WO2023248187A1 - Composition orale comprenant un modulateur de récepteur - Google Patents

Composition orale comprenant un modulateur de récepteur Download PDF

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Publication number
WO2023248187A1
WO2023248187A1 PCT/IB2023/056478 IB2023056478W WO2023248187A1 WO 2023248187 A1 WO2023248187 A1 WO 2023248187A1 IB 2023056478 W IB2023056478 W IB 2023056478W WO 2023248187 A1 WO2023248187 A1 WO 2023248187A1
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WIPO (PCT)
Prior art keywords
composition
acid
weight
trpa1
nicotine
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Application number
PCT/IB2023/056478
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English (en)
Inventor
Michael S. Daniel
Shahin ROOHINEJAD
Michael F. Davis
Brian M. KEYSER
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Nicoventures Trading Limited
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Publication of WO2023248187A1 publication Critical patent/WO2023248187A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
    • A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
    • A24B15/18—Treatment of tobacco products or tobacco substitutes
    • A24B15/28—Treatment of tobacco products or tobacco substitutes by chemical substances
    • A24B15/30—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances
    • A24B15/302—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances by natural substances obtained from animals or plants
    • A24B15/303—Plant extracts other than tobacco
    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
    • A24B13/00—Tobacco for pipes, for cigars, e.g. cigar inserts, or for cigarettes; Chewing tobacco; Snuff
    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
    • A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
    • A24B15/10—Chemical features of tobacco products or tobacco substitutes
    • A24B15/16—Chemical features of tobacco products or tobacco substitutes of tobacco substitutes
    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
    • A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
    • A24B15/18—Treatment of tobacco products or tobacco substitutes
    • A24B15/28—Treatment of tobacco products or tobacco substitutes by chemical substances
    • A24B15/30—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances
    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
    • A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
    • A24B15/18—Treatment of tobacco products or tobacco substitutes
    • A24B15/28—Treatment of tobacco products or tobacco substitutes by chemical substances
    • A24B15/30—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances
    • A24B15/301—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances by aromatic compounds

Definitions

  • compositions intended for human use are adapted for oral use and deliver substances such as nicotine, flavors, and/or active ingredients during use.
  • Such compositions may include tobacco or a product derived from tobacco, or may be tobacco-free alternatives.
  • Such products typically contain flavorants and/or active ingredients such as nicotine, caffeine, botanicals, or cannabidiol.
  • the format of such products can vary and include pouched products containing a powdered or granular composition, lozenges, pastilles, liquids, gels, emulsions, meltable compositions, and the like. See, for example, the types of products described in US Patent App. Pub. Nos.
  • Oral products such as those including a nicotine containing matrix, are used by placing the product between the cheek and the gum.
  • An active ingredient in the oral product such as nicotine
  • Positive sensory attributes are important elements to a consumer-acceptable oral product.
  • Some consumers may prefer an oral product that closely 'mimics' the oral and throat sensations produced by tobacco-containing products or may prefer an oral product providing a reduction in or an alternative to the oral and throat sensations produced by tobacco-containing products.
  • it may be desirable to provide oral products with varying sensorial attributes such as flavor, intensity/quality, impact, irritation, smoothness, and reward.
  • inclusion in an oral product of modulators of certain ion channels may favorably influence the user experience of an oral product, for example, by reducing the burning sensation or "harshness" sometimes associated with nicotine-containing oral products.
  • compositions configured for oral use, the composition comprising: at least one filler; at least one active ingredient selected from the group consisting of botanical materials, stimulants, amino acids, vitamins, antioxidants, nutraceuticals, cannabinoids, cannabimimetics, terpenes, pharmaceutical agents, and combinations thereof; and an ion channel modulator selected from the group consisting of TRPA1 agonists, TRPA1 antagonists, TRPA1 inhibitors, TRPV1 agonists, TRPV3 agonists, TRPM8 agonists, NaV1.7 antagonists, P2X 3 antagonists, and combinations thereof.
  • active ingredient selected from the group consisting of botanical materials, stimulants, amino acids, vitamins, antioxidants, nutraceuticals, cannabinoids, cannabimimetics, terpenes, pharmaceutical agents, and combinations thereof
  • an ion channel modulator selected from the group consisting of TRPA1 agonists, TRPA1 antagonists, TRPA1 inhibitors, TRPV1 agonists, TRPV3 agonists
  • the ion channel modulator is selected from the group consisting of TRPA1 agonists, TRPM8 agonists, TRPV1 agonists, TRPV3 agonists, and combinations thereof. In some embodiments, the ion channel modulator is: (i) a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, or a combination thereof; and (ii) an TRPA1 antagonist or a TRPA1 channel blocker.
  • the ion channel modulator is: (i) a TRPM8 agonist or a TRPV1 agonist; and (ii) a TRPA1 antagonist or a TRPA1 inhibitor. In some embodiments, the ion channel modulator is a TRPA1 antagonist or a TRPA1 channel blocker.
  • the ion channel modulator is selected from the group consisting of caryophyllene oxide, alpha-irone, phenethyl phenylacetate, gamma-dodecalactone, beta-caryophyllene, 2- hexenal, eucalyptol, L-menthol, 3-phenylpropyl homovanillate, benzyl cinnamate, beta-bourbonene, cinnamyl cinnamate, citronellyl acetate, hydroxy-alpha-sanshool, liquiritin, methyl-alpha-ionone, phytol, spathulenol, and combinations thereof.
  • the ion channel modulator is a combination of benzyl cinnamate, caryophyllene oxide, and nootkatone. In some embodiments, the ion channel modulator is a combination of benzyl cinnamate, caryophyllene oxide, and alpha-irone. In some embodiments, the ion channel modulator is a combination of benzyl cinnamate and caryophyllene oxide.
  • the active ingredient comprises a basic amine functionality. In some embodiments, the active ingredient comprising the basic amine functionality is nicotine. In some embodiments, the composition comprises nicotine in an amount of from about 0.001 to about 10% by weight of the composition, calculated as the free base and based on the total weight of the composition.
  • the at least one filler comprises a cellulose material.
  • the cellulose material comprises microcrystalline cellulose.
  • the at least one filler further comprises a cellulose derivative in an amount by weight of from about 1% to about 3%, based on the total weight of the composition.
  • the cellulose derivative is hydroxypropylcellulose.
  • the composition further comprises an organic acid, an alkali metal salt of an organic acid, or a combination thereof.
  • the alkali metal is sodium or potassium.
  • the composition comprises an organic acid and a sodium salt of the organic acid.
  • a ratio of the organic acid to the sodium salt of the organic acid is from about 0.1 to about 10.
