto a carrier, the fill material disposed inside a saliva- permeable nonwoven fabric pouch, said method comprising: (1) preparing an aqueous solution or suspension comprising the (S)-nicotine, salt, or complex thereof, a polysaccharide or other naturally occurring hydrogel-forming polymer, a plasticizer, and a disintegrant and adsorbing the aqueous solution or suspension onto the carrier to form the fill material, and disposing the fill material inside the saliva-permeable nonwoven fabric pouch; or (2) dispersing the carrier in an aqueous solution or suspension comprising the (S)-nicotine, salt, or complex thereof, a polysaccharide or other naturally occurring hydrogel -forming polymer, a plasticizer, and a disintegrant, solidifying the dispersion into a hydrogel, and disposing the hydrogel as the fill material inside the saliva-permeable nonwoven fabric pouch; or (3) preparing an aqueous solution or suspension comprising the (S)-nicotine, salt, or complex thereof, a polysaccharide or other naturally occurring hydrogel-forming polymer, a plasticizer, and a disintegrant; solidifying the dispersion into a hydrogel, admixing the hydrogel with the carrier to form the fill material, and disposing the fill material inside the saliva-permeable nonwoven fabric pouch.

[0084] In several embodiments, the carrier is selected from the group consisting of agar, agarose, albumin, alginate, casein, chitin, chondroitin, dextrin, fibroin, fucoidans, galactans, gellan, guar, scleroglucan, pullulan, xyloglucan, pectin, xanthan, psyllium, silica gel, fumed silica, magnesium aluminum silicates, clay, bentonite, hectorite, mesoporous silica, cellulose, cellulose acetate, hyaluronan, various elastin-like polypeptides, P-cyclodextrin, collagen, gelatin, chitosan, carrageenan, polylactic acid, polyglycolic acid, poly(lactic-glycolic acid) (PLGA), poly(2- hydroxyethyl methacrylate), poly(2-hydroxypropyl methacrylate), poly(acrylic acid),carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, hydrophobically- modified hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose (MCC), nitrocellulose, polyvinyl alcohol, polyvinylpyrrolidone, poly(vinyl methacrylate), carboxy vinyl polymers, poly(vinyl acetate), polyvinyl co-polymers, starch, modified starch, and mixtures thereof. In several embodiments, the carrier is microcrystalline cellulose (MCC).

[0085] BRIEF DESCRIPTION OF THE FIGURES

[0086] The subject matter is pointed out with particularity and claimed distinctly in the concluding portion of the specification. A more complete understanding, however, may best be obtained by referring to the detailed description and claims when considered in connection with the following figures:

[0087] Figure 1 schematically illustrates various embodiments of hydrogels according to the present disclosure that are configured to swell and deliver nicotine while concomitantly disintegrating in the mouth of an individual.

[0088] Figure 2 illustrates various embodiments of hydrogel oral strip formation via a solventcasting process.

[0089] Figures 3A-3H sets forth photographs of hydrogel examples in accordance with the present disclosure, showing achievement of optical clarity when using the indicated polymers. Figure 3A shows use of acacia gum. Figure 3B shows use of sodium alginate. Figure 3C shows the use of carboxymethyl cellulose. Figure 3D shows the use of tapioca maltodextrin. Figure 3E shows use of hypromellose. Figure 3F shows use of pullulan. Figure 3G shows use of maltodextrin. Figure 3H shows use of gelatin.

[0090] Figures 4A-4B illustrates photographs of non-limiting embodiments of dosage forms and methods of use for hydrogel -based oral strips. Figure 4A shows oral application on the tongue and Figure 4B shows application across the teeth and gums.

[0091] Figure 5 illustrates an x / y plot of nicotine delivery over time from hydrogel -based oral strips comprising (S)-nicotine lactate in comparison to nicotine delivery over time from an oral nicotine pouch (ONP) comprising (S)-nicotine lactate and only microcrystalline cellulose (MCC).

[0092] Figures 6A-6B illustrate x / y plots of dissolution rate of (Figure 6A) caffeine-based hydrogels from five different polymers and (Figure 6B) melatonin-based hydrogels from three different polymers.

[0093] Figure 7 illustrates embodiments of oral nicotine pouches (ONPs), showing the options for traditional delivery of nicotine from a microcrystalline cellulose (MCC) carrier and modified delivery of nicotine when a novel hydrogel scaffold is used as the fill material for an ONP.

[0094] Figure 8 illustrates various embodiments of hydrogel -based oral nicotine pouch (ONP) preparation.

[0095] Figure 9 illustrates x / y plots of nicotine delivery over time from ONPs comprising (S)- nicotine lactate in a mixture of hydrogel and microcrystalline cellulose (MCC) carrier, in comparison to nicotine delivery over time from an ONP comprising (S)-nicotine lactate and only microcrystalline cellulose (MCC).

[0096] Figures 10A-10B illustrate (Figure 10A) an x / y plot of nicotine delivery over time from ONPs comprising (S)-nicotine lactate in a mixture of hydrogel and microcrystalline cellulose (MCC) carrier, in comparison to nicotine delivery overtime from an ONP comprising (S)-ni cotine lactate and only microcrystalline cellulose (MCC), with plot (Figure 10B) showing an expanded portion of the plot in (A).

[0097] Figure 11 sets forth TABLE 1 listing non-limiting embodiments of hydrogel-based nicotine oral strip formulations.

[0098] Figure 12 sets forth TABLE 2 listing non-limiting embodiments of hydrogel -based caffeine oral strip formulations.

[0099] Figure 13 sets forth TABLE 3 listing non-limiting embodiments of hydrogel -based melatonin oral strip formulations.

[0100] Figure 14 sets forth TABLE 4 listing non-limiting embodiments of hydrogel -based oral nicotine pouch (ONP) formulations.

[0101] Figure 15 schematically depicts the components of an Oral Nicotine Pouch (ONP) dosage form where the ONP employs a cellulose-hydrogel-emulsion matrix (referred to herein at times as a CHEM). According to several embodiments a combination of cellulose, such as microcrystalline cellulose, is formed with a hydrogel scaffold. Incorporated into the hydrogel scaffold is an emulsion comprising nicotine. As schematically illustrated, the cellulose-hydrogel-emulsion can be a water-oil -water emulsion, a water-oil emulsion, an oil-water-oil emulsion, an oil-water emulsion, a noisome, or a liposome, depending on the embodiment.

[0102] Figure 16 sets forth TABLE 5 listing non-limiting embodiments of hydrogel -emulsionbased oral nicotine pouch (ONP) formulations.

[0103] Figure 17 shows chemical structures of a variety of non-limiting components of hydrogels.

[0104] Figure 18 shows data related to modulation of release rate of a single ingredient from hydrogels as provided for herein.

[0105] Figures 19A-19B show data related to modulation of release rate of multiple ingredients (in this non-limiting example, nicotine and flavor (e.g., vanillin)) from hydrogels as provided for herein.

[0106] Figures 20A-20F show additional data related to modulation of release rate of multiple ingredients (in this non-limiting example, nicotine and flavor (e.g., vanillin)) from hydrogels as provided for herein.

[0107] Figures 21 A-21B show additional data related to modulation of release rate of multiple ingredients (in this non-limiting example, nicotine and flavor (e.g., cinnamaldehyde)) from hydrogels as provided for herein.

[0108] Figure 22 shows data related to the stability of oral nicotine pouches provided for herein, as represented by pouch mass over time.

[0109] Figure 23 shows data related to the stability of oral nicotine pouches provided for herein, as represented by measurement of pH over time.

[0110] Figure 24 shows data related to the stability of oral nicotine pouches provided for herein, as represented by nicotine mass over time.

[0111] Figure 25 shows data related to the stability of oral nicotine pouches provided for herein, as represented by flavorant mass over time.DETAILED DESCRIPTION

[0112] The detailed description of non-limiting embodiments makes reference to the accompanying drawings, which show non-limiting embodiments of embodiments by way of illustration and their best mode. While these non-limiting embodiments of embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, it shouldbe understood that other embodiments may be realized and that logical, chemical, and mechanical changes may be made without departing from the spirit and scope of the inventions. Thus, the detailed description is presented for purposes of illustration only and not of limitation. For example, unless otherwise noted, the steps recited in any of the method or process descriptions may be executed in any order and are not necessarily limited to the order presented. Furthermore, any reference to singular includes plural embodiments, and any reference to more than one component or step may include a singular embodiment or step. Also, any reference to attached, fixed, connected or the like may include permanent, removable, temporary, partial, full and / or any other possible attachment option. Additionally, any reference to without contact (or similar phrases) may also include reduced contact or minimal contact.

[0113] In various embodiments of the present disclosure, there is provided a hydrogel composition that comprises at least one active in a hydrogel, the hydrogel comprising a polymer, a plasticizer and a disintegrant. In certain embodiments, the active comprises at least one of (S)- nicotine, an (S)-nicotine salt, and an (S)-nicotine complex. In certain embodiments, the active comprises caffeine. In certain embodiments, the active comprises melatonin. In several embodiments, the active comprises menthol. In several embodiments, the active comprises melatonin. In several embodiments, the active comprises cannabidiol (CBD). In several embodiments, the active comprises tetrahydrocannabinol (THC). In several embodiments, the active comprises quercetin. In several embodiments, the active comprises y-aminobutyric acid (GABA). In several embodiments, the active comprises theanine. In several embodiments, the active comprises L-tryptophan. In several embodiments, the active comprises 5-hydroxy-L- tryptophan (5-HTP). In several embodiments, the active comprises serotonin or another neurotransmitter. In several embodiments, the active comprises psilocybin. In several embodiments, the active comprises psilocin. In several embodiments, the active comprises norpsilocin. In several embodiments, the active comprises baeocystin. In several embodiments, the active comprises norbaeocystin. In several embodiments, the active comprises aeruginascin. In several embodiments, the active comprises one or more of vitamin C, vitamin K, vitamin E, and vitamin A. In several embodiments, the active comprises one or more of potassium, calcium and iron. In several embodiments, the active comprises beta-carotene. In several embodiments, the active comprises one or more flavonoid.

[0114] In certain examples, the polymer comprises a biological macromolecule, preferably a polysaccharide or a naturally occurring polymer such as gelatin.

[0115] In various embodiments, a hydrogel composition comprises at least one of (S)-ni cotine, an (S)-nicotine salt, and an (S)-nicotine complex. Hydrogel compositions are optimized for rapid disintegration and controlled (S)-nicotine delivery in the oral cavity of an individual desirous of (S)-nicotine self-administration from a smokeless product. In various embodiments, a hydrogel composition comprises at least one active as provided for herein. Hydrogel compositions are optimized for tailored disintegration and controlled delivery of the active in the oral cavity of an individual desirous of self-administration of the active.

[0116] In various embodiments, hydrogels herein release free (S)-nicotine and optional flavoring agents in the oral cavity of an individual, with concomitant erosion, disintegration and dissolution of the hydrogel. (S)-Nicotine available from the present hydrogels is then absorbed via mucosal tissues to the bloodstream of the individual.

[0117] In various embodiments, hydrogels herein are entirely spit-free while present in the oral cavity of an individual, with the hydrogel, (S)-nicotine and flavoring agents seamlessly dissolving during use.

[0118] In various embodiments, hydrogels herein may be incorporated inside a nonwoven and saliva-insoluble pouch for a different type of oral administration, such as a pouch for placement under the tongue or in the buccal space between cheek and gums.Definitions and Interpretations:

[0119] As used herein, the term “active” takes on its ordinary meaning in pharmaceutical chemistry, meaning a drug capable of eliciting a physiological response in an individual having consumed the active in an indicated dosage form and dosage regimen. In various embodiments, an active herein comprises the alkaloid (S)-nicotine, and / or a form of (S)-nicotine capable of providing (S)-nicotine free base. Such other forms include, for example, (S)-nicotine salts and (S)-nicotine complexes (including emulsions comprising nicotine). In other embodiments, an active herein includes, but is not limited to, caffeine, menthol, melatonin, cannabidiol (CBD), tetrahydrocannabinol (THC), quercetin, y-aminobutyric acid (GABA), theanine, L-tryptophan, and 5-hydroxy-L -tryptophan (5-HTP).

[0120] As used herein, the acronym “NCT” refers to (S)-nicotine, such as the free base alkaloid and the (S)-nicotine that might have dissociated from a nicotine salt or from a nicotine complex. In some examples, the term “NCT” is used to simplify having to write out the full compound name (S)-ni cotine on an axis of a graph.

[0121] As used herein, the term “nicotine salt” refers to a compound comprising protonated (S)-nicotine in association with a negatively charged counterion (an anion), where the counterion is usually the conjugate base of the acid used to protonate (S)-nicotine free base alkaloid. Typically, a nicotine salt is formed by proton transfer between (S)-nicotine and an inorganic or organic acid, or a mixture of acids, in any combination, to protonate (S)-nicotine free base and form the corresponding salt. (S)-Nicotine salts are known and depending on the acid used to form the salt or mixed salt, stoichiometries besides a 1 : 1 acid to alkaloid ratio are formed. For example, (S)-nicotine salts made from a variety of organic acids have been described by T. A. Perfetti, “Structural Study of Nicotine Salts,” Beitrage zur Tabakforschung International 12(2), 43-54, 1983, where 1 : 1, 2: 1 and 3 : 1 acid to free base nicotine ratios were observed. Perfetti discloses that nicotine forms 3: 1 acid to base salts with aliphatic monocarboxylic acids, such as acetic acid, wherein one acid molecule is bound as in 1 : 1 salts and the other two acid molecules are bound to the nitrogen of the pyridine ring. Perfetti also observed that nicotine benzoate salts are 1 : 1 acid to base salts and that the citrate salt of nicotine is a 2: 1 acid to base salt. (S)-nicotine lactate and (S)- nicotine benzoate, for example, find use in vaping and other smokeless products. Examples of organic acids that may be used to form salts of (S)-ni cotine include, but are not limited to, formic acid, acetic acid, adipic acid, trifluoroacetic acid, aspartic acid, butanoic acid, butyric acid, 2- methylbutyric acid, 3 -methylbutyric acid, benzoic acid, caprylic acid, citric acid, crotonic acid, ethylenediaminetetraacetic acid (EDTA), fumaric acid, gluconic acid, glutamic acid, glyceric acid, glycolic acid, lactic acid, lauric acid, levulinic acid, maleic acid, L-(-)-malic acid, malonic acid, mandelic acid, methane sulfonic acid, oxalic acid, phenylacetic acid, phthalic acid, picric acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tannic acid, L-(+)-tartaric acid, tartronic acid, valeric acid, vanillic acid, and combinations thereof. Such (S)-nicotine salts can be prepared by reaction of the alkaloid free base with a suitable acid or mixture of acids in a manner known by those skilled in the art.

[0122] As used herein, the term “nicotine complex” refers to a compound comprising an unprotonated (S)-nicotine molecule in association with at least one other compound, wherein thecomplex is not crystalline, i.e., does not comprise a crystal lattice. The one other compound in association with (S)-nicotine may be, for example, a surfactant, a polymer, a polysaccharide such as a cyclodextrin, or an inorganic compound. Complexes may be characterized as a hydrogen bonded complex, a complex stabilized by nonionic interactions, a solubilized or micellular complex, or an inclusion complex. In some embodiments, complexes may be ionic, with charge transfer between (S)-nicotine and the at least one other compound, but not protonation. In some instances, the nature of a particular (S)-nicotine complex may be intractable, overly complicated, and not characterizable structurally. In various embodiments, (S)-nicotine-surfactant complexes are of interest, such as complexes formed from (S)-nicotine and preferably a nonionic or anionic surfactants. These types of complexes may comprise micellular structures. Also of interest herein are (S)-nicotine / cyclodextrin complexes. These types of complexes are known to be inclusion complexes wherein at least one (S)-nicotine molecule is enclosed within the cavity of the cyclodextrin molecule. Additional information regarding nicotine complexes can be found in International Patent Application No.: PCT / US24 / 48667, fded September 26, 2024, the entire contents of which are incorporated by reference herein.

[0123] As used herein, the term “cyclodextrin” refers to the entire class of cyclic polysaccharides obtained from starch. The bare term cyclodextrin used without further designation refers to any and all a-, P-, and y- forms of cyclodextrin, characterized as having six glucose subunits, seven glucose subunits, and eight glucose subunits, respectively, wherein the subunits are linked by 1,4-glycosidic bonds. At least 150 cyclodextrin compounds are known. Cyclodextrins are known to have toroidal shape, with an exterior sufficiently hydrophilic to impart water solubility and an interior cavity being less hydrophilic than the exterior but not entirely hydrophobic. Of particular interest herein is P-cyclodextrin, hydroxypropyl-P-cyclodextrin and methyl-P-cyclodextrin and the nicotine inclusion complexes formed by exposing (S)-nicotine to any of these or other cyclodextrin. The inner cavity of a cyclodextrin into which small molecules may be enclosed has been well studied. See, for example, A. A. Sandilya, et al., “Molecular View into the Cyclodextrin Cavity: Structure and Hydration,” ACS Omega, 5, 25655-25667, (2020). This study finds the inner cavity of a cyclodextrin molecule to have a conical hourglass shape, measuring about 4-8 angstroms (A).

