Patent Application
20250169531
The present disclosure relates to compositions and products for improved oral nicotine delivery and methods of their production and use.
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., Jan. 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, Jan. 2, 2014, Emerging nicotine delivery products. Implications for public health, Annals of the American Thoracic Society, Vol. 11, Issue 2.
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, Mar. 29, 2024, Nicotine: The Good, The Bad & The Ugly, Echelon Health: Advice, News, Regulation, Technology. While nicotine is a cheap, common, and mostly safe drug, in daily use for centuries by hundreds of millions of people, it only lately has been investigated for its therapeutic potential for a long 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, Nov. 16, 2004, Nicotine as Therapy, PLoS, 2(11):e404.
Nicotine, widely used in smoking cessation, faces challenges with stability and sensory appeal in wet pouch formats. This invention addresses these issues by incorporating a wet pouch format with encapsulated nicotine in a ternary composition (nicotine, cyclodextrins, polymer), providing controlled release and enhanced sensory characteristics.
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.
Oral nicotine pouches are witnessing significant demand growth as a preferred alternative to traditional smoking and vaping. This discreet, smoke-free format appeals to health-conscious consumers seeking convenient, on-the-go nicotine satisfaction without combustion or vapor, positioning it as a rapidly expanding category in the nicotine market.
As an oral pouch format, the demand for wet or pre-moistened nicotine pouches is rapidly growing, driven by consumers seeking enhanced flavor, convenience, and a more satisfying oral nicotine experience over the conventional dry nicotine oral pouch formats. This format offers improved nicotine experience making it increasingly popular among users looking for a discreet and effective alternative to traditional smoking, snus, vaping and dry pouches.
To overcome the challenges of the currently used methods for producing improved nicotine compositions, the present disclosure utilizes a ternary system comprising nicotine, cyclodextrin, and a polymer, which results in compositions with improved stability and processability of the complex under supercritical CO2 (scCO2) conditions. ScCO2 is also commonly referred to as sCO2, sCO2, scCO2, and scCO2, each of which is used interchangeably herein.
In some embodiments, the present disclosure provides stable, bioavailable, user-preferred nicotine delivery systems in a wet pouch format.
The present disclosure provides improved compositions for wet nicotine pouches with improved stability and user experiences, along with methods of their production and use.
In some embodiments, the present disclosure provides an encapsulation strategy that focuses on buccal absorption optimization while significantly improving stability under challenging environmental conditions using more intricate, precise formulation processes.
Typically, increasing stability can compromise aspects such as flavor or feel. The present disclosure provides methods, compositions and formulations that found a balance of ingredients which unexpectedly provided an improvement in both stability and the user experience.
In some embodiments, the present disclosure provides methods for producing a shelf-stable, wet nicotine powder optimized for buccal absorption and the compositions produced using such methods. In some embodiments, the present disclosure provides a more stable, wet powder format with more precise control over buccal absorption conditions than is presently available with the nicotine products commercially available for buccal administration.
In some embodiments, the present disclosure provides methods for combining an aqueous solution with ingredients like sweeteners, pH adjusters, humectants, and flavoring agents, then mixing this aqueous solution with a powder mixture containing microcrystalline cellulose (MCC), gelling agents, and anti-caking agents to produce a water-entrapped powder complex. In some embodiments, nicotine is encapsulated with polymers (polymeric stabilizers) and possibly cyclodextrins for enhanced stability and combined with the water-entrapped powder complex to produce a moistened nicotine powder composition. This nicotine powder composition can be packaged into pouches and administered orally to humans.
In some embodiments, the present disclosure provides for encapsulating nicotine with cyclodextrins and polymers under scCO2 conditions and mixing it with a water-entrapped powder complex to improve and maintain moisture content, improve sensory effects, and ensure shelf stability when compared to presently available nicotine delivery systems. In some embodiments, the present disclosure provides methods of encapsulating nicotine using polymers (polymeric stabilizers) and cyclodextrins to create a more stable composition environment that minimizes nicotine degradation in high-moisture environments, such as when the compositions are on the shelf and/or placed within a pouch. The encapsulation methods of the present disclosure enhance composition stability by isolating the nicotine from direct contact with moisture and reducing exposure of the nicotine to environmentally detrimental factors like light and air which exist during the transportation, storing, and administration of the resultant compositions.
In some embodiments, the present disclosure provides compositions comprising, consisting essentially of, or consisting of wet oral nicotine formulations with improved shelf stability. In some embodiments, the present disclosure provides a combination of microcrystalline cellulose (MCC), various gelling agents, encapsulated nicotine, and optional flavors and humectants to create a more stable product. In some embodiments, the present disclosure provides compositions wherein the stability of the nicotine over a longer shelf life has less than 30% degradation under accelerated conditions (i.e., 40° C., 75% relative humidity). In contrast, currently available commercial nicotine products experience 40%-90% degradation under the same accelerated conditions.