  • the composition comprises from about 0.05, about 0.1, about 1, about 1.5, about 2, or about 5, to about 10, about 15, or about 20 molar equivalents of the organic acid, the alkali metal salt thereof, or the combination thereof, relative to the active ingredient comprising the basic amine functionality, calculated as the amine free base. In some embodiments, the composition comprises from about 2 to about 10 molar equivalents of the organic acid, the alkali metal salt thereof, or the combination thereof, relative to the active ingredient comprising the basic amine functionality, calculated as the amine free base.
  • the organic acid has a logP value from about 1 to about 12. In some embodiments, the organic acid has a logP value from about 3 to about 12. In some embodiments, the organic acid has a logP value from about 3 to about 10. In some embodiments, the organic acid has a logP value from about 3 to about 8.
  • the organic acid is an alkyl carboxylic acid, an aryl carboxylic acid, an alkyl sulfonic acid, an aryl sulfonic acid, or a combination of any thereof.
  • the organic acid comprises a menthyl or tocopherol monoester of a dicarboxylic acid, or a combination thereof.
  • the dicarboxylic acid is malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, maleic acid, or a combination thereof.
  • the organic acid comprises tocopherol succinate, monomenthyl succinate, monomenthyl fumarate, monomenthyl glutarate, or a combination thereof.
  • the organic acid comprises octanoic acid, decanoic acid, benzoic acid, heptanesulfonic acid, or a combination thereof. In some embodiments, the organic acid comprises lactic acid. In some embodiments, the organic acid comprises benzoic acid. In some embodiments, the organic acid is benzoic acid, sodium benzoate, or a combination thereof.
  • At least a portion of the active ingredient comprising the basic amine functionality is associated with at least a portion of the organic acid or the alkali metal salt thereof, the association in the form of a basic amine-organic acid salt, an ion pair between the basic amine and a conjugate base of the organic acid, or both.
  • the pH of the composition is from about 4.0 to about 9.0. In some embodiments, the pH of the composition is from about 4.5 to about 7. In some embodiments, the pH of the composition is from about 5.5 to about 7. In some embodiments, wherein the pH of the composition is from about 4.0 to about 5.5. In some embodiments, the pH of the composition is from about 7.0 to about 9.0.
  • the composition further comprises a solubility enhancer.
  • the solubility enhancer is glycerol, propylene glycol, or another humectant as set forth herein.
  • the composition comprises from about 10 to about 50% of the at least one filler, and from about 5 to about 60% by weight of water, based on the total weight of the composition.
  • the composition further comprises one or more flavoring agents, one or more salts, one or more sweeteners, one or more binding agents, one or more humectants, one or more gums, a tobacco material, or combinations thereof.
  • the composition comprises no more than about 10% by weight of a tobacco material, excluding any nicotine component present, based on the total weight of the composition. In some embodiments, the composition is free of tobacco material.
  • the composition is enclosed in a pouch to form a pouched product, the composition optionally being in a granular form.
  • the composition is in the form of a gel, pastille, gum, chew, melt, tablet, lozenge, granular material, or powder.
  • Embodiment 1 A composition configured for oral use, the composition comprising: at least one active ingredient selected from the group consisting of botanical materials, stimulants, amino acids, vitamins, antioxidants, nutraceuticals, cannabinoids, cannabimimetics, terpenes, pharmaceutical agents, and combinations thereof; an ion channel modulator selected from the group consisting of TRPA1 agonists, TRPA1 antagonists, TRPA1 inhibitors, TRPV1 agonists, TRPV3 agonists, TRPM8 agonists, NaV1.7 antagonists, P2X 3 antagonists, and combinations thereof; and at least one filler.
  • Embodiment 2 The composition of embodiment 1, wherein the ion channel modulator is selected from the group consisting of TRPA1 agonists, TRPM8 agonists, TRPV1 agonists, TRPV3 agonists, and combinations thereof.
  • Embodiment 3 The composition of embodiment 1, wherein the ion channel modulator is:
  • Embodiment 4 The composition of claim 1, wherein the ion channel modulator is:
  • Embodiment 5 The composition of embodiment 1, wherein the ion channel modulator is a TRPA1 antagonist or a TRPA1 channel blocker.
  • Embodiment 6 The composition of any one of embodiments 1-5, wherein the active ingredient comprises nicotine.
  • Embodiment 7 The composition of embodiment 6, wherein the nicotine is present in an amount of from about 0.001 to about 10% by weight of the composition, calculated as the free base and based on the total weight of the composition.
  • Embodiment 8 The composition of any one of embodiments 1-7, wherein the at least one filler comprises a cellulose material.
  • Embodiment 9 The composition of embodiment 8, wherein the cellulose material comprises microcrystalline cellulose.
  • Embodiment 10 The composition of embodiment 8 or 9, wherein the at least one filler further comprises a cellulose derivative in an amount by weight of from about 1% to about 3%, based on the total weight of the composition.
  • Embodiment 11 The composition of embodiment 10, wherein the cellulose derivative is hydroxypropylcellulose.
  • Embodiment 12 The composition of any one of embodiments 1-11, further comprising one or more flavoring agents, one or more salts, one or more sweeteners, one or more binding agents, one or more humectants, one or more gums, a tobacco material, or combinations thereof.
  • Embodiment 13 The composition of any one of embodiments 1-12, comprising no more than about 10% by weight of a tobacco material, excluding any nicotine component present, based on the total weight of the composition.
  • Embodiment 14 The composition of any one of embodiments 1-12, wherein the composition is free of tobacco material.
  • Embodiment 15 The composition of any one of embodiments 1-14, enclosed in a pouch to form a pouched product, the composition optionally being in a granular form.
  • Embodiment 16 The composition of any one of embodiments 1-14, in the form of a gel, pastille, gum, chew, melt, tablet, lozenge, granular material, or powder.
  • the drawing is a perspective view of a pouched product embodiment according to an example embodiment of the present disclosure, including a pouch or fleece at least partially filled with a composition configured for oral use.
  • dry weight percent or “dry weight basis” refers to weight on the basis of dry ingredients (i.e., all ingredients except water).
  • wet weight refers to the weight of the mixture including water. Unless otherwise indicated, reference to “weight percent” of a mixture reflects the total wet weight of the mixture (i.e., including water).
  • compositions configured for oral use comprising at least one active ingredient and one or more modulators of certain receptors associated with sensations such as heat, cold, pain, bum, salty, sweet, sour, bitter, and umami.
  • modulating one or more ion channel receptors including but not limited to, TRPA1, TRPV1, TRPM8, P2Xi. and NaV1.7, may improve the sensorial properties encountered during the use of oral products including certain active ingredients such as nicotine, for example by reducing the harshness or burning sensation often associated with such products.
  • composition configured for oral use, the composition comprising: at least one active ingredient selected from the group consisting of botanical materials, stimulants, amino acids, vitamins, antioxidants, nutraceuticals, cannabinoids, cannabimimetics, terpenes, pharmaceutical agents, and combinations thereof; an ion channel modulator selected from the group consisting of TRPA1 agonists, TRPA1 antagonists, TRPA1 channel blockers, TRPV1 agonists, TRPV3 agonists, TRPM8 agonists, NaV1.7 antagonists, P2X 3 antagonists, and combinations thereof; and at least one filler.