[0124] As used herein, the term “surfactant” takes on its ordinary meaning in physical chemistry and surface science. Of interest herein are any and all zwitterionic, amphoteric,nonionic, and cationic polymers to form micellular complexes with (S)-nicotine. Included in the present definition of surfactant for the sake of convenience are nonionic polymers that may or may not be capable of acting as surface active agents but nonetheless are capable of at least emulsifying (S)-nicotine or micellizing (S)-nicotine. Of particular interest are lecithin, phosphatidylcholine, EO / PO / EO triblock copolymers (e.g., the pol oxamers, available under the trade name Pluronic®), and any polyethylene glycol (PEG, of any molecular weight). Exemplary anionic substances include, but are not limited to, fatty acids, alkyl sulfates, alkyl ether sulfates, alkyl aryl sulfonates, alkyl succinates, alkyl sulfosuccinates, N-alkoyl sarcosinates, alkyl phosphates, alkyl ether phosphates, alkyl ether carboxylates, alkylamino acids, alkyl peptides, alkoyl taurates, acyl and alkyl glutamates, alkyl isethionates, a-olefin sulfonates, and combinations thereof. Exemplary amphoteric substances include, but are not limited to, alkyl betaines, alkyl amidopropyl betaines, alkyl sulphobetaines, alkyl glycinates, alkyl carboxyglycinates, alkyl amphopropionates, alkyl amidopropyl hydroxysultaines, acyl taurates, acyl glutamates, and mixtures thereof. Exemplary nonionic surfactants include, but are not limited to, aliphatic primary or secondary linear or branched chain fatty alcohols or phenols, fatty acid esters, mono-, di-, and tri-fatty acid glycerides, alkyl alkoxylates, alkyl phenol alkoxylates, block alkylene oxide condensates of alkyl phenols, alkylene oxide condensates of alkanols, ethylene oxide / propylene oxide (EO / PO) block copolymers, EO / PO / EO triblock copolymers, amine oxides, phosphine oxides, mono- or di- alkyl alkanolamides, alkyl polysaccharides, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitol esters, polyoxyethylene esters, polyoxyethylene alcohols, mono- and diethanolamides, polyglycosides, polyglucosides, diglucoside, alkyl polyglucoside, polysorbates, alkoxylated fatty alcohols, alkoxylated fatty acid glycerides, and mixtures thereof. Of particular interest herein are the polysorbates, the group of nonionic emulsifiers characterized chemically as polyoxyethylene sorbitan fatty acid esters. Of use herein are polysorbate-20 (polyoxyethylene-20-sorbitan monolaurate), polysorbate-40 (polyoxyethylene-20-sorbitan monopalmitate), polysorbate-60 (polyoxyethylene-20-sorbitan monostearate) and polysorbate-80 (polyoxyethylene-20-sorbitan monooleate), amongst others. Polysorbate-80 may be obtained under the brand name Tween® 80 from several suppliers including WEGO Chemical Group, Great Neck, NY and Croda International, Snaith, England. Surfactants and polymeric substances under this broad definition are capable of forming complexes with (S)-nicotine. These complexes maybe micellular in form, although no theories are proffered as to the structure of (S)-nicotine- surfactant complexes.[001251 As used herein, the term “hydrogel” takes on its ordinary meaning in chemistry. The term may refer to a crosslinked polymer “network” (or “matrix”) having an observed rigidity and ability for absorbing a large amount of water and dimensionally swelling. A hydrogel is essentially a macromolecular polymer gel comprising a network of crosslinked polymer chains. Hydrogels are sometimes said to have both solid and liquid properties. Solid because there is no observable flow, and liquid because small molecules can diffuse in and out. Swelling of hydrogels is a response to stimulus including pH, temperature and ionic strength of the solution a hydrogel is exposed to. Hydrogels may be synthesized from hydrophilic monomers by either chain or step growth methods, along with a functional crosslinker to structure the network. Hydrogels can be prepared from natural, synthetic or synthetic / natural hybrid polymers. Synthetic or natural polymers, homopolymer or copolymer, are used to make three dimensional networks by molecular entanglements or by chemical crosslinking. Hydrogels according to the present disclosure are preferably constructed of polysaccharides rather than synthetic polymers. A variety of polysaccharides like starch (e.g., corn starch), gelatin, hemicelluloses (e.g., from wood pulp), lignin, cellulose, agarose, heparin, chitosan, dextran, guar gum, gellan gum, scleroglucan, and alginate have been explored as hydrogels for medical use owing to their biocompatibility and biodegradability, as well as excellent gel-forming properties. See, for example, A. Hoffman, “Hydrogels for biomedical applications,” Adv. Drug Deliver Rev., 43(1), 3-12 (2002). Polysaccharide hydrogels can be formed by covalent crosslinking, chemical conjugation, esterification and polymerization. In addition, polysaccharides have been combined with proteins such as collagen, gelatin, laminin and fibrin to form interpenetrating networks and composite hydrogels.

[0126] As used herein, the term “crosslinking agent” takes on its ordinary meaning in organic and polymer chemistry. The term may refer to a chemical compound having bis-reactive functionality and thus capable of covalent bonding to two separate polymer chains or to two locations on the same polymer chain to form a bridge. In various examples, a crosslinking agent may be a monomer included in a monomer mixture, such that when the monomer mixture is polymerized, the monomer having the crosslinking functionality is incorporated in various locations along polymer chains to crosslink during the polymerization process. For purposesherein, a crosslinking agent may be used to bridge polymer chains in a hydrogel to help structure a network of polymer chains. For example, citric acid, also functioning as a plasticizer, and with or without a catalyst such as sodium hypophosphite (SHP), can esterify hydroxyl groups of polymer chains and crosslink them. In certain embodiments, a hydrogel comprising a polysaccharide may not need a crosslinking agent due to strong hydrogen bonding between polymer chains.

[0127] As used herein, the term “disintegranf ’ takes on its ordinary meaning in pharmaceutical compounding. The term may refer to an additive capable of promoting rapid decomposition of a solid pharmaceutical dosage form when the dosage form is placed in contact with a liquid environment for the purpose of accelerating drug release. A disintegrant is more commonly found in pharmaceutical tablets configured to rapidly disintegrate in the G.I. tract of an individual who has swallowed such a tablet. For purposes herein, a disintegrant is an additive to hydrogel compositions according to the present disclosure. Disintegrants are used in the present hydrogel compositions to also accelerate decomposition, with the decomposition taking place in the oral cavity of an individual rather than in the G.I. tract of the individual. Regardless of the physical form of the product requiring accelerated decomposition, disintegrants work by increasing water wicking and by physically swelling to break apart a physical structure such as a compressed tablet or a polymer network in a hydrogel. Classes of disintegrants for pharmaceutical compounding include, but are not limited to, traditional disintegrants such as starch and derivatives therefrom and super disintegrants such as crosslinked polyvinylpyrrolidone (crospovidone). Examples of disintegrants include, but are not limited to, starch, pregelatinized starch, sodium starch glycolate, alginates and alginic acid, microcrystalline silica (e.g., Avicel® PH-101 or Avicel® PH-102), polyplasdone, croscarmellose sodium, crospovidone, polacrilin potassium, methyl cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose and hydroxypropyl methylcellulose.

[0128] As used herein, the term “plasticizer” takes on its ordinary meaning in organic and polymer chemistry. The term may refer to a chemical compound added to a polymer to make the polymer structure softer, more flexible and flexible and less brittle, and in some instances to make a polymer more processable, such as to aid extrusion. Although the mechanism of action by which a plasticizer modifies these properties is still to date not well understood, it is believed a plasticizer somehow effects movement of polymer chains in a polymer. There are tens of thousands of knownplasticizers for use in the polymer industry, many of which fall into broad chemical groups includes ortho-phthalate esters (high and low molecular weight), sebacates, adipates, terephthalates, dibenzoates, glutarates, and azelates. Perhaps one of the most common plasticizers is bis(2- ethylhexyl)phthalate (BEHP). For food-grade applications, such as hydrogels herein that are configured for oral use and oral delivery of an active, more acceptable plasticizers include, but are not limited to, citric acid and other organic acids, glycerin, sorbitol, mannitol, diethyl phthalate, tri ethyl citrate, tributyl citrate, macrogol, propylene glycol, citric acid ester, and urea. Of particular use herein is citric acid and other organic acids, or glycerin, the former also acting as a crosslinking agent by cross-esterifying hydroxyl groups present on polymer chains.

[0129] As used herein, the term “composition” takes on its ordinary meaning in formulation chemistry as a combination of ingredients. Simply written, a pharmaceutical composition may comprise one or more drug actives and a carrier, with the carrier comprising a suitable blend of excipients such that the final composition has the desired properties. In various embodiments, a composition is designed to adopt a particular physical form, or at least be amenable to physical manipulation into a desired physical form, which may be the dosage form for a particular usage regimen. For example, a composition may be a precursor mixture to a gel, or a polymer network hydrogel. Typically, a liquid composition is made homogeneous by mixing orblending, although not all liquid compositions are clear and transparent and / or homogeneous as to droplet size distribution. In various embodiments, a composition herein comprises a liquid mixture amenable to polymerization into a hydrogel. The hydrogel may be formed into any suitable shape and size amenable to oral administration. For a review, see A. Awad, et al., Chapter 19, “Solid Oral Dosage Forms,” Remington, 23rdEd., “The Science and Practice of Pharmacy,” 2021, pages 333-358.

[0130] Ingredients for a composition herein are generally shown “as added,” meaning there is a possibility for one or more chemical reactions between ingredients once the ingredients are mixed together, such as into a common carrier. One skilled in the art of formulation chemistry can recognize whether ingredients might react in a mixture. These reactions can include neutralization (e.g, between acid and alkali ingredients), mixed micelle formation (mixed surfactants in liquid systems) or other encapsulation phenomena, hydrolysis, polymerization of monomers, crosslinking of polymer chains, and so forth. In various embodiments, ingredients in a composition are listed in “weight percent,” (z.c., “wt.%”), based on the total weight of thecomposition. For example, 100 milligrams of a composition comprising 40 mg A and 60 mg B may be recited as “40 wt.% A and 60 wt.% B, based on the total weight of the composition f which necessarily totals to “100 wt.%.” The actual weight amounts, (c.g, milligrams or grams) generally refers to amounts added for a particular batch size (e.g., a batch size of a liquid usable for polymerization into 100, 1,000, 10,000, etc. oral strips).

[0131] As used herein, the terms “subject,” or “individual,” or the phrases “a subject in need thereof,” or “an individual in need thereof,” refers to any human or non-human animal requiring or desirous of a pharmacological change. For example, an individual in need thereof may be a smoker, male or female, who is desirous of using a smokeless product that is capable of providing nicotine.

[0132] As used herein, the term “modulate” includes to “increase” or “decrease” one or more quantifiable parameters, optionally by a defined and / or statistically significant amount. By “increasing,” or “enhancing,” or “decreasing” or “reducing,” one is referring to a change in the delivery of (S)-ni cotine in the oral cavity of an individual relative to a control composition. So for example, a control hydrogel will exhibit a measurable rate of nicotine delivery. In comparison, a new hydrogel in accordance with the present disclosure may then have a modulated (S)-nicotine delivery rate (increased or decreased) relative to the control delivery rate. An “increased” or “enhanced” amount is typically a “statistically significant” amount and may include an increase in nicotine delivery that is 1.1, 1.2, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50 or more times (e.g., 500, 1000 times), including all integers and decimal points in between and above 1 (e.g., 1.5, 1.6, 1.7. 1.8), the rate of (S)-nicotine delivery by a control composition. Similarly, an “decreased” or “lessened” or “reduced” amount is typically a “statistically significant” amount and may include a decrease in nicotine delivery that is 1.1, 1.2, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50 or more times (e.g., 500, 1000 times), including all integers and decimal points in between and above 1 (e.g., 1.5, 1.6, 1.7. 1.8), less than the rate of (S)-nicotine delivery from a control composition.

[0133] As used herein, the term “approximately” in reference to amounts refers to plus or minus 5% of the value given, such as wt.%. The term “about,” a in reference to amounts refers to plus or minus 10% of the value given, such as wt.%.General embodiments

[0134] In various embodiments, a hydrogel comprises:

[0135] an active;

[0136] a polymer;

[0137] a plasticizer; and

[0138] a disintegrant.

[0139] In various embodiments, the active is selected from the group consisting of (S)- nicotine, an (S)-nicotine salt, an (S)-nicotine complex, caffeine, menthol, melatonin, cannabidiol (CBD), tetrahydrocannabinol (THC), quercetin, y-aminobutyric acid (GABA), theanine, L- tryptophan, 5-hydroxy-L-tryptophan (5-HTP), and mixtures thereof.

[0140] In various embodiments, the active is an (S)-nicotine active selected from (S)-nicotine free base, an (S)-nicotine salt, an (S)-nicotine complex, and mixtures thereof.

[0141] In various embodiments of a hydrogel according to the present disclosure, an (S)- nicotine active comprises (S)-nicotine free base, an (S)-nicotine salt, and / or an (S)-nicotine complex, singly or in any combination. Polymers may comprise natural and / or synthetic materials, although in preferred embodiments the polymer comprises a polysaccharide. Preferred plasticizers include natural-based plasticizers. Preferred disintegrants include those disintegrants used, for example, in pharmaceutical tablets. The general and preferred options for these components are presented below and above in the definitions. No theories are proffered in regard to the mode of binding, occlusion, sequestration, entanglement, or possible complexation of (S)-nicotine, or salts or complexes thereof, within the polymer network of hydrogels according to the present disclosure. For a review, see L. Lei, et al., “Current Understanding of Hydrogel for Drug Release and Tissue Engineering,” Gels, 8(5), 301 (2022). Hydrogels in accordance with the present disclosure may comprise chemically crosslinked matrices or physically crosslinked matrices.

[0142] In various embodiments, a hydrogel may further include a flavoring agent.(S) -Nicotine Actives

[0143] In various embodiments, a hydrogel comprises at least one of (S)-ni cotine free base, an (S)-nicotine salt, and an (S)-nicotine complex as the active. In some examples, any single one or combination of these three different forms of (S)-ni cotine may be included in a hydrogel. The remainder of the hydrogel can be considered to be a carrier for the (S)-nicotine active(s), with the carrier comprising at least a polymer, a plasticizer, and a disintegrant.

[0144] In various embodiments, a hydrogel comprises from about 0.01 wt.% to about 10 wt.% of (S)-nicotine free base, including about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, or about 9%, and any values therebetween, based on the total weight of the hydrogel. In preferred embodiments, a hydrogel comprises about 1 wt.% (S)-nicotine free base, based on the total weight of the hydrogel.

[0145] In various embodiments, a hydrogel comprises from about 0.01 wt.% to about 10 wt.% of an (S)-nicotine salt, including about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, or about 9%, and any values therebetween. In preferred embodiments, a hydrogel comprises about 1 wt.% of an (S)-nicotine salt, based on the total weight of the hydrogel. An (S)-nicotine salt comprises protonated (S)-nicotine cation in association with a negatively charged counterion comprising a conjugate base of an organic acid.

[0146] In various embodiments, (S)-nicotine salts herein have anionic counterions corresponding to the conjugate base of an organic acid selected from, for example, formic acid, acetic acid, adipic acid, trifluoroacetic acid, aspartic acid, butanoic acid, butyric acid, 2- methylbutyric acid, 3 -methylbutyric acid, benzoic acid, caprylic acid, citric acid, crotonic acid, butanoic acid, ethylenedi aminetetraacetic acid (EDTA), fumaric acid, gluconic acid, glutamic acid, glyceric acid, glycidic acid, glycolic acid, glyoxylic acid, hexanoic acid, heptanoic acid, lactic acid, lauric acid, levulinic acid, maleic acid, L-(-)-malic acid, malonic acid, mandelic acid, mesooxalic acid, methane sulfonic acid, oxalic acid, pentanoic acid, phenylacetic acid, phthalic acid, picric acid, propionic acid, 3-oxopropanoic acid, 2,3-dioxopropanoic acid, 2, 3, -dihydroxypropanedioic acid, propiolic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tannic acid, L-(+)- tartaric acid, tartronic acid, valeric acid, vanillic acid, and mixtures thereof. This listing is not meant to be limiting, as any C2-C26 organic acid could be used to form a salt with (S)-ni cotine free base. As evident from the unlimited listing above, a conjugate base of an organic acid used to make a nicotine salt may comprise at least one additional functional group besides the primarycarboxylate substituent, including, for example, hydroxyl, oxo, carboxylate, thiol, heterocyclyl, aryl, heteroaryl, and so forth. In some examples, the organic acid may comprise an amino acid. In other examples, the organic acid may comprise a dicarboxylic acid or a tricarboxylic acid.

