Compositions, products, and systems for improved oral delivery of nicotine and methods of making and using same

Abstract

The present disclosure provides improved compositions, products, and systems for the oral delivery of nicotine and methods of their production and use.

Description

Attorney Docket No.7656-043030 COMPOSITIONS, PRODUCTS, AND SYSTEMS FOR IMPROVED ORAL DELIVERY OF NICOTINE AND METHODS OF MAKING AND USING SAME CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 691,190, filed on September 5, 2024, and to U.S. Provisional Application No.63 / 774,544, filed on March 19, 2025, which are hereby incorporated by reference in their entirety. FIELD OF THE INVENTION

[0002] The present disclosure relates to improved compositions for orally delivering nicotine and methods of their production and use. BACKGROUND OF THE DISCLOSURE

[0003] Nicotine, the main addictive ingredient of tobacco, facilitates the development and maintenance of tobacco use disorder (TUD). Nicotine, as nicotine replacement therapy (NRT), helps smokers quit smoking. Jensen et al., January 29, 2020, Differential effects of nicotine delivery rate on subjective drug effects, urges to smoke, heart rate and blood pressure in tobacco users, Psychopharmacology, Vol. 237, pages 1359-1369. The idea of clean nicotine delivery systems that would satisfy nicotine craving and promote smoking cessation has been considered as a possible public health tool for many years. Nicotine medications have been useful for smoking cessation but have not found widespread popularity among smokers, perhaps because of slow nicotine delivery and other sensory characteristics that differ from cigarettes. Neal L. Benowitz, January 2, 2014, Emerging nicotine delivery products. Implications for public health, Annals of the American Thoracic Society, Vol.11, Issue 2.

[0004] While nicotine is mainly associated with the harmful effects of smoking, it can also offer certain benefits. These include: (1) increased levels of alertness, euphoria, and relaxation; (2) improved concentration and memory – due to increased activity of the acetylcholine and norepinephrine neurotransmitters; and (3) reduced anxiety – due to increased levels of beta-endorphin, which reduces anxiety. Lucy Holl, March 29, 2024, Nicotine: The Good, The Bad & The Ugly, Echelon Health: Advice, News, Regulation,Attorney Docket No.7656-043030 Technology. While nicotine is a cheap, common, and mostly safe drug, in daily use for centuries by hundreds of millions of people, it has been investigated lately for its therapeutic potential for a lengthy list of common ills. The list includes Alzheimer disease, Parkinson disease, depression and anxiety, schizophrenia, attention deficit hyperactivity disorder (ADHD), and even pain and obesity. Tabitha M. Powledge, November 16, 2004, Nicotine as Therapy, PLoS, 2(11):e404.

[0005] Thus, there is presently a large unmet need for alternative formats of nicotine delivery to reduce smoking dependence, to maximize positive nicotine dosing, to treat and / or ameliorate diseases and disorders, and to improve user experiences. The present disclosure provides the methods and compositions to satisfy this large opportunity for such nicotine product development, deployment, and uses. SUMMARY OF THE DISCLOSURE

[0006] To overcome the challenges of the currently used methods for producing and administering improved nicotine compositions, the present disclosure utilizes a ternary system comprising consisting essentially of, or consisting of nicotine, cyclodextrin, and a polymer, which results in encapsulated nicotine complexes with improved stability and processability under scCO2 conditions. Supercritical CO2 is also commonly referred to as sCO2, sCO2, scCO2, and scCO2, each of which is used interchangeably herein.

[0007] In some embodiments, the present disclosure provides nicotine products and nicotine systems comprising oral nicotine formulations with improved shelf stability and methods of their use.

[0008] In some embodiments, the present disclosure provides nicotine products and nicotine systems comprising oral nicotine formulations with increased absorption across buccal tissues following their oral administration to users.

[0009] In some embodiments, the present disclosure provides nicotine product and nicotine systems with improved overall user experiences in orally delivered formats and methods of their use.

[0010] In some embodiments, the present disclosure provides oral nicotine products and oral nicotine systems with improved sensory organoleptic experiences and feedback following their oral administration to users.Attorney Docket No.7656-043030

[0011] In some embodiments, the present disclosure provides oral nicotine products and oral nicotine systems with reduced throat burn and faster onset following their oral administration to users.

[0012] In some embodiments, the present disclosure provides oral nicotine products and oral nicotine systems with longer lasting, more intense flavor following their oral administration to users.

[0013] In some embodiments, the present disclosure provides methods for preparing encapsulated nicotine complexes using scCO2, wherein the complexes can be used in compositions and formulations for oral and topical delivery.

[0014] In some embodiments, the present disclosure provides methods for producing encapsulated nicotine complexes involve using a ternary system comprising nicotine, cyclodextrin, and a polymer(s), such as poloxamer(s), which are mixed under scCO2 to obtain a homogeneous solid mixture. As disclosed herein the polymer, e.g., a poloxamer, acts as a co-solvent under high-pressure CO2 and plays a crucial role in improving the stability and bioavailability of nicotine.

[0015] In some embodiments, the methods of preparing encapsulated nicotine complexes of the present disclosure comprise, consist essentially of, or consist of the following steps: (1) placing the required amount of free-base nicotine or nicotine salt, at least one cyclodextrin, and at least one suitable polymer, e.g., a poloxamer, in a high-pressure vessel; (2) pressurizing the vessel by pumping CO2 to obtain supercritical CO2 conditions; (3) mixing all the ingredients under supercritical CO2 to obtain a homogeneous mixture; and (4) depressurizing the vessel to obtain solid powder products.

[0016] In some embodiments, the active nicotine ingredient in the nicotine compositions and formulations of the present disclosure can be in the form of free-base nicotine or nicotine salts, wherein such nicotine forms are naturally and / or synthetically derived.

[0017] In some embodiments, the present disclosure provides oral nicotine compositions and formulations produced using a sterile, single step process, without using organic solvents, and methods of their use.

[0018] In some embodiments, the nicotine compositions of the present disclosure provide versatility in their uses for a variety of different oral products (e.g., formulations), including but not limited to pouches (e.g., moistened pouches, dry pouches, flavored pouches, flavorlessAttorney Docket No.7656-043030 pouches), ellipses, ellipsoids, films (e.g., oral films), gums, tablets (e.g., sublingual tablets), capsules, lozenges, and strips (e.g., tongue strips).

[0019] In some embodiments, the nicotine compositions and formulations of the present disclosure further comprise a flavoring agent.

[0020] The nicotine compositions and formulations of the present disclosure may be in the form or category of a pharmaceutical, biological product, nutraceutical, botanical drug, supplement, food, or any combination product. The actual form or categorization of the nicotine compositions and formulations of the present disclosure will depend on a number of varied factors including but not limited to the composition’s intended usage, nicotine concentration, nicotine dosage, method of administration (e.g., oral versus topical), the focus and findings from clinical trials, the appropriate regulatory approval pathway, and product labeling.

[0021] In some embodiments, all, most, or some of the ingredients of the compositions and formulations of the present disclosure are each considered as Generally Recognized as Safe (GRAS) under Sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act.

[0022] In some embodiments, the present disclosure provides methods of making a homogeneous solid powder encapsulated nicotine complex composition comprising nicotine, wherein the method comprises, consists essentially of, or consists of loading ingredients into a high pressure vessel, wherein the ingredients comprise nicotine, one or more cyclodextrins, and one or more polymers; heating and pressuring the vessel; pumping CO2into the vessel to obtain supercritical CO2 conditions; mixing the ingredients under the supercritical CO2conditions to produce a homogenous mixture; and, depressurizing the vessel to obtain the homogeneous solid powder composition comprising nicotine.

[0023] In some embodiments, the present disclosure provides homogeneous solid powder compositions comprising nicotine obtained by the methods of making disclosed herein.

[0024] In some embodiments, the methods of making provided by the present disclosure comprise adding ingredients which comprise about 4% to about 15% nicotine, about 30% to about 55% of one or more polymers, and about 32% to about 58% of one or more cyclodextrins.Attorney Docket No.7656-043030

[0025] In some embodiments, the methods of making of the present disclosure utilize polymers that exhibit a melting point depression under supercritical CO2thereby allowing for dissolution of the nicotine and the one or more cyclodextrins to form a homogeneous mixture.

[0026] In some embodiments, the disclosed methods of making utilize one or more polymers that are poloxamers. In some embodiments, the one or more poloxamers are poloxamer-407 and / or poloxamer-188.

[0027] In some embodiments, the methods of making disclosed herein further comprise adding one or more flavorings as additional ingredients. In some embodiments, the one or more flavorings are menthol, eucalyptus oil, peppermint oil and / or cornmint oil.

[0028] In some embodiments, the methods of making disclosed herein further comprise adding one or more other excipients as additional ingredients.

[0029] In some embodiments, the methods of making disclosed herein do not involve using any organic solvents.

[0030] In some embodiments, the methods of making and the resultant compositions and formulations comprise nicotine freebase or nicotine bitartrate.

[0031] In some embodiments, the present disclosure provides a homogenous solid powder encapsulated nicotine complex for oral administration, wherein the composition comprises, consists essentially of, or consists of about 1.0% to about 20.0% nicotine, one or more poloxamers, and one or more cyclodextrins, and wherein the composition comprises a bulk density of about 0.35 g / ml to about 0.65 g / ml, a tap density of about 0.6 g / ml to about 0.8 g / ml, and a water content of about 2% to about 15%. In some embodiments these complexes further comprise one or more flavorings. In some embodiments, these complexes further comprise one or more additional excipients.

[0032] In some embodiments, the compositions and formulations provided by the present disclosure exhibit longer shelf life when subjected to accelerated storage conditions when compared in side-by-side tests with compositions and formulations comprising nicotine which do not comprise the one or more cyclodextrins and one or more poloxamers as disclosed herein.

[0033] In some embodiments, the compositions and formulations provided by the present disclosure exhibit faster permeation of nicotine across buccal membranes when compared inAttorney Docket No.7656-043030 side-by-side tests with compositions comprising nicotine which do not comprise the one or more cyclodextrins and one or more poloxamers as disclosed herein.

[0034] In some embodiments, the compositions and formulations provided by the present disclosure provide a user with a qualitatively better organoleptic sensory experience when compared in side-by-side tests with compositions comprising nicotine which do not comprise the one or more cyclodextrins and one or more poloxamers as disclosed herein. In some embodiments, the improved organoleptic sensory experience is one or more organoleptic sensory experiences selected from the group consisting of throat burn, bitterness, taste, and onset time.

[0035] In some embodiments, the present disclosure provides methods of treating or ameliorating a disease, symptom, and / or disorder in a patient in need thereof, wherein the methods comprise, consist essentially of, or consist of orally administrating the compositions and formulations of the present disclosure to the patient. In some embodiments, such methods utilize compositions formulated as a pouch (e.g., moistened pouches, dry pouches, flavored pouches, flavorless pouches), ellipse, ellipsoid, film (e.g., oral films), gum, tablet (e.g., sublingual tablets), capsule, lozenge, and strip (e.g., tongue strips).

[0036] In some embodiments, the present disclosure provides methods of making a homogeneous solid powder composition comprising nicotine, wherein the methods comprise, consist essentially of, or consist of loading ingredients into a high pressure vessel, wherein the ingredients comprises, consists essentially of, or consists of nicotine, one or more cyclodextrins, and one or more polymers; heating and pressuring the vessel; pumping CO2into the vessel to obtain supercritical CO2 conditions; mixing the ingredients under the supercritical CO2 conditions to produce a homogenous mixture; and, depressurizing the vessel to obtain the homogeneous solid powder composition comprising nicotine, wherein the methods do not include a spraying step. In some embodiments, homogeneous solid powder compositions comprising nicotine are obtained by these methods.

[0037] In some embodiments, the loaded ingredients used in the methods comprise, consist essentially of, or consist of on a weight / weight basis about 4% to about 15% nicotine, about 30% to about 55% of one or more polymers, and about 32% to about 58% of one or more cyclodextrins. In some embodiments, the one or more polymers used in the methods are polymers that exhibit a melting point depression under supercritical CO2thereby allowing forAttorney Docket No.7656-043030 dissolution of the nicotine and the one or more cyclodextrins to form a homogeneous mixture. In some embodiments, the one or more polymers used in the methods are poloxamers. In some embodiments, the one or more poloxamers used in the methods are poloxamer-407 and / or poloxamer-188. In some embodiments, the ingredients used in the methods further comprise one or more flavorings. In some embodiments, the one or more flavorings used in the methods are peppermint oil, eucalyptus oil, and / or cornmint. In some embodiments, the ingredients used in the methods further comprise one or more other excipients. In some embodiments, the methods do not involve using any organic solvents. In some embodiments, the nicotine used in the methods is nicotine freebase and / or nicotine bitartrate.

[0038] In some embodiments, the present disclosure provides homogenous solid powder compositions for oral administration, wherein the compositions comprise, consist essentially of, or consist of on a weight / weight basis about 1.0% to about 20.0% nicotine, one or more poloxamers, and one or more cyclodextrins, and wherein the compositions comprise a bulk density of about 0.35 g / ml to about 0.65 g / ml, a tap density of about 0.6 g / ml to about 0.8 g / ml, and a water content of about 2% to about 15%. In some embodiments, the nicotine in the compositions is nicotine freebase and / or nicotine bitartrate. In some embodiments, the compositions further comprise one or more flavorings. In some embodiments, the compositions comprise peppermint oil, eucalyptus oil, and / or cornmint. In some embodiments, the compositions further comprise one or more pH adjustors. In some embodiments, the compositions further comprise one or more additional excipients.

[0039] In some embodiments, the present disclosure provides compositions formulated as a pouch. In some embodiments, the pouch is a moistened pouch. In some embodiments, the moisture content of the moistened pouch is maintained at 5% weight / weight to 15% weight / weight. In some embodiments, the moistened pouch has a width of 10 mm to 20 mm and a length of 20 mm to 30 mm.

[0040] In other embodiments, the pouch is a flavorless dry pouch. In some embodiments, the moisture content of the flavorless dry pouch is maintained at less than 5% weight / weight. In some embodiments, the flavorless dry pouch has a width of 10 mm to 20 mm and a length of 20 mm to 30 mm in length. In some embodiments, the flavorless dry pouch has a pH of about 7.5 to about 8.5.Attorney Docket No.7656-043030

[0041] In some embodiments, the present disclosure provides methods of making a composition wherein the nicotine is encapsulated within a cyclodextrin-polymer complex. In some embodiments, the encapsulation of the nicotine provides a physical barrier between the nicotine and the pH adjusters.

[0042] In other embodiments, the pouch is a flavored dry pouch. In some embodiments, the moisture content of the flavored dry pouch is maintained at less than 5% weight / weight. In some embodiments, the flavored dry pouch has a width of 10 mm to 20 mm and a length of 20 mm to 30 mm in length. In some embodiments, the flavoring of the flavored dry pouch is supplied in part or in whole by peppermint oil, eucalyptus oil, and / or cornmint.

[0043] In some embodiments, the present disclosure provides compositions formulated as a dissolvable ellipse. In some embodiments, the moisture content of the dissolvable ellipse is maintained at 10% weight / weight to 30% weight / weight. In some embodiments, the dissolvable ellipse has a length of 20 mm to 40 mm, a width of 10 mm to 30 mm, and a thickness of 1 mm to 5 mm. In some embodiments, the dissolvable ellipse has a thickness of 3 mm to 5 mm.

[0044] In some embodiments, the present disclosure provides the compositions formulated as an oral thin film with a length of 20 mm to 40 mm, a width of 10 mm to 30 mm, and a thickness of 50 µm to 2.5 mm.

[0045] In some embodiments, the present disclosure provides compositions and formulations which exhibit longer shelf life when subjected to accelerated storage conditions when compared in side-by-side tests with compositions comprising nicotine which do not comprise the one or more cyclodextrins and one or more poloxamers.

[0046] In some embodiments, the present disclosure provides compositions and formulations wherein the compositions and formulations exhibit faster permeation of nicotine across buccal membranes when compared in side-by-side tests with compositions and formulations comprising nicotine which do not comprise the one or more cyclodextrins and one or more poloxamers.

[0047] In some embodiments, the present disclosure provides compositions and formulations which provide a user with a qualitatively better organoleptic sensory experience when compared in side-by-side tests with compositions and formulations comprising nicotine which do not comprise the one or more cyclodextrins and one or more poloxamers. In someAttorney Docket No.7656-043030 embodiments, the organoleptic sensory experience is one or more organoleptic sensory experiences selected from the group consisting of throat burn, bitterness, taste, and onset time.

[0048] In some embodiments, the present disclosure provides methods of delivering nicotine to an individual, wherein the methods comprise, consist essentially of, or consist of orally administrating the compositions and formulations of the present disclosure to the individual. In some embodiments, the individual is being administered an efficacious dose of nicotine that treats or ameliorates a disease, symptom, and / or disorder. In some embodiments, the methods comprise administering compositions and formulations which further comprise one or more flavorings. In some embodiments, the methods comprise administering compositions and formulations which further comprise one or more flavorings that include peppermint oil, eucalyptus oil, and / or cornmint. In some embodiments, the compositions are formulated to be administered as a moistened pouch, a flavorless dry pouch, a flavored dry pouch, an oral thin film, an ellipse, or a dissolvable ellipse, wherein each of these different formulations have the various features and attributes as disclosed herein.

[0049] Additional benefits and variations of the disclosed nicotine compositions, products, systems, and methods of producing them will become apparent upon reading the present disclosure and examples. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] FIG.1 provides a process flow chart of an exemplary cyclodextrin-polymer-nicotine complexation produced according to the present disclosure.

[0051] FIG 2 provides an engineering diagram of a supercritical CO2 system for the production of cyclodextrin-polymer-nicotine complexation according to the present disclosure. Components of the diagram are as follows: 100: CO2 inlet; 101: check valve; 102: flow control valve; 103: condenser; 104: pump; 105: back pressure regulator; 106: high- pressure mixing vessel; 107: heater; 108: rupture disc; and 109: venting valve.

[0052] FIG. 3a and FIG.3b provide bar charts of the stability of freebase formulations of the present disclosure (FIG. 3b: ES_01, ES_02, and ES_03) as compared to prior art formulations (FIG. 3a: FB_01, FB_02, and FB_03) starting at T0 and as measured weekly over a 4-week time period (Twk1, Twk2, Twk3, and Twk4). The X-axis provides the designation of the formulations. The Y-axis provides the percent of nicotine remaining based on the nicotine amount measured at T0 as 100%. The stability percentages that are greaterAttorney Docket No.7656-043030 than 100% are due to minor calibration variations resulting from, e.g., environmental errors, human error, and / or equipment error.

[0053] FIG. 4 provides a bar chart of the stability of nicotine bitartrate oral pouch formulations of the present disclosure (ENP_02) as compared to commercially available reference formulations (CP_01 and CP_02) starting at T0 and as measured weekly over a 4- week time period (Twk1, Twk2, Twk3, and Twk4). The X-axis provides the designation of the formulations. The Y-axis provides the percent of nicotine remaining based on the nicotine amount measured at T0 as 100%. The stability percentages that are greater than 100% are due to minor calibration variations resulting from, e.g., environmental errors, human error, and / or equipment error.

[0054] FIG. 5 provides a graph of polyether sulfonate (PES) membrane release profiles of nicotine bitartrate oral pouch formulations of the present disclosure (ENP_02) as compared to a commercially available reference formulation (CP_02) and a prior art reference formulation (CP_03). The X-axis provides time in minutes from 0 minutes to 120 minutes. The Y-axis provides the nicotine concentration (ppm).

[0055] FIG.6 provides a process flow chart for an exemplary dry pouch (“ENP”) formulation of the present disclosure.

[0056] FIG.7 provides a process flow chart for an exemplary ellipse (“ELS”) formulation of the present disclosure.

[0057] FIG.8 provides a graph of the fit of the Weibull drug pouch release model for each formulation (i.e., CP_04, CP_05, ENP_02, and ENP_03). The X-axis provides the time in minutes from 0 minutes to 30 minutes. The Y-axis provides the percentage (%) of drug release over time. DETAILED DESCRIPTION OF THE DISCLOSURE I. Definitions

[0058] Unless stated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the disclosure belongs. While the following terms are believed to be well understood by one of ordinary skills in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, preferredAttorney Docket No.7656-043030 methods and materials are described. The following terms are defined below. These definitions are for illustrative purposes and are not intended to limit the common meaning in the art of the defined terms.

[0059] The term “a” or “an” refers to one or more of that entity, i.e., can refer to a plural referent. As such, the terms “a” or “an,” “one or more” and “at least one” are used interchangeably herein. In addition, reference to “an element” by the indefinite article “a” or “an” does not exclude the possibility that more than one of the elements is present, unless the context clearly requires that there be one and only one of the elements.

[0060] As used in this specification, the term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

[0061] Throughout this specification, unless the context requires otherwise, the words “comprise,” or variations such as “comprises” or “comprising,” will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.

[0062] As used in this application, the terms “about” and “approximately” are used as equivalents. Any numerals used in this application with or without about / approximately are meant to cover any normal fluctuations appreciated by one of ordinary skill in the relevant art. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0063] As used herein, a “formulation” refers to a mixture, product, or a structure such as but not limited to a capsule, tablet, emulsion, pouch, ellipse, or oral thin film prepared according to a specific procedure (called a "formula").

[0064] As used herein, a “composition” refers to the nature of something's ingredients or constituents; the way in which a whole or mixture is made up. In some contexts herein, the terms “formulation” and “composition” are used interchangeably where they both refer to a specific mixture.Attorney Docket No.7656-043030

[0065] As used herein, “homogeneous” refers to a substance that is identical or nearly identical wherever it is sampled. A composition is considered homogeneous if it has uniform composition and properties throughout.

[0066] As used herein, “freebase,” “freebasing,” or “freebase nicotine” refer to pure nicotine which is a liquid at room temperature. Freebase nicotine has slightly different properties from nicotine salts (e.g., nicotine bitartrate). Freebase is also referred to herein as “FB” when referring to specific compositions or products, including commercially available products..