  • the relative amounts of the various components within the composition may vary, and typically are selected so as to provide the desired sensory and performance characteristics to the composition. The example individual components of the composition are described further hereinbelow.
  • composition as disclosed herein comprises an active ingredient.
  • an active ingredient refers to one or more substances belonging to any of the following categories: API (active pharmaceutical substances), food additives, natural medicaments, and naturally occurring substances that can have an effect on humans.
  • Example active ingredients include any ingredient known to impact one or more biological functions within the body, such as ingredients that furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or which affect the structure or any function of the body of humans (e.g., provide a stimulating action on the central nervous system, have an energizing effect, an antipyretic or analgesic action, or an otherwise useful effect on the body).
  • the active ingredient may be of the type generally referred to as dietary supplements, nutraceuticals, "phytochemicals” or "functional foods”.
  • dietary supplements e.g., nutraceuticals, "phytochemicals” or “functional foods”.
  • Non-limiting examples of active ingredients include those falling in the categories of nicotine, botanical ingredients, stimulants, amino acids, and/or pharmaceutical, nutraceutical, and medicinal ingredients (e.g., vitamins, such as B6, B12, and C, and/or cannabinoids, such as tetrahydrocannabinol (THC) and cannabidiol (CBD)). Each of these categories is further described herein below.
  • the particular choice of active ingredients will vary depending upon the desired flavor, texture, and desired characteristics of the particular product.
  • an active ingredient or combination thereof is present in a total concentration of at least about 0.001% by weight of the composition, such as in a range from about 0.001% to about 30%.
  • the active ingredient or combination of active ingredients is present in a concentration from about 0.1% w/w to about 10%, about 20%, or about 30% by weight, such as, e.g., from about 0.5% w/w to about 30%, from about 0.5% w/w to about 20%, from about 0.5% w/w to about 10%, from about 1% to about 10%, or from about 1% to about 5% by weight, based on the total weight of the composition.
  • the active ingredient or combination of active ingredients is present in a concentration of from about 0.001%, about 0.01%, about 0.1% , or about 1%, up to about 20% by weight, such as, e.g., from about from about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5% about 0.6%, about 0.7%, about 0.8%, or about 0.9%, to 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
  • Active ingredient comprising basic amine functionality
  • the composition as disclosed herein comprises as an active ingredient a substance comprising a basic amine functionality.
  • basic amine is meant a molecule including at least one basic amine functional group. Examples of basic amines include, but are not limited to, alkaloids.
  • basic amine functionality or “basic amine functional group” is meant a group containing a nitrogen atom having a lone pair of electrons. The basic amine functional group is attached to or incorporated within the molecule through one or more covalent bonds to the said nitrogen atom.
  • the basic amine may be a primary, secondary, or tertiary amine, meaning the nitrogen bears one, two, or three covalent bonds to carbon atoms.
  • basic meaning the lone electron pair is available for hydrogen bonding.
  • the basicity (i.e., the electron density on the nitrogen atom and consequently the availability and strength of hydrogen bonding to the nitrogen atom) of the basic amine may be influenced by the nature of neighboring atoms, the steric bulk of the molecule, and the like.
  • the active ingredient comprising the basic amine functionality is nicotine or a nicotine component.
  • nicotine component is meant any suitable form of nicotine (e.g., free base, salt, or ion pair) for providing oral absorption of at least a portion of the nicotine present. Nicotine is released from the composition and absorbed through the oral mucosa, thereby entering the blood stream, where it is circulated systemically.
  • the source of the nicotine may vary, and may be natural or synthetic.
  • Nicotine may be tobacco-derived (e.g., a tobacco extract) or non-tobacco derived (e.g., synthetic or otherwise obtained). Most preferably, the nicotine is naturally occurring and obtained as an extract from a Nicotiana species (e.g., tobacco).
  • the nicotine can have the enantiomeric form S(-)-nicotine, R(+)-nicotine, or a mixture of .S'(-)-nicotinc and R (+) -nicotine.
  • the nicotine is in the form of .S'(-)-nicotinc (e.g., in a form that is virtually all S(-)-nicotine) or a racemic mixture composed primarily or predominantly of .S'(-)-nicotinc (e.g., a mixture composed of about 95 weight parts .S'(-)-nicotinc and about 5 weight parts R(+)-nicotine).
  • the nicotine is employed in virtually pure form or in an essentially pure form. Highly preferred nicotine that is employed has a purity of greater than about 95 percent, more preferably greater than about 98 percent, and most preferably greater than about 99 percent, on a weight basis.
  • the nicotine component is selected from the group consisting of nicotine free base, nicotine as an ion pair, and a nicotine salt.
  • nicotine is in its free base form.
  • at least a portion of the nicotine is present as a nicotine salt, or at least a portion of the nicotine is present as an ion pair with at least a portion of the organic acid or the conjugate base thereof, as described further herein below.
  • the nicotine component (calculated as the free base) is present in a concentration of at least about 0.001% by weight of the composition, such as in a range from about 0.001% to about 10%.
  • the nicotine component is present in a concentration from about 0.1% w/w to about 10% by weight, such as, e.g., from about from about 0.1% w/w, about 0.2%, about 0.3%, about 0.4%, about 0.5% about 0.6%, about 0.7%, about 0.8%, or about 0.9%, to about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight, calculated as the free base and based on the total weight of the composition.
  • the nicotine component is present in a concentration from about 0.1% w/w to about 3% by weight, such as, e.g., from about from about 0.1% w/w to about 2.5%, from about 0.1% to about 2.0%, from about 0.1% to about 1.5%, or from about 0.1% to about 1% by weight, calculated as the free base and based on the total weight of the composition.
  • the active ingredient comprises a botanical ingredient.
  • botanical ingredient or “botanical” refers to any plant material or fungal-derived material, including plant material in its natural form and plant material derived from natural plant materials, such as extracts or isolates from plant materials or treated plant materials (e.g., plant materials subjected to heat treatment, fermentation, bleaching, or other treatment processes capable of altering the physical and/or chemical nature of the material).
  • a “botanical” includes, but is not limited to, “herbal materials,” which refer to seed-producing plants that do not develop persistent woody tissue and are often valued for their medicinal or sensory characteristics (e.g., teas or tisanes).
  • Reference to botanical material as "non-tobacco” is intended to exclude tobacco materials (i.e., does not include any Nicotiana species).
  • a botanical When present, a botanical is typically at a concentration of from about 0.01% w/w to about 10% by weight, such as, e.g., from about from about 0.01% w/w, about 0.05%, about 0.1%, or about 0.5%, to about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% by weight, based on the total weight of the composition.