[0147] In various embodiments, any one of more of the aforementioned (S)-nicotine salts may be incorporated into a hydrogel according to the present disclosure.

[0148] In various embodiments, a hydrogel comprises from about 0.01 wt.% to about 10 wt.% of an (S)-nicotine complex, including about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, or about 9%, and any values therebetween, based on the total weight of the hydrogel. In preferred embodiments, a hydrogel comprises about 1 wt.% of an (S)-nicotine complex, based on the total weight of the hydrogel. An (S)-ni cotine complex comprises (S)-ni cotine in association with at least one other molecule, wherein the complex is devoid of a crystal lattice structure.

[0149] For each nicotine complex herein, the (S)-nicotine is not protonated and does not carry a formal positive charge. However, certain complexes may involve charge transfer such that a “8+” charge may be present on one of the nitrogen atoms of the (S)-nicotine molecule and a corresponding “8-” charge may be present on the one other compound associated with the (S)- nicotine molecule in the complex.

[0150] For certain embodiments of nicotine complexes as provided for herein, the (S)-nicotine is not predominantly or primarily (e.g., >50% unprotonated) protonated and does not carry a formal positive charge. Depending on the embodiment, the degree of (S)-nicotine in an unprotonated form can vary (with protonated (either monoprotonated or diprotonated) (S)-nicotine being present in reciprocally varied amounts. In several embodiments, unprotonated (S)-nicotine makes up about 15% to about 100% of the nicotine in a given complex, including about 15% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 75%, about 75% to about 80%, about 80% to about 90%, about 90% to about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%, including any values in between those ranges (including endpoints). In several embodiments, unprotonated (S)-nicotine makes up about 70% to about 99% of the nicotine in a given complex, including about 70% to about 75%, about 75% to about 80%, about 81%, about82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, including any values in between those ranges (including endpoints). In several embodiments, unprotonated (S)-nicotine makes up about 70% to about 98%, about 72 to about 98%, about 74% to about 98%, about 76% to about 98%, about 78% to about 98%, about 80% to about 98%, about 88% to about 95%, about 84 to about 98%, about 86 to about 98%, about 88 to about 98%, about 90 to about 98%, about 92% to about 98%, about 94% to about 98%, about 96% to about 98% of the nicotine in a given complex, including any values in between those ranges (including endpoints). However, certain complexes may involve charge transfer such that a “6+” charge may be present on one of the nitrogen atoms of the (S)-nicotine molecule and a corresponding “8-” charge may be present on the one other compound associated with the (S)- nicotine molecule. Such charge transfer may be important for (S)-nicotine transition metal complexes.

[0151] In various embodiments, the at least one other compound in association with the (S)- nicotine molecule in the complex comprises at least one of a surfactant, a polymer, a polysaccharide such as a cyclodextrin, a metal, or an inorganic compound. Depending on the nature of this compound, the complex may be characterizable as a charge transfer complex, a Van der Waals complex, a hydrogen bonded complex, a micellular complex, or an inclusion complex, or some other complex that might not be readily characterizable, such as a microemulsion.

[0152] In certain embodiments, an (S)-ni cotine salt may be complexed with a surfactant, and the resulting complex may be characterized as reverse micelles wherein the nicotine salt and perhaps associated water molecules may be surrounded by the polar ends of surfactant molecules.

[0153] In various embodiments, a nicotine complex herein comprises (S)-nicotine in association with a surfactant, wherein the complex is devoid of a crystal lattice structure, and wherein at least a portion of the (S)-nicotine resides within micelles of the surfactant.

[0154] In various embodiments, the surfactant may be anionic, nonionic, cationic or zwitterionic. In some instances, a surfactant is chosen for its ability to form stable micelles in water, PG or VG, or mixtures therefore, and / or for its ability to micellize (S)-nicotine.

[0155] In various embodiments, micelles may be orientated either way, such as with polar heads forming a spherical structure with the micellized compound inside or organized withhydrophobic tails organizing around the micellized compound and the polar heads projecting out into a polar solution.[001561 In several embodiments, there is provided for herein a nicotine complex comprising nicotine (e.g., (S)-nicotine) and one or more ingredients suitable for forming a complex with the (S)-nicotine, wherein the complex is in a form selected from: a charge transfer complex, a hydrogen bonded complex, a Van der Waals complex, a complex stabilized by nonionic interactions, a solubilized complex, a micellular complex, and an inclusion complex, wherein the one or more ingredients for forming a complex with the (S)-nicotine is selected from the group consisting of: a fatty acid having a polar and / or hydrophilic functional group, a surfactant, a solubilizer (e.g., oil), and / or a polysaccharide.

[0157] In several embodiments, the nicotine complexed with the fatty acid is in the form of a free base alkaloid (e.g., a non-salt form). In several embodiments, the nicotine comprises less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, or less than about 10% monoprotonated (e.g., salt) nicotine. In other words, according to several embodiments, the nicotine is substantially in a form without a positive formal charge.

[0158] In several embodiments, oils can serve as a solubilizer and a source of the fatty acid. In several embodiments, the solubilizer comprises a mono-, di-, or tri-fatty acid glyceride. For example, in several embodiments, the fatty acid glyceride comprises medium-chain length triglyceride (MCT) oil. In several embodiments, the fatty acid comprises sunflower oil, canola oil, palm oil, coconut oil, safflower oil, olive oil, sesame oil, peanut oil, avocado oil, and soybean oil. In some embodiments, the ratio stoichiometric ratio of fatty acid to nicotine can range from about 100: 1, about 75: 1, about 50: 1, about 40: 1, about 30: 1, about 20: 1, about 15: 1, about 10: 1, about 5: 1, about 1 :5, about 1 : 10, about 1 : 15, about 1 :20, about 1 :30, about 1 :40, about 1 :50, about 1 :75, about 1 : 100, or ratios between those listed.

[0159] In several embodiments, the fatty acids have at least one carboxyl group. In several embodiments, the fatty acids are unsaturated. In several embodiments, the unsaturated fatty acids comprise monounsaturated fatty acids. In several embodiments, the unsaturated fatty acids comprise polyunsaturated fatty acids. In several embodiments, however, the fatty acids are saturated. In several embodiments, the fatty acids include between 6 and 30 carbons in the backbone. In several embodiments, the fatty acid is a Ce fatty acid. In several embodiments, the fatty acid is a C? fatty acid. In several embodiments, the fatty acid is a Cio fatty acid. In severalembodiments, the fatty acid is a C12 fatty acid. In several embodiments, the fatty acid is a C14 fatty acid. In several embodiments, the fatty acid is a Ci6 fatty acid. In several embodiments, the fatty acid is a Cis fatty acid. In several embodiments, the fatty acid is a C20 fatty acid. In several embodiments, the fatty acid is a C22 fatty acid. In several embodiments, the fatty acid is a C24 fatty acid. In several embodiments, the fatty acid is a C26 fatty acid. In several embodiments, the fatty acid is a C28 fatty acid. In several embodiments, the fatty acid is a C30 fatty acid. In several embodiments, the fatty acid comprises a C8-C24 fatty acid. In several embodiments, the fatty acid comprises a C8-C24 unsaturated fatty acid.

[0160] In several embodiments, the fatty acids comprises caprylic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, icosanoic acid, docosanoic acid, tetracosanoic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic acid, eicosenoic acid, erucic acid, nervonic acid, linoleic acid, a-linolenic acid, y-linolenic acid, mead acid, stearidonic acid, arachidonic acid, eicosapentaenoic acid, cervonic acid (docosahexaenoic acid), conjugated linoleic acid, eicosadienoic acid, docosadienoic acid, pinolenic acid, a-eleostearic acid, P-eleostearic acid, catalpic acid, dihomo-y- linolenic acid, eicosatrienoic acid, eicosatetraenoic acid, adrenic acid, bosseopentaenoic acid, ozubondo acid, sardine acid, tetracosapentaenoic acid, herring acid, conjugated linoleic acid, punicic acid, jacaric acid, calendid acid, catapic acid, alpha-eleostearic acid, beta-eleostearic acid, parinaric acid, anadiplosis acid, tung acid, or combinations of any of the foregoing. In various embodiments, a saturated, monounsaturated, or polyunsaturated fatty acid usable in the formation of (S)-nicotine complexes include, but are not limited to, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecenoic acid, octadecanoic acid, icosanoic acid, docosanoic acid, tetracosanoic acid, a-linolenic acid, stearidonic acid, eicosapentaenoic acid, cervonic acid, linoleic acid, linolelaidic acid, y-linolenic acid, arachidonic acid, docosatetraenoic acid, palmitoleic acid, vaccenic acid, paullinic acid, oleic acid, elaidic acid, gondoic acid, erucic acid, nervonic acid, mead acid, and the like.

[0161] In several embodiments, the fatty acid comprises conjugated linoleic acid.

[0162] In several embodiments, medium chain triglycerides are used. In several embodiments, sunflower oil is used.

[0163] In various embodiments, the at least one other compound in association with the (S)- nicotine molecule in the complex comprises at least one of a surfactant, a polymer, apolysaccharide such as a cyclodextrin, or an inorganic compound. Depending on the nature of this compound, the complex may be characterizable as a charge transfer complex, a Van der Waals complex, a hydrogen bonded complex, a micellular complex, or an inclusion complex, or some other complex that might not be readily characterizable, such as a microemulsion.

[0164] In various embodiments, a nicotine complex comprises (S)-ni cotine in association with a cyclodextrin, wherein the complex is devoid of a crystal lattice structure. In various examples, the (S)-nicotine molecule is occluded within the inner cavity of the cyclodextrin molecule, and thus the complex may be characterized as an inclusion complex.

[0165] In various examples, the cyclodextrin may comprise any known or yet to be discovered a-, 0-, or y-cyclodextrin. In preferred examples, the cyclodextrin comprises 0-cyclodextrin (unsubstituted) or a 0-cyclodextrin such as hydroxypropyl-0-cyclodextrin, methyl-0-cyclodextrin, dimethyl-0-cyclodextrin, heptakis(2,6-di-O-)ethyl-0-cyclodextrin, 6-O-a-maltosyl-0- cyclodextrin, randomly methylated 0-cyclodextrin (RAMEB), sulfobutylether-0-cyclodextrin, and sulfolipo-0-cyclodextrin, y-cyclodextrin (unsubstituted) or a y-cyclodextrin such as hydroxypropyl -y-cyclodextrin, octakis-(6-bromo-6-deoxy)-y-cyclodextrin, octakis-(6-amino-6- deoxy)-y-cyclodextrin, octakis-(6-chloro-6-deoxy)-y-cyclodextrin, octakis-(6-deoxy-6-iodo)-y- cyclodextrin, octakis-(6-deoxy-6-mercapto)-y-cyclodextrin, octakis-(2,3,6-tri-O-methyl)-y- cyclodextrin, octakis-(2,3-diacetyl-6-sulfato)-y-cyclodextrin, octakis-(3-O-butyryl-2,6-di-O- pentyl)-y-cyclodextrin, and octakis-6-sulfato-y-cyclodextrin. The present disclosure is not bound by any theories as to how many (S)-nicotine molecules may be occluded inside a single inner cavity of a cyclodextrin molecule.

[0166] In various embodiments, any one of more of the aforementioned (S)-nicotine complexes may be incorporated into a hydrogel according to the present disclosure.Polymer

[0167] Hydrogels according to embodiments of present disclosure include a polymer network capable of occluding (S)-nicotine actives and later delivering said (S)-nicotine actives. Polymers for use in forming the present hydrogels include water-soluble polymers, water-swellable polymers, water-insoluble polymers, or a combination of one or more of either water-soluble, water-swellable or water-insoluble polymers. Polymers may be entirely synthetic, partially synthetic from natural starting products, or entirely naturally occurring.

[0168] Synthetic polymers capable of forming hydrogels include, but are not limited to, polyvinyl alcohol, polyethylene glycol (PEG), polyethylene oxide (PEO), polyacrylic acid / methyl methacrylate copolymer, carboxy vinyl copolymers, polymethyl methacrylate, poly(hydroxymethyl acrylate), poly(acrylic-co-vinylsulfonic) acid, polyacrylamide, poly(N- isopropylacrylamide), poly(N-isopropylacrylamide), polyurethane, poly(amino acid), and polyvinylpyrrolidone (PVP).

[0169] Natural polymers capable of forming hydrogels include, but are not limited to, sodium alginate, pectin, pullulan, glucan (dextran), dextrin, maltodextrin, xanthan gum, xyloglucan, tragacanth gum, guar gum, acacia gum, Arabic gum, starch, agarose, gelatin, gellan, chitosan, carrageenan, chondroitin sulfate, collagen, silk fibroin, sericin, scleroglucan, cellulose, hyaluronic acid, hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (ELEC), hydroxypropyl cellulose (EIPC), carboxymethyl cellulose (CMC), ethyl cellulose (EC), hydroxypropyl ethyl cellulose (HPEC), and combinations thereof.

[0170] Preferred for use herein are polysaccharide polymers, such as for example, sodium alginate, pectin, pullulan, glucan (dextran), dextrin, maltodextrin (e.g., tapioca maltodextrin powder), xanthan gum, tragacanth gum, guar gum, acacia gum, Arabic gum, starch, agarose, gelatin, chitosan, carrageenan, hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (EIPC), carboxymethyl cellulose (CMC), ethyl cellulose (EC), hydroxypropyl ethyl cellulose (HPEC), and combinations thereof. See, S.M. Fijul Kabir, et al., “Cellulose-based hydrogel materials: Chemistry, properties and their prospective applications,” Prog. Biomater., 7, 153-174 (2018).

[0171] More preferred polymers for preparing hydrogels according to the present disclosure include gelatin, pullulan, acacia gum, sodium alginate, carboxymethylcellulose (CMC), and hydroxypropyl methylcellulose (HPMC). HPMC (or “Hypromellose”) is a nonionic polymer having linear glucose molecular structure stabilized by hydrogen bonds. The methyl substitution of HPMC is performed using the substitution of free hydroxyl groups of glucose with hydroxypropyl groups, in order to enhance the viscosity, solubility, gelation, and film-forming ability of the cellulose backbone. Other advantages of HPMC are that it is a stable, odorless, flavorless, and edible substance.

[0172] As detailed further below, forming a hydrogel from a polysaccharide, such as a polysaccharide from the aforementioned list, can be as simple as dissolving the polysaccharide in heated deionized water and then allowing the mixture to cool into a gel.

[0173] In various embodiments, a dry polysaccharide such as pullulan, sodium alginate, and hydroxypropyl methylcellulose (HPMC), may be dissolved at a level of about 1 wt.% to about 10 wt.% in hot deionized water prior to cooling into a network polymer gel. In certain examples, the level of polysaccharide or other naturally occurring hydrogel -forming polymer is from about 0.5 wt.% to about 30 wt.%, based on the total weight of the aqueous solution.Plasticizer

[0174] In various embodiments, a hydrogel according to the present disclosure comprises from about 0.1 wt.% to about 10 wt.% of at least one plasticizer including about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, or about 9%, and any values therebetween, based on the total weight of the hydrogel. Plasticizers for use in hydrogels of the present disclosure fall into chemical groups that include, but are not limited to, citric acid and other organic acids, glycerin, sorbitol, mannitol, diethyl phthalate, triethyl citrate, tributyl citrate, macrogol (PEG, of any molecular weight), propylene glycol, citric acid ester, and urea compounds.