In some embodiments, the present disclosure provides methods of encapsulating nicotine in a polymer (polymeric stabilizer) to prevent degradation during storage and/or inside a pouch.
In some embodiments, the present disclosure provides compositions of wet oral pouch nicotine formulations with increased absorption across buccal tissues following their oral administration to users.
In some embodiments, the present disclosure provides wet pouches offering an optimal buccal absorption experience with a balanced moisture content for user comfort. Product feedback trials of the pouches produced according to the present disclosure indicate a preference for these pouches based on their flavor and onset of the nicotine effects/experience as compared to existing commercial pouch products. In some embodiments, consumer studies have validated that the present disclosure provides wet pouches that have a more rapid onset of nicotine effects and a more favorable flavor profile when compared to existing commercial pouch products.
In some embodiments, the present disclosure provides nicotine compositions with an improved overall user experience in orally delivered formats.
In some embodiments, the present disclosure provides wet oral nicotine compositions with improved sensory organoleptic experiences and feedback following their oral administration to users.
In some embodiments, the present disclosure provides wet oral nicotine pouch compositions with reduced throat burn and faster onset following their oral administration to users.
In some embodiments, the present disclosure provides wet oral nicotine pouch compositions with longer lasting, more intense flavor following their oral administration to users.
In some embodiments, the present disclosure provides methods for preparing nicotine-cyclodextrin-polymer complexes using scCO2, wherein the complexes can be used in compositions and formulations for oral delivery.
In some embodiments, the methods of the present disclosure provide methods for producing nicotine compositions that involve using a ternary system comprising nicotine, cyclodextrin, and a polymer(s), such as poloxamer(s), which are mixed under scCO2 to obtain a nearly homogeneous, mostly homogeneous, or homogeneous solid mixture. As disclosed herein the polymer, e.g., a poloxamer, acts as a co-solvent under high-pressure CO2 and plays a role in improving the stability and bioavailability of nicotine.
In some embodiments, the methods of preparing nicotine-cyclodextrin-polymer compositions of the present disclosure involve 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 in CO2 to obtain scCO2 conditions; (3) mixing all the ingredients under scCO2 to obtain a homogeneous mixture; and (4) depressurizing the vessel to obtain a solid nicotine powder mixture.
In some embodiments, the processes of the present disclosure include: (1) preparing a base formulation by encapsulating nicotine with polymers (polymeric stabilizers) and cyclodextrins under scCO2, with optional oil-based flavors and sweeteners for enhanced sensory experience; (2) forming a water-entrapped powder complex by combining an aqueous solution of sweeteners, pH adjusters, and optional liquid flavors with a water-absorbing powder blend of MCC, gelling, and anticaking agents; (3) creating a moistened nicotine powder composite by mixing encapsulated nicotine powder mixture and hydrated powder; and (4) packaging the moistened composite into pouches, where additional water may be added to achieve the desired moisture content.
In some embodiments, the present disclosure provides (1) preparing an aqueous solution with sweeteners, pH adjusters, and humectants; (2) mixing the resulting aqueous solution with a powder comprising microcrystalline cellulose (MCC), gelling agents, and anti-caking agents; (3) preparing a nicotine mixture comprising encapsulating the nicotine (either free base or salt) with a polymer (polymeric stabilizer) and/or cyclodextrins; and (4) producing a final product assembled into a wet pouch formulation designed for enhanced shelf stability and reduced nicotine degradation when compared to presently available nicotine pouch products that are commercially available.
In some embodiments, the encapsulation technologies provided by the present disclosure combine using polymer (polymeric stabilizer) with cyclodextrins for preparing moisture-sensitive nicotine to be used in a high-moisture pouch that is tailored to balance moisture for effective nicotine release during buccal absorption while maintaining much-needed nicotine stability.
In some embodiments, menthol is incorporated into the compositions and formulations of the present disclosure for flavor enhancement and to create an even better hydrophobic environment around the nicotine so as to further isolate it from moisture. Therefore, this optional adjustment of adding menthol to the methods, compositions and formulations of the present disclosure further contributes to reducing nicotine degradation. Combining the encapsulation of nicotine with cyclodextrins and polymer (polymeric stabilizer) with menthol provides an unexpected synergistic effect leading to an even more stable nicotine composition or formulation with less degradation when compared to commercially available nicotine products for buccal administration.
In some embodiments, the active nicotine ingredient in the nicotine base 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.
In some embodiments, the present disclosure provides oral nicotine compositions produced without using organic solvents.