[0067] As used herein, “treatment” “treat” or “treating” refers to a method for obtaining beneficial or desired results for a patient, including clinical results. For purposes of the present disclosure, beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from the disease, condition, disorder, and / or symptom; reducing the severity of the disease, condition, disorder, and / or symptom; stabilizing the disease, condition, disorder, and / or symptom (e.g., preventing or delaying its worsening); preventing or delaying the spread of the disease (e.g., metastasis), condition, disorder, and / or symptom; preventing or delaying the recurrence of the disease, condition, disorder, and / or symptom; delaying or slowing the progression of the disease, condition, disorder, and / or symptom; ameliorating the state of the disease, condition, disorder, and / or symptom; providing response (partial or total) to the disease, condition, disorder, and / or symptom; reducing the dose of one or more other drugs required to treat the disease, condition, disorder, and / or symptom; delaying the progression of the disease, condition, disorder, and / or symptom; improving the quality of life, and / or prolonging survival time. The compositions and methods of the present disclosure contemplate any one or more of these treatment aspects.

[0068] As used herein, a “pharmaceutically effective amount” refers to an amount sufficient to ameliorate or prevent a symptom or a sign of a medical disorder. Pharmaceutically effective amount also refers to an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient may vary depending on factors such as the disease to be treated, the general health of the patient, the route of method, the dose of administration, and the severity of side effects. The pharmaceutically effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxic effects. The effect will result in an improvement of the diagnostic measure or parameter by at least 5%, such as atAttorney Docket No.7656-043030 least 10%, further such as at least 20%, further such as at least 30%, further such as at least 40%, further such as at least 50%, further such as at least 60%, further such as at least 70%, further such as at least 80%, and even further such as at least 90%, wherein 100% is defined as the diagnostic parameter displayed by a normal subject.

[0069] The term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are suitable for being in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio. For example, a pharmaceutically acceptable substance may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. The pharmaceutically acceptable carrier or excipient preferably meets the requisite toxicological and manufacturing test standards and / or is included in the Inactive Ingredient Guide provided by U.S. Food and Drug Administration.

[0070] The term “pharmaceutically acceptable carrier” as used herein includes any and all solvents, dispersion media, coating agents, surfactants, antioxidants, preservatives (e.g., antibacterial agents or antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, as known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th edition, Mack Printing Company, 1990, 1289-1329). The use of any conventional carrier in therapeutic or pharmaceutical compositions is contemplated herein unless it is incompatible with the active ingredient(s) of the present disclosure.

[0071] As used herein, “active ingredient” refers to any component that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or animals.

[0072] As used herein, “active pharmaceutical ingredient,” “pharmaceutically active ingredient,” or “API” each refer to the active ingredient(s) contained in medicines.

[0073] The term “carrier” refers to a substance that serves as a vehicle for improving the efficiency of delivery and the effectiveness of a pharmaceutical composition.Attorney Docket No.7656-043030

[0074] The term “binder” refers to a substance or compound that promotes, provides, or improves cohesion, i.e., a substance that causes the components of a mixture to cohere to form a solid item that possesses integrity.

[0075] The term “excipient” refers to a pharmacologically inactive substance that is formulated in combination with a pharmacologically active ingredient of a pharmaceutical composition and is inclusive of, but not limited to, disintegrants, lubricants, flavorings, bulking agents, binders, fillers, diluents, preservatives, antioxidants, and adjuvants, synergists and products used for facilitating drug absorption or solubility or for other pharmacokinetic considerations. See, also, The Handbook of Pharmaceutical Excipients, 4th edition, ed. by Rowe et al., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, 20th edition, Gennaro (ed.), Lippincott Williams & Wilkins (2003).

[0076] As used herein, “disease” refers to a pathological process having a characteristic set of signs and symptoms. It may affect the whole body or any of its parts, and its etiology, pathology, and prognosis may be known or unknown.

[0077] As used herein, “symptom” refers to any morbid phenomenon or departure from the normal in structure, function, or sensation experienced by a patient and indicative of disease.

[0078] As used herein, “disorder” refers to an abnormality, alteration, or derangement of function leading to a morbid physical or mental state.

[0079] As used herein, a “medical condition” refers to its use as a broad term that includes all diseases, lesions, and disorders. The Diagnostic and Statistical Manual of Mental Disorders (DSM) uses the term "general medical condition" to refer to all diseases, illnesses, and injuries except for mental disorder. In some contexts, the term medical condition is also a synonym for medical state, which describes an individual patient's current state from a medical standpoint.

[0080] The term “administered in combination with” or “co-administration” as used herein refers to the simultaneous or separate sequential administration in any manner of a solid or liquid oral pharmaceutical dosage form containing the drug-carrier complex disclosed herein and one or more other active agents known to be useful in the treatment of nervous system and / or mental diseases, conditions, disorders, and / or symptoms. The term “other one or more active agent” as used herein includes any compound or therapeutic agent known or proven to exhibit advantageous properties when administered to a patient in need of treatment.Attorney Docket No.7656-043030

[0081] As used herein, the term “appropriate period of time” or “suitable period of time” refers to the period necessary to achieve a desired effect or result. For example, a mixture may be blended until a potency distribution is reached that is within an acceptable qualitative range for a given application or use of the blended mixture.

[0082] As used herein, the term “dose” or “unit dose” or “unit dosage” refers to a physically discrete unit that contains a predetermined quantity of active ingredient calculated to produce a desired therapeutic effect. The unit dose or unit dosage may be in the form of a tablet, capsule, sachet, liquid dispensing device, etc. referred to herein as a “unit dosage form.”

[0083] As used herein, “throat burn” refers to a scratchy or tender sensation in the back of the throat typically experienced when ingesting nicotine, especially when swallowing afterwards. As used herein, “throat burn” is synonymous with “throat grab,” “throat hit,” and / or “biting sensation.”

[0084] As used herein, the terms “pouch” or “pouches” refer to oral nicotine products comprising an outer water-permeable pouch defining a cavity containing a composition comprising a water-soluble nicotine component capable of being released through the water- permeable pouch. In some embodiments, the pouch material is non-dissolvable and / or it is non-water soluble. Exemplary nicotine pouch compositions and / or products of the present disclosure are also referred to herein as “ENP”.

[0085] As used herein, the term “dry pouch” refers to a pouch wherein the moisture content is maintained at less than 5% weight / weight to ensure stability.

[0086] As used herein, the terms “moistened pouch” or “wet pouch” refer to a pouch wherein the moisture content is maintained to be between 5% weight / weight to 65% weight / weight. In some embodiments, the moisture content is maintained to be between 10% weight / weight to 40% weight / weight. This moisture range helps prevent nicotine loss from evaporation.

[0087] As used herein, the terms “ellipse,” “ellipsoid,” and “nicotine ellipses” all refer to an elliptical or ellipsoid-shaped oral product that is sized and configured to fit inside the mouth, between a user’s check and gum (i.e., it is placed completely in, partially in, or near the buccal vestibule). In some embodiments of the present disclosure the ellipse is a dissolvable ellipse. Exemplary nicotine ellipse compositions and / or products of the present disclosure are also referred to herein as “ELS”.Attorney Docket No.7656-043030

[0088] As used herein, the terms “encapsulated nicotine complex,” “nicotine-cyclodextrin- polymer complex”, “core”, “core composition”, or “core formulation” all refer to any of the encapsulated nicotine complexes provided by the present disclosure. Exemplary encapsulated nicotine complex compositions and / or products of the present disclosure are also referred to herein as “ES”. The encapsulated nicotine complexes (“ES”) of the present disclosure can be used to produce the pouches (“ENP”) (e.g., unflavored dry pouches and flavored dry pouches), ellipses (“ELS”), and oral thin films of the present disclosure according to the methods as provided herein.

[0089] In some examples provided herein, ES formulations are compared to FB formulations.

[0090] As used herein, a “nicotine delivery product” refers to any product, device, or formulation intended to deliver nicotine into the human body, wherein the nicotine delivery products are used for the purposes including but not limited to recreational use, dependence maintenance, and / or cessation support.

[0091] As used herein, a “nicotine delivery system” refers to any device or method designed to administer nicotine into the human body, wherein the nicotine delivery system includes administration methods including but not limited to inhalation, oral absorption, and / or transdermal absorption.

[0092] As used herein, “tobacco" includes any part, such as the leaves, flowers, or stems, of any member of the genus Nicotiana and reconstituted materials thereof. In some embodiments, it includes treated tobacco. In some embodiments, it includes derivatives such as specific compounds found in natural tobacco, such as nicotine, whether extracted or synthesized, as well as structural derivatives such as the fibrous portion of a tobacco leaf. In some embodiments, it further includes tobacco substitutes which comprise individual chemicals and / or complex chemical entities which, when prepared, physically resemble natural tobacco. The term "tobacco" as used herein includes tobacco extract.

[0093] As used herein, "smokeless tobacco product" is used to denote any tobacco product which is not intended for combustion. For information on smokeless tobacco products see, e.g., European Patent Specification EP 2217102 B1; European Patent Application No. EP 4248766 A2; and Smokeless Tobacco Products 1stedition, February 4, 2020, Wallace B. Pickworth (editor), Elesvier, 240 pages.Attorney Docket No.7656-043030

[0094] As used herein, "smokeless oral tobacco product" denotes any smokeless tobacco product designed to be placed in the oral cavity of a user for a limited period of time, during which there is contact between the user’s saliva and the product. The term "smokeless oral tobacco product", as used herein, does not include heat-not-burn products. II. Nicotine

[0095] Nicotine, a major component of cigarettes and e-cigarettes, is a naturally occurring plant alkaloid. Synthetic nicotine is a form of nicotine that is created in a lab and not made from tobacco leaves. Although no tobacco is involved, the nicotine content in synthetic nicotine is the same as the nicotine content found in naturally-derived products. The methods and compositions of the present disclosure may utilize natural and / or synthetic nicotine.

[0096] Nicotine is a pale-yellow liquid with a density of 1.01 g / cm3. It is a bicyclic compound of a molecular weight 162.23 g / mol with one pyridine and pyrrolidine ring. With two nitrogen’s, one on each ring, nicotine exhibits two pKa’s. The nitrogen of the pyrrolidine ring is more basic (pka = 8.10 at 25°C) than that of the pyridine ring (pka = 3.41 at 25°C). Although nicotine is a lipophilic molecule with a log P of 1.17, it is water miscible. Based on the two pKa’s, nicotine can exist in three forms depending on the pH of the solvent. These three forms are diprotonated, mono-protonated, and freebase (un-protonated) nicotine.

[0097] Nicotine is a potent alkaloid found in tobacco leaves and is widely used in smoking cessation therapies and nicotine replacement therapies. However, the poor stability and bioavailability of nicotine limit its therapeutic efficacy and pose a challenge in the formulation of effective delivery systems. Nicotine replacement therapy (NRT) is a widely used treatment to help smokers quit smoking. NRT products such as gum, lozenges, patches, and inhalers provide a lower dose of nicotine than smoking and can help reduce cravings and withdrawal symptoms. Nicotine gum is a fast-acting form of replacement. Nicotine is taken in through the mucous membrane of the mouth. Nicotine gum can be bought over the counter (without a prescription). It generally comes in 2 mg and 4 mg strengths. Nicotine lozenges can also be bought without a prescription. The lozenge is generally available in 2 mg and 4 mg strengths.

[0098] Nicotine has been shown to improve cognitive function, including attention, memory, and learning. Nicotine has also been investigated as a potential treatment for cognitiveAttorney Docket No.7656-043030 impairments associated with Alzheimer's disease, schizophrenia, and Adult Attention-Deficit Hyperactivity Disorder (ADHD).

[0099] Nicotine also acts as a pain reliever and has been studied as a potential treatment for chronic pain conditions, such as neuropathic pain and fibromyalgia. Nicotine has been shown to reduce inflammation in the gut, improving symptoms of inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn's disease. Furthermore, nicotine has been investigated as a potential treatment for Parkinson's disease due to its ability to stimulate dopamine release and improve motor function.

[0100] Nicotine sources that may be used in the methods and compositions of the present disclosure include but are not limited to nicotine free base, nicotine bitartrate, nicotine benzoate, nicotine salicylate, and nicotine citrate.

[0101] If nicotine freebase is used in the methods and compositions of the present disclosure, acids (e.g., citric acid, ascorbic acid, acetic acid, tartaric acid, etc.) can be added to adjust pH as needed and to help reduce degradation of the nicotine. III. Polymers

[0102] Polymers are substances or materials consisting of very large molecules called macromolecules. Polymers can be natural, synthetic, or a combination of both types. As disclosed herein, certain polymers function as co-solvents under high-pressure CO2, becoming liquid and facilitating the mixing of the ingredients.

[0103] The polymer used in the ternary system of the present disclosure may be selected from a range of polymers that can function as stabilizers, co-solvents, or process aids, such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), poly(lactic-co-glycolic acid) (PLGA), polyethylene oxides and polypropylene oxides and their block copolymer (poloxamer).

[0104] In accordance with the present disclosure, suitable polymers for the process are those that exhibit a melting depression under supercritical CO2, allowing for the dissolution of cyclodextrins and nicotine to form a homogeneous mixture. Such polymers may be selected from a group of polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyethyleneimine (PEI), poly(acrylic acid) (PAA), poly(ethylene oxide)- poly(propylene oxide) block copolymers (poloxamer), poly(caprolactone) (PCL), poly(lactic-Attorney Docket No.7656-043030 co-glycolic acid) (PLGA), and cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC) and hydroxyethyl cellulose (HEC).

[0105] Exemplary PVP polymers that may be used in the methods and compositions of the present disclosure include but are not limited to PVP K-17, PVP K-25, PVP K-30, and PVP K-90. PEG polymers suitable for use include PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 1450, PEG 3350, PEG 6000, and PEG 8000. Additional, non-limiting examples of some specific polyglycol derivatives that can be used in the methods and compositions of the present disclosure include but are not limited to (a) PEG-laureates and dilaureates (e.g., PEG-10-, PEG-12-, PEG-20, PEG-32-laurates, PEG-20- and PEG-32-dilaurates, PEG-20- glyceryl-, PEG-30-glyceryl- and PEG-40-glyceryl-laurates, and PEG-80-sorbitan laurate); (b) PEG-oleates, dioleates and trioleates (e.g., PEG-12-, PEG-15-, PEG-20-, PEG-32, PEG- 200- and PEG-400-oleates, PEG-20- and PEG-32-dioleates, PEG-20-trioleate, PEG-25- glyceryl trioleate, PEG-20-glyceryl- and PEG-30-glyceryl-oleates, and PEG-40-sorbitan oleate); (c) PEG-stearates and distearates (e.g., PEG-15-, PEG-40-, PEG-100-stearates, PEG- 32-distearate and PEG-20-glyceryl stearate) (d) castor, palm kernel, corn and soya oil derivatives of PEG (e.g., PEG-35-, PEG-40- and PEG-60-castor oils, PEG-40-, PEG-50- and PEG-60-hydrogenated castor oils, PEG-40-palm kernel oil, PEG-60-corn oil, and PEG-30- soya sterol); and (e) other PEG derivatives (e.g., PEG-24- and PEG-30-cholesterol, PEG-25- phytosterol, PEG-6- and PEG-8-caprate / caprylate glycerides, tocopheryl PEG-100 succinate, PEG-15-100 octylphenol products and PEG-10-100 nonylphenol products).

[0106] Poloxamers are nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)). Nonlimiting examples of suitable poloxamers that may be used in the methods and compositions of the present disclosure include but are not limited to Poloxamer 188, Poloxamer 237, Poloxamer 338, and Poloxamer 407. Additional poloxamer(s) that may be used in the methods and compositions of the present disclosure include but are not limited to one or more of the following poloxamers: poloxamer-101, poloxamer-105, poloxamer-108, poloxamer-122, poloxamer- 123, poloxamer-124, poloxamer-181, poloxamer-182, poloxamer-183, poloxamer-184, poloxamer-185, poloxamer- 212, poloxamer-215, poloxamer-217, poloxamer-231, poloxamer-234, poloxamer-235, poloxamer- 238, poloxamer-282, poloxamer-284,Attorney Docket No.7656-043030 poloxamer-288, poloxamer-331, poloxamer-333, poloxamer-334, poloxamer-335, poloxamer-401, poloxamer-402, and / or poloxamer-403. Poloxamer-407 and poloxamer-188 have performed particularly well in some embodiments of the methods and compositions of the present disclosure. The poloxamer(s) is added not only as a permeation enhancer but also as a processing aid. In some embodiments, to produce solid products(powders) from a single- step CO2 process, poloxamers are used as a processing aid. The poloxamers become liquid and enable uniform mixing with other ingredients during the process.

[0107] Nonlimiting examples of HPMC polymers that may be used in the methods and compositions of the present disclosure include but are not limited to HPMC E5, HPMC E6, HPMC E15, HPMC E50, and HPMC K100. PVA polymers that may be used include PVA 17-88, PVA 20-88, PVA 24-88, and PVA 49-88.

[0108] Some nonlimiting examples of PEI that may be used in the methods and compositions of the present disclosure include but are not limited to Linear polyethyleneimine (LPEI), Branched polyethyleneimine (BPEI), PEI-graft-poly(ethylene glycol) (PEI-PEG). Example of suitable PAA include Poly(acrylic acid-co-maleic acid), Poly(acrylic acid-co-2- ethylhexyl acrylate), Poly(acrylic acid-co-vinyl acetate), Poly(acrylic acid-co-2-hydroxyethyl methacrylate), Poly(acrylic acid-co-itaconic acid), Poly(acrylic acid-co-styrene), Poly(acrylic acid-co-acrylamide), Poly(acrylic acid-co-methacrylic acid), Poly(acrylic acid-co-methyl methacrylate), Poly(acrylic acid-co-butyl acrylate), Poly(acrylic acid-co-ethyl acrylate), Poly(acrylic acid-co-methyl acrylate) and Poly(acrylic acid-co-acrylonitrile).

[0109] Nonlimiting examples of cellulose-derived polymers that may be used in the methods and compositions of the present disclosure include but are not limited to HPMC E3, HPMC E5, HPMC E15, HPMC K4, HPMC K15, HPMC K100, sodium carboxymethyl cellulose (Na-CMC), calcium carboxymethyl cellulose (Ca-CMC), HEC E5, HEC E15, and HEC F4M. IV. Cyclodextrin

[0110] Cyclodextrins (CDs) are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of glucose subunits joined by α-1,4 glycosidic bonds.

[0111] Cyclodextrins can be produced from starch by enzymatic conversion. They are used in food, pharmaceutical, drug delivery, and chemical industries, as well as agriculture and environmental engineering. CDs are cyclic oligosaccharides widely used as carriers and protectants for bioactive compounds. CDs form inclusion complexes with hydrophobicAttorney Docket No.7656-043030 compounds such as nicotine, enhancing their stability and protecting them from degradation or volatilization.

[0112] These compounds are composed of glucose units arranged in a ring structure, with a hydrophobic interior and a hydrophilic exterior. This unique structure makes cyclodextrins well-suited for encapsulating and delivering hydrophobic drugs that would otherwise be poorly soluble in water and have limited bioavailability.

[0113] One of the main advantages of cyclodextrins in drug delivery is their ability to improve the solubility and stability of drugs. By encapsulating hydrophobic drugs within the hydrophobic cavity of cyclodextrin, the drug can be solubilized in water and protected from degradation, improving its bioavailability and therapeutic efficacy. This is crucially and critically important in nicotine formulations as freebase nicotine shows rapid degradation under standard conditions.

[0114] Cyclodextrins also have the ability to target specific tissues and cells, which can enhance the effectiveness of drug delivery and allow for multiple product offerings to maximize user experience. Additionally, the cyclodextrin's hydrophilic exterior can prevent rapid drug clearance by the reticuloendothelial system (RES), which can increase the drug's circulation time and improve its therapeutic efficacy, and thus, the cessation effect of the nicotine formulation.

[0115] Other advantages of cyclodextrins are their biocompatibility and low toxicity. Cyclodextrins are generally well-tolerated by the body and have low immunogenicity, which reduces the risk of adverse reactions or immune responses. This makes them a safe and effective option for drug delivery and consumer products.

[0116] However, CDs alone may not be sufficient to stabilize the complex and prevent its degradation or aggregation during processing under scCO2.

[0117] The cyclodextrin that may be used in the methods and compositions of the present disclosure can be any cyclodextrin(s) that are suitable for use in food and pharmaceutical formulations, including natural and / or synthetic cyclodextrins. Nonlimiting examples of cyclodextrin(s) that may be used in the methods and compositions of the present disclosure include but are not limited to one or more of the following: α-cyclodextrin (α-CD or Alpha- CD), β-cyclodextrin (β-CD or Beta-CD), γ-cyclodextrin (γ-CD or Gamma-CD), α- cyclodextrin exadeacetate (AACD), β-cyclodextrin heneicosaacetate (ABCD), γ-cyclodextrinAttorney Docket No.7656-043030 octadeacetate (AGCD), hydroxypropyl-α-cyclodextrin (HPαCD), hydroxypropyl-β- cyclodextrin (HPβCD), hydroxypropyl-γ-cyclodextrin (HPγCD), methyl-α-cyclodextrin (MαCD), methyl-β-cyclodextrin (MβCD), methyl-γ-cyclodextrin (MγCD), sulfobutylether- α-cyclodextrin (SBEαCD), sulfobutylether-β-cyclodextrin (SBEβCD), sulfobutylether-γ- cyclodextrin (SBEγCD), acetylated-beta-cyclodextrin (AcβCD), methylated-beta- cyclodextrin (Me-β-CD), carboxymethyl-beta-cyclodextrin (CM-β-CD), hydroxyethyl-beta- cyclodextrin (HE-β-CD), glucosyl-beta-cyclodextrin (Glu-β-CD), acetylated-alpha- cyclodextrin (AcαCD), methylated-alpha-cyclodextrin (Me-α-CD), carboxymethyl-alpha- cyclodextrin (CM-α-CD), hydroxyethyl-alpha-cyclodextrin (HE-α-CD), glucosyl-alpha- cyclodextrin (Glu-α-CD), acetylated-gamma-cyclodextrin (AcγCD), hydroxypropyl-gamma- cyclodextrin (HPγCD), methylated-gamma-cyclodextrin (Me-γ-CD), carboxymethyl- gamma-cyclodextrin (CM-γ-CD), hydroxyethyl-gamma-cyclodextrin (HE-γ-CD), and / or glucosyl-gamma-cyclodextrin (Glu-γ-CD). Additionally, polymer-modified cyclodextrins can be utilized where the polymer content selected from polymer groups such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), and poly(lactic-co-glycolic acid) (PLGA).