[0175] Specific plasticizers include, but are not limited to, tris-2-ethylhexyltrimellitate, dioctyl terephthalate, di-isobutyl terephthalate, N-butylbenzene sulfonamide, di-isodecylsebacate, di-2- ethylhexylsebacate, dibutylsebacate, dimethyl sebacate, tris(2-ethylhexyl) phosphate, 2-ethylhexyl diphenyl phosphate, triphenyl phosphate, 2,2,4-trimethyl-l,3 pentanediol di -isobutyrate, di-Ci6-i8 alkyl phthalate, benzyl C?-9-branched and linear alkyl phthalate, di-isotridecyl phthalate, diisoundecyl phthalate, di(2-propyl heptyl) phthalate, di-isodecyl phthalate, di-isononyl phthalate, bis(2-ethylhexyl) phthalate, di-isooctyl phthalate, di-n-octyl phthalate, di-isoheptyl phthalate, dicyclohexyl phthalate, di-isohexyl phthalate, di-n-hexyl phthalate, di-n-pentyl phthalate, benzyl butyl phthalate, di-isobutyl phthalate, di-n-butyl phthalate, di-n-propyl phthalate, diethyl phthalate, dimethyl phthalate, epoxidized triglyceride vegetable oils from soybean oil, linseed oil, castor oil, and sunflower oil, di-isononyl cyclohexane dicarboxylate, citric acid, acetyl tributyl citrate,tributyl citrate, tri ethyl citrate, tri ethylene glycol dibenzoate, isodecyl benzoate, isononyl benzoate, dipropylene glycol dibenzoate, diethylene glycol dibenzoate, neopentylglycol dibenzoate, diisodecyl azelate, bis[2-(2-butoxyethoxy)ethyl] adipate, di(butoxyethyl) adipate, di-n-butyl adipate, ditridecyl adipate, diisodecyl adipate, diisononyl adipate, di-2-ethylhexyl adipate, benzyl 2-ethylhexyl adipate, diisobutyl adipate, glyceryl triacetate, diethyl succinate, dibutyl succinate, dihexyl succinate, diethylhexyl succinate, didecyl succinate, didodecyl succinate, poly(hexylene succinate), poly(butylene succinate), poly (propylene glycol succinate), polyethylene glycol succinate), 1,2-propylene glycol, di ethylene glycol, various fatty acid esters (FAEs), glycerin, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol (PEGs), sorbitol, mannitol, xylitol, glucose, mannose, fructose, sucrose, and urea.

[0176] For hydrogels according to the present disclosure, natural-based plasticizers are preferred. These include, but are not limited to, triglyceride vegetable oils from soybean oil, linseed oil, castor oil, and sunflower oil, fatty acid esters (FAEs), citric acid, glycerin, 1,2- propylene glycol, diethylene glycol, sorbitol, and polyethylene glycol succinate). In several embodiments, one or more of canola oil, palm oil, coconut oil, safflower oil, olive oil, sesame oil, peanut oil, avocado oil, and soybean oil are used in hydrogel preparation.

[0177] Citric acid is particularly preferred as a plasticizer for use in hydrogels according to the present disclosure in view that citric acid also functions as a crosslinking agent. The ready solubility of citric acid in heated water makes it convenient to add into the heated solution of polysaccharide polymer prior to cooling into the desired hydrogel. Further, citric acid is known as a saliva stimulating agent. Thus, in the present hydrogels, citric acid can act as crosslinker, plasticizer, and saliva stimulant. In several embodiments, citric acid is present in an amount of about 0.1 wt.% to about 10 wt.%, including about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, or about 9%, and any values therebetween, based on the total weight of the hydrogel.

[0178] In various embodiments, any one of more of the aforementioned plasticizers may be incorporated into a hydrogel according to the present disclosure.Disintegrant

[0179] In various embodiments, a hydrogel according to the present disclosure comprises a disintegrant. Examples of a disintegrant include, but are not limited to, various starches (e.g., corn, potato, pregelatinized starch, etc.), sodium starch glycolate (Type A or B), powdered microcrystalline cellulose (MCC), guar gum, xanthan gum, locust bean gum, chitosan hydrochloride, alginic acid, calcium alginate, sodium alginate, docusate sodium, dicalcium phosphate, tricalcium phosphate, magnesium aluminum silicate, bentonite, guargalactomannan, crosslinked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, methylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, calcium cellulose glycolate, crospovidone (crosslinked polyvinylpyrrolidone), and combinations thereof.

[0180] In various embodiments, any one of more of the aforementioned disintegrants may be incorporated into a hydrogel according to the present disclosure.

[0181] In various embodiments, a hydrogel according to the present disclosure comprises from about 0.01 wt.% to about 5 wt.% of a disintegrant, including about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 3%, about 4%, about 5%, and any values therebetween, based on the total weight of the hydrogel.Optional Flavoring Agent

[0182] Hydrogels according to the present disclosure may optionally include a flavoring agent. Flavoring agents are preferably added to a solution of a chosen polymer prior to the solution setting up as a network polymer gel. For synthesized hydrogels, a flavoring agent may be added to a monomer mixture which is then polymerized. In these ways, the flavoring agent is integrated into the scaffold of the hydrogel, later to be released into the oral cavity as the hydrogel swells, entrains saliva, and falls apart by action of saliva enzymes and accelerating effects of the disintegrant in the matrix.

[0183] Flavoring agents for use herein include, but are not limited to, oleocanthal, 4-hydroxy- 2-nonenal, 4-oxo-2-nonenal, allicin, allyl isothiocyanate, icilin, polygodial, cinnamaldehyde, / ra / 7.s-p-methoxycinnamaldehyde, methyl syringate, 2-chlorobenzylidene malononitrile, 1- chloroacetophenone, ethyl bromoacetate, 4-hydroxyhexenal, toluene diisocyanate, p- benzoquinone, methyl p-hydroxybenzoate, flufenamic acid, niflumic acid, mefenamic acid,diclofenac, hydroxy-a-sanshool, 6-paradol, linalool, carvacrol, eugenol, thymol, vanillin, methyl eugenol, 2,6-dimethylphenol, 2,5-dimethylphenol, 3,4-dimethylphenol, 2,6-diisopropylphenol, caffeine, farnesyl thiosalicylic acid, 4-allylanisole, curcumin, niacin, camphor, olvanil, arvanil, nabilone, various phytochemicals from Euphorbia reinifera, Euenia carophyllata, Ocimum gratissiumum , Panax Aframomum melgueta, Evodia rutaecarpa, Drymis winter!, Cinnamosma fragrans, Warburgia, Scutellaria baicalensis, Vitex agnus, Pterodon pubescens, Croton macrostachyus, Angelicae pubescentis, Ephedra sinica, Amphilophium crucigerum, Bosewellia carter ii, Commiphora myrrha, Echinophora platyloba, Nypa fruticans, Corydalis saxicola, Coptis chinensis, Ononis spinosa, Parkia platycephala, Cymbopogon citratus, Capsicum annuum, Zingiber officiale, and Piper nigrum, geraniol, geranial, valeric acid, methyl salicylate, ethyl maltol, ethyl butyrate, ethyl acetate, maltol, menthol, ethyl vanillin, ethyl 3-methyl-3- phenylglycidate, furaneol, methyl cyclopentenolone, methyl cyclopentenolone, ethyl cyclopentenol one, 8-decalactone, ' -decal actone, a-nonalactone, -nonalactone, cis-3 -hexanol, isoamyl acetate, ethyl-2-methyl butyrate, butyric acid, ethyl butyrate, 2-methylbutyric acid, benzyl alcohol, ethyl hexanoate, benzaldehyde, zso-amyl isovalerate, hexanoic acid, ethyl propionate, y- undecalactone, acetyl propionyl, raspberry ketone, furfural, 5-methylfurfural, maltol, 2- acetylpyrazine, 2,3,5-trimethylpyrazine, 2-acetylpyrrole, 2-isopropyl-4-methylthiazole, 2- isobutylthi azole, furfuryl mercaptan, thiomenthone, p-menthene-8-thiol, tropathiane, hexyl acetate and mixtures thereof. This listing is by no means meant to be limiting, as many other flavoring agents exist in the food, beverage, and tobacco industries, and many more are yet to be discovered.Hydrogel Considerations

[0184] In various embodiments, a hydrogel according to the present disclosure may be characterizable as chemically crosslinked or physically crosslinked, depending on the reaction conditions used to make the hydrogel or to later modify it.

[0185] Chemically crosslinked hydrogels are made by dissolving substances containing reactive groups with crosslinking agents in water under certain reaction conditions. The structure of such hydrogels is relatively stable, and they are often referred to as “permanent” gels. Common chemical crosslinking methods include, for example, ultraviolet radiation crosslinking, reactions at both functional ends of a bi-functional monomer, and Schiff base crosslinking.

[0186] Physically crosslinked hydrogels are structured with noncovalent bonds, such as hydrogen bonds, ionic bonds, and Van der Waals forces, with this structured state sometimeschanging in accordance with external conditions. Physically crosslinked hydrogels are often referred to as “reversible” hydrogels. Common physical crosslinking modes include ion crosslinking, hydrophobic interaction, physical entanglement, and hydrogen bonding.

[0187] Hydrogels according to the present disclosure may be tested and / or analyzed for chemical composition, mechanical properties, swelling and water uptake rate, texture and morphology, and for microbiologic contamination.

[0188] Hydrogels according to the present disclosure may also be tested for toxicity and environmental impact, such as by MTT, NRU or Ames testing, in vitro cytotoxicity, genotoxicity and enzyme inhibition, as well as biocompatibility and biodegradability.Hydrogel Uses(a) Hydrogel-Based Oral Strips

[0189] In various embodiments, a hydrogel according to the present disclosure is cast into molds (sometimes referred to as “solvent casting”) or extruded into thin strips and cut to size to make oral hydrogel strips. In various embodiments, a hydrogel-based oral strip measures from about 3 cm2(0.5 in2) to about 13 cm2(2.0 in2) in surface area, and from about 20pm (0.8 mil) to about 3,000pm (118 mil) in thickness. A preferred size for a hydrogel -based oral strip is about 3.25cm (1.28 in) x 2.2cm (0.875 in) with a thickness of about 625pm (25 mil). The dimensions for a hydrogel -based strip may be chosen, for example, on the basis of its feel inside the mouth of an individual, the targeted (S)-nicotine, salt or complex loading in the hydrogel, and the targeted dissolution rate. For the above preferred strip size, a loading of from about 1 mg to about 10 mg (S)-nicotine, salt or complex is used, including about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and any value therebetween. Dissolution rates can range from about 15 seconds up to several hours (including about 20 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours, and any time therebetween) depending on the thickness of the oral strip and the composition of the hydrogel used to make the strip.(b) Hydrogel-based Oral Nicotine Pouches (ONPs)

[0190] A pouch for oral use comprises a relatively small (e.g., 0.5in x 0.75in) saliva-permeable saliva-insoluble fabric material enclosure containing a powder or gel sealed therein, capable ofreleasing (S)-nicotine active into the oral cavity of an individual when the pouch is placed sublingually or in the buccal cavity of the individual.

[0191] In various embodiments, a hydrogel according to the present disclosure is disposed inside a saliva-permeable insoluble nonwoven pouch, so as to form an oral nicotine pouch. In various embodiments, a hydrogel comprising a nicotine-containing emulsion according to the present disclosure is disposed inside a saliva-permeable oral nicotine pouch. Typically, an ONP comprises (S)-nicotine adsorbed onto, or admixed with, powdered microcrystalline cellulose (MCC). In various examples, this typical ONP comprising microcrystalline cellulose (MCC) carrier can be used as a “control” for various experiments designed to test (S)-nicotine delivery rates from oral pouches comprising other types of fill material.

[0192] In various embodiments, versions of hydrogels in accordance with the present disclosure find use in oral nicotine pouches (ONPs). As such, the carrier within the pouch can be thought of as a novel hydrogel scaffold carrier rather than a microcrystalline cellulose (MCC) carrier.

[0193] An ONP according to the present disclosure is configured to release (S)-ni cotine over time. In some embodiments, release of (S)-nicotine into the oral cavity of an individual from an ONP may be characterized as “time release,” but can, in accordance with various examples, be modulated (S)-nicotine release, including release at a faster or slower rate compared to oral nicotine pouches not comprising the presently disclosed hydrogels.

[0194] In general embodiments, an ONP adapted for modulated release of (S)-nicotine into the oral cavity of an individual, comprises:

[0195] a saliva-permeable nonwoven fabric, or other vessel, defining an enclosure containing a hydrogel therein, said hydrogel comprising:

[0196] (S)-nicotine, or a salt or a complex thereof;

[0197] a polymer;

[0198] a plasticizer;

[0199] and a disintegrant.

[0200] In various embodiments, an ONP adapted for modulated release of (S)-nicotine into the oral cavity of an individual further comprises a carrier within the nonwoven enclosure, wherein the hydrogel is admixed with the carrier and / or is absorbed onto the carrier.

[0201] In certain embodiments, a liquid polymer solution that could otherwise be used to form a hydrogel is instead absorbed onto a carrier such as MCC without the need to first form a network polymer gel. In this way, the pouch fill material is obtained as a free-flowing powder. In other embodiments, the liquid polymer solution can be provided in an excess by volume, and the carrier such as MCC dispersed into the polymer solution. Then the resulting mixture is cooled into a hydrogel composite comprising dispersed carrier particles for use inside a nonwoven pouch.(b)(1) Saliva-permeable fabric for pouches

[0202] Pouch material for use herein is chosen for its insolubility in water and for its permeability to water and saliva. Material is sized such that a filled pouch is appropriate for sublingual or buccal placement for extended periods of time. Subjectively, an ONP is configured for comfortable mouth feel, including size of the filled and sealed pouch and texture of the pouch fabric.

[0203] Pouch material for use herein may be constructed from any number of various waterinsoluble nonwoven materials, called “fabrics”. Nonwoven fabrics, with their multitude of uses, are well known to those skilled in textiles. Nonwovens are described very thoroughly in “Nonwoven Fabrics: Raw Materials, Manufacture, Applications, Characteristics, Testing Processes,” editors W. Albrecht, H. Fuchs and W. Kittelmann, Wiley-VCH Verlag GmbH & Co. KgaA Weinheim, 2003. Such material can be prepared by forming a web of continuous filament and / or staple fibers and optionally bonding these fibers at fiber-to-fiber contact points to provide fabrics with the desired properties. The term “bonded nonwoven fabric” is used to include nonwoven fabrics where a major portion of the fiber-to-fiber bonding is achieved by either thermal fusion of adjacent fibers, or adhesive bonding that is accomplished through incorporation of adhesives in the web to “glue” fibers together, or by other bonding such as obtained by the use of liquid or gaseous bonding agents (usually in conjunction with heating) to render the fibers cohesive. Chemical bonding may be accomplished through the use of adhesive or latex powders dispersed between the fibers in the web, which is then activated by heat, ultraviolet or infrared radiation, or other suitable activation method. Thermally and chemically bonded carded webs are described in U.S. Pat. No. 6,689,242 to Bodaghi, the subject matter of which is incorporated herein in its entirety. Thermally and / or chemically bonded nonwovens may be used as the pouch material herein. Powder bonding is a dry process that starts with the carding of staple fibers to form afibrous web, which is then treated with powdered thermal plastic adhesive or latex materials and subjected to a series of ovens and calendar rolls to produce the nonwoven.

[0204] Nonwovens may also comprise fibers known as “bi-component fibers”, for example “sheath / core bi-component fibers”, which are fibers having an outer sheath area or layer with a lower melting point than the inner core area, allowing for efficient and controlled thermal bonding through melting of just the outer layer of each fiber. That is, the outer surface of a bi-component fiber can be made to have a lower melting point than the core of the fiber. For example, binder bi- component fibers where one component has adhesive properties under bonding conditions are widely employed to provide integrity to fibrous webs used as absorbents in personal care products or in filtration products. Additionally, multi-component fibers are similarly known and commercially incorporated into nonwovens. Examples of Such multi-component fibers are described in U.S. Pat. Nos. 5,382,400 (Pike et al.) and U.S. Pat. No. 5,866,488 (Terada et al.) which are incorporated herein in their entireties.

[0205] During the bonding of the fibers, the web may be simultaneously subjected to mechanical compression to obtain the desired bonding, weights and thicknesses in a process known as “thermal compression bonding.” Thermal compression bonding may be accomplished by using a hot embossing roll and a heat flat calendar roll and incorporating a method in which a heat-treating machine such as a hot blast-circulating type, a hot through-air type, an infrared heater type or a vertical hot blast-blowing type is used to carry out thermal compression bonding. Mechanical compression may be used to set the loft or thickness of fabrics with similar basis weights. Normally, increasing the basis weight, or the mass per square area increases thickness, and increasing bonding and compression, decreases loft.

[0206] Nonwoven webs may be formed from a number of processes, for example, melt-blown, spun-bonded or spun-laid, toe-opened, wet-laid, air-laid, carded, and high-pressure hydroentangled. The basis weight of nonwoven webs is usually expressed in ounces of material per square yard (osy) or grams per square meter (gsm) and the fiber diameters are usually expressed in microns, or in the case of staple fibers, “denier.” Denier is defined as grams per 9000 meters of fiber length. For a fiber having circular cross-section, denier may be calculated as fiber diameter in microns squared, multiplied by the density in grams / cc, multiplied by 0.00707. A lower denier indicates a finer fiber and a higher denier indicates a thicker or heavier fiber. The “mean fiber denier” is the sum of tile deniers for each fiber, divided by the number of fibers. A distribution ofdeniers or an “average fiber denier” refers to a distribution of fiber diameters around a specific value. As used herein, the term “bulk density” refers to the weight of a material per unit of volume and usually is expressed in units of mass per unit of bulk volume (e.g., grams per cubic centimeter). Nonwovens may be produced by fibers having a single average value of diameters or denier, or two or more average value diameter fibers may be used together. For example, two or more distributions of fiber deniers may be combined into separate fiber webs (2 / 2 denier and 4 denier fibers carded together for example). Then separate fiber webs may be laminated together. For example, a single nonwoven may comprise 214, 4, 6, and 15 denier fibers, meaning it was constructed with four separate denier fibers (four separate average diameters of fibers.