  • the botanical materials useful in the present disclosure may comprise, without limitation, any of the compounds and sources set forth herein, including mixtures thereof. Certain botanical materials of this type are sometimes referred to as dietary supplements, nutraceuticals, "phytochemicals" or "functional foods.” Certain botanicals, as the plant material or an extract thereof, have found use in traditional herbal medicine, and are described further herein.
  • Non-limiting examples of non-tobacco botanical materials include without limitation acai berry (Euterpe oleracea martius), acerola (Malpighia glabra), alfalfa, allspice, Angelica root, anise (e.g., star anise), annatto seed, apple (Malus domestica), apricot oil, ashwagandha, Bacopa monniera, baobab, basil (Ocimum basilicum), bay, bee balm, beet root, bergamot, blackberry (Morus nigra), black cohosh, black pepper, black tea, blueberries, boldo (Peumus boldus), borage, bugleweed, cacao, calamus root, camu (Myrcaria dubia), cannabis/hemp, caraway seed, cardamom, cassis, catnip, catuaba, cayenne pepper, Centella asiatica, chaga mushroom, Chai-hu, cham
  • the active ingredient comprises one or more stimulants.
  • stimulants refers to a material that increases activity of the central nervous system and/or the body, for example, enhancing focus, cognition, vigor, mood, alertness, and the like.
  • Non-limiting examples of stimulants include caffeine, theacrine, theobromine, and theophylline.
  • Theacrine (1,3,7,9-tetramethyluric acid) is a purine alkaloid which is structurally related to caffeine, and possesses stimulant, analgesic, and anti-inflammatory effects.
  • Present stimulants may be natural, naturally derived, or wholly synthetic.
  • certain botanical materials may possess a stimulant effect by virtue of the presence of e.g., caffeine or related alkaloids, and accordingly are “natural” stimulants.
  • the stimulant e.g., caffeine, theacrine
  • caffeine can be obtained by extraction and purification from botanical sources (e.g., tea).
  • whole synthetic it is meant that the stimulant has been obtained by chemical synthesis.
  • the active ingredient comprises caffeine.
  • the active ingredient is caffeine.
  • the caffeine is present in an encapsulated form.
  • Vitashure® available from Balchem Corp., 52 Sunrise Park Road, New Hampton, NY, 10958.
  • a stimulant or combination of stimulants is typically at a concentration of from about 0.1% w/w to about 15% by weight, such as, e.g., from about from about 0.1% w/w, about 0.2%, about 0.3%, about 0.4%, about 0.5% about 0.6%, about 0.7%, about 0.8%, or about 0.9%, to 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%, or about 15% by weight, based on the total weight of the composition.
  • the active ingredient comprises an amino acid.
  • amino acid refers to an organic compound that contains amine (-NH2) and carboxyl (-COOH) or sulfonic acid (SO3H) functional groups, along with a side chain (R group), which is specific to each amino acid.
  • Amino acids may be proteinogenic or non-proteinogenic. By “proteinogenic” is meant that the amino acid is one of the twenty naturally occurring amino acids found in proteins.
  • the proteinogenic amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
  • non-proteinogenic is meant that either the amino acid is not found naturally in protein or is not directly produced by cellular machinery (e.g., is the product of post-tranlational modification).
  • Non-limiting examples of non-proteinogenic amino acids include gamma-aminobutyric acid (GABA), taurine (2- aminoethanesulfonic acid), theanine (L-y-glutamylethylamide), hydroxyproline, and beta-alanine.
  • GABA gamma-aminobutyric acid
  • taurine (2- aminoethanesulfonic acid
  • theanine L-y-glutamylethylamide
  • hydroxyproline hydroxyproline
  • beta-alanine beta-alanine
  • an amino acid or combination of amino acids is typically at a concentration of from about 0.1% w/w to about 15% by weight, such as, e.g., from about from about 0.1% w/w, about 0.2%, about 0.3%, about 0.4%, about 0.5% about 0.6%, about 0.7%, about 0.8%, or about 0.9%, to 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%, or about 15% by weight, based on the total weight of the composition.
  • the active ingredient comprises a vitamin or combination of vitamins.
  • vitamin refers to an organic molecule (or related set of molecules) that is an essential micronutrient needed for the proper functioning of metabolism in a mammal.
  • vitamins required by human metabolism which are: vitamin A (as all-trans-retinol, all-trans-retinyl-esters, as well as all-trans-beta-carotene and other provitamin A carotenoids), vitamin Bl (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B9 (folic acid or folate), vitamin B12 (cobalamins), vitamin C (ascorbic acid), vitamin D (calciferols), vitamin E (tocopherols and tocotrienols), and vitamin K (quinones).
  • the active ingredient comprises vitamin C. In some embodiments, the active ingredient is a combination of vitamin C, caffeine, and taurine. In some embodiments, the active ingredient comprises one or more of vitamin B6 and B12. In some embodiments, the active ingredient comprises theanine and one or more of vitamin B6 and B12.
  • a vitamin or combination of vitamins is typically at a concentration of from about 0.01% w/w to about 1% by weight, such as, e.g., from about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, or about 0.1% w/w, to about 0.2%, about 0.3%, about 0.4%, about 0.5% about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1% by weight, based on the total weight of the composition.
  • the active ingredient comprises vitamin A.
  • the vitamin A is encapsulated.
  • the vitamin is vitamin B6, vitamin B12, vitamin E, vitamin C, or a combination thereof.
  • the active ingredient comprises a mineral.
  • mineral refers to an inorganic molecule (or related set of molecules) that is an essential micronutrient needed for the proper functioning of various systems in a mammal.
  • minerals include iron, zinc, copper, selenium, chromium, cobalt, manganese, calcium, phosphorus, sulfur, magnesium, and the like.
  • the active ingredient comprises iron. Suitable sources of iron include, but are not limited to, ferrous salts such as ferrous sulfate and ferrous gluconate. In some embodiments, the iron is encapsulated.
  • the active ingredient comprises calcium, magnesium, or a combination thereof.
  • the calcium, magnesium, or combination thereof is present as a soluble salt of calcium and/or magnesium, such that calcium and/or magnesium ions are present in the composition during use and are available in the oral cavity of the user.
  • Examples salts include acetates, citrates, gluconates, lactates, nitrates, glycerophosphates, threonates, and the like.
  • Other divalent metal cations, and salts thereof could also be used, such as those containing copper or zinc.
  • the presence of calcium and/or magnesium ions may enhance or reduce activation of certain receptors (e.g., TRPA1).
  • TRPA1 e.g., Zhao et al. Nature 2020 Sep;585(7823):141-145, which suggests that the TRPA1 exhibits a bimodal response to Ca ions with sensitization at low calcium ion concentrations and desensitization at high Ca ion concentrations.