In some embodiments, the present disclosure provides oral nicotine base formulations produced using a sterile process without using organic solvents.
In some embodiments, the present disclosure provides oral nicotine compositions produced without using the physical parts of a tobacco plant, where such physical parts include but are not limited to leaves, petioles, stems, etc. In some embodiments, the present disclosure provides oral nicotine compositions produced using a sterile process without using the physical parts of a tobacco plant, where such physical parts include but are not limited to leaves, petioles, stems, etc.
In some embodiments, the nicotine compositions and formulations of the present disclosure further comprise a flavoring agent.
The nicotine compositions of the present disclosure may be in the form or category of a pharmaceutical, biological product, nutraceutical, botanical or synthetic drug, supplement, food, or any combination product. The actual form or categorization of the nicotine compositions of the present disclosure will depend on a number of different 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.
In some embodiments, the present disclosure provides homogeneous solid powder compositions comprising nicotine obtained by the methods of making disclosed herein.
In some embodiments, the methods of making provided by the present disclosure comprise adding ingredients which comprise about 0.5% to about 10% nicotine, about 0.5% to about 50% of one or more polymers, about 0.5% to about 50% of one or more cyclodextrins, about 0% to about 20% of one or more pH adjusters, about 0% to 20% of one or more sweeteners, about 0% to about 20% of one or more flavors, about 0% to 30% of one or more gelling agents, about 0% to about 30% of one or more anti-caking agents, about 10% to 70% of one or more fillers and containing a moisture content between about 5% and about 50%.
In some embodiments, the methods of making the present disclosure utilize polymers that exhibit a melting point depression under scCO2 thereby allowing for dissolution of the nicotine and the one or more cyclodextrins to form a homogeneous mixture.
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.
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 peppermint oil and/or cornmint.
In some embodiments, the methods of making disclosed herein further comprise adding one or more other excipients as additional ingredients.
In some embodiments, the methods of making disclosed herein do not involve using any organic solvents.
In some embodiments, the methods of making and the resultant compositions comprise nicotine freebase or nicotine bitartrate.
In some embodiments, the present disclosure provides a moistened nicotine powder composite composition for oral administration, wherein the composition comprises about 0.5% to about 10.0% nicotine, one or more poloxamers, and one or more cyclodextrins, one or more flavors, one or more sweeteners, one or more gelling agents, one or more anticaking agents and wherein the composition comprises a bulk density of about 0.25 g/ml to about 0.75 g/ml, a tap density of about 0.4 g/ml to about 0.9 g/ml, and a water content of about 5% to about 50 w/w %. In some embodiments, these compositions further comprise one or more additional excipients.
In some embodiments, the compositions provided by the present disclosure 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 as disclosed herein.
In some embodiments, the compositions provided by the present disclosure exhibit faster permeation of nicotine across buccal membranes 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 compositions 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.
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 method comprises orally administrating the compositions of the present disclosure to the patient.
Additional benefits and variations of the disclosed nicotine compositions and methods of producing such nicotine compositions will become apparent upon reading the present disclosure and examples.
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 skill 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, preferred 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.
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 is one and only one of the elements.
As used herein, the term “and/or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.
As used herein, 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.
As used herein, 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).
Powder density is classified into two subclasses: bulk density and tapped density, wherein both density measurements are expressed in units such as g/cm3, kg/m3, g/ml, or g/100 ml.
As used herein, “bulk density” refers to the ratio of the mass of an untapped powder sample to its volume. Bulk density is affected by the arrangement of the powder particles, the density of the particles, and how the sample was prepared, treated, and stored.
As used herein, “tapped density” refers to the ratio of the mass of a powder sample to its volume after the sample has been mechanically tapped to rearrange the particles and reduce the volume of voids between them. Tapped density is always greater than bulk density.
As used herein, a “formulation” refers to a mixture or a structure such as a capsule, tablet, or an emulsion, prepared according to a specific procedure (called a “formula”).
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 mixture.
As used herein, microcrystalline cellulose (“MCC”) refers to a pharmaceutical excipient that is used in many pharmaceutical compositions. MCC is a white, chemically inert, free-flowing powder that is made from purified wood cellulose. It is synthesized from α-cellulose precursor using processes such as acid hydrolysis, steam explosion, reactive extrusion, or ultrasonication. MCC is also used in food, cosmetic, and other industries. See, e.g., Thoorens et al., October 2014, Microcrystalline cellulose, a direct compression binder in a quality by design environment—A review, International Journal of Pharmaceutics, Vol. 473, Issues 1-2, pages 64-72.
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.
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.
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 at 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.
As used herein, 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.
As used herein, 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.
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.