[0207] “Spun-bonded fibers” refers to fibers formed by extrusion of molten thermoplastic material as filaments, described for example in U.S. Pat. Nos. 4,340,563 to Appel; U.S. Pat. No. 3,692,618 to Dorschner; U.S. Pat. No. 3,802,817 to Matsuki; U.S. Pat. No. 3,338,992 and U.S. Pat. No. 3,341,394 to Kinney; U.S. Pat. No. 3,502,763 to Hartman; U.S. Pat. No. 3,542,615 to Dobo; and, U.S. Pat. No. 5,382,400 to Pike, the entire contents of each of which is incorporated herein by reference. Spun-bond fibers are generally not tacky when they are deposited onto a collecting surface. Spun-bond fibers are generally continuous and have average diameter from about 7 microns to about 60 microns, and most often between about 15 and 25 microns.

[0208] ‘ ‘Melt-blown” refers to fibers formed by extruding molten thermoplastic material through a plurality of fine, normally circular, die capillaries as molten threads or filaments into converging high velocity, usually hot, gas / air streams that attenuate the filaments of molten thermoplastic material to reduce their diameter, which may end up at micro-fiber diameter. Thereafter, the melt-blown fibers are carried by tile high velocity gas stream and are deposited on a collecting surface to form a web of randomly dispersed fibers. Such a process is disclosed, for example, in U.S. Pat. No. 3,849,241 (Butin et al.). Melt-blown fibers are micro-fibers that may be continuous or discontinuous and are generally smaller than 10 microns in average diameter and are generally tacky when deposited onto a collecting surface.

[0209] “Air-laid” is a well-known process by which a fibrous nonwoven layer can be formed. In the air-laid process, bundles of small fibers having typical lengths of from about 3 to about 52 millimeters are separated and entrained in an air supply and deposited onto a forming screen, usually with the assistance of a vacuum. The randomly deposited fibers then are bonded to one another using, for example, hot air to activate a binder component or latex adhesive. The air-layingprocess is taught in, for example, U.S. Pat. Nos. 4,640,810 to Laursen and U.S. Pat. No. 5,885,516 to Christensen.

[0210] The preferred fibers incorporated in pouch fabric for use herein may be single-, bi- (e.g., sheath / core), or multi-component fibers, made from; poly-olefins such as polypropylene, polyethylene; various polyesters such as poly(ethylene terephthalate)-PET, poly(butylene terephthalate)-PBT or poly(trimethylene terephthalate)-PTT, polycarbonates, or polybutyrates and tile like; viscose rayon; various polyamides such as nylons; polyacrylates; and, modacrylics, and mixtures of these types of polymers. In various preferred examples, viscose is used as the saliva- permeable nonwoven pouch fabric for ONPs herein.

[0211] Filling and sealing methods for pouches comprising nonwoven fabrics are disclosed in U.S. Patent Application Publication US 2023 / 0211907, published July 6, 2023 and assigned to Swedish Match North Europe AB, incorporated herein by reference, recognizing the prior art only discloses crystalline carriers, such as microcrystalline cellulose (MCC), and not hydrogel fdl material constituting an entirely novel scaffold-type fdl for an ONP.

[0212] In various embodiments, an ONP herein comprises a fdl weight of a hydrogel of from about 100 mg to about 500 mg, preferably about 200 mg to about 400 mg. In several embodiments, the fdl weight of a hydrogel ranges from 100 mg to 150 mg, 150 mg to 200 mg, 200 mg to 250 mg, 250 mg to 300 mg, 300 mg to 350 mg, 350 mg to 400 mg, or any value within those ranges, including endpoints. In several embodiments, an ONP comprises a fdl weigh of hydrogel of from about 5 mg to about 500 mg, including about 5 mg to about 10 mg, about 10 mg to about 25 mg, about 25 mg to about 50 mg, about 50 mg to about 75 mg, about 75 mg to about 100 mg, about 100 mg to about 125 mg, about 125 mg to about 150 mg, about 150 mg to about 175 mg, about175 mg to about 200 mg, about 200 to about 225 mg, about 225 mg to about 250 mg, about 250 mg to about 275 mg, about 275 mg to about 300 mg, about 300 mg to about 325 mg, about 325 mg to about 350 mg, about 350 mg to about 375 mg, about 375 mg to about 400 mg, about 400 mg to about 425 mg, about 425 mg to about 450 mg, about 450 mg to about 475 mg, about 475 mg to about 500 mg, and any amount within those ranges, including endpoints. In several embodiments, an ONP comprises a fdl weight of a hydrogel of from about 10 mg to about 400 mg, including about 10 mg to about 25 mg, about 25 mg to about 50 mg, about 50 mg to about 75 mg, about 75 mg to about 100 mg, about 100 mg to about 125 mg, about 125 mg to about 150 mg, about 150 mg to about 175 mg, about 175 mg to about 200 mg, about 200 to about 225 mg, about225 mg to about 250 mg, about 250 mg to about 275 mg, about 275 mg to about 300 mg, about 300 mg to about 325 mg, about 325 mg to about 350 mg, about 350 mg to about 375 mg, about 375 mg to about 400 mg, and any amount within those ranges, including endpoints. An upper limit is reached when pouches no longer fit comfortably sublingually or within the buccal cavity. The weight of the small piece of nonwoven fabric used per pouch is considered insignificant compared to the weight of the hydrogel fill material inside.

[0213] In various embodiments, an ONP measures from about 0.12 inches to about 0.50 inches in width (or diameter) and from about 0.25 to about 0.75 inches in height. In some examples, a pouch may appear as a small pillow (square, or rectangular), or more like a capsule or having a cylindrical shape.(b)(2) Hydrogel fill compositions for oral nicotine pouches ONPs

[0214] In various embodiments, oral nicotine pouches ONPs herein comprise a hydrogel further comprising (S)-nicotine or a salt or a complex thereof, a polymer, a plasticizer, and a disintegrant, in accordance with the present disclosure. Hydrogels that can be used in ONPs are amply described herein.(b)(3) Hydrogel-carrier combination fill compositions for oral nicotine pouches ONPs

[0215] In various embodiments, both a carrier and a hydrogel are used as the fill material for an ONP. This combination fill material may be prepared several different ways.

[0216] For example, a heated solution of polymer, (S)-nicotine or salt or complex, plasticizer and disintegrant can be cooled into a hydrogel, such as in a block. The block of hydrogel may then be extruded into a granular form that can be admixed with the chosen carrier. In certain examples, the granulated hydrogel is admixed with microcrystalline cellulose (MCC) carrier. This dry material is then filled and sealed into nonwoven pouches.

[0217] For example, a heated solution of polymer, an emulsion comprising (S)-nicotine or salt or complex, plasticizer and disintegrant can be cooled into a hydrogel, such as in a block. The block of hydrogel may then be extruded into a granular form that can be admixed with the chosen carrier. In certain examples, the granulated hydrogel is admixed with cellulose, such asmicrocrystalline cellulose (MCC) as a carrier. This dry material is then filled and sealed into nonwoven pouches.

[0218] In other examples, a heated solution of polymer, (S)-nicotine or salt or complex, plasticizer and disintegrant such as what would be used to form a hydrogel upon cooling, is mixed with a carrier, and then that mixture is cooled into a hydrogel wherein the carrier is dispersed within the network polymer gel. A portion of the resulting hydrogel, or an extruded granulate of the hydrogel may then be used as a fill material for the nonwoven pouches.

[0219] In other examples, a heated solution of polymer, an emulsion comprising (S)-nicotine, plasticizer and disintegrant such as what would be used to form a hydrogel upon cooling, is mixed with a carrier, and then that mixture is cooled into a hydrogel wherein the carrier is dispersed within the network polymer gel. A portion of the resulting hydrogel, or an extruded granulate of the hydrogel may then be used as a fill material for the nonwoven pouches.

[0220] Carriers for use in forming hydrogel -carrier combination fill material include, but are not limited to, agar, agarose, albumin, alginate, casein, chitin, chondroitin, dextrin, fibroin, fucoidans, galactans, gellan, guar, scleroglucan, pullulan, xyloglucan, pectin, xanthan, psyllium, silica gel, fumed silica, magnesium aluminum silicates, clay, bentonite, hectorite, mesoporous silica, cellulose, cellulose acetate, hyaluronan, various elastin-like polypeptides, P-cyclodextrin, collagen, gelatin, chitosan, carrageenan, polylactic acid, polyglycolic acid, poly actic-glycolic acid) (PLGA), poly(2-hydroxyethyl methacrylate), poly(2-hydroxypropyl methacrylate), poly(acrylic acid), carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, hydrophobically-modified hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose (MCC), nitrocellulose, polyvinyl alcohol, polyvinylpyrrolidone, poly(vinyl methacrylate), carboxy vinyl polymers, poly(vinyl acetate), polyvinyl co-polymers, various starches, modified starches, and combinations thereof. In several embodiments, the carrier used in combination with a hydrogel comprises microcrystalline cellulose (MCC). In several embodiments, the carrier comprises bamboo fibers, lignin, wheat fibers, pea fibers, maize fibers, rice fiber, oat fibers, barley fibers, buckwheat fibers, cellulose fibers, bran fibers, powdered cellulose, or combinations thereof. In several embodiments, the carrier comprises a water insoluble fiber.

[0221] Carriers may be chosen on the basis of absorptive capacity and, to a lesser extent, taste. In instances where a carrier does not dissolve at all in the saliva present in the oral cavity, taste will not be a factor, and it is unlikely any insoluble carrier will pass between fibers of a nonwoven. In other examples, a carrier may be soluble, and will pass through the porous pouch fabric along with the (S)-ni cotine, salt or complex thereof.ExperimentalAppearance of Hydrogels and nicotine delivery therefrom

[0222] With reference now to Figure 2, various polysaccharides were used to make hydrogels capable of nicotine delivery. Hydrogels were made by adding to a heated aqueous mixture of the chosen polysaccharide, (S)-nicotine lactate (or other active), a plasticizer, a disintegrant, and optionally, a flavoring agent, and then casting the hydrogel mixture into a thin film comprising a network polymer gel. The illustrated method should not be construed as being limited to an (S)- nicotine active. Various compositions that can be used in this way to solvent-cast thin films are shown in TABLE 1 in Figure 11, TABLE 2 in Figure 12, and TABLE 3 in Figure 13.

[0223] Figure 3 sets forth photographs of various hydrogels prepared in the manner above from polymers that included acacia gum, sodium alginate, hydroxypropyl methylcellulose, pullulan, gelatin, carboxymethyl cellulose, maltodextrin and tapioca maltodextrin.

[0224] Figure 4 illustrates examples of hydrogel-based oral strips, obtainable by casting mixtures per above into thin sheets and then cutting into strips. These strips may be used on the tongue or across the teeth and / or gums for oral delivery of (S)-nicotine as shown in the example photographs.

[0225] With reference now to Figure 5, nicotine delivery from various hydrogels was measured over time and plotted to show the rate differences visually. Figure 5 sets forth nicotine delivery rates measured for various hydrogels comprising (S)-nicotine lactate in comparison to a “control” oral nicotine pouch (ONP) comprising only (S)-nicotine lactate and microcrystalline cellulose (MCC). For these experiments, a measured portion of a test hydrogel or the ONP control was submerged in PBS buffer and the amount of (S)-nicotine in the buffer measured at regular time intervals. The plotted data show rate of nicotine delivery.

[0226] For these experiments, the same amount of (S)-nicotine lactate (1%) was incorporated in each test hydrogel and in the control ONP having the microcrystalline cellulose (MCC) carrier. The plotted data show that each hydrogel tested outperformed the control ONP, showing significantly higher nicotine release rate in dissolution testing in PBS buffer. The significant difference observed may be attributable to the superior disintegration of hydrogels of the present disclosure compared to microcrystalline cellulose (MCC) powder.

[0227] With continued reference to Figure 5, it was also apparent that the rate of nicotine delivery from hydrogels comprising (S)-nicotine lactate depended on the nature of the polysaccharide used to make the network polymer gel. As noted from the data, nicotine delivery rates were fastest for pullulan hydrogels and slowest for carboxymethylcellulose (CMC) hydrogels.

[0228] With reference now to Figure 6, caffeine-based hydrogels having compositions according to the table in Figure 12, and melatonin-based hydrogels having compositions according to the table in Figure 13 were prepared and their dissolution rates measured. Plot (A) in Figure 6 sets forth dissolution rates of caffeine-based hydrogels for hydrogels comprising CMC, gelatin, hydroxypropyl methylcellulose (HPMC), pullulan or sodium alginate. As shown in the plot (A), the gelatin hydrogel exhibited the slowest release of caffeine whereas the hydroxypropyl methylcellulose (HPMC) hydrogel exhibited the fastest release of caffeine. Plot (B) in Figure 6 sets forth dissolution rates of melatonin-based hydrogels for hydrogels comprising CMC, gelatin, or sodium alginate. As shown in the plot (B), the sodium alginate hydrogel exhibited the slowest release of melatonin whereas the gelatin hydrogel exhibited the fastest release of melatonin.

[0229] Figure 7 illustrates the general concept of an oral nicotine pouch (ONP), with the inset diagrams showing the fill material to be (1) a powdered mixture of (S)-nicotine or a salt or a complex thereof, and a carrier; (2) a hydrogel comprising (S)-nicotine or a salt or a complex thereof, a polymer, a plasticizer, and a disintegrant; or (3) a combination of a hydrogel comprising (S)-nicotine or a salt or a complex thereof, a polymer, a plasticizer, and a disintegrant with a carrier.

[0230] In various embodiments, and with continued reference to Figure 7, the hydrogel fill material without carrier may be a rigid portion of hydrogel, or in the form of a desiccated hydrogel, or extruded hydrogel, such as in granular form. The hydrogel fill material in combination with a carrier may be in the physical form of (a) an admixture of carrier and desiccated or extruded hydrogel; or (b) a hydrogel comprising a carrier dispersed therein. The carrier in these instancesmay be any of the carriers described herein, with a preference for microcrystalline cellulose (MCC).

[0231] Figure 8 illustrates general embodiments of a method of making hydrogel-based oral pouches. The illustration should not be construed as limited to nicotine, nor limiting the precise steps to the method. As shown, the chosen hydrogel polymer is dissolved or suspended in water and the active(s), plasticizer, disintegrant, and optional flavoring agent(s) are added. The resulting suspension with actives is then poured into and mixed with microcrystalline cellulose (MCC) or other desired carrier(s). In this way, the liquid mixture is absorbed onto the MCC carrier to produce a dry and free-flowing mixture. The mixture is then loaded into the cavities of nonwoven pouches to form the oral delivery pouches. In other embodiments not illustrated, the carrier such as MCC can be dispersed into the polymer solution or suspension with actives and then solidified into the corresponding hydrogel. The hydrogel scaffold with dispersed carrier can be macerated as necessary to fit within a nonwoven pouch. In yet other embodiments, the polymer solution or suspension with actives is first solidified into the corresponding hydrogel, and then the hydrogel is macerated and mixed with a carrier such as MCC.

[0232] With reference now to Figure 9, nicotine delivery rates were measured for various hydrogel-MCC based ONPs comprising (S)-nicotine lactate in comparison to a traditional ONP comprising (S)-nicotine lactate and only microcrystalline cellulose (MCC). Each of the seven test ONPs comprised the chosen polysaccharide in combination with microcrystalline cellulose (MCC), at 2.5 wt.% of polymer. The test fill materials included hydrogels made from (S)-ni cotine lactate, MCC, and the choice of acacia gum, CMC, gelatin, HPMC, tapioca maltodextrin, pullulan or sodium alginate. As evident from the plotted data, use of a hydrogel in combination with microcrystalline cellulose (MCC) carrier as the fill material in an ONP modulates (S)-nicotine delivery into PBS buffer over the control ONP comprising (S)-nicotine lactate and only microcrystalline cellulose (MCC) as the fill material. The choice between a variety of hydrogel polymers demonstrates the flexibility to either decrease nicotine release (gelatin, HPMC, or pullulan) or increase nicotine release (acacia gum, CMC, tapioca maltodextrin, or sodium alginate) relative to an ONP using only MCC as the carrier.