  • icilin AG-3-5; l-(2-hydroxyphenyl)-4-(3-nitrophenyl)-3,6-dihydropyrimidin-2-one
  • TRPM8 evokes [Ca2+] dependent responses in standard physiological solutions of pH 7.3.
  • the active ingredient comprises one or more cannabinoids.
  • cannabinoid refers to a class of diverse natural or synthetic chemical compounds that acts on cannabinoid receptors (i.e., CB1 and CB2) in cells that alter neurotransmitter release in the brain.
  • Cannabinoids are cyclic molecules exhibiting particular properties such as the ability to easily cross the blood-brain barrier.
  • Cannabinoids may be naturally occurring (Phytocannabinoids) from plants such as cannabis, (endocannabinoids) from animals, or artificially manufactured (synthetic cannabinoids).
  • Cannabis species express at least 85 different phytocannabinoids, and these may be divided into subclasses, including cannabigerols, cannabichromenes, cannabidiols, tetrahydrocannabinols, cannabinols and cannabinodiols, and other cannabinoids, such as cannabigerol (CBG), cannabichromene (CBC), cannabidiol (CBD), tetrahydrocannabinol (THC), cannabinol (CBN) and cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerolic acid, can
  • the cannabinoid is selected from the group consisting of cannabigerol (CBG), cannabichromene (CBC), cannabidiol (CBD), tetrahydrocannabinol (THC), cannabinol (CBN) and cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerolic acid, cannabidiolic acid (CBDA), Cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabmolic acid (THCA), tetrahydrocannabivarinic acid (THCV A), and mixtures thereof.
  • CBG
  • the cannabinoid comprises at least tetrahydrocannabinol (THC). In some embodiments, the cannabinoid is tetrahydrocannabinol (THC). In some embodiments, the cannabinoid comprises at least cannabidiol (CBD). In some embodiments, the cannabinoid is cannabidiol (CBD). In some embodiments, the CBD is synthetic CBD.
  • the cannabinoid e.g., CBD
  • CBD cannabinoid
  • An isolate is an extract from a plant, such as cannabis, where the active material of interest (in this case the cannabinoid, such as CBD) is present in a high degree of purity, for example greater than 95%, greater than 96%, greater than 97%, greater than 98%, or around 99% purity.
  • the cannabinoid is an isolate of CBD in a high degree of purity, and the amount of any other cannabinoid in the composition is no greater than about 1% by weight of the composition, such as no greater than about 0.5% by weight of the composition, such as no greater than about 0.1% by weight of the composition, such as no greater than about 0.01% by weight of the composition.
  • cannabinoid and the particular percentages thereof which may be present within the disclosed composition will vary depending upon the desired flavor, texture, and other characteristics of the composition.
  • the cannabinoid (such as CBD) is present in the composition in a concentration of at least about 0.001% by weight of the composition, such as in a range from about 0.001% to about 2% by weight of the composition. In some embodiments, the cannabinoid (such as CBD) is present in the composition in a concentration of from about 0.1% to about 1.5% by weight, based on the total weight of the composition. In some embodiments, the cannabinoid (such as CBD) is present in a concentration from about 0.4% to about 1.5% by weight, based on the total weight of the oral composition.
  • the active ingredient may include a cannabimimetic, which is a class of compounds derived from plants other than cannabis that have biological effects on the endocannabinoid system similar to cannabinoids.
  • cannabimimetic is a class of compounds derived from plants other than cannabis that have biological effects on the endocannabinoid system similar to cannabinoids. Examples include yangonin, alpha-amyrin or beta-amyrin (also classified as terpenes), cyanidin, curcumin (tumeric), catechin, quercetin, salvinorin A, N- acylethanolamines, and N-alkylamide lipids. Such compounds can be used in the same amounts and ratios noted herein for cannabinoids.
  • Active ingredients suitable for use in the present disclosure can also be classified as terpenes, many of which are associated with biological effects, such as calming effects.
  • Terpenes are understood to have the general formula of (C5H 8 ) n and include monoterpenes, sesquiterpenes, and diterpenes.
  • Terpenes can be acyclic, monocyclic or bicyclic in structure. Some terpenes provide an entourage effect when used in combination with cannabinoids or cannabimimetics.
  • Examples include beta-caryophyllene, linalool, limonene, beta-citronellol, linalyl acetate, pinene (alpha or beta), geraniol, carvone, eucalyptol, menthone, iso-menthone, piperitone, myrcene, beta-bourbonene, and germacrene, which may be used singly or in combination.
  • the terpene is a terpene derivable from a phytocannabinoid producing plant, such as a plant from the stain of the cannabis sativa species, such as hemp.
  • Suitable terpenes in this regard include so-called “CIO” terpenes, which are those terpenes comprising 10 carbon atoms, and so-called “C15” terpenes, which are those terpenes comprising 15 carbon atoms.
  • the active ingredient comprises more than one terpene.
  • the active ingredient may comprise one, two, three, four, five, six, seven, eight, nine, ten or more terpenes as defined herein.
  • the terpene is selected from pinene (alpha and beta), geraniol, linalool, limonene, carvone, eucalyptol, menthone, iso-menthone, piperitone, myrcene, beta-bourbonene, germacrene and mixtures thereof.
  • the active ingredient comprises one or more antioxidants.
  • antioxidant refers to a substance which prevents or suppresses oxidation by terminating free radical reactions, and may delay or prevent some types of cellular damage. Antioxidants may be naturally occurring or synthetic. Naturally occurring antioxidants include those found in foods and botanical materials. Non-limiting examples of antioxidants include certain botanical materials, vitamins, polyphenols, and phenol derivatives.
  • Examples of botanical materials which are associated with antioxidant characteristics include without limitation acai berry, alfalfa, allspice, annatto seed, apricot oil, basil, bee balm, wild bergamot, black pepper, blueberries, borage seed oil, bugleweed, cacao, calamus root, catnip, catuaba, cayenne pepper, chaga mushroom, chervil, cinnamon, dark chocolate, potato peel, grape seed, ginseng, gingko biloba, Saint John's Wort, saw palmetto, green tea, black tea, black cohosh, cayenne, chamomile, cloves, cocoa powder, cranberry, dandelion, grapefruit, honeybush, echinacea, garlic, evening primrose, feverfew, ginger, goldenseal, hawthorn, hibiscus flower, jiaogulan, kava, lavender, licorice, magoram, milk thistle, mints (menthe), oo
  • Such botanical materials may be provided in fresh or dry form, essential oils, or may be in the form of an extracts.
  • the botanical materials (as well as their extracts) often include compounds from various classes known to provide antioxidant effects, such as minerals, vitamins, isoflavones, phytoesterols, allyl sulfides, dithiolthiones, isothiocyanates, indoles, lignans, flavonoids, polyphenols, and carotenoids.