[0118] β-cyclodextrin has performed particularly well in masking bitterness and increasing shelf life in some embodiments of the methods and compositions of the present disclosure. V. Optional Flavorings

[0119] Optional flavorings may be added to the methods and compositions of the present disclosure. Flavorings that may be used in the methods and compositions of the present disclosure include but are not limited to one or more flavoring oils, such as, for example, essential oils with cooling effect (e.g., high in menthol). Examples of such essential oils include but are not limited to peppermint oil, eucalyptus oil, cornmint oil, camphor oil, and / or spearmint oil. In some embodiments, the present disclosure provides such methods and compositions wherein the one or more natural or synthetic flavorings include but not are limited to cinnamon, vanilla, monk fruit, blueberry, citrus, cherry, chocolate, mango, chili, tropical fruit punch, orange, strawberry, raspberry, stevia, and combinations thereof.

[0120] Peppermint oil and / or cornmint have performed particularly well in some embodiments of the methods and compositions of the present disclosure and can be optionally added to the formulation to reduce the throat burn from nicotine.Attorney Docket No.7656-043030 VI. Supercritical Carbon Dioxide

[0121] The methods of the present disclosure offer a simple, efficient, and versatile approach for the development of oral and topical delivery systems for nicotine and other bioactive compounds. The use of a ternary system comprising nicotine, cyclodextrin, and polymer can improve the stability, bioavailability, and formulation process of the complex, and the use of supercritical CO2 as a processing aid can reduce the need for organic solvents and offer a green and sustainable approach to complex formation.

[0122] International Patent Publication No. WO 2000 / 54751 discloses a method for producing solid dosage forms involving an active component, polymeric binders, and cyclodextrins. The method has several limitations that may affect the quality and effectiveness of the final product. First, the method requires elevated temperatures of up to 220°C, which may pose a risk of evaporation or degradation of the active component. Secondly, the disclosed method is conducted in an atmospheric environment, which may lead to the oxidation of the active component, reducing its quality and effectiveness. Finally, the resulting product of this disclosure may be a dense and agglomerated solid, which could affect the dissolution profile and bioavailability of the active component.

[0123] International Patent Application Nos. PCT / US2020 / 056729 and PCT / US2020 / 056731 disclose methods of producing superfine cyclodextrin-encapsulated active pharmaceutical ingredients, particularly cannabinoids, using supercritical, subcritical, high-pressure gas or liquid carbon dioxide to form an active pharmaceutical ingredient (API) solution. While the formulations produced by the methods of these disclosures focused primarily on API bioavailability, they lack having a suitable, practical shelf life; suffer from issues involved with unacceptable sensory organoleptic characteristics (e.g., cause throat burn, have bitterness, or contain little or no flavoring, etc.); and need to have improved or increased absorption rates and / or absorption amounts traverse across buccal tissues. While nicotine is water soluble, cannabinoids differ in having low water solubility. Therefore, the methods of producing nicotine compositions as disclosed herein differ from the methods of producing cannabinoid compositions as disclosed and claimed PCT / US2020 / 056729 and PCT / US2020 / 056731. For example, both PCT / US2020 / 056729 and PCT / US2020 / 056731 include a step of using a nozzle sprayer, whereas the methods of the present disclosure do not include using a spraying step.Attorney Docket No.7656-043030

[0124] In contrast to the prior art discussed above, the present disclosure provides methods of making nicotine compositions that utilize a ternary system comprising nicotine, cyclodextrin, and a polymer, which improves the stability and processability of the complex resulting in a composition with increased shelf life, improved buccal tissue absorption rates, and improved sensory organoleptic qualities.

[0125] Supercritical carbon dioxide (aka sCO2, sCO2, scCO2, and scCO2) is a fluid state of carbon dioxide where it is held at or above its critical point temperature (304.128° K, 30.978° C, 87.76048° F) and critical point pressure (73.773 bar, 7.3773 MP, 1,070 psi). Carbon dioxide usually behaves as a gas in air at standard temperature and pressure (STP), or as a solid called dry ice when frozen. If the temperature and pressure are both increased from STP to be at or above the critical point for carbon dioxide, it can adopt properties midway between a gas and a liquid. More specifically, it behaves as a supercritical fluid above its critical temperature https: / / en.wikipedia.org / wiki / Supercritical_carbon_dioxide and critical pressure, expanding to fill its container like a gas but with a density like that of a liquid. At this state, sCO2 can be used efficiently throughout the entire Brayton cycle.

[0126] In some embodiments, the temperature utilized in the scCO2 methods and compositions of the present disclosure may be about 30°C to about 55°C. In some embodiments, the temperature may be about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, or about 55°C.

[0127] In some embodiments, the pressure utilized in the scCO2 methods and compositions of the present disclosure may be about 2,000 psi to about 6,500 psi or about 2,500 psi to about 6,500 psi. In some embodiments, the pressure may be about 2,000 psi, about 2,500 psi, about 3,000 psi, about 3,500 psi, about 4,000 psi, about 4,500 psi, about 5,000 psi, about 5,500 psi, about 6,000 psi, or about 6,500 psi.

[0128] The use of scCO2 as a processing aid as disclosed herein not only allows for the incorporation of these polymers but also reduces the need for organic solvents. Organic solvents are commonly used in traditional complex formation methods, but they can be harmful to the environment and human health. Using scCO2 as disclosed herein offers a green (environmentally friendly) and sustainable approach to complex formation that is becoming increasingly popular in the pharmaceutical industry. VII. Nicotine Compositions and Methods of Making ThemAttorney Docket No.7656-043030

[0129] The present disclosure provides methods for preparing stable and bioavailable nicotine-cyclodextrin-polymer complexes using supercritical CO2 for oral and topical delivery. The production methods involve the use of a ternary system comprising nicotine, cyclodextrin, and a polymer, which are mixed under supercritical CO2 to obtain a homogeneous solid mixture. The polymer acts as a co-solvent under high-pressure CO2 and plays a crucial role in improving the stability and bioavailability of nicotine. The resulting complex can be used for various applications, including nicotine replacement therapy, cognitive enhancement, pain relief, anti-inflammatory, and Parkinson's disease treatment. The use of supercritical CO2 and the ternary system offers advantages over existing methods, including improved stability and processability of the complex, reduced risk of evaporation, oxidation, and degradation of the active component, and enhanced dissolution profile and bioavailability of the active component. The methods of the present disclosure can be used to produce a range of oral and topical dosage forms, including tablets, capsules, gels, and creams, and has the potential to revolutionize nicotine and other bioactive compound delivery systems.

[0130] The overall processes for producing the exemplary dry pouch (ENP) ellipse (ELS) formulations of the present disclosure are provided in the flow diagrams of FIG.6 and FIG. 7, respectively.

[0131] Table 1 provides alternative, exemplary ranges of initial dry weight / weight percentages for each of the starting, primary ingredients used to produce the nicotine- cyclodextrin-polymer complexes (i.e., core compositions or core formulations) produced according to the present disclosure.

[0132] Table 1. Percentage dry weight / weight ranges of starting ingredients in exemplary encapsulated nicotine complex compositions. Set 1 Set 2 Set 3 Nicotine About 4% - About 15% About 3% - About 20% About 1% - About 33% source(s) Poloxamer(s) About 30% - About About 15% - About 75% About 10% - About 80% 55% Cyclodextrin( About 32% - About About 15% - About 75% 0% - About 90% s) 58%Attorney Docket No.7656-043030 Set 1 Set 2 Set 3 Flavoring 0% - About 9% 0% - About 15% 0% - About 20% oil(s) (optional) Other <7% <10% <20% Excipients (antioxidants, pH adjusters)

[0133] The initial amount of the nicotine source utilized in the methods and compositions of the present disclosure in dry weight / weight may be 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%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, or about 50%. In some embodiments, the initial amount of the nicotine source utilized in the methods and compositions of the present disclosure in dry weight / weight ranges from about 1% to about 5%, about 1% to about 10%, about 1% to about 15%, about 1% to about 20%, about 1% to about 30%, about 1% to about 40%, about 3% to about 5%, about 3% to about 10%, about 3% to about 15%, about 3% to about 20%, about 4% to about 10%, about 4% to about 15%, and about 4% to about 20%.

[0134] The initial amount of the polymer and / or poloxamer utilized in the methods and compositions of the present disclosure in dry weight / weight may be 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%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, aboutAttorney Docket No.7656-043030 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, or about 90%. In some embodiments, the initial amount of the polymer or poloxamer utilized in the methods and compositions of the present disclosure in dry weight / weight ranges from about 10% to about 15%, about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 45%, about 10% to about 50%, about 10% to about 55%, about 10% to about 60%, about 10% to about 65%, about 10% to about 70%, about 10% to about 75%, about 10% to about 80%, about 10% to about 85%, about 10% to about 90%, about 10% to about 95%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 45%, about 15% to about 50%, about 15% to about 55%, about 15% to about 60%, about 15% to about 65%, about 15% to about 70%, about 15% to about 75%, about 15% to about 80%, about 15% to about 85%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 30% to about 55%, about 30% to about 60%, or about 30% to about 65%.

[0135] The initial amount of the cyclodextrin utilized in the methods and compositions of the present disclosure in dry weight / weight may be 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%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, or about 90%. In some embodiments, the initial amount of the cyclodextrin utilized in the methods and compositions of the present disclosure in dry weight / weight ranges from about 1% to about 15%, about 1% to about 20%, about 1% to about 25%, about 1% to about 30%, about 1% to about 35%, about 1% to about 40%, about 1% to about 45%, about 1% to about 50%, about 1% to about 55%, about 1% to about 60%, about 1% to about 65%, about 1% to about 70%,Attorney Docket No.7656-043030 about 1% to about 75%, about 1% to about 80%, about 1% to about 85%, about 1% to about 90%, about 1% to about 95%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 45%, about 15% to about 50%, about 15% to about 55%, about 15% to about 60%, about 15% to about 65%, about 15% to about 70%, about 15% to about 75%, about 15% to about 80%, about 15% to about 85%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 30% to about 55%, about 30% to about 60%, or about 30% to about 65%.

[0136] The initial amount of the flavoring and / or flavoring oil utilized in the methods and compositions of the present disclosure in dry weight / weight may be 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%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%. In some embodiments, the initial amount of the flavoring and / or flavoring oil utilized in the methods and compositions of the present disclosure in dry weight / weight ranges from about 0.1% to about 1%, about 0.1% to about 2%, about 0.1% to about 3%, about 0.1% to about 4%, about 0.1% to about 5%, about 0.1% to about 6%, 0.1% to about 7%, 0.1% to about 8%, 0.1% to about 9%, 0.1% to about 10%, about 0.1% to about 11%, about 0.1% to about 12%, about 0.1% to about 13%, about 0.1% to about 14%, about 0.1% to about 15%, about 0.1% to about 16%, 0.1% to about 17%, 0.1% to about 18%, 0.1% to about 19%, 0.1% to about 20%, about 0.1% to about 21%, about 0.1% to about 22%, about 0.1% to about 23%, about 0.1% to about 24%, or about 0.1% to about 25%. In some embodiments, the initial amount of flavoring and / or flavoring oil utilized in the methods and compositions of the present disclosure is zero (i.e., no flavoring or flavoring oil is added).

[0137] The initial amount of the other excipients utilized in the methods and compositions of the present disclosure in dry weight / weight may be 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%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%. In some embodiments, the initial amount of the otherAttorney Docket No.7656-043030 excipients utilized in the methods and compositions of the present disclosure in dry weight / weight ranges from about 0.1% to about 1%, about 0.1% to about 2%, about 0.1% to about 3%, about 0.1% to about 4%, about 0.1% to about 5%, about 0.1% to about 6%, 0.1% to about 7%, 0.1% to about 8%, 0.1% to about 9%, 0.1% to about 10%, about 0.1% to about 11%, about 0.1% to about 12%, about 0.1% to about 13%, about 0.1% to about 14%, about 0.1% to about 15%, about 0.1% to about 16%, 0.1% to about 17%, 0.1% to about 18%, 0.1% to about 19%, 0.1% to about 20%, about 0.1% to about 21%, about 0.1% to about 22%, about 0.1% to about 23%, about 0.1% to about 24%, or about 0.1% to about 25%. In some embodiments, the initial amount of other excipients utilized in the methods and compositions of the present disclosure is zero (i.e., no extra excipients).

[0138] The final amount of the nicotine in the compositions and products of the present disclosure in percentages based on total net content weight may be about 0.005%, about 0.01%, 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 1.0%, about 2.0%, about 3.0%, about 4.0%, about 5.0%, about 6.0%, about 7.0%, about 8.0%, about 9.0%, about 10.0%, about 11.0%, about 12.0%, about 13.0%, about 14.0%, about 15.0%, about 16.0%, about 17.0%, about 18.0%, about 19.0%, about 20.0%, about 21.0%, about 22.0%, about 23.0%, about 24.0%, or about 25.0%. In some embodiments, the final amount of the nicotine in the compositions and products of the present disclosure in percentages based on total net content weight ranges may be about 0.01% to about 20%, about 1% to about 20%, about 5% to about 20%, or about 10% to about 20.0%. In some embodiments, the final amount of the nicotine source in the compositions and products of the present disclosure in percentages based on dry weight / weight may be about 6.5%, about 13.0%, about 18.0%, or about 21.5%.

[0139] The final amount of the nicotine in the compositions and products of the present disclosure in weight may be about 0.5 mg, about 1.0 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, about 16.0 mg, about 17.0 mg, about 18.0 mg, about 19.0 mg, about 20.0 mg, about 21.0 mg, about 22.0 mg, about 23.0 mg, about 24.0 mg, about 25.0 mg, about 26.0 mg, about 27.0 mg, about 28.0 mg, about 29.0 mg, about 30.0 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, or about 35 mg. In some embodiments, the final amount of the nicotine in the compositions andAttorney Docket No.7656-043030 products of the present disclosure by weight may be about 1.0 mg to 30.0 mg, about 5.0 mg to about 30.0 mg, about 10.0 mg to about 30.0 mg, about 15.0 mg to about 30.0 mg, about 20.0 mg to about 30.0 mg, or about 25.0 mg to about 30.0 mg.

[0140] The amount of nicotine per unit of the compositions or products can be measured, e.g., by HPLC Shimadzhu Prominence LC-2050 with UV detector and / or by Waters Acquity UPC2with PDA detector.

[0141] While not wishing to be bound by any particular theory, the intermediate compound produced can be demonstrated through analytical techniques such as Nuclear Magnetic Resonance (NMR), Gel Permeation Chromatography (GPC), or several types of mass spectrometry as containing poloxamer(s) and cyclodextrins(s). In addition, the intermediate composition would also be discernable through techniques such as differential scanning calorimetry which can be used to see the change in properties in the complexation of nicotine, poloxamer and cyclodextrin compared to the poloxamer and cyclodextrin as received.

[0142] In some embodiments of the present disclosure, the route of administration for the compositions of the present disclosure is oral without further dilution or reconstitution.

[0143] In some embodiments of the present disclosure, the compositions of the present disclosure, can be stored under US Pharmacopeia (USP) controlled room temperature conditions of about 20°C to about 25°C (about 68°F to about 77°F) with excursions permitted between about 15°C to about 30°C (about 59°F to about 86°F). In some embodiments, the compositions of the present disclosure can be stored at room temperature. While room temperature is defined differently in various places, it generally refers to a range somewhere between about 68 degrees Fahrenheit and about 74 degrees Fahrenheit. Stability tests are being conducted to obtain a more exact time limit for storage. VIII. Pouches

[0144] In some embodiments, the pouch materials that can be used with the compositions of the present disclosure are non-dissolvable and / or non-water soluble.

[0145] In some embodiments, the pouches that can be used with the compositions of the present disclosure may be manufactured from materials, and in such a manner, such as during use by the user, the pouch undergoes a controlled dispersion or dissolution. Such pouch materials may have the form of a mesh, screen, perforated paper, permeable fabric, or the like. For example, pouch material manufactured from a mesh-like form of rice paper, orAttorney Docket No.7656-043030 perforated rice paper, may dissolve in the mouth of the user. As a result, the pouch and mixture may undergo complete dispersion within the mouth of the user during normal conditions of use, and hence the user may ingest both the pouch and mixture. Other examples of pouch materials that can be used with the compositions of the present disclosure may be manufactured using water dispersible film forming materials (e.g., binding agents such as alginates, carboxymethylcellulose, xanthan gum, pullulan, and the like), as well as those materials in combination with materials such as ground cellulosics (e.g., fine particle size wood pulp). The pouch materials, though water dispersible or dissolvable, may be designed and manufactured such that under conditions of normal use, a significant amount of the mixture contents permeate through the pouch material prior to the time that the pouch undergoes loss of its physical integrity. If desired, flavoring ingredients, disintegration aids, and other desired components, may be incorporated within, or applied to, the pouch material. See, WIPO International Publication No. WO 2024 / 095163 A1 (WIPO International Application No. PCT / IP2023 / 060979) for this and additional information on pouches that can be used for the compositions of the present disclosure.

[0146] For examples of suitable pouches that can be used to orally deliver the compositions of the present disclosure, see, e.g., U.S. Patent No. 5,167,244; U.S. Patent No. 8,931,493; U.S. Patent Application Publication No.2016 / 0000140; U.S. Patent Application Publication No.2016 / 0157515; U.S. Patent Application Publication No.2016 / 0157515; and U.S. Patent Application Publication No.2016 / 0192703.

[0147] For additional information on various types of nicotine pouches and their uses, see, e.g., Stanfill et al., Characterization of total and unprotonated (free) nicotine content of nicotine pouch products, Nicotine Tob Res. 2021, 23(9):1590–1596; Robichaud et al., Tobacco companies introduce 'tobacco-free' nicotine pouches, Tobacco Control.2020;29:e145–e146; Marynak et al., Nicotine pouch unit sales in the US, 2016- 2020, JAMA.2021, 326(6):566–568; Tobacco Tactics, Nicotine pouches, University of Bath. Accessed November 7, 2024; Yuan et al., Nicotine and the adolescent brain, J Physiol.2015, 593(16):3397–3412; Dai and Leventhal, Prevalence of nicotine pouch use among US adults, JAMA, 332(9):755–757; Park-Lee et la., Notes from the field: e-cigarette and nicotine pouch use among middle and high school students — United States, 2024, MMWR Morb Mortal Wkly Rep.2024, 73(35):774–778; and Majmundar et al., Nicotine pouch sales trends in theAttorney Docket No.7656-043030 US by volume and nicotine concentration levels from 2019 to 2022, JAMA Netw Open.2022, 5(11):e2242235.

[0148] U.S. Patent No. 8,695,609 discloses a water-permeable pouch including tobacco materials and a plurality of microcapsules dispersed with the outer shell encapsulating an internal payload, wherein the microcapsules have a diameter of less than about 100 microns. U.S. Patent No.8,747,562 discloses a tobacco-free oral pouch containing only tobacco-free flavor beads. U.S. Patent Nos.9,161,908 and 9,402,810 disclose pouches containing a powder of at least one free nicotine salt, wherein when contacted with purified water gives a pH of at least 6. U.S. Patent No. 8,978,661 discloses a smokeless tobacco product comprising smokeless tobacco and a polymeric material. U.S. Patent No.9,375,033 discloses a tobacco- containing gel composition, wherein the tobacco material is particulate tobacco or a tobacco extract such as tobacco-derived nicotine. U.S. Patent No. 11,096,412 discloses a nicotine pouch comprising a free-base nicotine mixed with an ion exchange resin. U.S. Patent No. 11,406,630 discloses a pouch comprising a water-insoluble composition and granules consisting of a combination of nicotine, wherein the water-insoluble composition comprises microcrystalline cellulose (“MCC”). MCC is a term for refined wood pulp and is used as a texturizer, an anti-caking agent, a fat substitute, an emulsifier, an extender, and a bulking agent in food and medicine production. U.S. Patent No.11,717,017 discloses an oral pouched nicotine product comprising a nicotine source, a non-encapsulated flavoring agent, a pH adjusting agent, MCC and a triglyceride. U.S. Patent Application Publication No. 2023 / 0148652 and International Publication No. WO 2024 / 095163 disclose pouches comprising a nicotine-polymer complex comprising a polymeric cation exchange resin.

[0149] In some embodiments, the pouches of the present disclosure exhibit an increase in nicotine flux across a polyethersulfone (PES) membrane as compared to presently available commercial pouches from 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%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, 51%, about 52%,Attorney Docket No.7656-043030 about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, or greater.

[0150] In some embodiments, the pouches of the present disclosure exhibit an increase in nicotine flux across a polyethersulfone (PES) membrane as compared to presently available commercial pouches from about 10% to about 15%, about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 45%, about 10% to about 50%, about 10% to about 55%, about 10% to about 60%, about 10% to about 65%, about 10% to about 70%, about 10% to about 75%, about 10% to about 80%, about 10% to about 85%, about 10% to about 90%, about 10% to about 95%, about 10% to about 100%, about 10% to about 115%, about 10% to about 120%, about 10% to about 125%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 45%, about 15% to about 50%, about 15% to about 55%, about 15% to about 60%, about 15% to about 65%, about 15% to about 70%, about 15% to about 75%, about 15% to about 80%, about 15% to about 85%, about 15% to about 90%, about 15% to about 95%, about 15% to about 100%, about 15% to about 115%, about 15% to about 120%, about 15% to about 125%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 30% to about 55%, about 30% to about 60%, about 30% to about 65% about 30% to about 70%, about 30% to about 75%, about 30% to about 80%, about 30% to about 85%, about 30% to about 90%, about 30% to about 95%, about 30% to about 100%, about 30% to about 115%, about 30% to about 120%, about 30% to about 125%, about 40% to 50%, or about 45% to about 50%, or about 110% to about 115%.