[0233] Figure 10 sets forth delivery rates for just two select ONPs comprising a combination of hydrogel and MCC carrier in comparison to a traditional ONP comprising (S)-nicotine lactate and only microcrystalline cellulose (MCC). As evident from the plotted data, a combination ofacacia gum and MCC in a hydrogel, and a combination of CMC and MCC in a hydrogel, show significant increases in (S)-nicotine delivery compared to (S)-nicotine delivery from a traditional ONP comprising (S)-nicotine lactate and only microcrystalline cellulose (MCC) as carrier. In Figure 10, plot (A) sets forth the overall results monitored over 20 minutes whereas plot (B) shows an expanded portion of the results over just the first 5 minutes of the experiment.

[0234] Figure 11 sets forth TABLE 1 listing of non-limiting examples of hydrogel-based nicotine oral strip formulations. As discussed, a variety of polysaccharides or other naturally occurring hydrogel-forming polymers may be employed. These examples also demonstrate use of a flavoring agent such as menthol, and a sweetener such as stevia.

[0235] Figure 12 sets forth TABLE 2 listing of non-limiting examples of hydrogel-based caffeine oral strip formulations. As discussed, a variety of polysaccharides or other naturally occurring hydrogel-forming polymers may be employed. These examples also demonstrate use of a flavoring agent such as menthol, and a sweetener such as stevia.

[0236] Figure 13 sets forth TABLE 3 listing of non-limiting examples of hydrogel -based melatonin oral strip formulations. As discussed, a variety of polysaccharides or other naturally occurring hydrogel-forming polymers may be employed. These examples also demonstrate use of a sweetener such as stevia in the compositions.

[0237] Figure 14 sets forth TABLE 4 listing of non-limiting examples of hydrogel -based oral nicotine pouch (ONP) formulations. As discussed, a variety of polysaccharides or other naturally occurring hydrogel-forming polymers may be employed. These examples also demonstrate use of a flavoring agent such as menthol, and a sweetener such as stevia.

[0238] Figure 15 schematically summarizes a non-limiting embodiment an Oral Nicotine Pouch (ONP) dosage form where the ONP employs a cellulose-hydrogel-emulsion matrix (referred to herein at times as a CHEM). According to several embodiments a combination of cellulose, such as microcrystalline cellulose, is formed with a hydrogel scaffold. Incorporated into the hydrogel scaffold is an emulsion comprising nicotine. As schematically illustrated, the cellulose- hydrogel-emulsion can be a water-oil-water emulsion (“W / O / W”), a water-oil emulsion (“W / O”), an oil-water-oil emulsion (“O / W / O”), an oil-water emulsion (“O / W”), a noisome, or a liposome, depending on the embodiment. In several such embodiments, the nicotine within the emulsion is not in the form of a salt. In several embodiments, the nicotine complexed with the fatty acid is in the form of a free base alkaloid (e.g., a non-salt form). In several embodiments, the nicotinecomprises less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, or less than about 10% monoprotonated (e.g., salt) nicotine. In other words, according to several embodiments, the nicotine is substantially in a form without a positive formal charge. In other embodiments, the nicotine is free base nicotine or is a salt or other complex (e.g., a cyclodextrin inclusion complex).

[0239] Figure 16 depicts TABLE 5, which shows various non-limiting embodiments, of hydrogel emulsion formulations and their component ingredients and relative percentages. Other formulations can be generated, based on other combinations or amounts of ingredients disclosed herein.

[0240] Figure 17 shows various non-limiting chemical structures of ingredients of hydrogels provided for herein.

[0241] Figure 18 depicts experimental data comparing the nicotine release rate from various non-limiting examples of hydrogel. Release rates measured herein are performed using a system comprising a piston pump that draws media from a media reservoir and pumps media along a closed-loop fluid flow pathway 1820 through a heat exchanger and then to a flow through cell, with the heat exchanger functioning to maintain the temperature of the media passing through the cell. The dosage form being tested, here oral pouches comprising hydrogel -nicotine emulsion formulations as provided for herein, is positioned within the flow cell and the media is passed through the flow cell and returns to the media reservoir in a closed-loop fashion. Samples can be withdrawn from the media reservoir at predetermined time intervals either manually or by an automated syringe system. The samples can be analyzed for concentration of API release from the dosage form.

[0242] The three test formulations were (i) a control, which does not include a hydrogel comprising a nicotine emulsion, rather it includes nicotine in water in place of the emulsion; (ii) a first CHEM (referring to a Cellulose-Hydrogel-Emulsion-Matric) formulation using gelatin as the hydrogel material; and (iii) a second CHEM using carboxymethyl cellulose (CMC) as the hydrogel material were also tested. The nicotine release rate was measured over 120 minutes with samples collected every five minutes for the first 20 minutes followed by samples at 10- or 20-minute intervals thereafter. As depicted in Figure 17, the gelatin-based CHEM release nicotine at an increased rate as compared to the water-based control. In contrast, the CMC -based CHEM released nicotine at a slower rate than both the gelatin-based CHEM and the water-based control.These data show that the composition of the hydrogel emulsion can be used to modulate the release rate of nicotine (or another active) in order to increase or decrease the rate to a desired profile. This tunable nature has practical implications in some embodiments, in that an enhanced release rate suggests that, over a given time interval, a greater percentage of the active within the pouch is released. This coordinately means that over a usage time frame, there is a decrease in waste (e.g., active that remains in the pouch after use). Thus, actives integrated into hydrogel emulsions as provided for herein allow for more efficient overall release and less active agent being wasted. Also, in some cases, that means that a smaller amount of active agent can be included in such a product, reducing production costs.

[0243] Having determined that the hydrogel-emulsion formulation can modulate at least one ingredient release rate, further tests were performed to measure multiple rates. Figures 19A-19B show data for the release rate of nicotine (19A) and a non-limiting example of a flavorant, herein vanillin (VL) (19B). As shown in Figure 19A, four different vanillin containing CHEM-ONPs were tested, acacia gum-based (AG), gelatin-based (Gel), pullulan-based (Pol), and hydroxypropyl methylcellulose-based (HPMC). Each of these four formulations exhibited similar nicotine release rates over the course of the experiment. In contrast, as shown in Figure 19B, the formulations exhibited different vanillin release rates, with the AG-based formulation showing the greatest vanillin release rate. The HPMC-based formulation showed a reduced vanillin rate (as compared to the AG formulation), followed by the Pol-based formulation and the Gel-based formulation, which showed the lowest rate. These data, taken together suggest that hydrogel -emulsion formulations can be tailored for multiple ingredients. Using the data from Figures 19A-19B as a non-limiting example, these formulations could allow an ONP to deliver a robust flavor release along with the nicotine release (e.g., the AG-based formulation), or a mild flavor release (e.g., the Gel -based formulation). Together with the data from Figure 18, in which the nicotine release rate is modulated, CHEM formulations could allow robust nicotine release coupled with robust flavor release, modest nicotine release coupled with modest flavor release, mild nicotine release coupled with mild flavor release, robust nicotine release coupled with modest or mild flavor release, modest nicotine release coupled with robust or mild flavor release, nicotine release coupled with robust or mild flavor release, etc. In addition, formulations can be combined in several embodiments, to allow any combination of flavor and nicotine (or other active) desired (e.g., those falling between or beyond, “robust”, “modest”, or “mild”).

[0244] Additional data was generated regarding release rate modulation of multiple ingredients. Figures 20A-20F show data related to release rate of nicotine and vanillin from five different CA containing CHEM-ONPs were tested, acacia gum-based (AG) (20A), carboxymethyl cellulose-based (CMC) (20B), gelatin-based (Gel) (20C), water-based control (H2O) (20D), hydroxypropyl methylcellulose-based (HPMC) (20E), and pullulan-based (Pol) (20F). As shown in Figure 20A, AG-based formulation allowed parallel release of nicotine and vanillin, both greater than the rates from water-based control (20D). Figures 20B, 20C, 20E and 20F each show that the respective formulations tested offer different nicotine and vanillin release rate profdes than control. Again, these data reinforce that, in several embodiments, modulation of both active agent and another ingredient, like a flavorant, can be modulated to achieve a desired overall profde.

[0245] Additional data was collected that shows that release profdes of two ingredients could be harmonized, or otherwise run in parallel with one another, if desired. Figures 21A-21B show data for the release rate of nicotine (21 A) and a non-limiting example of a flavorant, herein cinnamaldehyde (CA) (2 IB). As shown in Figure 21 A, five different CA containing CHEM-ONPs were tested, acacia gum-based (AG), carboxymethyl cellulose-based (CMC), gelatin-based (Gel), hydroxypropyl methylcellulose-based (HPMC), and pullulan-based (Pol). The long-term release rate of nicotine was similar for each formulation, with the Gel-based formulation showing a more rapid early release phase. Similarly, the flavorant release rate was similar for each formulation (2 IB), with the Gel -based formulation showing a somewhat increased rate of release. These data demonstrated that CHEM ONPs as provided for herein can also provide a “matched” or “mirrored” release profde of active and another ingredient like a flavorant. These suggest that the formulations provided for herein can be used to modulate ingredient release rates in several ways to achieve a desired profde(s) and user experience of a product comprising these formulations.

[0246] Having established that the release profdes of ingredients can be modulated, experiments were undertaken to evaluate the stability of CHEM-based ONPs. Five different nicotine and vanillin containing CHEM-ONPs were tested, acacia gum-based (AG), carboxymethyl cellulose-based (CMC), gelatin-based (Gel), hydroxypropyl methylcellulose- based (HPMC), and pullulan-based (Pol) were tested as compared to nicotine in a non-CHEM format (water, “H2O”). Oral pouches were fdled with 5.0 ± 0.1 mg of an individual CHEM formulation or H2O control. Total pouch weight for each test group was measured after fdling. Pouches were placed into a closed container (glass vial) and held at 40 °C for the duration of theexperiment. These experimental conditions are designed to simulate a harsh environment and represent what would be considered suitable to induce accelerated loss of stability. Total pouch weight was measured at 1 day, 7 days, 14 days, and 21 days. The results are shown in Figure 22. Despite having different and tunable nicotine release profiles, the test nicotine CHEM-ONPs show comparable stability as comparted to control. Each of the tested pouches exhibited a decline in total mass throughout the experiment, but none of the test groups showed significant variability from the steady decline exhibited by the control group. Similar results are shown for pH (see Figure 23) At each data collection point for pouch mass, a pouch from each group was placed in 10 mL of deionized water and stirred for 10 minutes, followed by obtaining the pH of the deionized water. While there was some variability in pH at the outset, each of the test groups exhibited a relative decrease in pH over the experiment and exhibited relatively similar overall profiles. After pH measurements, the deionized water in which the pouches resided was stirred for an additional 60 minutes to allow complete nicotine and flavorant extraction from the test pouches. HPLC was used to determine the mass of extracted nicotine and flavorant. The data are shown in Figure 24 and 25, respectively. As seen in Figure 24, the eluted nicotine mass showed a similar profile (declining over time) for each of the tested groups over time. Figure 25 shows similar data, which the AG-based formulation retaining slightly more vanillin than the other groups at the end of the stability test, which were essentially not distinguishable from one another. Of note, at earlier time points, like Day 7, the AG-based formulation retained substantially more vanillin within the ONP as compared to all other formulations. Given that the harsh conditions used, the greater retention of vanillin shows that the hydrogel choice can also improve stability and allow for greater ingredient retention, here a flavorant. As such, the hydrogel and ingredient choices, like flavorants, can be used to generate tailored release profiles in some embodiments. Thus, taken together, these data demonstrate that CHEM-formulations and the ONPs incorporating such formulations as provided for herein exhibit similar stability and degrees of degradation over time as compared to non-CHEM formulations, yet retain the ability to provide tailored ingredient release profiles, if desired.NUMBERED EMBODIMENTS

[0247] Among the embodiments provided for herein are:

[0248] 1 A hydrogel comprising:

[0249] an active;

[0250] a polymer;

[0251] a plasticizer; and

[0252] a disintegrant;

[0253] wherein the active is selected from the group consisting of (S)-nicotine, an (S)-nicotine salt, an (S)-nicotine complex, caffeine, menthol, melatonin, cannabidiol (CBD), tetrahydrocannabinol (THC), quercetin, y-aminobutyric acid (GABA), theanine, L-tryptophan, 5- hydroxy-L-tryptophan (5-HTP), and mixtures thereof.

[0254] 2. The hydrogel of embodiment 1, wherein the polymer is selected from the group consisting of sodium alginate, pectin, pullulan, glucan, dextrin, maltodextrin, xanthan gum, xyloglucan, tragacanth gum, guar gum, acacia gum, Arabic gum, starch, agarose, gelatin, gellan, chitosan, carrageenan, chondroitin sulfate, collagen, silk fibroin, sericin, scleroglucan, cellulose, hyaluronic acid, hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), ethyl cellulose (EC), hydroxypropyl ethyl cellulose (HPEC), and combinations thereof.

[0255] 3. The hydrogel of embodiment 2, wherein the polymer comprises gelatin, pullulan, acacia gum, sodium alginate, carboxymethylcellulose (CMC), hydroxypropyl methylcellulose (HPMC), or mixtures thereof.

[0256] 4. The hydrogel of embodiment 1, comprising an (S)-nicotine salt, further comprising protonated (S)-nicotine cation in association with a negatively charged counterion comprising a conjugate base of an organic acid selected from the group consisting of formic acid, acetic acid, adipic acid, trifluoroacetic acid, aspartic acid, butanoic acid, butyric acid, 2-methylbutyric acid, 3- methylbutyric acid, benzoic acid, caprylic acid, citric acid, crotonic acid, butanoic acid, ethylenediaminetetraacetic acid (EDTA), C8-C26 saturated, monounsaturated, or polyunsaturated fatty acids, fumaric acid, gluconic acid, glutamic acid, glyceric acid, glycidic acid, glycolic acid, glyoxylic acid, hexanoic acid, heptanoic acid, lactic acid, lauric acid, levulinic acid, maleic acid, L-(-)-malic acid, malonic acid, mandelic acid, mesooxalic acid, methane sulfonic acid, oxalic acid, pentanoic acid, phenylacetic acid, phthalic acid, picric acid, propionic acid, 3-oxopropanoic acid, 2,3-dioxopropanoic acid, 2, 3, -dihydroxypropanedioic acid, propiolic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tannic acid, L-(+)-tartaric acid, tartronic acid, valeric acid, vanillic acid, and mixtures thereof.

[0257] 5. The hydrogel of embodiment 4, wherein the (S)-nicotine salt comprises (S)-nicotine lactate.

[0258] 6. The hydrogel of embodiment 1, comprising an (S)-nicotine inclusion complex further comprising (S)-nicotine in association with a cyclodextrin.

[0259] 7. The hydrogel of embodiment 6, wherein the cyclodextrin is selected from the group consisting of |3-cyclodextrin, hydroxypropyl-P-cyclodextrin, methyl-[3-cyclodextrin, dimethyl-P- cyclodextrin, heptakis(2,6-di-O-)ethyl-P-cyclodextrin, 6-O-a-maltosyl-P-cyclodextrin, randomly methylated P-cyclodextrin (RAMEB), sulfobutylether-P-cyclodextrin, sulfolipo-P-cyclodextrin, y- cyclodextrin, hydroxypropyl-y-cyclodextrin, octakis-(6-bromo-6-deoxy)-y-cyclodextrin, octakis- (6-amino-6-deoxy)-Y-cyclodextrin, octakis-(6-chloro-6-deoxy)-Y-cyclodextrin, octakis-(6-deoxy- 6-iodo)-y-cyclodextrin, octakis-(6-deoxy-6-mercapto)-y-cyclodextrin, octakis-(2,3,6-tri-O- methyl)-Y-cyclodextrin, octakis-(2,3-diacetyl-6-sulfato)-y-cyclodextrin, octakis-(3-O-butyryl-2,6- di-O-pentyl)-Y-cyclodextrin, octakis-6-sulfato-y-cydodextrin, and mixtures thereof.