As used herein, “pharmaceutically active ingredient” or API refer to the active ingredient(s) contained in medicines.
As used herein, a “powder” or “pharmaceutical powder” refer to a mixture of finely divided particles or drug particles, respectively, alone or mixed with other powdered excipients in dried form.
As used herein, 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.
As used herein, 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.
As used herein, 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).
As used herein, “organoleptic” refers to being, affecting, or relating to qualities (e.g., taste, color, odor, and feel) of a substance such as a food or drug that stimulate the sense organs.
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.
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.
As used herein, “disorder” refers to an abnormality, alteration, or derangement of function leading to a morbid physical or mental state.
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.
As used herein, 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.
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 within an acceptable qualitative range for a given application or use of the blended mixture.
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.”
As used herein, the term “wet” is synonymous with the term “moist” and refers to pouches with a moisture content of >15%.
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.”
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.
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.
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.
Nicotine has been shown to improve cognitive function, including attention, memory, and learning. Nicotine has also been investigated as a potential treatment for cognitive impairments associated with Alzheimer's disease, schizophrenia, and Adult Attention-Deficit Hyperactivity Disorder (ADHD).
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.
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, nicotine citrate, and tobacco plant extract.
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.
For additional information on nicotine see, e.g., Gorrod and Wahren (editors), Sep. 30, 1993, Nicotine and related alkaloids: absorption, distribution, metabolism and excretion, Springer, 1st edition, 320 pages; and Gorrod and Jacob, Nov. 16, 1999, Analytical determination of nicotine and related compounds and their metabolites, Elsevier Science, 1st edition, 772 pages.
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 act as co-solvents under high-pressure CO2, becoming liquid and facilitating the mixing of the ingredients. The polymers and related chemicals are used for stabilization of the active ingredient(s) against, e.g., oxidation and/or degradation. In some specific contexts as used herein, polymers may be referred to as polymer stabilizers, polymeric stabilizers, or stabilizers.
The polymer used in the ternary system of the present disclosure may be selected from a range of polymers that can act 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).
In accordance with the present disclosure, suitable polymers for the process are those that exhibit a melting depression under scCO2, 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-co-glycolic acid) (PLGA), and cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC) and hydroxyethyl cellulose (HEC).
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).
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, 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.
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.
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).
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.
Cyclodextrins (CDs) are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of glucose subunits joined by α-1,4 glycosidic bonds.
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 hydrophobic compounds such as nicotine, enhancing their stability and protecting them from degradation or volatilization.
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.
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.
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.
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.
However, CDs alone may not be sufficient to stabilize the complex and prevent its degradation or aggregation during processing under scCO2.
The cyclodextrin that may be used in the methods and compositions of the present disclosure can be any cyclodextrin 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 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-cyclodextrin 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).
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.
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 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, cinnamon, chocolate, mango, chili, tropical fruit punch, orange, strawberry, raspberry, stevia, and combinations thereof.
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.
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, advantame, sucrose, fructose, maltitol, xylitol, sorbitol, gelatin, sodium saccharin, mannitol, and stevioside.
The sweeteners that can be used for formulating dosage forms of the present disclosure can include lipophilic sweeteners including but not limited to neohesperidin dihydrochalcone, which is sometimes abbreviated to neohesperidin DC or simply NHDC. NHDC is an artificial sweetener derived from citrus.
Gelling agents may be included in the methods and compositions of the present disclosure to absorb and retain moisture, thereby minimizing the impact of moisture on other components of the formulation, such as preventing the degradation of nicotine. Additionally, the inclusion of gelling agents can enhance the mouthfeel of oral pouch formulations, contributing to improved consumer experience through controlled texture and consistency. Suitable gelling agents include, but are not limited to, sodium alginate, sodium hyaluronate, xanthan gum, guar gum, pullulan, agar, alginic acid, locust bean gum, gum tragacanth, gum arabic, carrageenan, karaya gum, tara gum, gellan gum, glucomannan, pectin, starch, carbomer, and gelatin.
An anti-caking agent is an additive used in powdered or granulated materials to prevent the formation of lumps and ensure the product remains dry and free-flowing. They help maintain the uniformity of the powder, ensuring that each dose contains the correct amount of active ingredients. By preventing clumping, anti-caking agents improve the flow properties of powders, making them easier to handle during manufacturing and packaging. Additionally, anti-caking agents can influence the mouth feel of oral pouches ensuring that powders and granules do not clump together, which can make the formulation more pleasant to consume.