[0151] In some embodiments, the pouches of the present disclosure exhibit an increase in organoleptic sensory feedback evaluations as compared to presently available commercial pouches from about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%,Attorney Docket No.7656-043030 about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100%.

[0152] In some embodiments, the pouches of the present disclosure exhibit an increase in organoleptic sensory feedback evaluations as compared to presently available commercial pouches from about 51% to about 60%, about 61% to about 70%, about 71% to about 80%, about 81% to about 90%, or about 91% to 100%. IX. Ellipses

[0153] Dissolvable ellipses, ellipses, ellipsoids, and nicotine ellipses are compositions produced in a solid molded form without the need for an external pouch or envelope for delivery of the composition, designed for pouch-less delivery of nicotine to the target buccal vestibule achieved by dissolution of the products between the buccal mucosa and gingiva. These products therefore generate no material waste because they do not require the user to remove and dispose of any residual pouch material, as is the case with a traditional nicotine pouch.

[0154] Ellipse products are characterized as being a potent and eco-friendly alternative which dissolve in your mouth thereby delivering a robust nicotine hit. The ellipse design ensures a clean, hassle-free experience while the dissolving feature allows for optimal nicotine absorption. Ellipse products offer a convenient and discreet way to enjoy nicotine without the need for traditional tobacco products. The ellipse products are usually placed under the top or bottom lip and positioned to the side of the lip for comfort. Ellipse products normally dissolve after about 30 minutes to about 60 minutes. X. Oral Thin Films

[0155] As used herein, the terms “oral thin films”, “thin-films” or “thin-film delivery” refer to an API delivery product or system that uses a dissolving film or oral drug strip to administer API’s via absorption in the mouth (buccally or sublingually). A film is prepared using hydrophilic polymers that rapidly dissolve on the tongue or buccal cavity, delivering the drug to the systemic circulation via dissolution when contact with liquid is made.

[0156] For references how to make and use oral thin films, see, e.g., the following published application: Indian Patent Application Nos. IN202411105041, IN202441100658, IN202441089353, and IN202411068122; Chinese Patent Application Nos. WOCN24112911,Attorney Docket No.7656-043030 WOCN24109572, , CN202410952321, CN202411379292, and CN202411275033; and U.S. Patent Application No. US17311153. XI. Representative Nervous System and Mental Diseases, Conditions, Disorders, and / or Symptoms Treated by the Present Disclosure

[0157] In some embodiments, the nicotine compositions of the present disclosure can be used to treat and / or ameliorate a wide range of nervous, nervous-associated, pain, pain- associated, inflammation, inflammation-associated, mental, and mental -associated diseases, conditions, disorders, and / or symptoms. The nicotine compositions of the present disclosure may be in the form of a pharmaceutical, a nutraceutical, a botanical drug, a supplement, and / or a food depending on its usage, dosage, regulatory approval pathway, and labeling.

[0158] In some embodiments, the nicotine compositions of the present disclosure can also be used to treat and / or ameliorate metabolic conditions such as Adrenoleukodystrophy, Diabetes Type 1, Gaucher disease, Glucose galactose malabsorption, Hereditary hemochromatosis, Lesch-Nyhan syndrome, Maple syrup urine disease, Menkes syndrome, Niemann-Pick disease, Obesity, Pancreatic cancer, Phenylketonuria, Prader-Willi syndrome, Porphyria, Refsum disease, Tangier disease, Tay-Sachs disease, Wilson's disease, and Zellweger syndrome.

[0159] Nervous system diseases, also known as nervous system or neurological disorders, refer to over 600 medical conditions affecting the nervous system. Examples of nervous system diseases, disorders, conditions, and / or symptoms that can be treated and / or ameliorated according to the present disclosure include but are not limited to Acute Spinal Cord Injury, Alzheimer's Disease, Amyotrophic Lateral Sclerosis (ALS), Ataxia, Bell's Palsy, Brain Tumors, Cerebral Palsy, Cerebral Aneurysm, Epilepsy, Seizures, Lennox-Gastaut syndrome (LGS), Dravet syndrome, and Tuberous Sclerosis Complex (TSC), Guillain-Barré Syndrome, Headache Head Injury, Hydrocephalus, Lumbar Disk Disease (Herniated Disk), Meningitis, Motor Neurone Disease (MND), Multiple Sclerosis, Muscular Dystrophy, Seizure Disorder, Neurofibromatosis, Neurocutaneous Syndromes, Parkinson's Disease, Stroke (Brain Attack), Cluster Headaches, Tension Headaches, Migraine Headaches, Encephalitis, Sciatica, Shingles, Septicemia, Types of Muscular Dystrophy and Neuromuscular Diseases, Myasthenia Gravis, Huntington’s Disease, Charcot-Marie-Tooth Disease, Polyneuropathy, Moyamoya Disease, Multiple System Atrophy, Neoplasm, ChronicAttorney Docket No.7656-043030 Inflammatory, Acute Motor Axonal Neuropathy, Angelman Syndrome, Progressive multifocal leukoencephalopathy (PML), Canavan Disease, Medical Medullary Syndrome, Demyelinating Polyradiculoneuropathy, Spina Bifida, Autism Spectrum Disorder, Strokes, 16P11.2 Deletion Syndrome, Prader-Willi Syndrome, Sotos Syndrome, 22q11 Deletion Syndrome, Rett Syndrome, 1P36 Deletion Syndrome, and Sturge-Weber Syndrome.

[0160] Autoimmune and inflammatory diseases that can be treated and / or ameliorated according to the present disclosure include but are not limited to Ankylosing Spondylitis, Antiphospholipid Antibody Syndrome, Autoimmune Encephalitis, Chronic Recurrent Multifocal Osteomyelitis, Gout, Henoch-Schonlein Purpura, Juvenile Dermatomyositis, Juvenile Idiopathic Arthritis, Juvenile Lupus (SLE), Juvenile Scleroderma, Juvenile Vasculitis, Kawasaki Disease, Lupus (Systemic Lupus Erythematosus), Mixed Connective Tissue Disease, Myositis, Poststreptococcal Inflammatory Syndromes, Psoriatic Arthritis, Reactive Arthritis, Rheumatoid Arthritis, Scleroderma, Sjogren's Syndrome, Spondyloarthritis / Spondyloarthropathy, Systemic Juvenile Idiopathic Arthritis, Undifferentiated Connective Tissue Disease, Uveitis, and Vasculitis.

[0161] The compositions of the present disclosure can also be used to treat and / or ameliorate pain, including but not limited to temporary, acute, chronic, or permanent pain. Acute pain is pain that may come from inflammation, tissue damage, injury, illness, or recent surgery. It usually lasts less than a week or two. The pain usually ends after the underlying cause is treated or has been resolved. Chronic pain is pain that persists for months or even years. The pain may come from inflammation, tissue damage, injury, illness, or recent surgery. The pain may be associated with headaches including but not limited to the most common types of chronic headaches such as migraines, cluster headaches, and tension headaches. The pain may be low back pain. Other pain disorders that can be treated according to the present disclosure include but are not limited to neuralgias and neuropathies that affect nerves throughout the body, pain due to damage to the central nervous system (the brain and spinal cord), as well as pain where no physical cause can be found--psychogenic pain. Common types of pain that can be treated according to the present disclosure include but are not limited to arthritis (.e.g., osteoarthritis, rheumatoid arthritis), muscle pain, bone pain, joint pain, back pain, neck pain, musculoskeletal pain, cancer pain (e.g., near a tumor), headaches, including migraines, testicular pain (orchialgia), lasting pain in scar tissue, muscle pain all over (such as withAttorney Docket No.7656-043030 fibromyalgia), multiple sclerosis, neurogenic pain (e.g., from damage or pressure to the nerves or other parts of the nervous system), AIDS, gall bladder disease, problems with the CNS (e.g., diabetes, shingles, sciatica), and organ pain because of injuries, infections, or health problems such as inflammatory bowel disease, irritable bowel syndrome, pelvic pain, and stomach ulcers. Many of these types of pain can be chronic and a person can have more than one kind of pain at the same time (e.g., fibromyalgia can cause pain in muscles and nerves).

[0162] The compositions of the present disclosure can also be used to treat and / or ameliorate mental illness. Mental illness is a general term for a group of illnesses that may include symptoms that can affect a person’s thinking, perceptions, mood, and / or behavior. Mental illness can make it difficult for someone to cope with work, relationships, and other demands. Examples of mental and / or psychiatric diseases, disorders, conditions and / or symptoms that can be treated according to the present disclosure include but are not limited to Schizophrenia, Bipolar Affective Disorder, Psychosis, Depression, Dissociation and Dissociative Disorders, Personality Disorder, Paranoia, Anxiety Disorders, Eating Disorders, Mood Disorders, Obsessive-Compulsive Disorders, Post-Traumatic Stress (PTS) Disorders, Dissociative Disorders, Panic Disorders, Substance Use Disorders, behavioral and emotional disorders in children and adults, and Schizoaffective disorder. In some embodiments, the compositions and treatments of the present disclosure can be used to treat schizophreniform disorder (acute schizophrenic episode); schizoaffective disorder; bipolar I disorder (mania, manic disorder, manic-depressive psychosis); bipolar II disorder; major depressive disorder with psychotic feature (psychotic depression); delusional disorders (paranoia); shared psychotic disorder (shared paranoia disorder); brief psychotic disorder (other and unspecified reactive psychosis); psychotic disorder not otherwise specified (unspecified psychosis); paranoid personality disorder; schizoid personality disorder; and schizotypal personality disorder. See, e.g., US Patent No.9,017,737.

[0163] Disorders that can be treated and / or ameliorated according to the present disclosure include but are not limited to antisocial personality disorder, anxiety disorder, Asperger symptom / disorder, attention deficit disorder, autistic disorder, bipolar disorder, body dysmorphic disorder, borderline personality disorder, central auditory processing disorder, chromosome disorder, compulsive personality disorder, conversion disorder, cruise-Attorney Docket No.7656-043030 associated diarrheal disorder, cumulative trauma disorder, delusional disorder, dependent personality disorder, depersonalization disorder, depressive disorder, developmental disorder, dissociative identity disorder, dysthymic disorder, eating disorder, anorexia nervosa, bulimia nervosa, binge-eating disorder, EBV-associated lymphoproliferative disorder, endometrial disorder, expressive disorder, expressive language disorder, factitious disorder, functional disorder, gender identify disorder, generalized anxiety disorder, genetic disorders, hearing disorder, histrionic personality disorder, identity disorder, internet addiction disorder, iodine deficiency disorder, language disorder, late luteal phase dysphoric disorder, lymphoproliferative disorder, major depressive disorder, Matha Stewart disorder, Mendelian disorder, mental disorder, motor speech disorder, movement disorder, multiple autoimmune disorder, multiple personality disorder, musculoskeletal disorder, myeloproliferative disorder, narcissistic personality disorder, neurodegenerative disorder, neurogenic communication disorder, neurotic disorder, non-Mendelian disorder, obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder, Pan-ethnic disorder, panic disorder, partial syndrome eating disorder, passive-aggressive personality disorder, post- translation lymphoproliferative disorder, post-traumatic stress disorder (PTSD), Prader-Willi syndrome, premenstrual dysphoric disorder, psychotic disorder, reactive attachment disorder of infancy or early childhood, reading disorder, S-100-positive T-cell lymphoproliferative disorder, schizoid personality disorder, seasonal affective disorder, seizure disorder, sexual pain disorder, shared psychotic disorder, silicone-reactive disorder, single gene disorder, sleep disorder, sleep terror disorder, smell disorder, social anxiety disorder, somatization disorder, speech disorder, swallowing disorder, taste disorder, thought disorder, throat disorder, thyroid disorder, urea cycle disorder, urologic disorder, voice disorder, treatment- resistant depression, and X-linked disorder. This list is adapted from McGraw-Hill Concise Dictionary of Modern Medicine (2002) The McGraw Hill Companies, Inc.

[0164] The compositions of the present disclosure can also be used to treat and / or ameliorate Autism spectrum disorder (ASD), which is a neurological and developmental disorder that affects how people interact with others, communicate, learn, and behave. Although autism can be diagnosed at any age, it is described as a “developmental disorder” because symptoms generally appear in the first 2 years of life. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), a guide created by the American PsychiatricAttorney Docket No.7656-043030 Association that health care providers use to diagnose mental disorders, people with ASD often have difficulty with communication and interaction with other people; restricted interests and repetitive behaviors; and symptoms that affect their ability to function in school, work, and other areas of life. Autism is known as a “spectrum” disorder because there is wide variation in the type and severity of symptoms people experience. People of all genders, races, ethnicities, and economic backgrounds can be diagnosed with ASD. Although ASD can be a lifelong disorder, treatments and services can improve a person’s symptoms and daily functioning. The American Academy of Pediatrics recommends that all children receive screening for autism. The compositions of the present disclosure can be used to treat or ameliorate all symptoms associated with autism and orphan conditions that share similar symptomatology. Examples of such symptoms include but are not limited to the following: stereotypic behavior, irritability, social anxiety, social withdrawal, inappropriate speech, hyperactivity / non-compliance, seizures, lethargy, depressive symptoms / depression. Adapted from a list provided by the National Institute of Mental Health (February 2023). Thus, one example of a CNS-associated disease that can be treated and / or ameliorated using the compositions and methods of the present disclosure includes but is not limited to autism spectrum disorder (ASD). It is estimated that 1 in 36 children may have ASD (Maenner et al., 2020). ASD is characterized by deficits in social communication, irritability, repetitive behaviors, impulsivity, temper tantrums, and high caregiver burden (Lecavalier et al., 2006). XII. Pharmaceutical Compositions and Their Administration

[0165] Administration of the compositions of the present disclosure can be via any method which delivers a compound of this disclosure systemically and / or locally, including oral routes, transdermal routes, etc. Generally, the compositions of the present disclosure are administered orally, but the following administration methods may also be utilized where necessary and / or appropriate: parenteral administration (e.g., intravenous (IV), intramuscular, subcutaneous (SQ or Sub-Q) injections, or intramedullary), transdermal, via inhalation, topically, via suppository, sublingual administration, and buccal administration.

[0166] The following references, some of which were relied upon for the following disclosure, provide detailed, background information on methods of preparing pharmaceutical compositions and methods of their administration: US Published Patent Application Nos. 20230029180 A1 (01 / 26 / 2023), 20210393719 A1 (12 / 23 / 2021),Attorney Docket No.7656-043030 20190142756 A1 (05 / 16 / 2019), 20200009060 A1 (01 / 09 / 2020); and US Patent Nos. 6,503,532, 6,635,237, 6,730,330, 6,734,176, 6,946,150, 7,025,992, 7,094,930, 7,344,736, 7,709,536, 7,968,594, 8,211,946, 8,445,023, 8,481,091, 8,512,767, 8,603,515, 8,470,874, 8,652,529, 9,023,400, 9,044,390, 9,186,386, 9,498,444, 9,572,851, 9,789,105, 9,980,996, 10,004,684, 10,064,905, 10,092,611, 10,213,391, 10,238,705, 10,517,911, 10,561,694, 10,568,920, 10,624,940, 10,639,339, 10,729,665, 11,234,944, 11,266,702, 11,318,109, 11,331,358, 11,311,587, 11,344,591, and 11,478,520. Some of the detailed description in this section are derived from one or more of these references.

[0167] In some embodiments, the nicotine compositions, including pharmaceutical compositions, disclosed herein may also comprise other conventional pharmaceutically acceptable ingredients, commonly referred to as carriers, excipients, or adjuvants. Excipients or adjuvants include, but are not limited to: disintegrants, binders, lubricants, glidants, stabilizers, fillers, diluents, colorants, sweeteners, flavoring agents, and preservatives. For example, useful additives include materials such as agents for retarding dissolution (e.g., paraffin), resorption accelerators (e.g., quaternary ammonium compounds), surface active agents (e.g., cetyl alcohol, glycerol monostearate, and sodium lauryl sulfate), adsorptive carriers (e.g., kaolin and bentonite), preservatives, sweeteners, coloring agents, flavoring agents (e.g., chocolate mint, citric acid, menthol, glycine or orange powder), stabilizers (e.g., xanthan gum, locust bean gum, agar, citric acid or sodium citrate), binders (e.g., hydroxypropylmethylcellulose), and mixtures thereof. Those of ordinary skill in the art may, by conventional experimentation, select one or more of the above carriers based on the desired properties of the dosage form without undue burden. The amount of each carrier used is within the conventional range in the art.

[0168] In some embodiments, the nicotine compositions of the present disclosure may be a powdered extract which may optionally be combined with one or more inactive, neutral compounds / ingredients which can be pharmaceutically acceptable excipients or carriers, including, but not limited to, binders, antioxidants, adjuvants, synergists, and / or preservatives.

[0169] Some embodiments of the present disclosure are directed to dosage forms that are formulated as solid articles suitable for sublingual or oral administration, such as troches, lozenges, pills, oral dissolving strips, caps, pouches, or boluses. These solid dosage formsAttorney Docket No.7656-043030 may comprise additional excipients. Both hard and chewable lozenges and troches are within the scope of the present disclosure. In some embodiments, the oral dosage forms are formulated as capsules in which the compositions of the present disclosure are encapsulated in soft or hard gelatin capsules.

[0170] Some embodiments of the present disclosure are directed to dosage forms that are formulated as topical formulations, including but not limited to creams, ointments, and gel, using formulation methods as are known in the art. In one embodiment, the topical formulation is a transdermal patch, using formulation methods and technologies as are known in the art.

[0171] Some embodiments of the present disclosure are directed to dosage forms that are formulated as solid articles suitable for administration as vaginal ovules or rectal suppositories, using formulation methods as are known in the art.

[0172] Some embodiments of the present disclosure are directed to dosage forms that are formulated as liquids, including but not limited to emulsions, liposomes, dispersions, oils, and tinctures, using formulation methods as are known in the art. A dispersible or liquid format is probably required for pediatric medical delivery.

[0173] Some embodiments of the present disclosure are directed to dosage forms that are formulated as beverages and edibles, wherein the compositions are incorporated into food and drink products.

[0174] Some embodiments of the present disclosure are directed to dosage forms that are formulated as smokeable or vaporizable formulations.

[0175] In some embodiments, the dosage forms of the present disclosure can be formulated, as appropriate, to include disintegrants, including but not limited to starch, cellulose derivatives and alginates, crosslinked sodium carboxymethyl cellulose (corscarmellose sodium) (e.g., AC-DI-SOL from FMC), hydroxypropylmethyl cellulose (HPMC), crosslinked polyvinylpyrrolidone (crospovidone), clay, cellulose, gum, crosslinked polymers (e.g., crospolyvinylpyrrolidone or crospovidone, such as POLYPLASDONE XL from ISP (International Specialty Products, Wayne, N.J.)), croscarmellose calcium, soybean polysaccharide, and guar gum.

[0176] The dosage forms of the present disclosure can be formulated, as appropriate, to include glidants, including but not limited to silicon dioxide, colloidal anhydrous silicon, andAttorney Docket No.7656-043030 other silica compounds, and / or and or lubricants including stearic acid and salts thereof, such as magnesium stearate.

[0177] In some embodiments, sweeteners that can be used for formulating dosage forms of the present disclosure include but are not limited to sucralose, neotame, modified steviol glycosides, neohesperidin dihydrochalcone, aspartame, acesulfame potassium (aka acesulfame K), advantame, sucrose, fructose, maltitol, xylitol, sorbitol, gelatin, sodium saccharin, mannitol, and stevioside.

[0178] In some embodiments, the dosage forms of the present disclosure may optionally be formulated to further comprise one or several antioxidants. Examples of pharmaceutically acceptable antioxidants include but are not limited to: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite and sodium sulfite; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate and α tocopherol; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid and phosphoric acid. Additional examples of oxidants that could be used according to the present disclosure include but are not limited to α-tocopherol acetate, acetone sodium bisulfite, acetylcysteine, cysteine, tocopherol natural, tocopherol synthetic, dithiothreitol, monothioglycerol, nordihydroguaiaretic acid, propyl gallate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, thiourea and tocopherols.

[0179] In some embodiments, the dosage forms of the present disclosure may optionally be formulated to further comprise one or several adjuvants or synergists. If adjuvants or synergists are used, non-limiting examples of those that can be used include citric acid, EDTA (ethylenediaminetetraacetate) and salts, hydroxyquinoline sulfate, phosphoric acid, and tartaric acid.

[0180] In some embodiments, the dosage forms of the present disclosure may optionally further comprise one or several preservatives. If preservatives are used, non-limiting examples of those that can be used include benzalkonium chloride, benzethonium chloride, benzoic acid and salts, benzyl alcohol, boric acid and salts, cetylpyridinium chloride, cetyltrimethyl ammonium bromide, chlorobutanol, chlorocresol, chorhexidine gluconate or chlorhexidine acetate, cresol, ethanol, imidazolidinyl urea, metacresol, methylparaben,Attorney Docket No.7656-043030 nitromersol, o-phenyl phenol, parabens, phenol, phenylmercuric acetate / nitrate, propylparaben, sodium benzoate, sodium nitrate, potassium sorbate, sorbic acids and salts, o- phenylethyl alcohol, and thimerosal.

[0181] Examples of pharmaceutically acceptable surfactants for use in the present disclosure include but are not limited to polyvinylpyrrolidone, polyethylene glycol surfactants, oleic acid, and lecithin.

[0182] Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to: silica gel, magnesium trisilicate, starch, talc, tricalcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose, and microcrystalline cellulose.