[0260] 8. The hydrogel of claim 1, wherein the plasticizer is selected from the group consisting of tris-2-ethylhexyltrimellitate, dioctyl terephthalate, di-isobutyl terephthalate, N-butylbenzene sulfonamide, di-isodecylsebacate, di-2-ethylhexylsebacate, dibutyl sebacate, dimethylsebacate, tri s(2 -ethyl hexyl) phosphate, 2-ethylhexyl diphenyl phosphate, triphenyl phosphate, 2,2,4- trimethyl-1,3 pentanediol di-isobutyrate, di-C16-18 alkyl phthalate, benzyl C7-9-branched and linear alkyl phthalate, di-isotridecyl phthalate, di-isoundecyl phthalate, di(2-propyl heptyl) phthalate, di-isodecyl phthalate, di-isononyl phthalate, bis(2-ethylhexyl) phthalate, di-isooctyl phthalate, di-n-octyl phthalate, di-isoheptyl phthalate, di-cyclohexyl phthalate, di-isohexyl phthalate, di-n-hexyl phthalate, di-n-pentyl phthalate, benzyl butyl phthalate, di-isobutyl phthalate, di-n-butyl phthalate, di-n-propyl phthalate, diethyl phthalate, dimethyl phthalate, epoxidized triglyceride vegetable oils from soybean oil, linseed oil, castor oil, or sunflower oil, di-isononyl cyclohexane di carb oxy late, citric acid, acetyl tributyl citrate, tributyl citrate, triethyl citrate, triethylene glycol dibenzoate, isodecyl benzoate, isononyl benzoate, dipropylene glycol dibenzoate, diethylene glycol dibenzoate, neopentylglycol dibenzoate, diisodecyl azelate, bis[2- (2-butoxyethoxy)ethyl] adipate, di(butoxyethyl) adipate, di-n-butyl adipate, ditridecyl adipate, diisodecyl adipate, diisononyl adipate, di-2-ethylhexyl adipate, benzyl 2-ethylhexyl adipate, diisobutyl adipate, glyceryl triacetate, diethyl succinate, dibutyl succinate, dihexyl succinate, diethylhexyl succinate, didecyl succinate, didodecyl succinate, poly(hexylene succinate),poly(butylene succinate), polypropylene glycol succinate), poly(ethylene glycol succinate), 1 ,2- propylene glycol, diethylene glycol, various fatty acid esters (FAEs), glycerin, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol (PEGs), sorbitol, mannitol, xylitol, glucose, mannose, fructose, sucrose, urea, and mixtures thereof

[0261] 9. The hydrogel of embodiment 8, wherein the plasticizer comprises at least one of an epoxidized triglyceride vegetable oil from soybean oil, linseed oil, castor oil, or sunflower oil, citric acid, glycerin, 1,2-propylene glycol, di ethylene glycol, sorbitol, and poly(ethylene glycol succinate).

[0262] 10. The hydrogel of embodiment 9, wherein the plasticizer is at least one of glycerin and citric acid.

[0263] 11. The hydrogel of embodiment 1, wherein the disintegrant is selected from the group consisting of starch, sodium starch glycolate Type A, sodium starch glycolate Type B, powdered microcrystalline cellulose (MCC), guar gum, xanthan gum, locust bean gum, chitosan hydrochloride, alginic acid, calcium alginate, sodium alginate, docusate sodium, dicalcium phosphate, tricalcium phosphate, magnesium aluminum silicate, bentonite, guargalactomannan, crosslinked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, methylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, calcium cellulose glycolate, crospovidone, and mixtures thereof.

[0264] 12. The hydrogel of embodiment 11, wherein the disintegrant comprises powdered microcrystalline cellulose (MCC).

[0265] 13. The hydrogel of embodiment 1, further comprising a flavoring agent.

[0266] 14. A hydrogel-based oral strip comprising:

[0267] an active;

[0268] a polymer;

[0269] a plasticizer; and

[0270] a disintegrant;

[0271] wherein the active is selected from the group consisting of (S)-nicotine, an (S)-nicotine salt, an (S)-nicotine complex, caffeine, menthol, melatonin, cannabidiol (CBD), tetrahydrocannabinol (THC), quercetin, y-aminobutyric acid (GABA), theanine, L-tryptophan, 5- hydroxy-L-tryptophan (5-HTP), and mixtures thereof.

[0272] 15 The hydrogel -based oral strip of embodiment 14, wherein the active is an (S)- nicotine salt comprising (S)-nicotine lactate.

[0273] 16. The hydrogel-based oral strip of embodiment 14, further comprising a flavoring agent.

[0274] 17. The hydrogel-based oral strip of embodiment 14, each strip configured as a thin rectangular shape measuring from about 3 cm2 (0.5 in2) to about 13 cm2 (2.0 in2) in surface area, and from about 20pm (0.8 mil) to about 3,000pm (118 mil) in thickness.

[0275] 18. The hydrogel-based nicotine oral strip of embodiment 17, wherein each strip includes from about Img to about lOmg of (S)-nicotine lactate as the active.

[0276] 19. The hydrogel-based oral strip of embodiment 14, wherein the polymer is selected from the group consisting of gelatin, pullulan, acacia gum, sodium alginate, carboxymethylcellulose (CMC), hydroxypropyl methylcellulose (HPMC), and mixtures thereof.

[0277] 20. An oral nicotine pouch (ONP) comprising a saliva-permeable nonwoven fabric defining an enclosure containing a hydrogel therein, said hydrogel comprising (S)-nicotine, or a salt or a complex thereof, a polymer, a plasticizer, and a disintegrant.

[0278] 21. The oral nicotine pouch (ONP) of embodiment 20, wherein the hydrogel further comprises a carrier.

[0279] 22. The oral nicotine pouch (ONP) of embodiment 21, wherein the carrier is selected from the group consisting of agar, agarose, albumin, alginate, casein, chitin, chondroitin, dextrin, fibroin, fucoidans, galactans, gellan, guar, scleroglucan, pullulan, xyloglucan, pectin, xanthan, psyllium, silica gel, fumed silica, magnesium aluminum silicates, clay, bentonite, hectorite, mesoporous silica, cellulose, cellulose acetate, hyaluronan, various elastin-like polypeptides, [3- cyclodextrin, collagen, gelatin, chitosan, carrageenan, polylactic acid, polyglycolic acid, poly(lactic-glycolic acid) (PLGA), poly(2-hydroxyethyl methacrylate), poly(2-hydroxypropyl methacrylate), poly(acrylic acid), carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, hydrophobically-modified hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose (MCC), nitrocellulose, polyvinyl alcohol, polyvinylpyrrolidone, poly(vinyl methacrylate), carboxy vinyl polymers, poly(vinyl acetate), polyvinyl co-polymers, starch, modified starch, and mixtures thereof.

[0280] 23. The oral nicotine pouch (ONP) of embodiment 22, wherein the carrier is microcrystalline cellulose (MCC).

[0281] 24. A method of manufacturing an oral nicotine pouch (ONP), the method comprising:

[0282] providing a saliva-permeable nonwoven fabric defining an enclosure;

[0283] preparing an aqueous mixture of (S)-nicotine, a salt or a complex thereof, at least a polysaccharide or other naturally occurring hydrogel-forming polymer, at least a plasticizer, and at least a disintegrant in water;

[0284] absorbing the aqueous mixture onto a carrier to form a free-flowing mixture; and

[0285] disposing a portion of the free-flowing mixture in the enclosure.

[0286] 25. The method of embodiment 24, wherein the (S)-nicotine, a salt or a complex thereof is (S)-nicotine lactate.

[0287] 26. The method of embodiment 24, wherein the carrier is microcrystalline cellulose(MCC).

[0288] 27. The method of embodiment 24, wherein the portion of free-flowing mixture disposed in said enclosure weighs from about 10 mg to about 2000 mg.

[0289] 28. A method of increasing a rate of (S)-ni cotine delivery from an oral nicotine pouch comprising a fill material consisting of (S)-nicotine, or a salt or a complex thereof, admixed with or adsorbed onto a carrier, the fill material disposed inside a saliva-permeable nonwoven fabric pouch, said method comprising:

[0290] (1) preparing an aqueous solution or suspension comprising the (S)-nicotine, salt, or complex thereof, a polysaccharide or other naturally occurring hydrogel -forming polymer, a plasticizer, and a disintegrant; adsorbing the aqueous solution or suspension onto the carrier to form the fill material; and disposing the fill material inside the saliva-permeable nonwoven fabric pouch; or

[0291] (2) dispersing the carrier in an aqueous solution or suspension comprising the (S)- nicotine, salt, or complex thereof, a polysaccharide or other naturally occurring hydrogel-forming polymer, a plasticizer, and a disintegrant; solidifying the dispersion into a hydrogel; and disposing the hydrogel as the fill material inside the saliva-permeable nonwoven fabric pouch; or

[0292] (3) preparing an aqueous solution or suspension comprising the (S)-nicotine, salt, or complex thereof, a polysaccharide or other naturally occurring hydrogel-forming polymer, a plasticizer, and a disintegrant; solidifying the dispersion into a hydrogel; admixing the hydrogelwith the carrier to form the fill material; and disposing the fill material inside the saliva-permeable nonwoven fabric pouch.[002931 29. The method of embodiment 28, wherein the carrier is selected from the group consisting of agar, agarose, albumin, alginate, casein, chitin, chondroitin, dextrin, fibroin, fucoidans, galactans, gellan, guar, scleroglucan, pullulan, xyloglucan, pectin, xanthan, psyllium, silica gel, fumed silica, magnesium aluminum silicates, clay, bentonite, hectorite, mesoporous silica, cellulose, cellulose acetate, hyaluronan, various elastin-like polypeptides, P-cyclodextrin, collagen, gelatin, chitosan, carrageenan, polylactic acid, polyglycolic acid, poly(lactic-glycolic acid) (PLGA), poly(2-hydroxyethyl methacrylate), poly(2-hydroxypropyl methacrylate), poly(acrylic acid), carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, hydrophobically-modified hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose (MCC), nitrocellulose, polyvinyl alcohol, polyvinylpyrrolidone, poly(vinyl methacrylate), carboxy vinyl polymers, poly(vinyl acetate), polyvinyl co-polymers, starch, modified starch, and mixtures thereof.

[0294] 30. The method of embodiment 28, wherein the carrier is microcrystalline cellulose(MCC).

[0295] In the detailed description, references to “various embodiments”, "one embodiment", "an embodiment", "an example embodiment", etc., indicate that the embodiment described may include a particular feature, structure, or characteristic, but every embodiment may not necessarily include the particular feature, structure, or characteristic. Moreover, such phrases are not necessarily referring to the same embodiment. Further, when a particular feature, structure, or characteristic is described in connection with an embodiment, it is submitted that it is within the knowledge of one skilled in the art to affect such feature, structure, or characteristic in connection with other embodiments whether or not explicitly described. After reading the description, it will be apparent to one skilled in the relevant art(s) how to implement the disclosure in alternative embodiments.

[0296] Steps recited in any of the method or process descriptions may be executed in any order and are not necessarily limited to the order presented. Furthermore, any reference to singular includes plural embodiments, and any reference to more than one component or step may include a singular embodiment or step. Also, any reference to attached, fixed, connected, coupled or thelike may include permanent (e.g, integral), removable, temporary, partial, full, and / or any other possible attachment option. Any of the components may be coupled to each other via friction, snap, sleeves, brackets, clips or other means now known in the art or hereinafter developed. Additionally, any reference to without contact (or similar phrases) may also include reduced contact or minimal contact.

[0297] With respect to ingredients that are grouped by function or characterized herein, unless otherwise expressly stated herein, it is not precluded that such an ingredient could be grouped with or characterized by another function. For example, an ingredient discussed herein as a solubilizer could also function as a surfactant and vice versa. The ranges disclosed herein also encompass any and all overlap, sub-ranges, and combinations thereof. Language such as “up to,” “at least,” “greater than,” “less than,” “between,” and the like includes the number recited. Numbers preceded by a term such as “about” or “approximately” include the recited numbers. For example, “about 90%” includes “90%. ” Language such as “at least 95% (S)-nicotine in the form of a free base alkaloid includes 96%, 97%, 98%, 99%, and 100% (S)-nicotine in the form of a free base alkaloid. Any titles or subheadings used herein are for organization purposes and should not be used to limit the scope of embodiments disclosed herein.

[0298] Benefits, other advantages, and solutions to problems have been described herein with regard to specific embodiments. However, the benefits, advantages, solutions to problems, and any elements that may cause any benefit, advantage, or solution to occur or become more pronounced are not to be construed as critical, required, or essential features or elements of the disclosure. The scope of the disclosure is accordingly to be limited by nothing other than the appended claims, in which reference to an element in the singular is not intended to mean "one and only one" unless explicitly so stated, but rather "one or more." Moreover, where a phrase similar to 'at least one of A, B, and C or 'at least one of A, B, or C is used in the claims or specification, it is intended that the phrase be interpreted to mean that A alone may be present in an embodiment, B alone may be present in an embodiment, C alone may be present in an embodiment, or that any combination of the elements A, B and C may be present in a single embodiment; for example, A and B, A and C, B and C, or A and B and C.

[0299] All structural, chemical, and functional equivalents to the elements of the abovedescribed various embodiments that are known to those of ordinary skill in the art are expressly incorporated herein by reference and are intended to be encompassed by the present claims.Moreover, it is not necessary for an apparatus or component of an apparatus, or method in using an apparatus to address each and every problem sought to be solved by the present disclosure, for it to be encompassed by the present claims. Furthermore, no element, component, or method step in the present disclosure is intended to be dedicated to the public regardless of whether the element, component, or method step is explicitly recited in the claims. No claim element is intended to invoke 35 U.S.C. 112(f) unless the element is expressly recited using the phrase “means for.” As used herein, the terms “comprises”, “comprising”, or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a chemical, chemical composition, process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such chemical, chemical composition, process, method, article, or apparatus.

Claims

CLAIMS1. A hydrogel comprising: an active; a polymer; a plasticizer; and a disintegrant; wherein the active is selected from the group consisting of (S)-nicotine, an (S)- nicotine salt, an (S)-nicotine complex, caffeine, menthol, melatonin, cannabidiol (CBD), tetrahydrocannabinol (THC), quercetin, y-aminobutyric acid (GABA), theanine, L-tryptophan, 5 -hydroxy -L-tryptophan (5-HTP), and mixtures thereof2. The hydrogel of Claim 1, wherein the polymer is selected from the group consisting of sodium alginate, pectin, pullulan, glucan, dextrin, maltodextrin, xanthan gum, xyloglucan, tragacanth gum, guar gum, acacia gum, Arabic gum, starch, agarose, gelatin, gellan, chitosan, carrageenan, chondroitin sulfate, collagen, silk fibroin, sericin, scleroglucan, cellulose, hyaluronic acid, hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), ethyl cellulose (EC), hydroxypropyl ethyl cellulose (HPEC), and combinations thereof.

3. The hydrogel of Claim 2, wherein the polymer comprises gelatin, pullulan, acacia gum, sodium alginate, carboxymethylcellulose (CMC), hydroxypropyl methylcellulose (HPMC), or mixtures thereof.

4. The hydrogel of Claim 1, wherein the active comprises (S)-ni cotine, wherein the (S)- nicotine is in the form of free base nicotine without positive charge.

5. The hydrogel of Claim 1, wherein the active comprises an (S)-nicotine salt, the (S)-nicotine salt further comprising a protonated (S)-nicotine cation in association with a negatively charged counterion comprising a conjugate base of an organic acid.

6. The hydrogel of Claim 5, wherein the organic acid is selected from the group consisting of formic acid, acetic acid, adipic acid, trifluoroacetic acid, aspartic acid, butanoic acid, butyric acid, 2-methylbutyric acid, 3- methylbutyric acid, benzoic acid, caprylic acid, citric acid, crotonic acid, butanoic acid, ethylenedi aminetetraacetic acid (EDTA), C8-C26 saturated, monounsaturated, or polyunsaturated fatty acids, fumaric acid, gluconic acid, glutamic acid, glyceric acid, glycidic acid, glycolic acid, glyoxylic acid, hexanoic acid, heptanoic acid, lactic acid, lauric acid, levulinic acid, maleic acid, L-(-)-malic acid, malonic acid, mandelic acid, mesooxalic acid, methane sulfonic acid, oxalic acid, pentanoic acid, phenylacetic acid, phthalic acid, picric acid, propionic acid, 3- oxopropanoic acid, 2,3-dioxopropanoic acid, 2, 3, -dihydroxypropanedioic acid, propiolic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tannic acid, L-(+)-tartaric acid, tartronic acid, valeric acid, vanillic acid, and mixtures thereof.

7. The hydrogel of Claim 1, wherein the (S)-nicotine salt comprises (S)-ni cotine lactate, nicotine benzoate, nicotine levulinate, nicotine salicylate, nicotine malate, and / or nicotine tartrate.

8. The hydrogel of Claim 1, wherein the (S)-nicotine complex comprises (S)-nicotine in association with a saturated fatty acid, a monounsaturated fatty acid, a polyunsaturated fatty acid, or mixtures thereof.

9. The hydrogel of Claim 1, wherein the active comprises an (S)-nicotine complex, wherein the (S)-nicotine complex is an (S)-nicotine inclusion complex comprising (S)-nicotine in association with a cyclodextrin.