  • Examples of compounds found in botanical extracts or oils include ascorbic acid, peanut endocarb, resveratrol, sulforaphane, beta-carotene, lycopene, lutein, coenzyme Q, carnitine, quercetin, kaempferol, and the like. See, e.g., Santhosh et al., Phytomedicine, 12(2005) 216-220, which is incorporated herein by reference.
  • Non-limiting examples of other suitable antioxidants include citric acid, Vitamin E or a derivative thereof, a tocopherol, epicatechol, epigallocatechol, epigallocatechol gallate, erythorbic acid, sodium erythorbate, 4-hexylresorcinol, theaflavin, theaflavin monogallate A or B, theaflavin digallate, phenolic acids, glycosides, quercitrin, isoquercitrin, hyperoside, polyphenols, catechols, resveratrols, oleuropein, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tertiary butylhydroquinone (TBHQ), and combinations thereof.
  • a tocopherol epicatechol, epigallocatechol, epigallocatechol gallate
  • erythorbic acid sodium erythorbate
  • 4-hexylresorcinol theaf
  • an antioxidant is typically at a concentration of from about 0.001% w/w to about 10% by weight, such as, e.g., from about from about 0.001%, about 0.005%, about 0.01% w/w, about 0.05%, about 0.1%, or about 0.5%, to about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, based on the total weight of the composition.
  • the active ingredient comprises an active pharmaceutical ingredient (API).
  • API can be any known agent adapted for therapeutic, prophylactic, or diagnostic use. These can include, for example, synthetic organic compounds, proteins and peptides, polysaccharides and other sugars, lipids, phospholipids, inorganic compounds (e.g., magnesium, selenium, zinc, nitrate), neurotransmitters or precursors thereof (e.g., serotonin, 5 -hydroxy tryptophan, oxitriptan, acetylcholine, dopamine, melatonin), and nucleic acid sequences, having therapeutic, prophylactic, or diagnostic activity.
  • synthetic organic compounds proteins and peptides, polysaccharides and other sugars, lipids, phospholipids, inorganic compounds (e.g., magnesium, selenium, zinc, nitrate), neurotransmitters or precursors thereof (e.g., serotonin, 5 -hydroxy tryptophan, oxitriptan, ace
  • Non-limiting examples of APIs include analgesics and antipyretics (e.g., acetylsalicylic acid, acetaminophen, 3-(4- isobutylphenyl)propanoic acid), phosphatidylserine, myoinositol, docosahexaenoic acid (DHA, Omega-3), arachidonic acid (AA, Omega-6), S-adenosylmethionine (SAM), beta-hydroxy-beta-methylbutyrate (HMB), citicoline (cytidine-5'-diphosphate-choline), and cotinine.
  • analgesics and antipyretics e.g., acetylsalicylic acid, acetaminophen, 3-(4- isobutylphenyl)propanoic acid
  • phosphatidylserine myoinositol
  • DHA docosahexaenoic acid
  • an API is typically at a concentration of from about 0.001% w/w to about 10% by weight, such as, e.g., from about from about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1% w/w, about 0.2%, about 0.3%, about 0.4%, about 0.5% about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1%, to about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight, based on the total weight of the composition.
  • the active ingredient as described herein may be sensitive to degradation (e.g., oxidative, photolytic, thermal, evaporative) during processing or upon storage of the composition.
  • the active ingredient such as caffeine, vitamin A, and iron (Fe)
  • the active ingredient may be encapsulated, or the composition otherwise modified with suitable components (such as fillers, binders, and the like), to provide enhanced stability to the active ingredient.
  • suitable components such as fillers, binders, and the like
  • suitable components such as fillers, binders, and the like
  • binders such as functional celluloses (e.g., cellulose ethers including, but not limited to, hydroxypropyl cellulose) or alginate-based materials (e.g., cross linked alginate) may be employed to enhance stability of such actives toward degradation, or to provide extended and/or separate delivery of active ingredients.
  • encapsulated actives may need to be paired with an excipient in the composition to increase their solubility and/or bioavailability.
  • suitable excipients include beta-carotene, lycopene, Vitamin D, Vitamin E, Coenzyme Q10, Vitamin K, and curcumin.
  • an initial quantity of the active ingredient may be increased to compensate for a gradual degradative loss. Accordingly, larger initial amounts than those disclosed herein are contemplated by the present disclosure.
  • the composition as described herein comprises one or more ion channel modulators.
  • modulator means a substance which activates, potentiates, or inhibits (i.e., blocks) a particular ion channel, also referred to herein as a receptor.
  • the ion channel (i.e., receptor) modulated by the modulator is generally an ion channel which provides a sensation such as heat, cold, pain, bum, salty, sweet, sour, bitter, and umami.
  • the ion channel to be modulated is one which provides a sensation of heat, cold, pain, or bum.
  • TRP Transient receptor potential channels
  • TRPs are a family of nonselective cationic channel consisting of 28 mammalian members divided into 6 sub-families: canonical (TRPC), vanilloid (TRPV), ankyrin (TRP A), melastatin (TRPM), polycystin (TRPP) and mucolipin (TRPML) type.
  • TRPC canonical
  • TRPV vanilloid
  • TRP A ankyrin
  • TRPM melastatin
  • TRPP polycystin
  • TRPML mucolipin
  • a subset of TRP channels, essentially from M and V subfamilies as well as TRPA1 can be classified as thermo-sensitive channels, and together cover a broad range of sensitivity to temperature from noxiously cold to warm.
  • Ca 2+ ions Upon activation of TRP channels, Ca 2+ ions enter the cell through the channel and generate cell depolarization, leading to transduction of a sensory signal.
  • thermo-sensitive TRP channels are particularly sensitive to potentially irritant ingredients contained in plants and herbs and are responsible for the detection of potentially noxious environmental stimuli.
  • the subset of thermo-sensitive TRP channels is expressed, among other tissues, by sensory neurons of the trigeminal nerve in the oral cavity, where they participate in sensations related to irritation, pain, warmth, cooling, tingling, or numbing produced by certain substances, such as those found in herbs and spices.
  • Many or even all of the modulators disclosed herein may also be referred to as "sensates", which are compounds which chemically induce somatosensorial sensation through stimulation of the fifth cranial nerve (trigeminal nerve), in addition to or in place of aroma or taste nerves.
  • Sensates include agents providing warming/heating, cooling, tingling, and numbing effects by interacting with (e.g., stimulating) the trigeminal nerve.
  • the modulator is selected from any suitable compounds which provide the necessary modulating activity at the relevant receptor.
  • the modulator may bind with any suitable binding site of the receptor necessary to modulate the activity.
  • the modulator is a single compound which modulates a single receptor.
  • the modulator is a single compound which modulates two or more receptors. For example, hydroxy-o/ /zo-sanshool ((2/:'.6Z.8/i.