[0183] Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to: powdered sugar, compressible sugar, glucose binding agents, dextrin, dextrose, lactose, mannitol, maltitol, xylitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose, and talc.

[0184] The optimal dose of the compositions and formulations of the present disclosure can be determined empirically for everyone using known methods and will depend upon a variety of factors, including, but not limited to: the degree of progression of the disease; the age, body weight, general health, gender, and diet of the individual; the time and route of administration; and other medications the individual is taking. Optimal doses may be established using routine testing and procedures that are well known in the art.

[0185] The amount of each composition or formulation of the present disclosure that may be combined with the carrier materials to produce a single dosage form will vary depending upon the individual treated and the mode of administration. In some embodiments, when the composition or formulation comprises another active agent in addition to the nicotine, the unit dosage forms as described herein will contain a certain amount of each agent of the combination that is typically administered when the agent is administered alone.

[0186] In some embodiments, the drug-carrier complex disclosed herein is administered to a patient in the form of a pharmaceutical composition. In some embodiments, the drug-carrier complex disclosed herein is present in a pharmaceutically effective amount.Attorney Docket No.7656-043030 EXAMPLES

[0187] The present disclosure is further illustrated by the following examples that should not be construed as limiting. The contents of all references, patents, and published patent applications cited throughout this application, as well as the Figures, are incorporated herein by reference in their entirety for all purposes. Example 1: Method of Making

[0188] The general process of the present disclosure includes the following: (1) all of the ingredients are placed in a high-pressure vessel; (2) CO2 is introduced into the vessel, then pumped and heated until it reaches supercritical conditions; (3) the ingredients in the vessel are mixed under supercritical CO2 condition for about 30 minutes – about 1 hour; (4) the vessel is slowly vented until the vessel depressurizes to atmospheric pressure; and (5) the resulting powder encapsulated nicotine complex is collected.

[0189] FIG.1 provides an exemplary process flow chart of cyclodextrin-polymer-nicotine complexation of the present disclosure. FIG.2 provides an exemplary engineering diagram of a supercritical CO2 system used for the production of cyclodextrin-polymer-nicotine complexation of the present disclosure: 100 = CO2 inlet; 101 = check valve; 102 = flow control valve; 103 = condenser; 104 = pump; 105 = back pressure regulator; 106 = high- pressure mixing vessel; 107 = heater; 108 = rupture disc; and 109 = venting valve.

[0190] Table 2 and Table 3, below, provide exemplary target ranges for the encapsulated nicotine complexes (aka the core formulations or core compositions) based on the final desired composition and product for each product type (i.e., dry pouch and ellipse). These tables provide the relative ratios in percentages that can be utilized to prepare the encapsulated nicotine complexes but are not the ratios of ingredients in the final product as consumed, which are provided elsewhere herein.Attorney Docket No.7656-043030 Table 2. Target ranges for the encapsulated nicotine complexes (i.e., core composition) for use in the dry pouch compositions of the present disclosure. Dry Pouch Core CompositionExample Overall RangesNicotine(freebase / salt) 5.56% 3 - 20%Polymer 66.66% 30 - 55%CD 16.67% 32 - 58% Menthol 5.56% 0 - 10%Flavoring oil 5.56% 0 - 10% Table 3. Target ranges for the encapsulated nicotine complexes (i.e., core composition) for use in the ellipse compositions of the present disclosure. Ellipse Core CompositionExample Overall RangesNicotine (freebase) 5.56% 1 - 15% Polymer 66.66% 30 - 80%CD 16.67% 10 - 30%Menthol 5.56% 0 - 10% Flavoring oil 5.56% 0 - 10%

[0191] The amount of the nicotine in the final composition or product of the present disclosure in percentage based on dry weight / dry weight may be about 0.01%, 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 1.0%, about 2.0%, about 3.0%, about 4.0%, about 5.0%, about 6.0%, about 7.0%, about 8.0%, about 9.0%, about 10.0%, about 11.0%, about 12.0%, about 13.0%, about 14.0%, about 15.0%, about 16.0%, about 17.0%, about 18.0%, about 19.0%, about 20.0%, about 21%, about 22%, about 23%, about 24%, or about 25%. In some embodiments, the amount of the nicotine in the final composition or product of the present disclosure in dry weight / dry weight ranges from about 0.01% to 1.0%, about 0.1% to about 5.0%; about 1.0% to about 5.0%, about 5.0% to about 10.0%, about 10.0% to about 20.0%, about 1.0% to about 20%, about 0.1% to about 20.0%, about 0.01% to 20.0%, or about 0.01% to 25%. Example 2: Production of Comparative Formulations

[0192] Table 4 provides ranges of initial dry weight / dry weight percentages for each of the starting, primary ingredients used to produce the prior art comparative nicotine freebaseAttorney Docket No.7656-043030 formulations FB_01, FB_02, and FB_03. All freebase formulations were made according to the methods provided in Example 1 and the accompanying FIG.1 and FIG.2. The production of FB_03 is similar to that provided in Example 3 of PCT / US2020 / 056729 except that cannabinoid was the active ingredient used in that example instead of nicotine and that method had an additional nozzle spraying step at the end which was not part of the method set forth in Example 1 of the present disclosure.

[0193] Table 4. Percentage dry weight / weight ranges for starting ingredients for comparison freebase (“FB”) formulations. Exemplary FB Ingredients (Dry Weight / Dry Weight Percentages) Formulations FB_01 10% Nicotine freebase 80% PEG 3350 5% Alpha-tocopherol 5% Butylated hydroxytoluene FB_02 10% Nicotine freebase 90% Poloxamers FB_03 10% Nicotine freebase 90% Cyclodextrin Example 3: Exemplary Encapsulated Nicotine Complex Formulations of the Present Disclosure

[0194] Step 1 of the processes for producing the exemplary dry pouch (ENP) ellipse (ELS) formulations of the present disclosure involve the preparation of the encapsulated nicotine powder (i.e., the core formulations or core compositions). See, FIG. 6 and FIG. 7, respectively.

[0195] Table 5 provides the ranges of initial dry weight / weight percentages for each of the starting, primary ingredients used to produce the exemplary encapsulated nicotine freebase formulations ES_01, ES_02, ES_03, ES_05 and ES_07 and encapsulated nicotine bitartrate formulations ES_04, and ES_06 of the present disclosure. All exemplary encapsulated nicotine complex formulations were made according to the methods provided in Example 1 and the accompanying FIG.1 and FIG.2.Attorney Docket No.7656-043030

[0196] Table 5. Percentage dry weight / weight ranges for starting materials for exemplary encapsulated nicotine complex formulations (“ES”) of the Present Disclosure. Exemplary Formulations Ingredients (Dry Weight / Weight Percentages) ES_01 6.5% Nicotine freebase 32.3% Poloxamer 51.6% Cyclodextrin 6.5% Peppermint oil 3.2% Ascorbic Acid ES_02 6.5% Nicotine freebase 32.3% Poloxamer 51.6% Cyclodextrin 6.5% Eucalyptus oil 3.2% Ascorbic Acid ES_03 6.5% Nicotine freebase 32.3% Poloxamer 51.6% Cyclodextrin 6.5% Quercetin 3.2% Eucalyptus oil ES_04 12.9% Nicotine bitartrate 32.3% Poloxamer 51.6% Cyclodextrin 4.8% Peppermint oil ES_05 18.2% Nicotine freebase 42.4% Cyclodextrin 30.3% Poloxamer 9.1% Cornmint oil ES_06 21.4% Nicotine bitartrate 42.9% Cyclodextrin 35.7% Poloxamer ES_07 6.6% Nicotine freebase 13.2% Pullulan 39.5% Povidone 35.7% Cyclodextrin 7.1% Cornmint oil 1.4% Menthol

[0197] The encapsulated nicotine complex compositions or products of the methods of the present disclosure are produced according to the scCO2 process as provided in Example 1, but such encapsulated nicotine complexes have not yet been flavored and / or mixed with the necessary ingredients to be made into a delivery or administrative formulation or product suchAttorney Docket No.7656-043030 as a lozenge, gum, or tablet etc. Following is a description of the encapsulated nicotine complex compositions or products for ES_01=to ES_07: (1) white to off-white powder; (2) bulk density from about 0.35 g / ml to about 0.65 g / ml; (3) tap density from about 0.6 g / ml to about 0.8 g / ml; (4) pH range of the formulations based off nicotine salt from about 2.5 to about 3.5; (5) pH range of Freebase nicotine formulations from about 5.5 to about 8.5. Additionally, the water content was shown to be from about 2% to about 15%, and more specifically ES-01 has a water content of 11.3% and ES-04 has a water content of 6.8%.

[0198] The specifications for each of the possible final compositions or products is almost limitless in scope other than they each typically contain about 1.0 mg to about 30.0 mg of nicotine per unit as measured by HPLC Shimadzhu Prominence LC-2050 with UV detector and / or by Waters Acquity UPC2with PDA detector. In some embodiments they can contain about 0.01% to about 20.0% of nicotine per unit based on the same measurements. Example 4. Reference Commercial Formulations

[0199] Table 6 provides ranges of initial dry weight / weight percentages for each of the starting, primary ingredients used to produce the reference commercial nicotine formulations CP_01, CP_02, CP_04 and CP_05and reference prior art formulation CP_03. CP_03 was made by grinding the two ingredients (i.e., nicotine bitartrate and MCC) together and was not processed using scCO2.

[0200] Table 6. Reference Formulations. Reference Formulation Ingredients (Dry Weight / Weight Percentages) CP_01 Competitive Product purchased commercially CP_02 Competitive Product purchased commercially CP_03 13.5% Nicotine bitartrate 86.5% MCC CP_04 Competitive Product purchased commercially CP_05 Competitive Product purchased commercially Example 5. Stability Tests

[0201] Sample formulations were produced as set forth in Examples 2-4. All samples were packaged in polypropylene (PP) tubes and placed in a stability chamber at accelerated storage conditions (about 40oC / about 104° F; about 75% Relative Humidity). Every week the nicotine concentration of three tubes of each formulation was measured.Attorney Docket No.7656-043030

[0202] Stability results of the prior art nicotine freebase stability formulations (FB_01, FB_02, and FB_03) (Example 2) versus exemplary freebase nicotine formulations ES_01, ES_02, and ES_03 produced according to the present disclosure (Example 3) are provided in FIG. 3a and FIG. 3b. Every one of the exemplary formulations produced according to the present disclosure demonstrated dramatically higher (i.e., greater) stability over time from week 1 to week 4 when compared head-to-head with the stability of any of the prior art formulations as measured over the same time periods.

[0203] Stability results of the nicotine bitartrate dry pouch formulation ENP_02 (Example 3) of the present disclosure versus the CP_01 and CP_02. reference formulations (Example 4) are provided in FIG.4. Formulation ENP_02 produced according to the present disclosure demonstrated higher (i.e., greater) stability over time from week 2 to week 4 when compared head-to-head with the stability of any of the reference formulations as measured over the same time periods. Example 6. Membrane Permeation Tests

[0204] A Franz-diffusion cell assay was used to mimic the permeation of nicotine across buccal membranes for exemplary nicotine bitartrate dry pouch formulation ENP_02(Example 3) versus the reference dry pouch formulations CP_02 and CP_03 (Example 4). A polyether sulfone (PES) membrane was used to mimic buccal absorption. The Franz cell was purchased from PermeGear, Inc., Hellertown, PA, USA. KH2PO4and K2HPO4were used to make the buffer solution (pH 7). For background information on making and using Franz cells see, e.g., Ng et al., 2010, Validation of a static Franz diffusion cell system for in vitro permeation studies, AAPS PharmSciTech 11(3):1432-41; Salamanca et al., 2018, Franz Diffusion Cell Approach for Pre-Formulation Characterisation of Ketoprofen Semi-Solid Dosage Forms, Pharmaceutics 10(3), 148; and Iliopoulos et al., 2020, Franz Cell Diffusion Testing and Quantitative Confocal Raman Spectroscopy: In Vitro-In Vivo Correlation. Pharmaceutics 12(9):887.

[0205] Membrane permeation test results are provided in FIG. 5. Exemplary composition ENP_02 produced according to the present disclosure demonstrated about 25% faster permeation in comparison to the reference compositions as measured over the same time periods.Attorney Docket No.7656-043030 Example 7. Organoleptic Sensory Feedback

[0206] Exemplary compositions ES_01 to ES_07 (Table 5) can be formatted into a wide range of consumer package goods products including but not limited to gums, lozenges, lip balms, pouches, ready to mix beverages, throat sprays, sublingual tablets, capsules, and effervescent tablets. These formulations have been explored in controlled focus group settings to determine the organoleptic properties of the exemplary compositions.

[0207] In one such study, focus group participants were asked to evaluate 3 different nicotine pouch formulations (i.e., ENP_01, ENP_02, and CP_02) (Examples 9, 9, and 4, respectively) and to rank the pouches based on their overall experience. The pouches utilized were saliva-permeable nonwoven cellulose fabric (Filter Khaini Making Paper, Kanishk Intertrade, Chirag Delli, New Delhi, India). Participants were directed to consider their experiences as related to throat burn / bitterness, onset time, and flavor intensity / longevity for each sample. All samples prepared contained identical flavoring amounts and were packaged in the same manufacturing process.

[0208] Overall, 75% of participants preferred either ENP_01 or ENP_02over CP_02. Furthermore, 63% of respondents preferred both ENP_01 and ENP_02 to CP-02, which is a commercially available product.

[0209] Anecdotal comments from participants highlighted that the exemplary compositions of the present disclosure (i.e., ENP_01 and ENP_02) resulted in them experiencing reduced throat burn and longer lasting flavor than CP_02, while maintaining a similar onset time to CP_02. Example 8. Flavorless Dry Pouches

[0210] In some embodiments, the compositions provided by the present disclosure are formulated as flavorless dry pouches, offering a neutral-tasting nicotine delivery system for users who prefer an unflavored option or where regulations restrict the use of flavoring agents. All exemplary nicotine formulations were made according to the methods provided in Example 1 and the accompanying FIG.1 and FIG.2.

[0211] These pouches maintain a balanced sensory profile while ensuring effective nicotine release and stability.

[0212] In some embodiments, the pouches of the present disclosure are typically sized between 10-20 mm in width and 20-30 mm in length.Attorney Docket No.7656-043030

[0213] In some embodiments, the width of the flavorless dry pouches of the present disclosure are about 9.0 mm, about 9.1 mm, about 9.2 mm, about 9.3 mm, about 9.4 mm, about 9.5 mm, about 9.6 mm, about 9.7 mm, about 9.8 mm, about 9.9 mm, about 10.0 mm, about 11.0 mm, about 12.0 mm, about 13.0 mm, about 14.0 mm, about 15.0 mm, about 16.0 mm, about 17.0 mm, about 18.0 mm, about 19.0 mm, about 19.5 mm, about 19.6 mm, about 19.7 mm, about 19.8 mm, about 19.9 mm, about 20.0 mm, about 20.1 mm, about 20.2 mm, about 20.3 mm, about 20.4 mm, about 20.5 mm, or about 21.0 mm.

[0214] In some embodiments, the length of the flavorless dry pouches of the present disclosure are about 19.0 mm, about 19.5 mm, about 19.6 mm, about 19.7 mm, about 19.8 mm, about 19.9 mm, about 20.0 mm, about 20.1 mm, about 20.2 mm, about 20.3 mm, about 20.4 mm, about 20.5 mm, about 21.0 mm, about 22.0 mm, about 23.0 mm, about 24.0 mm, about 25.0 mm, about 26.0 mm, about 27.0 mm, about 28.0 mm, about 29.0 mm, about 30.0 mm, about 30.1 mm, about 30.2 mm, about 30.3 mm, about 30.4 mm, about 30.5 mm, or about 31.0 mm.

[0215] The composition includes nicotine-cyclodextrin-polymer complexes as the primary nicotine source, optimizing nicotine stability and reducing the harshness associated with unencapsulated nicotine. To achieve a palatable formulation, sweeteners such as sucralose or acesulfame K, pH adjusters such as sodium bicarbonate and carbonate, and fillers / diluents such as microcrystalline cellulose or starch are incorporated. These components work together to modulate the overall mouthfeel, mitigate bitterness, and ensure a controlled nicotine release profile. The moisture content is maintained at less than 5% weight / weight to ensure stability.

[0216] In some embodiments, the moisture content of the flavorless dry pouches on a weight / weight basis are maintained at about 1.0%, at about 1.5%, at about 2.0%, at about 2.5%, at about 3.0%, about 3.5%, about 4.0%, about 4.5 %, about 4.6%, about 4.7 %, about 4.8 %, about 4.9%, about 5.0%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, or about 5.5%.

[0217] A key advantage of utilizing the disclosed composition is the significant reduction in nicotine’s inherent bitterness and irritation, enhancing user experience without the need for added flavors. This is particularly beneficial when employing nicotine salts such as nicotine bitartrate, where the encapsulation of nicotine within the cyclodextrin-polymer complexAttorney Docket No.7656-043030 provides a physical barrier between the nicotine and the pH adjusters required to achieve the target pH range of about 7.5 to about 8.5 in the final pouch formulation.

[0218] In some embodiments, the final flavorless dry pouch formulation has a pH of about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9, or about 9.0.

[0219] The controlled, physical separation utilized in this Example minimizes premature interactions, ensuring stability and optimizing the release characteristics of nicotine. According to this Example, the nicotine is encapsulated, holding it in an encapsulated environment apart from the additives introduced to adjust pH (which do not require encapsulation). Encapsulation is used in this Example to physically separate the nicotine salt (acid) from the pH adjusters (base) which keeps the nicotine in salt form and thereby maximizes stability.

[0220] Manufacturing Process. An overview of the process for making the dry pouches of the present disclosure, including flavorless dry pouches, is provided in FIG. 6, which involves: (1) Mixing: The nicotine-cyclodextrin-polymer complex, sweeteners, pH adjusters, and fillers / diluents are mixed to form a uniform blend. (2) Forming Pouches: The mixture is portioned into individual pouches. Each pouch is sealed to ensure consistent nicotine release.

[0221] The dry pouch formulations of the present disclosure have the “ENP” prefix. These pouches can contain freebase nicotine or nicotine salt which is determined by the encapsulated nicotine complex (“ES”) formulation. The amount of encapsulated nicotine complex present in each ENP formulation dictates the amount of nicotine (mg) in each pouch and can vary between about 10% and about 50%.

[0222] Sensory Testing. Flavorless dry pouches formulated with nicotine-cyclodextrin- polymer complexes were evaluated in controlled focus group settings to determine their organoleptic properties compared to pouches without these complexes. Eight out of eight (100%) participants preferred the flavorless dry pouches (ENP_04) formulated with nicotine- cyclodextrin-polymer complexes over identical formulations that did not include the ternary complex described in the referenced patent.. Participants evaluated two different nicotine flavorless dry pouches and were asked to consider their experiences related to throat burn / bitterness and onset time for each sample. Sensory evaluations indicated that pouches with nicotine-cyclodextrin-polymer complexes exhibited superior bitterness masking andAttorney Docket No.7656-043030 enhanced nicotine release. Participants reported a smoother mouthfeel with reduced harshness and irritation. These findings highlight the advantages of nicotine-cyclodextrin-polymer complexes in optimizing both nicotine delivery and user experience. Example 9. Flavored Dry Pouches

[0223] In some embodiments, the compositions provided by the present disclosure are formulated as flavored dry pouches, offering a controlled and long-lasting nicotine experience with enhanced sensory appeal. All exemplary nicotine formulations were made according to the methods provided in Example 1 and the accompanying FIG.1 and FIG.2.

[0224] These pouches retain all the advantages of the flavorless variant, including improved nicotine stability, reduced bitterness, and optimized pH balance, while incorporating an additional benefit—integrated flavoring for a superior user experience.

[0225] The pouches are typically sized between 10-20 mm in width and 20-30 mm in length.

[0226] In some embodiments, the width of the flavored dry pouches of the present disclosure are about 9 mm, about 9.1 mm, about 9.2 mm, about 9.3 mm, about 9.4 mm, about 9.5 mm, about 9.6 mm, about 9.7 mm, about 9.8 mm, about 9.9 mm, about 10.0 mm, about 11.0 mm, about 12.0 mm, about 13.0 mm, about 14.0 mm, about 15.0 mm, about 16.0 mm, about 17.0 mm, about 18.0 mm, about 19.0 mm, about 19.5 mm, about 19.6 mm, about 19.7 mm, about 19.8 mm, about 19.9 mm, about 20.0 mm, about 20.1 mm, about 20.2 mm, about 20.3 mm, about 20.4 mm, about 20.5 mm, or about 21.0 mm.

[0227] In some embodiments, the length of the flavored dry pouches of the present disclosure are about 19.0 mm, about 19.5 mm, about 19.6 mm, about 19.7 mm, about 19.8 mm, about 19.9 mm, about 20.0 mm, about 20.1 mm, about 20.2 mm, about 20.3 mm, about 20.4 mm, about 20.5 mm, about 21.0 mm, about 22.0 mm, about 23.0 mm, about 24.0 mm, about 25.0 mm, about 26.0 mm, about 27.0 mm, about 28.0 mm, about 29.0 mm, about 30.0 mm, about 30.1 mm, about 30.2 mm, about 30.3 mm, about 30.4 mm, about 30.5 mm, or about 31.0 mm.

[0228] The composition includes nicotine-cyclodextrin-polymer complexes as the primary nicotine source, ensuring stability and mitigating the harshness associated with free nicotine. To enhance palatability, sweeteners such as sucralose or acesulfame K, pH adjusters such as sodium bicarbonate and carbonate, and fillers / diluents such as microcrystalline cellulose or starch are incorporated. These components work synergistically to optimize mouthfeel andAttorney Docket No.7656-043030 regulate nicotine release. The moisture content is maintained at less than 5% weight / weight to ensure stability.