Anti caking agents used in wet pouch formulations include Silicon Dioxide (Silica), Calcium Silicate, Magnesium Stearate, Sodium Aluminum Silicate, Microcrystalline Cellulose, Tricalcium Phosphate, Talc, Calcium Carbonate, Magnesium Carbonate, Potassium Ferrocyanide, Magnesium Oxide, Starch, Sodium Bicarbonate, Calcium Phosphate, Sodium Silicoaluminate, Sodium Ferrocyanide, Sodium Carboxymethyl Cellulose, Polyvinylpyrrolidone (PVP), Lactose, Mannitol.
A pH adjuster is a substance used to modify the pH level of a solution, making it either more acidic or more alkaline. These include: Citric Acid, Hydrochloric Acid, Acetic Acid, Sodium Hydroxide, Potassium Hydroxide, Sodium Bicarbonate, Ammonium Hydroxide, Lactic Acid, Phosphoric Acid, Tartaric Acid, Sodium Citrate, Potassium Citrate, Calcium Hydroxide, Magnesium Hydroxide, Sodium Acetate, Potassium Acetate, Sodium Phosphate, Potassium Phosphate, Tris (Hydroxymethyl)aminomethane (TRIS), Bis-Tris, HEPES, MES, Imidazole, Glycine, Sodium Carbonate, Potassium Carbonate, Sodium Lactate, Ammonium Chloride, Sodium Formate, Sodium Tartrate. In some embodiments, citric acid and sodium citrate are used in the present methods and compositions as pH stabilizers to target and achieve the desired final pH level of the resulting products, including pouch products.
Fillers, bulking agents, and diluents are utilized to ensure reproducible filling of pouches and to ensure a satisfactory and enjoyable mouth feel leading to a positive wet nicotine pouch experience and 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.
Humectants can be utilized in the methods and compositions of the present disclosure to help maintain moisture levels in the pouch formulations, which helps enhance the solubility and stability of nicotine. Humectants can also improve the texture and mouth feel of the pouch products, thereby helping to ensure better absorption and efficacy. Humectants that can be utilized in the methods and compositions of the present disclosure include but are not limited to glycerin, hyaluronic acid, urea, propylene glycol, honey, sorbitol, sodium PCA (Pyrrolidone Carboxylic Acid), panthenol (Vitamin B5), aloe vera, butylene glycol, and hexylene glycol.
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 high 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.
International Publication No. WO 2021/081138 (International Patent Application No. PCT/US2020/056729), International Publication No. WO 2021/081140 (International Patent Application No. PCT/US2020/056731), and U.S. Published Patent Application No. U.S. 2022/0387339 (U.S. patent application Ser. No. 17/768,132) disclose methods of producing superfine cyclodextrin-encapsulated active pharmaceutical ingredients 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. 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.
In contrast to the prior art discussed above, the present disclosure provides methods of making wet oral nicotine compositions that utilize a ternary system comprising nicotine, cyclodextrin, and a polymer. This composition is used as the nicotine source for a moistened nicotine powder composite. This improves the stability and processability of the complex resulting in a composition with increased shelf life, and improved sensory organoleptic qualities.
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 NIP, 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 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.
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. Cyclodextrins are a class of cyclic oligosaccharides that have been widely studied for their potential as drug-delivery vehicles.
The methods of the present disclosure offer a simple, efficient, and versatile approach for the development of oral nicotine. The use of a ternary system comprising nicotine, cyclodextrin, and polymer can improve the stability, and formulation process of the complex, and the use of scCO2 as a processing aid can reduce the need for organic solvents and offer a green and sustainable approach to complex formation.
The present disclosure provides methods for preparing stable nicotine-cyclodextrin-polymer (i.e., encapsulated nicotine powders or base formulations) with enhanced user experience. The production methods involve the use of a ternary system comprising nicotine, cyclodextrin, and a polymer, which are mixed under scCO2 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 use of scCO2 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 wet nicotine pouches.
Table 1 provides alternative ranges of initial dry weight/weight percentages for each of the starting, primary ingredients used to produce the encapsulated nicotine powders (base formulation) produced according to the present disclosure.
The initial amount of the nicotine source as 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 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 11%, about 4% to about 12%, about 4% to about 13%, about 4% to about 14%, or about 4% to about 15%.
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%, 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 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%.
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%, 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%.
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).
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 other 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).
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 different 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.
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.
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 different 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 timeframe for storage.
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.
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.
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, Chronic 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.
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.
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 with 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).
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., U.S. Pat. No. 9,017,737.
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-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.
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 Psychiatric 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).