  • IO/'j- ⁇ -(2-hydroxy-2- methylpropyl)dodeca-2,6,8,10-tetraenamide) a molecule found in plants from the genus Zanthoxylum and believed to be responsible for the numbing and tingling sensation caused by Sichuan peppercorns, is an agonist at TRPV1 and TRPA1, but evidence suggests that KCNK3, KCNK9, and KCNK18 potassium channels are primarily responsible for sanshoofs effects. See, e.g., Bautista et al. Nat. Neurosci. 2008, 11 (7): 772-9.
  • modulation of more than one receptor type by any particular compound may occur, and such combinations are contemplated herein.
  • the modulator is selected from 3 -phenylpropionic acid; acetic acid; benzaldehyde; benzoic acid; benzyl Alcohol; 1-butanol; butyric acid; 4-isopropylbenzaldehyde; 2-methoxy- 4-vinylphenol; octanoic acid; octanal; guaiacol; lactic acid; 3,4-dihydrocoumarin; ethanol; glycerol; 1- octanol; phenylacetaldehyde; phenylacetic acid; propylene glycol; propionic acid; pyruvic acid; dimethyl sulfide; 4-methyl-5-thiazoleethanol; vanillin; menthol; camphor; eucalyptol; decanoic acid; eugenol; hexylresorcinol; lauric acid; triacetin; 2-phenylethanol; hexanal; 1-pentan
  • the modulator is selected from the group consisting of caryophyllene oxide, alpha-irone, phenethyl phenylacetate, gamma-dodecalactone, beta-caryophyllene, 2-hexenal, eucalyptol, L- menthol, 3 -phenylpropyl homovanillate, benzyl cinnamate, beta-bourbonene, cinnamyl cinnamate, citronellyl acetate, hydroxy-alpha-sanshool, liquiritin, methyl-alpha-ionone, phytol, spathulenol, and combinations thereof.
  • the modulator comprises a combination of benzyl cinnamate, caryophyllene oxide, and nootkatone. In some embodiments, the modulator comprises a combination of benzyl cinnamate, caryophyllene oxide, and alpha-irone. In some embodiments, the modulator comprises a combination of benzyl cinnamate and caryophyllene oxide.
  • the composition comprises a modulator or sensate which provides to the user of such composition a cooling effect.
  • Suitable cooling agents include, but are not limited to, menthane, menthone, menthone ketals, menthone glycerol ketals, substituted p-menthanes, acyclic carboxamides, monomenthyl glutarate, substituted cyclohexanamides, substituted cyclohexane carboxamides, substituted ureas and sulfonamides, substituted menthanols, hydroxymethyl and hydroxymethyl derivatives of p- menthane, 2-mercapto-cyclo-decanone, hydroxycarboxylic acids with 2-6 carbon atoms, cyclohexanamides, menthyl acetate, menthyl salicylate, N, 2, 3 -trimethy 1-2 -isopropyl butanamide (WS-23), N-ethyl-2,2- diisoprop
  • Pat. No. 7,189,760 to Erman, et al which is incorporated in its entirety herein by reference, isopulegol, menthyloxy propane diol, 3-(l- menthoxyjpropane- 1,2 -diol, 3 -(l-menthoxy)-2 -methylpropane- 1,2-diol, p-menthane-2,3-diol, p-menthane- 3,8-diol, 6-isopropyl-9-methyl-l,4-dioxaspiro[4,5]decane-2-methanol, menthyl succinate and its alkaline earth metal salts, trimethy Icy clohexanol, N-ethy 1-2 -isopropyl-5 -methylcyclohexanecarboxamide, Japanese mint oil, peppermint oil, 3 -(1-menthoxy jethan- l-ol, 3-(l-menthoxy)propan-l-ol
  • l)-heptane-2 -carboxamide (WS3), menthol methyl ether, menthyl pyrrolidone carboxylate, 2,5- dimethyl-4-(l-pyrrolidinyl)-3(2H)-furanone, cyclic a-keto enamines, and cyclotene derivatives such as cyclopentenes, including 3-methyl-2-(l-pyrrolidinyl)-2-cyclopenten-l-one and 5-methyl-2-(l-pyrrolidinyl)- 2-cyclopenten-l-one.
  • Other compounds include the alpha-keto enamines disclosed in U.S. Pat. No.
  • the cooling agent comprises menthol, eucalyptus, mint, menthol, menthyl esters, eucolyptol, WS-3, WS-23, WS-5, EvercoolTM 180 ((lR,2S,5R)-N-(4-(cyanomethyl)phenyl)menthylcarboxamide), EvercoolTM 190 ((lR,2S,5R)-N-(2-(pyridin- 2-yl)ethyl)menthylcarboxamide), or a combination thereof.
  • the composition comprises a modulator or sensate which provides to the user of such composition a warming effect.
  • Suitable warming agents include, but are not limited to, vanillyl alcohol n-butyl ether, vanillyl alcohol n-propylether, vanillyl alcohol isopropyl ether, vanillyl alcohol isobutyl ether, vanillyl alcohol n-aminoether, vanillyl alcohol isoamyl ether, vanillyl alcohol n-hexyle ther, vanillyl alcohol methyl ether, vanillyl alcohol ethyl ether, gingerol, shogaol, paradol, zingerone, capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, ethanol, isopropol alcohol, iso-amylalcohol, benzyl alcohol, glycerin, and combinations thereof.
  • the composition comprises a modulator or sensate which provides to the user of such composition a tingling, stinging, or numbing effect.
  • Tingling agents include, but are not limited to Jambu Oleoresin or paracress (Spilanthes sp.), in which the active ingredient is Spilanthol; Japanese pepper extract (Zanthoxylum peperitum), including the ingredients known as Saanshool-I, Saanshool-II, and Sanshoamide; perillartine; 4-(l-menthoxymethyl)-2-phenyl-l,3-dioxolane; black pepper extract (piper nigrum), including the active ingredients chavicine and piperine; Echinacea extract; Northern Prickly Ash extract; trans-pellitorin, and red pepper oleoresin.
  • alkylamides extracted from materials such as jambu or sanshool may be included.
  • "tingling" type sensates include those disclosed in U.S. Pat. Nos. 6,780,443, 6,159,509, 5,545,424, and 5,407,665, each of which is incorporated by reference herein in its entirety.
  • the composition comprises a modulator of die P2X 3 receptor.
  • the P2X 3 receptors are adenosine triphosphate (ATP)-activated ion channels expressed on peripheral sensory neurons and are recognized as playing a role in the generation of pathological pain, such as neuropathic orofacial pain.
  • P2X 3 receptors are expressed in, for example, lingual mucosa and may be at least partially responsible for burning mouth syndrome.
  • the modulator binds to a TRP receptor (e.g., TRPA1, TRPV1, TRPV3, TRPM8, or a combination thereof), a voltage-gated sodium channel receptor subtype (e.g., Navl.7), a purinergic (e.g., P2X 3 ) receptor, or a combination thereof.