[0229] In some embodiments, the moisture content of the flavored dry pouches on a weight / weight basis are maintained at about 1.0%, at about 1.5%, at about 2.0%, at about 2.5%, at about 3.0%, about 3.5%, about 4.0%, about 4.5 %, about 4.6%, about 4.7 %, about 4.8 %, about 4.9%, about 5.0%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, or about 5.5%.

[0230] A key advantage of this formulation is the incorporation of flavoring oils directly within the nicotine-cyclodextrin-polymer complex. By encapsulating hydrophobic molecules such as flavoring oils, this approach enables a prolonged and controlled flavor release, ensuring a consistent sensory experience throughout use. This method is particularly advantageous when space for additional flavoring agents in the dry pouch matrix is limited, as it efficiently transforms liquid oils into a high-concentration powdered form, preserving a robust and stable flavor profile.

[0231] Manufacturing Process. An overview of the process for making the dry pouches of the present disclosure, including for flavored dry pouches, is provided in FIG.6, wherein the manufacturing process involves: (1). Incorporating Flavoring Oils: Flavoring oils are encapsulated within the nicotine-cyclodextrin-polymer complex. (2). Mixing: The nicotine- cyclodextrin-polymer complex, sweeteners, pH adjusters, and fillers / diluents are mixed together to form a uniform blend. (3). Forming Pouches: The mixture is portioned into individual pouches. Each pouch is sealed to ensure consistent nicotine and flavor release.

[0232] The dry pouch formulations of the present disclosure have the “ENP” prefix. These pouches can contain freebase nicotine or nicotine salt which is determined by the encapsulated nicotine complex (“ES”) formulation. The amount of encapsulated nicotine complex present in each ENP formulation dictates the amount of nicotine (mg) in each pouch and can vary between about 10% and about 50%.

[0233] Exemplary flavored dry pouch (ENP) formulations are provided in the following table.Attorney Docket No.7656-043030 Table 7. Exemplary flavored dry pouch (ENP) formulations according to the present disclosure. Ingredients Percentage (w / w%)ENP_01 ENP_02 ENP_03 ENP_04 ENP_05Encapsulated nicotine 15% 22% 44% 51% 32% complex (ES_03) (ES_04) (ES_04) (ES_06) (ES_05) Flavoring powder11% 11% 11% 0% 11%Menthol 1% 1% 1% 0% 1% MCC 25% 25% 25% 25% 25% Sucralose 1% 1% 1% 1% 1% Sodium Chloride1% 1% 1% 1% 1%Sodium bicarbonate1% 3% 4% 3% 3%Sodium carbonate1% 2% 4% 8% 2%Sorbitol 44% 34% 9% 11% 24%

[0234] ENP_01 comprises 3 - 4 mg of nicotine per pouch, is mint flavored, utilizes ES_03 encapsulated nicotine complex for its preparation, and has a moisture content of about 2.8%.

[0235] ENP_02 comprises 3 - 4 mg of nicotine per pouch, is mint flavored, utilizes ES_04 encapsulated nicotine complex for its preparation, and has a moisture content of about 2.5%.

[0236] ENP_03 comprises 6 - 7 mg of nicotine per pouch, is citrus mint flavored, utilizes ES_04 encapsulated nicotine complex for its preparation, and has a moisture content of about 2.5%.

[0237] ENP_04 comprises 12 - 13 mg of nicotine per pouch, has no flavors added, utilizes ES_06 encapsulated nicotine complex for its preparation, and has a moisture content of about 2.1%.

[0238] ENP_05 comprises 20 - 21 mg of nicotine per pouch, is mint flavored, utilizes ES_05 encapsulated nicotine complex for its preparation, and has a moisture content of about 2.3%.

[0239] Sensory Testing. Flavored dry pouches formulated with nicotine-cyclodextrin- polymer complexes were evaluated in controlled focus group settings to determine their organoleptic properties compared to pouches without these complexes. Six out of eight (75%) participants preferred the flavored dry pouches formulated with nicotine-cyclodextrin-Attorney Docket No.7656-043030 polymer complexes over those without. Participants evaluated two different nicotine flavored dry pouches and were asked to consider their experiences related to throat burn / bitterness, onset time, and flavor intensity / longevity for each sample. Sensory evaluations indicated that pouches with nicotine-cyclodextrin-polymer complexes exhibited superior bitterness masking and enhanced flavor longevity. Participants reported a smoother mouthfeel with reduced harshness and irritation, while the embedded flavors remained perceptible for a longer duration. These findings highlight the advantages of nicotine-cyclodextrin-polymer complexes in optimizing both nicotine delivery and user experience. All samples contained identical flavoring amounts and were packaged using the same manufacturing process. Example 10. Moistened Pouches

[0240] In some embodiments, the compositions provided by the present disclosure are formulated as moistened pouches, offering an enhanced nicotine delivery system with improved sensory characteristics and stability. These pouches are designed to maintain controlled moisture content, ensuring consistent and efficient nicotine release. All exemplary nicotine formulations were made according to the methods provided in Example 1 and the accompanying FIG.1 and FIG.2.

[0241] The composition includes nicotine-cyclodextrin-polymer complexes as the primary nicotine source, optimizing nicotine stability and reducing the harshness associated with unencapsulated nicotine. This formulation is particularly beneficial when employing freebase nicotine. Maintaining a moisture content between 5-15% weight / weight helps prevent nicotine loss from evaporation. The pouches are typically sized between 10-20 mm in width and 20-30 mm in length.

[0242] In some embodiments, the moisture content of the moistened pouches on a weight / weight basis are maintained at about 4%, about 4.5%, about 4.6 %, about 4.7 %, about 4.8%, about 4.9%, about 5.0%, about 5.1%, about 5.2%, about 5.3%, about 5.4 %, about 5.5%, about 6.0%, about 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, about 10.0%, about 10.5%, about 11.0%, about 11.5%, about 12.0%, about 12.5%, about 13.0%, about 13.5%, about 14.0%, about 14.5%, about 15.0%, about 15.1%, about 15.2%, about15.3%, about 15.4%, about 15.5%, or about 16%.

[0243] In some embodiments, the width of the moistened pouches of the present disclosure are about 9.0 mm, about 9.1 mm, about 9.2 mm, about 9.3 mm, about 9.4 mm, about 9.5 mm,Attorney Docket No.7656-043030 about 9.6 mm, about 9.7 mm, about 9.8 mm, about 9.9 mm, about 10.0 mm, about 11.0 mm, about 12.0 mm, about 13.0 mm, about 14.0 mm, about 15.0 mm, about 16.0 mm, about 17.0 mm, about 18.0 mm, about 19.0 mm, about 19.5 mm, about 19.6 mm, about 19.7 mm, about 19.8 mm, about 19.9 mm, about 20.0 mm, about 20.1 mm, about 20.2 mm, about 20.3 mm, about 20.4 mm, about 20.5 mm, or about 21.0 mm.

[0244] In some embodiments, the length of the moistened pouches of the present disclosure are about 19.0 mm, about 19.5 mm, about 19.6 mm, about 19.7 mm, about 19.8 mm, about 19.9 mm, about 20.0 mm, about 20.1 mm, about 20.2 mm, about 20.3 mm, about 20.4 mm, about 20.5 mm, about 21.0 mm, about 22.0 mm, about 23.0 mm, about 24.0 mm, about 25.0 mm, about 26.0 mm, about 27.0 mm, about 28.0 mm, about 29.0 mm, about 30.0 mm, about 30.1 mm, about 30.2 mm, about 30.3 mm, about 30.4 mm, about 30.5 mm, or about 31.0 mm.

[0245] Manufacturing Process. (1). Mixing: The nicotine-cyclodextrin-polymer complex, sweeteners, and fillers / diluents are mixed together to form a uniform blend. (2). Adding Moisture: Water and / or glycerin is then added to the mixture to raise the moisture level to the desired range of 5-15% weight / weight. This step ensures the mixture is adequately moistened while maintaining stability. (3). Forming Pouches: The moistened mixture is then portioned into individual pouches. Each pouch is sealed to maintain the controlled moisture content and ensure consistent nicotine release. (4). Optional Moisture Addition: After forming the pouches, an additional step can be taken to add moisture. This involves lightly misting the pouches with water or a glycerin solution to ensure optimal moisture content is maintained.

[0246] Sensory Testing. Moistened pouches formulated with nicotine-cyclodextrin- polymer complexes were evaluated in controlled focus group settings to determine their organoleptic properties compared to pouches without these complexes. Seven out of eight (87.5%) participants preferred the moistened pouches formulated with nicotine-cyclodextrin- polymer complexes over those without. Participants evaluated two different nicotine moistened pouches and were asked to consider their experiences related to throat burn / bitterness, onset time, and flavor intensity / longevity for each sample. Sensory evaluations indicated that pouches with nicotine-cyclodextrin-polymer complexes exhibited superior bitterness masking and enhanced flavor longevity. Participants reported a smoother mouthfeel with reduced harshness and irritation, while the embedded flavors remained perceptible for a longer duration. These findings highlight the advantages of nicotine-Attorney Docket No.7656-043030 cyclodextrin-polymer complexes in optimizing both nicotine delivery and user experience. All samples contained identical flavoring amounts and were packaged using the same manufacturing process. Example 11. Oral Thin Films

[0247] In some embodiments, the compositions provided by the present disclosure are formulated as oral thin films, offering a discrete and efficient nicotine delivery system. The composition includes nicotine-cyclodextrin-polymer complexes as the primary or only nicotine source, ensuring controlled release and enhanced stability. A film-forming polymer (e.g., hydroxypropyl methylcellulose, pullulan, or pectin) is incorporated at 20-60% by dry weight, providing the structural matrix for the film. All exemplary encapsulated nicotine formulations were made according to the methods provided in Example 1 and the accompanying FIG.1 and FIG.2.

[0248] In some embodiments, the film-forming polymer is incorporated on a per dry weight basis at about 19.0%, about 19.5%, about 20.0%, about 20.5%, about 21.0%, about 22.0%, about 23.0%, about 24.0%, about 25.0%, about 26.0%, about 27.0%, about 28.0%, about 29.0%, about 30.0%, about 31.0%, about 32.0%, about 33.0%, about 34.0%, about 35.0%, about 36.0%, about 37.0%, about 38.0%, about 39.0%, about 40.0%, about 41.0%, about 42.0%, about 43.0%, about 44.0%, about 45.0%, about 46.0%, about 47.0%, about 48.0%, about 49.0%, about 50.0%, about 51.0%, about 52.0%, about 53.0%, about 54.0%, about 55.0%, about 56.0%, about 57.0%, about 58.0%, about 59.0%, about 60.0%, about 60.5%, or about 61%.

[0249] A plasticizer (e.g., glycerin, PEG 400, or propylene glycol) at 2-15% by dry weight is included to optimize flexibility and mechanical properties. Flavoring agents, if required, may be integrated within the nicotine-cyclodextrin-polymer complex, offering prolonged flavor retention and minimizing volatilization during the drying process. Additional components may include sweeteners (e.g., sucralose or acesulfame K) and pH modifiers (e.g., sodium carbonate) to optimize nicotine absorption.

[0250] In some embodiments, the plasticizer is utilized on a per dry weight basis at about 1.0%, about 1.5%, about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%,about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5 %, about 5.0%, about 6.0%, about 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%,Attorney Docket No.7656-043030 about 10.0%, about 10.5%, about 11.0%, about 11.5%, about 12.0%, about 12.5%, about 13.0%, about 13.5%, about 14.0%, about 14.5%, about 15.0%, about 15.1%, about 15.2%, about 15.3%, about 15.4%, about 15.5%, or about 16%.

[0251] Manufacturing Process. (1). Dissolving and Mixing: The film-forming polymer, plasticizer, and other components (e.g., sweeteners, pH modifiers) are dissolved or dispersed in an aqueous solution at controlled temperatures to ensure proper hydration and dispersion. (2). Incorporating the Nicotine Complex: The nicotine-cyclodextrin-polymer complex is gently incorporated into the mixture to maintain uniform distribution. (3). Casting: The mixture is cast onto a substrate to form a thin film. The casting process ensures uniform thickness and consistency. (4). Drying: The cast film is dried under controlled conditions to achieve the desired thickness and mechanical properties. This step ensures the film is sufficiently dry while maintaining flexibility. (5). Cutting: The dried film is cut into uniform strips, ensuring consistent dosing. The dimensions of the films typically range from 20-40 mm in length, 10-30 mm in width, and 50 µm to 2.5 mm in thickness, providing a balance of comfort, adhesion, and dissolution efficiency.

[0252] In some embodiments, the length of the oral thin films of the present disclosure are about 19.0 mm, about 19.5 mm, about 19.6 mm, about 19.7 mm, about 19.8 mm, about 19.9 mm, about 20.0 mm, about 20.1 mm, about 20.2 mm, about 20.3 mm, about 20.4 mm, about 20.5 mm, about 21.0 mm, about 22.0 mm, about 23.0 mm, about 24.0 mm, about 25.0 mm, about 26.0 mm, about 27.0 mm, about 28.0 mm, about 29.0 mm, about 30.0 mm, about 31.0 mm, about 32.0 mm, about 33.0 mm, about 34.0 mm, about 35.0 mm, about 36.0 mm, about 37.0 mm, about 38.0 mm, about 39.0 mm, about 40.0 mm, about 40.1 mm, about 40.2 mm, about 40.3 mm, about 40.4 mm, about 40.5 mm, or about 41.0 mm.

[0253] In some embodiments, the width of the oral thin films of the present disclosure are about 9.0 mm, about 9.1 mm, about 9.2 mm, about 9.3 mm, about 9.4 mm, about 9.5 mm, about 9.6 mm, about 9.7 mm, about 9.8 mm, about 9.9 mm, about 10.0 mm, about 11.0 mm, about 12.0 mm, about 13.0 mm, about 14.0 mm, about 15.0 mm, about 16.0 mm, about 17.0 mm, about 18.0 mm, about 19.0 mm, about 20.0 mm, or about 21.0 mm, about 22.0 mm, about 23.0 mm, about 24.0 mm, about 25.0 mm, about 26.0 mm, about 27.0 mm, about 28.0 mm, about 29.0 mm, about 30.0 mm, about 30.1 mm, about 30.2 mm, about 30.3 mm, about 30.4 mm, about 30.5 mm, or about 31.0 mm.Attorney Docket No.7656-043030

[0254] In some embodiments, the thickness of the oral thin films of the present disclosure are about 50.0 µm, about 60.0 µm, about 70.0 µm, about 80.0 µm, about 90.0 µm, about 0.1 mm, about 0.2 mm, about 0.3 mm, about 0.4 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, about 1.0 mm, about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, about 1.7 mm, about 1.8 mm, about 1.9 mm, about 2.0 mm, about 2.1 mm, about 2.2 mm, about 2.3 mm, about 2.4 mm, or about 2.5 mm.

[0255] The resulting oral thin films exhibit rapid dissolution upon contact with saliva, leading to efficient transmucosal nicotine absorption. The films demonstrate high mechanical flexibility, uniform drug distribution, and improved palatability.

[0256] Sensory Testing. Oral thin films formulated with nicotine-cyclodextrin-polymer complexes were evaluated in controlled focus group settings to determine their organoleptic properties compared to films without these complexes. Six out of eight (75%) participants preferred the oral thin films formulated with nicotine-cyclodextrin-polymer complexes over those without. Participants evaluated two different nicotine oral thin films and were asked to consider their experiences related to throat burn / bitterness, onset time, and flavor intensity / longevity for each sample. Sensory evaluations indicated that films with nicotine- cyclodextrin-polymer complexes exhibited superior bitterness masking and enhanced flavor longevity. Participants reported a smoother mouthfeel with reduced harshness and irritation, while the embedded flavors remained perceptible for a longer duration. These findings highlight the advantages of nicotine-cyclodextrin-polymer complexes in optimizing both nicotine delivery and user experience. All samples contained identical flavoring amounts and were packaged using the same manufacturing process. Example 12. Dissolvable Ellipses

[0257] In some embodiments, the compositions provided by the present disclosure are formulated as dissolvable ellipses, designed for placement within the buccal vestibule to provide controlled nicotine release. A dissolvable ellipse, so called after its ellipsoid shape, is a solid composition which allows for a gradual softening and dissolution process, facilitating sustained nicotine delivery while optimizing user comfort and sensory experience. All exemplary nicotine formulations were made according to the methods provided in Example 1 and the accompanying FIG.1 and FIG.2.Attorney Docket No.7656-043030

[0258] The moisture content is maintained between 10-30% by weight / weight, ensuring the gel is sufficiently rigid for application while still allowing for controlled dissolution.

[0259] In some embodiments, the moisture content by weight / weight of the dissolvable ellipses is about 8.5%, about 9.0%, about 9.5%, about 10.0%, about 10.5%, about 11.0%, about 11.5%, about 12.0%, about 12.5%, about 13.0%, about 13.5%, about 14.0%, about 14.5%, about 15.0%, about 16%, about 16.5%, about 17.0%, about 17.5%, about 18.0%, about 18.5%, about 19.0%, about 19.5%, about 20.0%, about 20.5%, about 21.0%, about 22.0%, about 23.0%, about 24.0%, about 25.0%, about 26.0%, about 27.0%, about 28.0%, about 29.0%, about 30.0%, about 31.0%. In some embodiments, the ellipses of the present disclosure are typically sized between 20- 40 mm in length, 10-30 mm in width, and 1-5 mm in thickness. In some embodiments, the thickness of the ellipses is 3-5 mm.

[0260] In some embodiments, the length of the dissolvable ellipses of the present disclosure are about 19.0 mm, about 19.5 mm, about 19.6 mm, about 19.7 mm, about 19.8 mm, about 19.9 mm, about 20.0 mm, about 20.1 mm, about 20.2 mm, about 20.3 mm, about 20.4 mm, about 20.5 mm, about 21.0 mm, about 22.0 mm, about 23.0 mm, about 24.0 mm, about 25.0 mm, about 26.0 mm, about 27.0 mm, about 28.0 mm, about 29.0 mm, about 30.0 mm, about 30.1 mm, about 30.2 mm, about 30.3 mm, about 30.4 mm, about 30.5 mm, about 31.0 mm, about 32.0 mm, about 33.0 mm, about 34.0 mm, about 35.0 mm, about 36.0 mm, about 37.0 mm, about 38.0 mm, about 39.0 mm, about 40.0 mm, about 40.1 mm, about 40.2 mm, about 40.3 mm, about 40.4 mm, about 40.5 mm, or about 41.0 mm.

[0261] In some embodiments, the width of the dissolvable ellipses of the present disclosure are about 9.0 mm, about 9.1 mm, about 9.2 mm, about 9.3 mm, about 9.4 mm, about 9.5 mm, about 9.6 mm, about 9.7 mm, about 9.8 mm, about 9.9 mm, about 10.0 mm, about 11.0 mm, about 12.0 mm, about 13.0 mm, about 14.0 mm, about 15.0 mm, about 16.0 mm, about 17.0 mm, about 18.0 mm, about 19.0 mm, about 19.5 mm, about 19.6 mm, about 19.7 mm, about 19.8 mm, about 19.9 mm, about 20.0 mm, about 20.1 mm, about 20.2 mm, about 20.3 mm, about 20.4 mm, about 20.5 mm, or about 21.0 mm, about 22.0 mm, about 23.0 mm, about 24.0 mm, about 25.0 mm, about 26.0 mm, about 27.0 mm, about 28.0 mm, about 29.0 mm, about 30.0 mm, about 30.1 mm, about 30.2 mm, about 30.3 mm, about 30.4 mm, about 30.5 mm, or about 31.0 mm.Attorney Docket No.7656-043030

[0262] In some embodiments, the thickness of the dissolvable ellipses of the present disclosure is about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, about 1.0 mm, about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, about 1.7 mm, about 1.8 mm, about 1.9 mm, about 2.0 mm, about 2.5 mm, about 3.0 mm, about 3.5 mm, about 4.0 mm, about 4.5 mm, about 5.0 mm, about 5.1 mm, about 5.2 mm, about 5.3 mm, about 5.4 mm, 5.5 mm, 5.6 mm, 5.7 mm, 5.8 mm, 5.9 mm, or about 6 mm.

[0263] The resulting ellipses exhibit rapid dissolution upon contact with saliva, leading to efficient transmucosal nicotine absorption. The ellipses demonstrate high mechanical flexibility, uniform drug distribution, and improved palatability

[0264] The composition includes nicotine-cyclodextrin-polymer complexes incorporating free-base nicotine to ensure stability in the aqueous formulation and enhance nicotine bioavailability. The base matrix consists of gel-forming agents (such as gelatin, pectin, carrageenan, carbomer, xanthan gum, or locust bean gum) at 5-30% by weight, humectants (such as glycerin, maltitol, or sorbitol) at 2-15% by weight, and stabilizers to maintain the integrity of the ellipse. Flavoring agents, when encapsulated within the nicotine-cyclodextrin- polymer complex, contribute to prolonged flavor retention and reduced volatilization. Additional components may include sweeteners (e.g., sucralose or acesulfame K) and pH modifiers (e.g., sodium carbonate) to optimize nicotine absorption.

[0265] In some embodiments, the gel-forming agents of the base matrix on a per weight basis are about 4%, about 4.5%, about 4.6 %, about 4.7 %, about 4.8%, about 4.9%, about 5.0%, about 5.1%, about 5.2%, about 5.3%, about 5.4 %, about 5.5%, about 6.0%, about 6.5%, about 7%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, about 10.0%, about 10.5%, about 11.0%, about 11.5%, about 12.0%, about 12.5%, about 13.0%, about 13.5%, about 14.0%, about 14.5%, about 15.0%, about 16%, about 16.5%, about 17.0%, about 17.5%, about 18.0%, about 18.5%, about 19.0%, about 19.5%, about 20.0%, about 20.5%, about 21.0%, about 22.0%, about 23.0%, about 24.0%, about 25.0%, about 26.0%, about 27.0%, about 28.0%, about 29.0%, about 30.0%, about 31.0%.