10. The hydrogel of Claim 9, wherein the cyclodextrin is selected from the group consisting of P- cyclodextrin, hydroxypropyl-P-cyclodextrin, methyl-P-cyclodextrin, dimethyl- -cyclodextrin, heptakis(2,6-di-O-)ethyl-P-cyclodextrin, 6-O-a-maltosyl-P-cyclodextrin, randomly methylated P- 15 cyclodextrin (RAMEB), sulfobutylether-P-cyclodextrin, sulfolipo-P-cyclodextrin, y- cyclodextrin, hydroxypropyl-y-cyclodextrin, octakis-(6-bromo-6-deoxy)-y-cyclodextrin, octakis- (6-amino-6- deoxy)-y-cyclodextrin, octakis-(6-chloro-6-deoxy)-y-cyclodextrin, octakis-(6-deoxy- 6-iodo)-y- cyclodextrin, octakis-(6-deoxy-6-mercapto)-'y-cyclodextrin, octakis-(2,3,6-tri-O-methyl)-' / - cyclodextrin, octakis-(2,3-diacetyl-6-sulfato)-y-cyclodextrin, octakis-(3-O-butyryl- 2,6-di-O-pentyl)- / -cyclodextrin, octakis-6-sulfato- / -cyclodextrin, and mixtures thereof.

11. The hydrogel of Claim 1, wherein the plasticizer is selected from the group consisting of tris- 2- ethylhexyltrimellitate, dioctyl terephthalate, di-isobutyl terephthalate, N-butylbenzene sulfonamide, di-isodecylsebacate, di-2-ethylhexylsebacate, dibutylsebacate, dimethylsebacate, 25 tri s(2 -ethyl hexyl) phosphate, 2-ethylhexyl diphenyl phosphate, triphenyl phosphate, 2,2,4- trimethyl-1,3 pentanediol di-isobutyrate, di-C16-18 alkyl phthalate, benzyl C7-9-branched and linear alkyl phthalate, di-isotridecyl phthalate, di-isoundecyl phthalate, di(2-propyl heptyl) phthalate, di- isodecyl phthalate, di-isononyl phthalate, bis(2-ethylhexyl) phthalate, di-isooctyl phthalate, di-n- octyl phthalate, di-isoheptyl phthalate, di-cyclohexyl phthalate, di-isohexyl phthalate, di-n-hexylphthalate, di-n-pentyl phthalate, benzyl butyl phthalate, di-isobutyl phthalate, di-n-butyl phthalate, di-n-propyl phthalate, diethyl phthalate, dimethyl phthalate, epoxidized triglyceride vegetable oils from soybean oil, linseed oil, castor oil, or sunflower oil, di-isononyl cyclohexane di carb oxy late, citric acid, acetyl tributyl citrate, tributyl citrate, triethyl citrate, triethylene glycol dibenzoate, isodecyl benzoate, isononyl benzoate, dipropylene glycol dibenzoate, diethylene glycol dibenzoate, neopentylglycol dibenzoate, diisodecyl azelate, bis[2- (2-butoxyethoxy)ethyl] adipate, di(butoxyethyl) adipate, di-n-butyl adipate, ditridecyl adipate, diisodecyl adipate, diisononyl adipate, di-2-ethylhexyl adipate, benzyl 2-ethylhexyl adipate, diisobutyl adipate, glyceryl triacetate, diethyl succinate, dibutyl succinate, dihexyl succinate, diethylhexyl succinate, didecyl succinate, didodecyl succinate, poly(hexylene succinate), poly(butylene succinate), polypropylene glycol succinate), poly(ethylene glycol succinate), 1,2- propylene glycol, diethylene glycol, various fatty acid esters (FAEs), glycerin, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol (PEGs), propylene glycol, sorbitol, mannitol, xylitol, glucose, mannose, fructose, sucrose, urea, fatty acid glyceride comprises medium-chain length triglyceride (MCT) oil, sunflower oil, canola oil, palm oil, coconut oil, safflower oil, olive oil, sesame oil, peanut oil, avocado oil, and soybean oil, and mixtures thereof.

12. The hydrogel of Claim 11 , wherein the plasticizer comprises at least one of an triglyceride vegetable oil from soybean oil, linseed oil, castor oil, or sunflower oil, citric acid, glycerin, 1,2- propylene glycol, diethylene glycol, sorbitol, and polyethylene glycol succinate).

13. The hydrogel of Claim 1, wherein the disintegrant is selected from the group consisting of starch, sodium starch glycolate Type A, sodium starch glycolate Type B, powdered microcrystalline cellulose (MCC), guar gum, xanthan gum, locust bean gum, chitosan hydrochloride, alginic acid, calcium alginate, sodium alginate, docusate sodium, dicalcium phosphate, tricalcium phosphate, magnesium aluminum silicate, bentonite, guargalactomannan, crosslinked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, methylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, calcium cellulose glycolate, crospovidone, and mixtures thereof.

14. The hydrogel of Claim 1, wherein the disintegrant comprises powdered microcrystalline cellulose (MCC).

15. The hydrogel of Claim 1, wherein the disintegrant comprises a surfactant selected from the group consisting of lecithin, phosphatidylcholine, EO / PO block copolymers, EO / PO / EO triblock copolymers, polyethylene glycol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, span 20, span 40, span 60, span 80, and mixtures thereof.

16. The hydrogel of any one of Claims 1 to 15, further comprising a sol vent / co- solvent selected from water, or a fatty acid glyceride selected from the group consisting of sunflower oil, canola oil, palm oil, coconut oil, safflower oil, olive oil, sesame oil, peanut oil, avocado oil, soybean oil, and combinations thereof.

17. The hydrogel of any one of Claims 1 to 15, further comprising a flavoring agent.

18. The hydrogel of any one of Claims 1 to 15, further comprising a sugar alcohol from the group consisting of sorbitol, xylitol, erythritol, lactitol, maltitol, mannitol, isomalt, hydrogenated starch hydrolysates, and combinations thereof.

19. A hydrogel-based oral strip comprising: an active; a polymer; a plasticizer; and a di si nt egrant; wherein the active is selected from the group consisting of (S)-nicotine, an (S)- nicotine salt, an (S)-nicotine complex, caffeine, menthol, melatonin, cannabidiol (CBD), tetrahydrocannabinol (THC), quercetin, y-aminobutyric acid (GABA), theanine, L-try ptophan, 5- hydroxy -L-tryptophan (5-HTP), and mixtures thereof.

20. The hydrogel -based oral strip of Claim 19, wherein the active is an (S)-nicotine salt comprising (S)-ni cotine lactate, nicotine benzoate, nicotine levulinate, nicotine salicylate, nicotine malate, and / or nicotine tartrate.

21. The hydrogel -based oral strip of Claim 19, wherein the strip is configured as a rectangular shape measuring from about 3 cm2(0.5 in2) to about 13 cm2(2.0 in2) in surface area, and from about 20pm (0.8 mil) to about 3,000pm (118 mil) in thickness.

22. The hydrogel-based nicotine oral strip of Claim 19, wherein each strip includes from about 1 mg to about 10 mg of free base nicotine as the active.

23. The hydrogel -based oral strip of Claim 19, wherein the polymer is selected from the group consisting of gelatin, pullulan, acacia gum, sodium alginate, carboxymethylcellulose (CMC), hydroxypropyl methylcellulose (HPMC), and mixtures thereof.

24. An oral nicotine pouch (ONP) comprising:a saliva-permeable nonwoven fabric defining an enclosure containing a hydrogel therein, wherein said hydrogel comprises (S)-ni cotine, or a salt or a complex thereof; a polymer; a surfactant; a flavoring agent; a polysaccharide; and a solvent / co-solvent.

25. The oral nicotine pouch (ONP) of Claim 24, wherein the hydrogel further comprises a carrier.

26. The oral nicotine pouch (ONP) of Claim 25, wherein the carrier is selected from the group consisting of agar, agarose, albumin, alginate, casein, chitin, chondroitin, dextrin, fibroin, fucoidans, galactans, gellan, guar, scleroglucan, pullulan, xyloglucan, pectin, xanthan, psyllium, silica gel, fumed silica, magnesium aluminum silicates, clay, bentonite, hectorite, mesoporous silica, cellulose, cellulose acetate, hyaluronan, various elastin-like polypeptides, P-cyclodextrin, collagen, gelatin, chitosan, carrageenan, polylactic acid, polyglycolic acid, poly(lactic- glycolicacid) (PLGA), poly(2-hydroxyethyl methacrylate), poly(2-hydroxypropyl methacrylate), poly(acrylic acid), carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, hydrophobically-modified hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose (MCC), nitrocellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyfvinyl methacrylate), carboxy vinyl polymers, poly(vinyl acetate), polyvinyl co-polymers, starch, modified starch, and mixtures thereof.

27. The oral nicotine pouch (ONP) of Claim 24, wherein the hydrogel is mixed with a carrier.

28. The oral nicotine pouch (ONP) of Claim 27, wherein the carrier comprises water insoluble fibers, microcrystalline cellulose, bamboo fibers, lignin, wheat fibers, pea fibers, maize fibers, rice fiber, oat fibers, barley fibers, buckwheat fibers, cellulose fibers, bran fibers, powdered cellulose, and combinations thereof.

29. The oral nicotine pouch (ONP) of Claim 28, wherein the carrier is microcrystalline cellulose (MCC).

30. The oral nicotine pouch (ONP) of any one of Claims 24 to 29, wherein the amount of nicotine is from 0.1% to 4% by weight of the pouch composition.

31. The oral nicotine pouch (ONP) of any one of Claims 24 to 30, wherein the amount of polymer is from 0.1% to 20% by weight of the pouch composition.

32. The oral nicotine pouch (ONP) of any one of Claims 24 to 31, wherein the amount of surfactant is from 0.01% to 10% by weight of the pouch composition.

33. The oral nicotine pouch (ONP) of any one of Claims 24 to 32, wherein the amount of polysaccharide is from 0.1% to 5% by weight of the pouch composition.

34. The oral nicotine pouch (ONP) of any one of Claims 24 to 33, wherein the amount of solvent / co-solvent or the combination of solvent / co-solvent is from 0.1% to 60% by weight of the pouch composition.

35. A method of manufacturing an oral nicotine pouch (ONP), the method comprising: providing a saliva-permeable nonwoven fabric defining an enclosure; preparing an aqueous mixture comprising:(S)-ni cotine, a salt or a complex thereof at least a polysaccharide or other naturally occurring hydrogel-forming polymer; at least a solvent; and at least a surfactant; absorbing the aqueous mixture onto a carrier to form a free-flowing mixture; and disposing a portion of the free-flowing mixture in the enclosure.

36. The method of Claim 35, wherein the (S)-nicotine, a salt or a complex thereof is free base nicotine.

37. The method of Claim 35, wherein the carrier is microcrystalline cellulose (MCC).

38. The method of Claim 35, wherein the portion of free-flowing mixture disposed in said enclosure weighs from about 10 mg to about 1000 mg.

39. A method of increasing a rate of (S)-nicotine delivery from an oral nicotine pouch comprising a fdl material consisting of (S)-nicotine, or a salt or a complex thereof, admixed with or adsorbed onto a carrier, the fdl material disposed inside a saliva-permeable nonwoven fabric pouch, said method comprising:(1) preparing an aqueous solution or suspension comprising the (S)-nicotine, salt, or complex thereof, a polysaccharide or other naturally occurring hydrogel -forming polymer, a plasticizer, and a disintegrant; adsorbing the aqueous solution or suspension onto the carrier to form the fdl material; and disposing the fdl material inside the saliva-permeable nonwoven fabric pouch; or(2) dispersing the carrier in an aqueous solution or suspension comprising the (S)-nicotine, salt, or complex thereof, a polysaccharide or other naturally occurring hydrogel -forming polymer, a plasticizer, and a disintegrant; solidifying the dispersion into a hydrogel; and disposing the hydrogel as the fdl material inside the saliva-permeable nonwoven fabric pouch; or(3) preparing an aqueous solution or suspension comprising the (S)-nicotine, salt, or complex thereof, a polysaccharide or other naturally occurring hydrogel -forming polymer, a plasticizer, and a disintegrant; solidifying the dispersion into a hydrogel; admixing the hydrogel with the carrier to form the fdl material; and disposing the fdl material inside the saliva-permeable nonwoven fabric pouch.

40. The method of Claim 39, wherein the carrier is selected from the group consisting of agar, agarose, albumin, alginate, casein, chitin, chondroitin, dextrin, fibroin, fucoidans, galactans, gellan, guar, scleroglucan, pullulan, xyloglucan, pectin, xanthan, psyllium, silica gel, fumed silica, magnesium aluminum silicates, clay, bentonite, hectorite, mesoporous silica, cellulose, celluloseacetate, hyaluronan, various elastin-like polypeptides, P-cyclodextrin, collagen, gelatin, chitosan, carrageenan, polylactic acid, polyglycolic acid, poly(lactic-glycolic acid) (PLGA), poly(2- hydroxyethyl methacrylate), poly(2-hydroxypropyl methacrylate), poly(acrylic acid), carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, hydrophobically- modified hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose (MCC), nitrocellulose, polyvinyl alcohol, polyvinylpyrrolidone, poly(vinyl methacrylate), carboxy vinyl polymers, poly(vinyl acetate), polyvinyl co-polymers, starch, modified starch, and mixtures thereof.

41. The method of Claim 39 or 40, wherein the carrier is microcrystalline cellulose (MCC).

42. The hydrogel of any one of Claims 1 to 18, wherein the hydrogel is configured for use in manufacturing one or more of: a. An oral spray; b. A transdermal patch; c. A nasal spray; d. An inhaler; and e. A sublingual tablet.

43. A fill material for an oral nicotine pouch, the fill material comprising: nicotine, wherein the nicotine is present in amount between 0.1% and 4%; one, or both, of lactic acid and citric acid, wherein the lactic acid and / or citric acid is present in an amount between 0.1% and 2%; cellulose, wherein the cellulose is present in an amount between 40% and 70%; glycerin, wherein the glycerin is present in amount between 0.1% and 4%; a hydrogel, wherein the hydrogel is present in an amount between 1% and 15%; an emulsion, wherein the emulsion is present in an amount between 0.01% and 30%, and water, wherein the water is present in an amount between 15% and 40%; wherein the amounts are by weight of the fill material.

44. The fill material of Claim 43, wherein the nicotine is present in an amount between 0.5% and 2%.

45. The fill material of Claim 43 or 44, wherein the fill material comprises both lactic acid and citric acid, wherein each of the lactic acid and citric acid are present in an amount between 0.2% and 1.2%.

46. The fill material according to any one of Claims 43 to 45, wherein the cellulose comprises microcrystalline cellulose and is present in an amount between 48% and 68%.

47. The fill material according to any one of Claims 43 to 46, wherein the glycerin is present in an amount between 0.3% and 2.5%.

48. The fill material according to any one of Claims 43 to 47, wherein the hydrogel comprises one or more of acacia gum, sodium alginate, carboxymethyl cellulose, guar gum, tapioca maltodextrin, tara gum, Hypromellose, pullulan, maltodextrin, and gelatin, and wherein the hydrogel is present in an amount between 3% and 12%.

49. The fill material according to any one of Claims 43 to 48, wherein the emulsion comprises an oil and a surfactant, wherein the oil is present in an amount between 0.05% and 18% and wherein the surfactant is present in an amount between 0.05% and 18%.

50. The fill material of Claim 49, wherein the oil is selected from the group consisting of sunflower oil, canola oil, palm oil, coconut oil, safflower oil, olive oil, sesame oil, peanut oil, avocado oil, soybean oil, and combinations thereof.

51. The fill material of Claim 49 or 50, wherein the surfactant is selected from the group consisting of lecithin, phosphatidylcholine, EO / PO block copolymers, EO / PO / EO triblock copolymers, polyethylene glycol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, span 20, span 40, span 60, span 80, and mixtures thereof.

52. The fill material of Claim 51, wherein the surfactant comprises polysorbate 80.

53. The fill material according to any one of Claims 43 to 52, wherein the water comprises deionized water and is present in an amount between 18% and 39%.

54. The fill material according to any one of Claims 43 to 53, further comprising one or both of a flavorant and a sweetener.

55. A fill material for an oral delivery pouch, the fill material comprising: an active agent, wherein the active agent is present in amount between 0.1% and 4%; one, or both, of lactic acid and citric acid, wherein the lactic acid and / or citric acid is present in an amount between 0.1% and 2%; cellulose, wherein the cellulose is present in an amount between 40% and 70%; glycerin, wherein the glycerin is present in amount between 0.1% and 4%; a hydrogel, wherein the hydrogel is present in an amount between 1% and 15%; an emulsion, wherein the emulsion is present in an amount between 0.01% and 30%, and water, wherein the water is present in an amount between 15% and 40%; wherein the amounts are by weight of the fill material.

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