For additional information on nicotine's pharmacological aspects see, e.g., Clarke et al. (editors), Dec. 6, 2012, Effects of nicotine on biological systems II (advances in pharmacological sciences), Birkhauser, 407 pages; Wonnacott et al. (editors), Jun. 21, 1990, Nicotine psychopharmacology: molecular, cellular, and behavioral aspects, Oxford Science Publications, Oxford University Press, 1st edition, 448 pages; Veljkovic et al. (editors), Jan. 2, 2018, Neurodegenerative and psychiatric diseases: overview of epidemiological data on smoking and preclinical and clinical data on nicotine, Academic Press, 1st edition, 141 pages; and Henningfield et al. (editors), Feb. 9, 2009, Nicotine psychopharmacology (handbook of experimental pharmacology, 192), Springer, 558 pages.
Oral nicotine products (ONPs) are non-combustible tobacco products that deliver nicotine through the mouth. Examples of ONPs include but are not limited to pouches, lozenges, pastilles, gels, tablets, gum (e.g., chewing gum), toothpicks, discs, sachets, and dissolvable tobacco. In general, ONPs differ from traditional smokeless tobacco products because they do not contain tobacco leaf.
ONPs deliver nicotine through the oral mucosa, the nicotine being absorbed via mucous membranes and entering the blood stream. Absorption via the oral mucosa includes absorption via the anatomical areas including but not limited to buccal (the cheeks and/or sides of the mouth), gingival (the gums), sublingual (under the tongue), and palatal (the palate or roof of the mouth).
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.
The pouches that can be used with the compositions of the present disclosure may be manufactured from materials, and in such a manner, such that 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, or 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 pouch and mixture both may be ingested by the user. 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.
For examples of suitable pouches that can be used to orally deliver the compositions of the present disclosure, see, e.g., U.S. Pat. Nos. 5,167,244; 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.
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 Nov. 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 the US by volume and nicotine concentration levels from 2019 to 2022, JAMA Netw Open. 2022, 5(11):e2242235.
U.S. Pat. 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. Pat. No. 8,747,562 discloses a tobacco-free oral pouch containing only tobacco-free flavor beads. U.S. Pat. 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. Pat. No. 8,978,661 discloses a smokeless tobacco product comprising smokeless tobacco and a polymeric material. U.S. Pat. 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. Pat. No. 11,096,412 discloses a nicotine pouch comprising a free-base nicotine mixed with an ion exchange resin. U.S. Pat. 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. U.S. Pat. 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.
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%, 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.
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%.
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%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100%.
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%.
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 (Jan. 26, 2023), 20210393719 A1 (Dec. 23, 2021), 20190142756 A1 (May 16, 2019), 20200009060 A1 (Jan. 9, 2020); and U.S. Pat. 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.
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, sodium chloride, citric acid, menthol, peppermint, lemon, wintergreen, lemon mint, glycine, and/or orange powder), pH stabilizers (e.g., 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.
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.
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.
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, and other silica compounds, and/or lubricants including stearic acid and salts thereof, such as magnesium stearate.
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, advantame, sucrose, fructose, maltitol, xylitol, sorbitol, gelatin, sodium saccharin, mannitol, and stevioside.
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 a 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.
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.
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, 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.
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.
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.
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.
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.
The general processes of the present disclosure include the methods and compositions as depicted in
Nicotine stable powders (i.e., the base formulation) are prepared by encapsulating nicotine with polymers (polymeric stabilizers) and cyclodextrins under scCO2, with optional oil-based flavors and sweeteners for enhanced sensory experience (A-1). More specifically, nicotine, polymer(s)/poloxamer(s), cyclodextrin(s), and optional flavor oil(s) and/or sweetener(s) are placed in a high-pressure vessel. CO2 is introduced into the vessel, then pumped and heated until it reaches supercritical conditions. The ingredients in the vessel are mixed under scCO2 condition for about 30 minutes-about 1 hour. Next, the vessel is slowly vented until the vessel depressurizes to atmospheric pressure. The resulting powder of the encapsulated nicotine base formulation is collected.
To create the nicotine powder mixtures, the encapsulated nicotine powder is mixed with flavoring powder(s) and a bulking agent(s) (A-2). High-volatile flavor(s) such as menthol can be added to create a better hydrophobic environment to protect nicotine from moisture.
Separately, a water-entrapped powder complex is formed by combining an aqueous solution of sweeteners, pH adjusters, and optional liquid flavors with a dry mix of microcrystalline cellulose (MCC), gelling, and anticaking agents (B). Water-soluble sweetener(s), pH adjuster(s) and salt are dissolved in purified water (B-1). Purified water is water that has been treated to remove contaminants, wherein such contaminants include but are not limited to algae, fungi, bacteria, copper, lead, parasites, and chemical pollutants. Purified water is generally classified as water having a Total Dissolved Solids (TDS) content of less than 10 parts per million (ppm), which means that around 99% of all contaminants have been removed. The amount of water can be adjusted to meet the target moisture content. MCC, gelling agent(s) and anti-caking agent(s) are blended uniformly to prepare a water absorbing powderblend (B-2).