[0266] In some embodiments, the humectants of the base matrix on a per weight basis are about 1.0%, about 1.5%, about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%,about 20.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5 %, aboutAttorney Docket No.7656-043030 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5.0%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, or about 5.5%, about 6.0%, about 6.5%, about 7%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, about 10.0%, about 10.5%, about 11.0%, about 11.5%, about 12.0%, about 12.5%, about 13.0%, about 13.5%, about 14.0%, about 14.5%, about 15.0%, about 15.1%, about 15.2%, about15.3%, about 15.4%, about 15.5%, or about 16%.

[0267] Manufacturing Process. An overview of the process for making the ellipse formulations of the present disclosure is provided in FIG. 7, wherein the manufacturing process begins with the following processes: (1). Dissolving and Mixing: Gel-forming agents, humectants, and stabilizers are dissolved and mixed in an aqueous medium at controlled temperatures to ensure proper hydration and dispersion. (2). Incorporating the Nicotine Complex: The nicotine-cyclodextrin-polymer complex is gently incorporated into the mixture to maintain uniform distribution. (3). Molding and Setting: The mixture is poured into molds and subjected to a controlled cooling and setting process to achieve the desired texture and mechanical properties. (4). Demolding and Surface Treatment: Once set, the ellipses are demolded. They may undergo optional surface treatment to enhance stability before being packaged for distribution. (5). Adhering ellipses (optional): Multiple ellipses can be adhered together using water, allowing the adhered sections to dry. This provides the option to create rectangular cuboids with thicknesses ranging from 2.5mm to 8mm. (6) Filler integration (optional): A filler material (e.g., sorbitol) can be inserted between two ellipses prior to adhesion. This configuration allows for the formation of pillow-shaped products with thickness ranging from 2.5mm to 8mm

[0268] Exemplary ellipse (ELS) formulations are provided in the following table. Table 8. Exemplary ellipse (ELS) formulations according to the present disclosure. IngredientsPercentage (w / w%)ELS_01 ELS_02Encapsulated nicotine complex30% (ES_07) 12% (ES_07)Gelatin 0% 2% Sucralose 1% 1% Glycerin 5% 2% Water 64% 83%

[0269] ELS_01 comprises 22 - 23 mg of nicotine per unit, is mint flavored, and utilizes ES_07 encapsulated nicotine complex for its preparation.Attorney Docket No.7656-043030

[0270] ELS_02 comprises 9 - 10 mg of nicotine per unit, is mint flavored, and utilizes ES_07 encapsulated nicotine complex for its preparation.

[0271] In some embodiments, the thickness of the rectangular cuboids of the present disclosure are about 1.0 mm, about 1.5 mm, about 2.0 mm, about 2.1 mm, about 2.2 mm, about 2.3 mm, about 2.4 mm, about 2.5 mm, about 3.0 mm, about 3.5 mm, about 4.0 mm, about 4.5 mm, about 5.0 mm, about 5.5 mm, about 6.0 mm about 6.5 mm, about 7.0 mm, about 7.5 mm, about 8.0 mm, about 8.1 mm, about 8.2 mm, about 8.3 mm, about 8.4 mm, about 8.5 mm, or about 9 mm.

[0272] The resulting dissolvable ellipse exhibits gradual hydration and controlled dissolution, allowing for an extended nicotine release profile. The texture is designed to be cohesive and structurally stable, ensuring it remains intact during application while slowly disintegrating over time. Compared to conventional formulations, this structure provides a more uniform and sustained nicotine delivery mechanism.

[0273] Sensory Testing. An exemplary dissolvable ellipse formulated with nicotine- cyclodextrin-polymer complexes (ELS_01) was evaluated in a controlled focus group setting to determine their organoleptic properties compared to ellipses without these complexes. Eight participants evaluated two different nicotine dissolvable ellipses and were asked to consider their experiences related to throat burn / bitterness, onset time, and flavor intensity / longevity for each sample. Sensory evaluations indicated that ellipses with nicotine- cyclodextrin-polymer complexes exhibited superior bitterness masking and prolonged flavor perception. All eight participants (100%) chose the dissolvable ellipses formulated with nicotine-cyclodextrin-polymer complexes for a more satisfactory experience. Participants reported a smoother mouthfeel with reduced harshness and irritation, while the embedded flavors remained perceptible for a longer duration. These findings demonstrate the advantages of nicotine-cyclodextrin-polymer complexes in enhancing both taste and overall user experience. All samples contained identical flavoring amounts and were packaged using the same manufacturing process. Example 13. Freeze-Dried Dissolvable Ellipses

[0274] In some embodiments, the compositions provided by the present disclosure are formulated as freeze-dried ellipses, designed to offer controlled nicotine release with a lower moisture content. This format maintains the structural integrity of the original gel whileAttorney Docket No.7656-043030 achieving a lightweight, porous texture that facilitates rapid hydration upon application. The reduced moisture content enhances stability and shelf life while preserving the functional benefits of the nicotine-cyclodextrin-polymer complex. All exemplary nicotine formulations were made according to the methods provided in Example 1 and the accompanying FIG. 1 and FIG.2.

[0275] The composition includes nicotine-cyclodextrin-polymer complexes to optimize nicotine stability and bioavailability. The base matrix consists of gel-forming agents (such as gelatin, pectin, or carrageenan) at 5-30% by weight, humectants (such as glycerin, sorbitol, or maltitol) at 2-15% by weight, and stabilizers (such as xanthan gum, locust bean gum, or agar) to maintain product integrity.

[0276] In some embodiments, the gel-forming agents of the base matrix on a per weight basis are about 4%, about 4.5%, about 4.6 %, about 4.7 %, about 4.8%, about 4.9%, about 5.0%, about 5.1%, about 5.2%, about 5.3%, about 5.4 %, about 5.5%, about 6.0%, about 6.5%, about 7%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, about 10.0%, about 10.5%, about 11.0%, about 11.5%, about 12.0%, about 12.5%, about 13.0%, about 13.5%, about 14.0%, about 14.5%, about 15.0%, about 16%, about 16.5%, about 17.0%, about 17.5%, about 18.0%, about 18.5%, about 19.0%, about 19.5%, about 20.0%, about 20.5%, about 21.0%, about 22.0%, about 23.0%, about 24.0%, about 25.0%, about 26.0%, about 27.0%, about 28.0%, about 29.0%, about 30.0%, about 31.0%.

[0277] In some embodiments, the humectants of the base matrix on a per weight basis are about 1.0%, about 1.5%, about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%,about 20.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5 %, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5.0%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, or about 5.5%, about 6.0%, about 6.5%, about 7%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, about 10.0%, about 10.5%, about 11.0%, about 11.5%, about 12.0%, about 12.5%, about 13.0%, about 13.5%, about 14.0%, about 14.5%, about 15.0%, about 15.1%, about 15.2%, about15.3%, about 15.4%, about 15.5%, or about 16%.

[0278] Additional components may include sweeteners (e.g., sucralose or acesulfame K) and pH modifiers (e.g., sodium carbonate) to optimize nicotine absorption. Flavoring agents, when encapsulated within the nicotine-cyclodextrin-polymer complex, enhance flavor longevity and minimize volatilization during processing. The moisture contentAttorney Docket No.7656-043030 of the final product is typically maintained under 10% by weight, ensuring structural stability while allowing for controlled dissolution. The ellipses are typically sized between 20-40 mm in length, 10-30 mm in width, and 1-5 mm in thickness.

[0279] In some embodiments, the moisture content of the final products of the freeze-dried dissolvable ellipses on a weight / weight basis are about 1.0%, about 1.5%, about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%,about 20.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5 %, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5.0%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, or about 5.5%, about 6.0%, about 6.5%, about 7%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, about 10.0%, or about 10.5%.

[0280] In some embodiments, the length of the freeze-dried dissolvable ellipses of the present disclosure are about 19.0 mm, about 19.5 mm, about 19.6 mm, about 19.7 mm, about 19.8 mm, about 19.9 mm, about 20.0 mm, about 20.1 mm, about 20.2 mm, about 20.3 mm, about 20.4 mm, about 20.5 mm, about 21.0 mm, about 22.0 mm, about 23.0 mm, about 24.0 mm, about 25.0 mm, about 26.0 mm, about 27.0 mm, about 28.0 mm, about 29.0 mm, about 30.0 mm, about 30.1 mm, about 30.2 mm, about 30.3 mm, about 30.4 mm, about 30.5 mm, about 31.0 mm, about 32.0 mm, about 33.0 mm, about 34.0 mm, about 35.0 mm, about 36.0 mm, about 37.0 mm, about 38.0 mm, about 39.0 mm, about 40.0 mm, about 40.1 mm, about 40.2 mm, about 40.3 mm, about 40.4 mm, about 40.5 mm, or about 41.0 mm.

[0281] In some embodiments, the width of the freeze-dried dissolvable ellipses of the present disclosure are about 9.0 mm, about 9.1 mm, about 9.2 mm, about 9.3 mm, about 9.4 mm, about 9.5 mm, about 9.6 mm, about 9.7 mm, about 9.8 mm, about 9.9 mm, about 10.0 mm, about 11.0 mm, about 12.0 mm, about 13.0 mm, about 14.0 mm, about 15.0 mm, about 16.0 mm, about 17.0 mm, about 18.0 mm, about 19.0 mm, about 19.5 mm, about 19.6 mm, about 19.7 mm, about 19.8 mm, about 19.9 mm, about 20.0 mm, about 20.1 mm, about 20.2 mm, about 20.3 mm, about 20.4 mm, about 20.5 mm, or about 21.0 mm, about 22.0 mm, about 23.0 mm, about 24.0 mm, about 25.0 mm, about 26.0 mm, about 27.0 mm, about 28.0 mm, about 29.0 mm, about 30.0 mm, about 30.1 mm, about 30.2 mm, about 30.3 mm, about 30.4 mm, about 30.5 mm, or about 31.0 mm.

[0282] In some embodiments, the thickness of the freeze-dried dissolvable ellipses of the present disclosure are about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9Attorney Docket No.7656-043030 mm, about 1.0 mm, about 1.5 mm, about 2.0 mm, about 2.5 mm, about 3.0 mm, about 3.5 mm, about 4.0 mm, about 4.5 mm, about 4.6 mm, about 4.7 mm, about 4.8 mm, about 4.9 mm, about 5.0 mm, about 5.1 mm, about 5.2 mm, about 5.3 mm, about 5.4 mm, about 5.5 mm, or about 6.0 mm.

[0283] Manufacturing Process: (1). Dissolving and Mixing: Gel-forming agents, humectants, and stabilizers are dissolved and mixed in an aqueous medium at controlled temperatures to ensure proper hydration and dispersion. (2). Incorporating the Nicotine Complex: The nicotine-cyclodextrin-polymer complex is gently incorporated into the mixture to maintain uniform distribution. (3). Molding and Setting: The mixture is poured into molds and set under controlled conditions to form a stable gel structure. (4). Freeze-Drying: Once formed, the gels undergo a freeze-drying process. They are rapidly frozen and then subjected to vacuum sublimation to remove moisture while retaining the intended shape and structure. This step significantly reduces the water content, yielding a lightweight, porous ellipse with enhanced stability. (5). Demolding and Surface Treatment: The freeze-dried ellipses are demolded and may undergo optional surface treatment to enhance stability before being packaged for distribution.

[0284] The resulting freeze-dried ellipse exhibits a firm yet porous structure that rapidly rehydrates in the oral cavity, allowing for controlled nicotine release. The moisture reduction contributes to improved product stability, resistance to microbial growth, and enhanced shelf life while maintaining a consistent dissolution profile.

[0285] Sensory Testing: Freeze-dried dissolvable ellipses formulated with nicotine- cyclodextrin-polymer complexes were evaluated in controlled focus group settings to determine their organoleptic properties compared to ellipses without these complexes. Seven out of eight (87.5%) participants preferred the freeze-dried dissolvable ellipses formulated with nicotine-cyclodextrin-polymer complexes over those without. Participants evaluated two different nicotine dissolvable ellipses and were asked to consider their experiences related to throat burn / bitterness, onset time, and flavor intensity / longevity for each sample. Sensory evaluations indicated that ellipses with nicotine-cyclodextrin-polymer complexes exhibited superior bitterness masking and enhanced flavor longevity. Participants reported a smoother mouthfeel with reduced harshness and irritation, while the embedded flavors remained perceptible for a longer duration. These findings highlight the advantages ofAttorney Docket No.7656-043030 nicotine-cyclodextrin-polymer complexes in optimizing both nicotine delivery and user experience. All samples contained identical flavoring amounts and were packaged using the same manufacturing process. Example 14. Pouch Release Testing

[0286] Rationale. Pouch release is a key metric in determining the acceptance of nicotine pouches because it directly affects how users experience the product and how effectively it delivers nicotine standards. As used herein, “pouch release” refers to the rate and amount of nicotine released from a pouch into an oral cavity. A well-balanced pouch release—fast yet controlled—is essential for optimizing user satisfaction. If nicotine is released too quickly, it can cause throat irritation or gum discomfort due to a sudden surge. On the other hand, if the release is too slow, it may fail to deliver the desired nicotine effect promptly. Therefore, achieving a release profile that is rapid enough for a quick onset but gentle enough to avoid irritation is crucial for both consumer appeal and product performance.

[0287] Testing Methods.

[0288] The testing methods used herein were adapted from a method for evaluating nicotine release from smokeless tobacco products as taught by Moheb M. Nasr et al., In Vitro Study of Nicotine Release from Smokeless Tobacco, 1998, Journal of AOAC International, Vol.81, No. 3, incorporated herein in its entirety. Specifically, they taught placing approximately 500^mg of tobacco in test tubes containing 10^mL of artificial saliva. The samples were then incubated in a precision oscillating shaker water bath maintained at 37^°C to simulate oral conditions. Aliquots were collected at predetermined time intervals—0.5, 1, 2, 5, 15, and 60 minutes—and analyzed using liquid chromatography to quantify nicotine release.

[0289] Based on the teachings of Nasr et al. (id.), we evaluated the release of nicotine from oral pouches using a jacketed glass cell system. The cell was equipped with a magnetic stir bar and surrounded by a circulating water jacket maintained at 37.5^°C to simulate oral conditions. The vessel was filled with 15^mL of phosphate-buffered saline (PBS, pH 6.9, 0.05^M), pre-warmed to the target temperature.

[0290] Nicotine pouches were directly submerged into the solution, and aliquots were withdrawn at predetermined time intervals: 2, 4, 8, 16, and 30 minutes. Each sample was immediately filtered through a 0.22^µm syringe filter and analyzed using high-performanceAttorney Docket No.7656-043030 liquid chromatography (HPLC). Chromatographic conditions were optimized to ensure high sensitivity and reproducibility in nicotine quantification. All experiments were performed in triplicate, and the average release values along with standard deviations were calculated.

[0291] Comparison of pouch release of exemplary formulations. Formulations ENP_02 and ENP_03 were evaluated alongside the commercially available products CP_04 and CP_05 for comparison. ENP_02 and CP_04 represent low-dose formulations containing 3 mg to 4 mg of nicotine, while ENP_03 and CP_05 are moderate-dose formulations with 6m g to 8 mg of nicotine. CP_04 is a 3 mg mint-flavored product, and CP_05 is a 6 mg citrus mint product, with both being available commercially. All samples were sealed into identical pouch materials, each containing 360 ± 10 mg of powder, and sealed using an induction sealer.

[0292] Results. As provided in the table below, the commercial products CP_04 and CP_05 released nicotine rapidly, with 68% and 80% of their total nicotine content delivered within the first two minutes, respectively. In contrast, ENP_02 and ENP_03, which were formulated with encapsulated nicotine, exhibited a more controlled, desirable release, with only 29% and 40% released at the same initial time point. Notably, all tested materials reached peak nicotine dissolution at around the 16-minute mark. CP_05, however, was an exception, showing equal levels of nicotine release at both the 8-minute and 16-minute time points. This indicates that despite the commercial products’ fast initial release, the total time required for full nicotine delivery is consistent across all samples.Attorney Docket No.7656-043030 Table 9. Nicotine release rates for CP_04, CP_05, ENP_02, and ENP_03. Released Nicotine (%) Sample CP_04 CP_05 ENP_02 ENP_03 Time Avg Std Avg Std Avg Std Avg Std (min) Release Dev Release Dev Release Dev Release Dev 2 68% 12% 80% 8% 29% 5% 40% 2% 4 82% 5% 91% 5% 37% 4% 73% 10% 8 92% 1% 97% 3% 69% 16% 93% 10% 16 100% 0% 97% 2% 93% 6% 100% 4% 30 97% 3% 95% 2% 99% 2% 98% 1%

[0293] Weibull Modeling and Interpretation. To further characterize the release kinetics, the data were fitted to a Weibull model:

[0294] The Weibull model is a mathematical function widely used to describe drug release kinetics, providing a flexible way to model how a drug is released over time from a delivery system. See, e.g., Papadopoulou, 2006, On the use of the Weibull function for the discernment of drug release mechanisms, International Journal of Pharmaceutics, 309: 44-50, which is incorporated herein in its entirety.

[0295] In this model F(t) represents the percentage of drug released at time t, ranging from 0 (no release) to 100% (complete release). The scale parameter, λ (lambda), determines the time scale of the release process. A larger λ means the drug is released more slowly, stretching the curve horizontally. A smaller λ indicates faster release. The shape parameter, β (beta), controls the form of the release curve. If β<1, the release is decelerating, typical of diffusion-Attorney Docket No.7656-043030 controlled systems. If β=1, the release follows an exponential pattern. If β>1, the release is sigmoidal, with a slow start, rapid middle phase, and plateau.

[0296] When this equation is fit to the pouch release data for CP_04, CP_05 ENP_02 and ENP_03, the resulting equations show an excellent correlation (R2≥ 0.99) with the experimental data. The graph provided in FIG.8 shows the fit of the Weibull model with each of the tested formulations.

[0297] The scale parameter(λ) and the shape parameter (β) are provided in the table below. Table 10. Scale parameter (λ) and the shape parameter (β) for the Weibull model results. Sample λ (Scale) β (Shape) CP_04 1.62 0.60 CP_05 0.69 0.47 ENP_02 6.99 1.05 ENP_03 3.34 1.25

[0298] CP_04 and CP_05 show low Scale parameter values (1.62 and 0.69, respectively), indicating rapid release. In contrast, ENP_02 and ENP_03 have higher Scale parameter values (6.99 and 3.34, respectively), reflecting slower, more desired, and more sustained delivery.

[0299] The Shape parameter values for CP_04 and CP_05 are less than 1 (0.60 and 0.47, respectively), suggesting a decelerating release rate. In contrast, ENP_02 and ENP_03 have Shape parameter values greater than 1 (1.05 and 1.25, respectively), indicating a sigmoidal release profile with increasing release rate over time. Thus, for ENP_02 and ENP_03 the pouch release profile fitted to the Weibull model the formulations of the present disclosure have Scale parameter values greater than 2.5 and Shape parameter values greater than 0.9.

[0300] In some embodiments, the dry pouch formulations of the present disclosure have a Weibull model Scale parameter value greater than 2.50, greater than 3.00, greater than 3.50, greater than 4.00, greater than 4.50, greater than 5.00, greater than 5.50, greater than 6.00, greater than 6.50, greater than 7.00, or greater than 7.50. In some embodiments, the dry pouch formulations of the present disclosure have a Weibull model Scale parameter value of aboutAttorney Docket No.7656-043030 2.50, about 3.00, about 3.50, about 4.00, about 4.50, about 5.00, about 5.50, about 6.00, about 6.50, about 7.00, or about 7.50.

[0301] In some embodiments, the dry pouch formulations of the present disclosure have a Weibull model Shape parameter value greater than 0.90, greater than 1.00, greater than 1.05, greater than 1.10, greater than 1.15, greater than 1.20, greater than 1.25, greater than 1.30, or greater than 1.35. In some embodiments, the dry pouch formulations of the present disclosure have a Weibull model Scale parameter value of about 0.90, about 1.00, about 1.05, about 1.10, about 1.15, about than 1.20, about 1.25, about 1.30, or about 1.35. CP_05 in particular exhibited a pronounced initial burst, while the compositions of ENP_02 and ENP_03 minimized this effect. Sustained release was poor in the commercial products but strong in the exemplary encapsulated formulations of the present disclosure, especially for ENP_02. Further Numbered Embodiments of the Disclosure Other subject matter contemplated by the present disclosure is set out in the following numbered embodiments: 1. A method of making a nicotine delivery product or nicotine delivery system comprising loading ingredients into a high pressure vessel, wherein the ingredients comprise nicotine, one or more cyclodextrins, and one or more polymers; heating and pressuring the vessel; pumping CO2into the vessel to obtain supercritical CO2 conditions; mixing the ingredients under the supercritical CO2conditions to produce a homogenous mixture; depressurizing the vessel to obtain an encapsulated nicotine complex, and using the encapsulated nicotine complex to produce the nicotine delivery product or nicotine delivery system, wherein the method does not include a spraying step, and wherein the encapsulated nicotine complex is a homogeneous solid powder. 2. The encapsulated nicotine complex obtained by the method of embodiment 1. 3. The method of embodiment 1, wherein the loaded ingredients comprise on a dry weight / dry weight basis about 5% to about 20% nicotine, about 30% to about 80% of one or more polymers, and about 10% to about 60% of one or more cyclodextrins. 4. The method of embodiment 1 or embodiment 3, wherein the nicotine delivery product or nicotine delivery system comprises on a dry weight / dry weight basis about 1% toAttorney Docket No.7656-043030 about 20% nicotine, about 30% to about 80% of one or more polymers, and about 10% to about 60% of one or more cyclodextrins. The method of any one of embodiments 1 and 3-4, wherein the one or more polymers are polymers that exhibit a melting point depression under supercritical CO2thereby allowing for dissolution of the nicotine and the one or more cyclodextrins to form a homogeneous mixture. The method of any one of embodiments 1 and 3-5, wherein the one or more polymers is a poloxamer. The method of embodiment 6, wherein the poloxamer is poloxamer-407 and / or poloxamer-188. The method of any one of embodiments 1 and 3-7, further comprising adding one or more flavorings to the loaded ingredients and / or to the nicotine delivery product or nicotine delivery system. The method of embodiment 8, wherein the one or more flavorings are selected from the group consisting of menthol, peppermint oil, eucalyptus oil, and cornmint oil. The method of any one of embodiments 1 and 3-9, further comprising adding one or more additional ingredients to the loaded ingredients and / or to the nicotine delivery product or nicotine delivery system, wherein the one or more additional ingredients are selected from the group consisting of plasticizers, sweeteners, polymers, flavors, pH adjustors, and bulking agents. The method of embodiment 10, wherein the pH adjusters are sodium bicarbonate and / or sodium carbonate. The method of embodiment 10, wherein the bulking agents are microcrystalline cellulose (MCC), sorbitol, maltitol, and / or mannitol. The method of embodiment 10, wherein the sweetener is a polyol. The method of embodiment 10, wherein the sweetener is an artificial sweetener. The method of any one of embodiments 1 and 3-14, wherein the nicotine is nicotine freebase. The method of any one of embodiments 1 and 3-14, wherein the nicotine is nicotine bitartrate.Attorney Docket No.7656-043030 A nicotine delivery product produced by the method of any one of embodiments 1 and 3-16, wherein the nicotine delivery product is selected from the group consisting of a flavored dry pouch, an unflavored dry pouch, an ellipse, and an oral thin film. The nicotine delivery product of embodiment 17, wherein the pouch has a moisture content maintained at less than 5% weight / weight. The nicotine delivery product of any one of embodiments 17-18, wherein the pouch has a width of 10 mm to 20 mm and a length of 20 mm to 30 mm in length. The nicotine delivery production of any one of embodiments 17-19, wherein the pouch has a pH of about 7.5 to about 8.5. The nicotine delivery product of embodiment 17, wherein the ellipse is a dissolvable ellipse. The nicotine delivery product of embodiment 21, wherein the moisture content of the dissolvable ellipse is maintained at 10% weight / weight to 30% weight / weight. The nicotine delivery composition of any one of embodiments 17 and 21-22, wherein the ellipse has a length of 20 mm to 40 mm, a width of 10 mm to 30 mm, and a thickness of 1 mm to 5 mm. The nicotine delivery product of any one of embodiments 17 and 21-23, wherein the ellipse has a thickness of 3 mm to 5 mm. The nicotine delivery product of embodiment 17, wherein the oral thin film has a length of 20 mm to 40 mm, a width of 10 mm to 30 mm, and a thickness of 50 µm to 2.5 mm. The nicotine delivery product of any one of embodiments 17-25, wherein the nicotine delivery product exhibits longer shelf life when subjected to accelerated storage conditions when compared in side-by-side tests with similar nicotine delivery products comprising nicotine which do not comprise the one or more cyclodextrins and one or more poloxamers. The nicotine delivery product of any one of embodiments 17-26, wherein the nicotine delivery product exhibits faster permeation of nicotine across buccal membranes when compared in side-by-side tests with similar nicotine delivery products comprising nicotine which do not comprise the one or more cyclodextrins and one or more poloxamers.Attorney Docket No.7656-043030 The nicotine delivery product of any one of embodiments 17-27, wherein the nicotine delivery product provides a user with a qualitatively better organoleptic sensory experience when compared in side-by-side tests with similar nicotine delivery products comprising nicotine which do not comprise the one or more cyclodextrins and one or more poloxamers. The nicotine delivery product of any one of embodiment 28, wherein the organoleptic sensory experience is one or more organoleptic sensory experiences selected from the group consisting of throat burn, bitterness, taste, and onset time. An encapsulated nicotine complex having on a weight / weight basis about 1.0% to about 20.0% nicotine, one or more poloxamers, one or more cyclodextrins, a bulk density of about 0.35 g / ml to about 0.65 g / ml, a tap density of about 0.6 g / ml to about 0.8 g / ml, and a water content of about 2% to about 15%. The encapsulated nicotine complex of embodiment 30, wherein the nicotine is nicotine freebase. The encapsulated nicotine complex of embodiment 30, wherein the nicotine is nicotine bitartrate. The encapsulated nicotine complex of any one of embodiments 30-32, further comprising one or more flavorings. The encapsulated nicotine complex of embodiment 33, wherein the one or more flavorings are selected from the group consisting of menthol, peppermint oil, eucalyptus oil, and cornmint oil. The encapsulated nicotine complex of any one of embodiments 30-34, further comprising adding one or more additional ingredients selected from the group consisting of plasticizers, sweeteners, polymers, flavors, pH adjustors, and bulking agents. A method of delivering nicotine to an individual, wherein the method comprises orally administrating a nicotine delivery product comprising the encapsulated nicotine complex of any one of embodiments 30-35 to the individual.Attorney Docket No.7656-043030 The method of embodiment 36, wherein the individual is being administered an efficacious dose of nicotine that treats or ameliorates a disease, symptom, and / or disorder. The method of embodiment 36 or embodiment 37 wherein the nicotine delivery product further comprises one or more flavorings. The method of embodiment 38, wherein the one or more flavorings are menthol, peppermint oil, eucalyptus oil, and / or cornmint oil. The method of any one of embodiments 30-39, wherein the nicotine delivery product is formulated as a pouch, an oral thin film, or an ellipse. The method of embodiment 40, wherein the pouch is a moistened pouch. The method of embodiment 41, wherein the moisture content of the moistened pouch is maintained at 5% weight / weight to 15% weight / weight. The method of embodiment 40 or embodiment 41, wherein the moistened pouch has a width of 10 mm to 20 mm and a length of 20 mm to 30 mm. The method of embodiment 40, wherein the pouch is a flavorless dry pouch. The method of embodiment 44, wherein the moisture content of the flavorless dry pouch is maintained at less than 5% weight / weight. The method of embodiment 44 or embodiment 45, wherein the flavorless dry pouch has a width of 10 mm to 20 mm and a length of 20 mm to 30 mm in length. The method of any one of embodiment 44-46, wherein the flavorless dry pouch has a pH of about 7.5 to about 8.5. The method of embodiment 40, wherein the pouch is a flavored dry pouch. The method of embodiment 49, wherein the moisture content of the flavored dry pouch is maintained at less than 5% weight / weight. The method of embodiment 48 or embodiment 49, wherein the flavored dry pouch has a width of 10 mm to 20 mm and a length of 20 mm to 30 mm in length. The method of any one of embodiment 48-50, wherein flavoring of the flavored dry pouch is supplied in part or in whole by menthol, peppermint oil, eucalyptus oil, and / or cornmint oil. The method of embodiment 40, wherein the ellipse is a dissolvable ellipse.Attorney Docket No.7656-043030 The method of embodiment 52, wherein the moisture content of the dissolvable ellipse is maintained at 10% weight / weight to 30% weight / weight. The method of embodiment 52 or embodiment 53, wherein the dissolvable ellipse has a length of 20 mm to 40 mm, a width of 10 mm to 30 mm, and a thickness of 1 mm to 5 mm. The method of any one of embodiments 52-54, wherein the dissolvable ellipse has a thickness of 3 mm to 5 mm. The method of any one of embodiments 52-55, wherein the dissolvable ellipse has a length of 20 mm to 40 mm, a width of 10 mm to 30 mm, and a thickness of 50 µm to 2.5 mm. A nicotine pouch produced by a method comprising loading ingredients into a high pressure vessel, wherein the ingredients comprise nicotine, one or more cyclodextrins, and one or more polymers; heating and pressuring the vessel; pumping CO2 into the vessel to obtain supercritical CO2 conditions; mixing the ingredients under the supercritical CO2conditions to produce a homogenous mixture; depressurizing the vessel to obtain an encapsulated nicotine complex, and using the encapsulated nicotine complex to produce the nicotine pouch, wherein the method does not include a spraying step, and wherein the encapsulated nicotine complex is a homogeneous solid powder, wherein the moisture content of the nicotine pouch is less than 5% w / w, and wherein pouch release of the nicotine from the nicotine pouch is 40% or less within two minutes and 98% or more within 30 minutes. The nicotine pouch of embodiment 57, wherein the at least one cyclodextrin is selected from the group consisting of α-cyclodextrin, ^-cyclodextrin, γ-cyclodextrin, hydrophilic α-cyclodextrin, hydrophilic ^-cyclodextrin, and hydrophilic γ- cyclodextrin. The nicotine pouch of embodiment 57 or embodiment 58, wherein the polymer is selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, and poloxamer. The nicotine pouch of any one of embodiments 57-59, wherein the polymer is poloxamer.Attorney Docket No.7656-043030 61. The nicotine pouch of any one of embodiments 57-60, wherein the nicotine is nicotine freebase. 62. The nicotine pouch of any one of embodiments 57-60, wherein the nicotine is nicotine bitartrate. 63. The nicotine pouch of any one of embodiments 57-62, wherein the nicotine in the nicotine pouch comprises about 15% w / w to about 50% w / w of the total weight of the nicotine-cyclodextrin-polymer complex. 64. The nicotine pouch of any one of embodiments 57-63, wherein the nicotine in the nicotine pouch further comprises one or more additional ingredients selected from the list consisting of one or more pH adjustors, one or more bulking agents, one or more sweeteners, and one or more flavoring agents. 65. The nicotine pouch of embodiment 64, wherein the one or more pH adjustors are selected from the group consisting of sodium bicarbonate and sodium carbonate. 66. The nicotine pouch of embodiment 64 or embodiment 65, wherein the one or more bulking agents are selected from the group consisting of microcrystalline cellulose (MCC), sorbitol, maltitol, and mannitol. 67. The nicotine pouch of any one of embodiments 64-66, wherein the one or more sweeteners are selected from the group consisting of artificial sweeteners and polyols. 68. The nicotine pouch of any one of embodiments 64-67, wherein the one or more flavoring agents are selected from the group consisting of menthol and a flavoring oil. 69. A nicotine pouch having nicotine release kinetics comprising a scale parameter ^^^^ greater than 2.50 and a shape parameter ^^^^ greater than 0.90, wherein the nicotine release kinetics are based on Weibull Modeling and Interpretation. INCORPORATION BY REFERENCE

[0302] All references, articles, publications, patents, patent publications, and patent applications cited herein within the above text and / or cited below are incorporated by reference in their entireties for all purposes. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world.

Claims

Attorney Docket No.7656-043030 CLAIMS What is claimed is:

1. A method of making a nicotine delivery product or nicotine delivery system comprising loading ingredients into a high pressure vessel, wherein the ingredients comprise nicotine, one or more cyclodextrins, and one or more polymers; heating and pressuring the vessel; pumping CO2into the vessel to obtain supercritical CO2 conditions; mixing the ingredients under the supercritical CO2conditions to produce a homogenous mixture; depressurizing the vessel to obtain an encapsulated nicotine complex, and using the encapsulated nicotine complex to produce the nicotine delivery product or nicotine delivery system, wherein the method does not include a spraying step, and wherein the encapsulated nicotine complex is a homogeneous solid powder.

2. The encapsulated nicotine complex obtained by the method of claim 1.

3. The method of claim 1, wherein the loaded ingredients comprise on a dry weight / dry weight basis about 5% to about 20% nicotine, about 30% to about 80% of one or more polymers, and about 10% to about 60% of one or more cyclodextrins.

4. The method of claim 1 or claim 3, wherein the nicotine delivery product or nicotine delivery system comprises on a dry weight / dry weight basis about 1% to about 20% nicotine, about 30% to about 80% of one or more polymers, and about 10% to about 60% of one or more cyclodextrins.

5. The method of any one of claims 1 and 3-4, wherein the one or more polymers are polymers that exhibit a melting point depression under supercritical CO2thereby allowing for dissolution of the nicotine and the one or more cyclodextrins to form a homogeneous mixture.

6. The method of any one of claims 1 and 3-5, wherein the one or more polymers is a poloxamer.

7. The method of claim 6, wherein the poloxamer is poloxamer-407 and / or poloxamer- 188.

8. The method of any one of claims 1 and 3-7, further comprising adding one or more flavorings to the loaded ingredients and / or to the nicotine delivery product or nicotine delivery system.Attorney Docket No.7656-043030 9. The method of claim 8, wherein the one or more flavorings are selected from the group consisting of menthol, peppermint oil, eucalyptus oil, and cornmint oil.

10. The method of any one of claims 1 and 3-9, further comprising adding one or more additional ingredients to the loaded ingredients and / or to the nicotine delivery product or nicotine delivery system, wherein the one or more additional ingredients are selected from the group consisting of plasticizers, sweeteners, polymers, flavors, pH adjustors, and bulking agents.

11. The method of claim 10, wherein the pH adjusters are sodium bicarbonate and / or sodium carbonate.

12. The method of claim 10, wherein the bulking agents are microcrystalline cellulose (MCC), sorbitol, maltitol, and / or mannitol.

13. The method of claim 10, wherein the sweetener is a polyol.

14. The method of claim 10, wherein the sweetener is an artificial sweetener.

15. The method of any one of claims 1 and 3-14, wherein the nicotine is nicotine freebase.

16. The method of any one of claims 1 and 3-14, wherein the nicotine is nicotine bitartrate.

17. A nicotine delivery product produced by the method of any one of claims 1 and 3-16, wherein the nicotine delivery product is selected from the group consisting of a flavored dry pouch, an unflavored dry pouch, an ellipse, and an oral thin film.

18. The nicotine delivery product of claim 17, wherein the pouch has a moisture content maintained at less than 5% weight / weight.

19. The nicotine delivery product of any one of claims 17-18, wherein the pouch has a width of 10 mm to 20 mm and a length of 20 mm to 30 mm in length.

20. The nicotine delivery production of any one of claims 17-19, wherein the pouch has a pH of about 7.5 to about 8.

5.

21. The nicotine delivery product of claim 17, wherein the ellipse is a dissolvable ellipse.

22. The nicotine delivery product of claim 21, wherein the moisture content of the dissolvable ellipse is maintained at 10% weight / weight to 30% weight / weight.

23. The nicotine delivery composition of any one of claims 17 and 21-22, wherein the ellipse has a length of 20 mm to 40 mm, a width of 10 mm to 30 mm, and a thickness of 1 mm to 5 mm.Attorney Docket No.7656-043030 24. The nicotine delivery product of any one of claims 17 and 21-23, wherein the ellipse has a thickness of 3 mm to 5 mm.

25. The nicotine delivery product of claim 17, wherein the oral thin film has a length of 20 mm to 40 mm, a width of 10 mm to 30 mm, and a thickness of 50 µm to 2.5 mm.

26. The nicotine delivery product of any one of claims 17-25, wherein the nicotine delivery product exhibits longer shelf life when subjected to accelerated storage conditions when compared in side-by-side tests with similar nicotine delivery products comprising nicotine which do not comprise the one or more cyclodextrins and one or more poloxamers.

27. The nicotine delivery product of any one of claims 17-26, wherein the nicotine delivery product exhibits faster permeation of nicotine across buccal membranes when compared in side-by-side tests with similar nicotine delivery products comprising nicotine which do not comprise the one or more cyclodextrins and one or more poloxamers.

28. The nicotine delivery product of any one of claims 17-27, wherein the nicotine delivery product provides a user with a qualitatively better organoleptic sensory experience when compared in side-by-side tests with similar nicotine delivery products comprising nicotine which do not comprise the one or more cyclodextrins and one or more poloxamers.

29. The nicotine delivery product of any one of claim 28, wherein the organoleptic sensory experience is one or more organoleptic sensory experiences selected from the group consisting of throat burn, bitterness, taste, and onset time.

30. An encapsulated nicotine complex having on a weight / weight basis about 1.0% to about 20.0% nicotine, one or more poloxamers, one or more cyclodextrins, a bulk density of about 0.35 g / ml to about 0.65 g / ml, a tap density of about 0.6 g / ml to about 0.8 g / ml, and a water content of about 2% to about 15%.

31. The encapsulated nicotine complex of claim 30, wherein the nicotine is nicotine freebase.

32. The encapsulated nicotine complex of claim 30, wherein the nicotine is nicotine bitartrate.Attorney Docket No.7656-043030 33. The encapsulated nicotine complex of any one of claims 30-32, further comprising one or more flavorings.

34. The encapsulated nicotine complex of claim 33, wherein the one or more flavorings are selected from the group consisting of menthol, peppermint oil, eucalyptus oil, and cornmint oil.

35. The encapsulated nicotine complex of any one of claims 30-34, further comprising adding one or more additional ingredients selected from the group consisting of plasticizers, sweeteners, polymers, flavors, pH adjustors, and bulking agents.

36. A method of delivering nicotine to an individual, wherein the method comprises orally administrating a nicotine delivery product comprising the encapsulated nicotine complex of any one of claims 30-35 to the individual.

37. The method of claim 36, wherein the individual is being administered an efficacious dose of nicotine that treats or ameliorates a disease, symptom, and / or disorder.

38. The method of claim 36 or claim 37 wherein the nicotine delivery product further comprises one or more flavorings.

39. The method of claim 38, wherein the one or more flavorings are menthol, peppermint oil, eucalyptus oil, and / or cornmint oil.

40. The method of any one of claims 30-39, wherein the nicotine delivery product is formulated as a pouch, an oral thin film, or an ellipse.

41. The method of claim 40, wherein the pouch is a moistened pouch.

42. The method of claim 41, wherein the moisture content of the moistened pouch is maintained at 5% weight / weight to 15% weight / weight.

43. The method of claim 40 or claim 41, wherein the moistened pouch has a width of 10 mm to 20 mm and a length of 20 mm to 30 mm.

44. The method of claim 40, wherein the pouch is a flavorless dry pouch.

45. The method of claim 44, wherein the moisture content of the flavorless dry pouch is maintained at less than 5% weight / weight.

46. The method of claim 44 or claim 45, wherein the flavorless dry pouch has a width of 10 mm to 20 mm and a length of 20 mm to 30 mm in length.Attorney Docket No.7656-043030 47. The method of any one of claim 44-46, wherein the flavorless dry pouch has a pH of about 7.5 to about 8.

5.

48. The method of claim 40, wherein the pouch is a flavored dry pouch.

49. The method of claim 49, wherein the moisture content of the flavored dry pouch is maintained at less than 5% weight / weight.

50. The method of claim 48 or claim 49, wherein the flavored dry pouch has a width of 10 mm to 20 mm and a length of 20 mm to 30 mm in length.

51. The method of any one of claim 48-50, wherein flavoring of the flavored dry pouch is supplied in part or in whole by menthol, peppermint oil, eucalyptus oil, and / or cornmint oil.

52. The method of claim 40, wherein the ellipse is a dissolvable ellipse.

53. The method of claim 52, wherein the moisture content of the dissolvable ellipse is maintained at 10% weight / weight to 30% weight / weight.

54. The method of claim 52 or claim 53, wherein the dissolvable ellipse has a length of 20 mm to 40 mm, a width of 10 mm to 30 mm, and a thickness of 1 mm to 5 mm.

55. The method of any one of claims 52-54, wherein the dissolvable ellipse has a thickness of 3 mm to 5 mm.

56. The method of any one of claims 52-55, wherein the dissolvable ellipse has a length of 20 mm to 40 mm, a width of 10 mm to 30 mm, and a thickness of 50 µm to 2.5 mm.

57. A nicotine pouch produced by a method comprising loading ingredients into a high pressure vessel, wherein the ingredients comprise nicotine, one or more cyclodextrins, and one or more polymers; heating and pressuring the vessel; pumping CO2into the vessel to obtain supercritical CO2 conditions; mixing the ingredients under the supercritical CO2conditions to produce a homogenous mixture; depressurizing the vessel to obtain an encapsulated nicotine complex, and using the encapsulated nicotine complex to produce the nicotine pouch, wherein the method does not include a spraying step, and wherein the encapsulated nicotine complex is a homogeneous solid powder, wherein the moisture content of the nicotine pouch is less than 5% w / w, and wherein pouch release of the nicotine from the nicotine pouch is 40% or less within two minutes and 98% or more within 30 minutes.Attorney Docket No.7656-043030 58. The nicotine pouch of claim 57, wherein the at least one cyclodextrin is selected from the group consisting of α-cyclodextrin, ^-cyclodextrin, γ-cyclodextrin, hydrophilic α- cyclodextrin, hydrophilic ^-cyclodextrin, and hydrophilic γ-cyclodextrin.

59. The nicotine pouch of claim 57 or claim 58, wherein the polymer is selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, and poloxamer.

60. The nicotine pouch of any one of claims 57-59, wherein the polymer is poloxamer.

61. The nicotine pouch of any one of claims 57-60, wherein the nicotine is nicotine freebase.

62. The nicotine pouch of any one of claims 57-60, wherein the nicotine is nicotine bitartrate.

63. The nicotine pouch of any one of claims 57-62, wherein the nicotine in the nicotine pouch comprises about 15% w / w to about 50% w / w of the total weight of the nicotine- cyclodextrin-polymer complex.

64. The nicotine pouch of any one of claims 57-63, wherein the nicotine in the nicotine pouch further comprises one or more additional ingredients selected from the list consisting of one or more pH adjustors, one or more bulking agents, one or more sweeteners, and one or more flavoring agents.

65. The nicotine pouch of claim 64, wherein the one or more pH adjustors are selected from the group consisting of sodium bicarbonate and sodium carbonate.

66. The nicotine pouch of claim 64 or claim 65, wherein the one or more bulking agents are selected from the group consisting of microcrystalline cellulose (MCC), sorbitol, maltitol, and mannitol.

67. The nicotine pouch of any one of claims 64-66, wherein the one or more sweeteners are selected from the group consisting of artificial sweeteners and polyols.

68. The nicotine pouch of any one of claims 64-67, wherein the one or more flavoring agents are selected from the group consisting of menthol and a flavoring oil.

69. A nicotine pouch having nicotine release kinetics comprising a scale parameter ^^^^ greater than 2.50 and a shape parameter ^^^^ greater than 0.90, wherein the nicotine release kinetics are based on Weibull Modeling and Interpretation.

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