To create an encapsulated hydrophobic nicotine powder mixture, the encapsulated nicotine powder is mixed with bulking agent(s) and flavoring powder(s) as necessary. High-volatile flavors such as menthol can optionally be added to create a better hydrophobic environment to protect nicotine from moisture. A water-entrapped powder complex is formed by combining an aqueous solution of sweeteners, pH adjusters, and optional liquid flavors with a dry mix of MCC, gelling, and anticaking agents. This solution is slowly poured into the powder blend under constant agitation to prepare the water entrapped nicotine powder complex. A moistened nicotine powder composite (C) is created by mixing the encapsulated hydrophobic nicotine powder (A) and hydrated (water-entrapped) powder complex (B). The moistened composite is packaged into pouches, where additional water may be added to achieve the desired moisture content (D).
In some embodiments, the amount of the nicotine in the final composition or final product (e.g., a finished pouch), of the present disclosure in dry weight/weight may be 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%, and all percentages between and within these percentages. In some embodiments, the amount of the nicotine in the final composition or product of the present disclosure in dry weight/weight may be from about 0.1% to about 0.2%, from about 0.1% to about 0.3%, from about 0.1% to about 0.4%, from about 0.1% to about 0.5%, from about 0.1% to about 0.6%, from about 0.1% to about 0.7%, from about 0.1% to about 0.8%, from about 0.1% to about 0.9%, from about 0.1% to about 1.0%, from about 0.1% to about 2.0%, from about 0.1% to about 3.0%, from about 0.1% to about 4.0%, from about 0.1% to about 5.0%, from about 0.1% to about 6.0%, from about 0.1% to about 7.0%, from about 0.1% to about 8.0%, from about 0.1% to about 9.0%, from about 0.1% to about 10.0%, from 0.5% to about 10.0%, about 1.0% to about 10.0%, and all ranges between and within these ranges.
In some embodiments, the compositions prepared according to the methods of the present disclosure maintain a pH range of 5.5 to 9.5.
Table 2 provides the types and amounts for each of the ingredients used to produce the exemplary nicotine freebase composite formulations ES-1, ES-2, and nicotine bitartrate composite formulation ES-3 of the present disclosure. All exemplary nicotine formulations were made according to the methods provided in Example 1 and the accompanying
As regards the nicotine content, the specifications for each of the possible final compositions or final products (e.g., a finished pouch) is almost limitless in scope other than they typically contain about 1.0 mg to about 20.0 mg per unit of nicotine as measured by HPLC Shimadzhu Prominence LC-2050 with UV detector and/or by Waters Acquity UPC2 with PDA detector. In some embodiments the final compositions can contain about 0.01% to about 20.0% per unit of nicotine based on the same measurements.
As regards the moisture content, the specifications for each of the possible final wet pouch compositions or products is almost limitless in scope other than they each typically contain a moisture content from about 5% to about 65% weight/weight. In some embodiments, the moisture content of the final wet pouch compositions ranges from about 5% to about 50% weight/weight.
Table 3 provides the moisture content, pH, and nicotine loading of the final prepared wet nicotine pouches based on the ingredient weights in Table 2.
Table 4 provides information on the reference commercially-available nicotine formulations CP-1, CP-2 and CP-3 (product names and manufacturers not provided).
Sample formulations were produced as set forth in Example 1. The exemplary nicotine formulations for ES-1, ES-2, and ES-3 are set forth in Example 2, Table 2; and, the reference commercial formulations for CP-1, CP-2, and CP-3 are set forth in Example 3, Table 3. A summary of the formulations is provided in Table 5.
All samples from Examples 2 and 3 were packaged in polypropylene (PP) tubes and placed in a stability chamber at accelerated storage conditions (about 40° C./about 104° F.; about 75% Relative Humidity). Every week the nicotine concentration of three tubes of each formulation was measured.
Stability results of the commercial products CP-1, CP-2 and CP-3 versus exemplary nicotine formulations ES-1, ES-2, and ES-3 are provided in
ES-1, ES-2, and ES-3 all had stability as measured by percent nicotine content relative to the beginning amount (i.e., T0=100%) that remained above about 80% nicotine content over 4 weeks of testing. In contrast, CP-1, CP-2, and CP-3 had about 60% or less of remaining nicotine content over the same time period under the same testing accelerated storage conditions. Thus, while exemplary formulations of the present disclosure maintained nicotine contents above about 65%, about 70%, about 75%, or about 80% from the beginning of the test (TO) until up to 4 weeks of testing (Twk4), the commercial formulations had nicotine contents below about 60%, about 55%, about 50%, about 45%, or lower over the same time period and testing conditions.
Exemplary nicotine formulations ES-1 to ES-2 of the present disclosure (Example 2, Table 2) were evaluated in controlled focus group settings to determine their organoleptic properties against reference commercial formulations CP-2 and CP-3 (Example 3, Table 3).
In these studies, two sets of focus group participants were each asked to test 2 different nicotine pouch formulations (either ES-1 versus CP-2, or ES-2 versus CP-3) 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.
Panel Test #1. Participants (N=8) in this organoleptic panel evaluated encapsulated nicotine samples of ES-1 against commercial product samples of CP-2 for overall experience and satisfaction with each sample. Participants were asked to indicate which sample they found more satisfactory overall by using a scoring system of either 1 (preferred) or 0 (not preferred). The resulting scores are provided in Table 6.
Samples of ES-1 were chosen as the more satisfactory experience by 7 out of 8 participants (87.5%), while only 1 of 8 (12.5%) chose CP-2 as the more satisfactory experience. See Table 6. These results suggest a strong overall preference for ES-1 over CP-2 based on actual participant feedback of their experiences.
Panel Test #2. Participants (N=6) in this organoleptic panel test evaluated encapsulated nicotine samples of ES-2 against commercial product samples of CP-3 for overall experience and satisfaction with each sample. Participants were asked to indicate which sample they found more satisfactory overall by using a scoring system of either 1 (preferred) or 0 (not preferred). The resulting scores are provided in Table 7.
Samples of ES-2 were chosen as the more satisfactory experience by 5 out of 6 participants (83.3%), while only 1 in 6 (16.7%) chose CP-3 as the more satisfactory experience. See Table 7. These results suggest a strong overall preference for ES-2 over CP-3 based on actual participant feedback of their experiences.
These above results for Panel Test #1 and Panel Test #2 highlight a consistent, significant preference for the encapsulated formulations of the present disclosure over the comparative commercial formulations, suggesting much stronger enhanced user experiences and satisfactions with the flavor and overall sensory qualities of the encapsulated formulations. Furthermore, anecdotal comments from the participants on these panels highlighted that the exemplary compositions of the present disclosure, i.e., ES-1 and ES-2, resulted in them experiencing reduced throat burn and longer lasting flavor as compared to the commercial formulations of CP-2 and CP-3, respectively.
Larger (N=about 30,000) user testing is in process and indicative initial results imply a response within +/−10% of the above results.
An in-vitro permeation experiment utilizing a horizontal Franz diffusion cell was performed as an analog of in-vitro buccal absorption of pouches formulated with compositions ES-1, ES-2, CP-2 and CP-3.
A polyethersulfone (PES) membrane in a horizontal Franz cell set up was used to act as an analog for buccal absorption (“Franz diffusion cell test using a polyethersulfone (PES) membrane”). This testing design was based on teachings of Brandl and Bauer-Brandel, 2019, Oromucosal drug delivery: trends in in-vitro biopharmaceutical assessment of new chemical entities and formulations, European Journal of Pharmaceutical Sciences, 128:112-117; Valetti et al., 2022, Oral transmucosal delivery of eletriptan for neurological diseases, International Journal of Pharmaceutics, 627:122222; Mustapha et al., 2011, Influence of drug concentration on the diffusion parameters of caffeine, Indian Journal of Pharmacology, 45(2):157-162; and Olariu et al., 2019, Evaluation of the barrier potential of some synthetic membranes in testing the in vitro tenoxicam release from hydrogels, using the experimental model with Franz diffusion cells, Farmacia, 67(1):73-80.
In summary, the Franz diffusion cell test using a PES membrane was used to test nicotine pouch samples. Donor and receiver compartments contained 15 mL of a phosphate buffered silane solution. The exposed membrane area was 1.7671 cm2.
Table 1 provides the ingredients used to make each of the tested exemplary nicotine formulations of the present disclosure (ES-1 and ES-2) versus the tested reference commercial formulations (CP-2 and CP-3). Example 1 and
Exemplary peppermint flavored formulation ES-1 showed a 47% increase in nicotine flux across the PES membrane as compared to the commercial peppermint flavored formulation CP-2.
Exemplary citrus (i.e., lemon) flavored formulation ES-2 shows a 111% increase in nicotine flux across the PES membrane as compared to the commercial lemon mint flavored formulation CP-3.
Other subject matter contemplated by the present disclosure is set out in the following numbered embodiments:
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.
This application claims priority under 35 U.S.C. § 119 to Provisional Patent Application Ser. No. 63/602,732, filed Nov. 27, 2023, herein incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 63602732 | Nov 2023 | US |