  • a TRP receptor e.g., TRPA1, TRPV1, TRPV3, TRPM8, or a combination thereof
  • a voltage-gated sodium channel receptor subtype e.g., Navl.7
  • a purinergic e.g., P2X 3
  • Suitable modulators bind to the relevant receptor via several potential molecular interactions between the receptor and the modulator (e.g., van der Waals, electrostatic, hydrogen bonds, hydrophobic, and others) and physical-chemical complementarity.
  • the modulator exhibits selective binding to one receptor with respect to other receptors (e.g., the modulator exhibits a relatively greater binding energy to the
  • each of the modulators disclosed herein is capable of binding to a suitable receptor or receptors to modulate the activity thereof (i.e., to act as an agonist, antagonist or inhibitor).
  • a potential modulator interacts with a receptor, the interaction will have a given binding energy.
  • the binding energy may be determined based on the follow equation:
  • the modulator following binding to the relevant receptor, activates (agonist) or inhibits (antagonizes) the receptor.
  • the modulator inhibits the receptor by channel blockade of the receptor (a channel blocker), which acts to prevent passage of ions through the channel by binding to some portion of the pore of the ion channel, which mechanism is different and distinct from that of classical antagonists acting by preventing channel opening.
  • the modulator is an agonist, antagonist, or channel blocker of one or more ion channels (e.g., TRPA1, TRPV1, TRPV3, TRPM8, Navl.7, P2X 3 , or a combination thereof).
  • the modulator is an agonist, antagonist, or channel blocker of one or more of TRPA1, TRPV1, TRPV3, TRPM8, Navl.7, and P2X 3 . It will be appreciated by one skilled in the art that a given compound may be a modulator of one or more of TRPA1, TRPV1, TRPV3, TRPM8, NaV1.7, and P2X 3 . In some embodiments, the modulator utilized is a single compound. In some embodiments, the modulator of each of the one or more of TRPA1, TRPV1, TRPV3, TRPM8, NaV1.7, and P2X 3 is a separate compound.
  • the modulator is an agonist, antagonist, or inhibitor (i.e., a channel blocker) of one or more of TRPA1, TRPV1, TRPV3, and TRPM8.
  • the modulators may bind with any suitable binding site (e.g., orthosteric, allosteric, or within the channel pore) necessary to modulate the activity.
  • the ion channel modulated is the Transient Receptor Potential cation channel, subfamily A, member 1, also known as transient receptor potential ankyrin 1 (TRPA1), sometimes referred to as the Wasabi Receptor.
  • TRP Al is best known as a sensor for pain, cold and itch in humans and other mammals, as well as a sensor for environmental irritants giving rise to other protective responses (lacrimation, airway resistance, and cough).
  • TRPA1 modulator may bind with any suitable binding site (i.e., within the TRPA1 protein) necessary to modulate the activity. In some embodiments, the modulator binds to the TRPA1 receptor.
  • the modulator is an TRPA1 agonist, a TRPA1 antagonist, or a TRPA1 channel blocker. In some embodiments, the modulator is a TRPA1 antagonist. In some embodiments, the modulator is a TRPA1 channel blocker.
  • the modulator is a TRPA1 antagonist which binds with one or more sites selected from Arg852, Gln979, His983, Ile858, Leu982, Met978, Trp711, Val861, Val967, Ala836, Gln940, Ile837, Leu847, Leu848, Leu863, Leu867, Leu871, Met844, Phe841, Phe884, Phe947, Ser887, Tyr840, and combinations thereof.
  • the TRPA1 antagonist binds with one or more sites selected from Arg852, Gln979, His983, Ile858, Leu982, Met978, Trp711, Val861, Val967, and combinations thereof.
  • the TRPA1 agonist binds with one or more sites selected from Ala836, Gln940, Ile837, Leu847, Leu848, Leu863, Leu867, Leu871, Met844, Phe841, Phe884, Phe947, Ser887, Tyr840, and combinations thereof.
  • the TRPA1 antagonist is selected from cinnamic acid, cinnamyl ester; hexylresorcinol; 1-menthol; 2-ethyl-6-methoxyphenol, linalyl oxide, 2-methoxy-6-methylphenol, methyl 2- (methylamino)benzoate, eucalyptol, and mixtures thereof.
  • the TRPA1 antagonist is selected from cinnamyl cinnamate, liquiritin, 3 -phenylpropyl homovanillate, benzyl cinnamate, caryophyllene (beta-), phenethyl phenylacetate, hydroxy -alpha-sanshool, phytol, bourbonene (beta), and mixtures thereof.
  • the modulator is a TRPA1 inhibitor.
  • the TRPA1 inhibitor binds with one or more sites selected from Leu867, Leu870, Leu871, Ile946, Ser873 Thr873, Thr874, Phe944, Val948, Phe877, Ile878, Leu880, Leu881, Met912, Phe909, Thr908, Ile906, Ile905, Ile950, Leu956, Val942, Met953, Leu952, Phe884; and combinations thereof.
  • the TRPA1 inhibitor is selected from 3 -phenylpropyl homovanillate; benzyl alcohol, cinnamate; benzyl phenylacetate; alpha-amylcinnamaldehyde; linalyl benzoate; phenethyl isovalerate; carvacrol; thymol; 5-ethyl-2-methoxyphenol; vanitrope; and mixtures thereof.
  • the TRPA1 inhibitor is selected from cinnamyl cinnamate, citronellyl acetate, eucalyptol, 2- hexenal, dodecalactone (gamma-), menthol (1-), spathulenol, bourbonene (beta), benzyl cinnamate, caryophyllene oxide, caryophyllene (beta-), alpha-irone, phenethyl phenylacetate, methyl-alpha-ionone, phytol, and mixtures thereof.
  • the TRPA1 inhibitor is a channel blocker, such as 2- ( l.3-Dimcth l-2.6-dioxo-l.2.3.6-tctrahydro-7//-purin-7-yl)- ⁇ -
  • the ion channel is the Transient Receptor Potential melastatin 8 (TRPM8), also known as the cold and menthol receptor 1 (CMR1).
  • TRPM8 When activated, TRPM8 provides a sensation of cooling.
  • TRPM8 is activated by certain "cooling agents” such as menthol, borneol, and linalool, or when ambient temperatures drop below about 26 °C.
  • the modulator binds to the TRPM8 receptor.
  • the modulator is a TRPM8 agonist.
  • the TRPM8 agonist binds with one or more sites selected from Argl007, Arg841, Asn741, Asp781, Ile845, LeulOOO, Phe738, Tyrl004, Tyr745, Val848; and combinations thereof.
  • the TRPM8 agonist is selected from (lZ,4E,8E)-2,6,6,9- tetramethylcycloundeca-l,4,8-triene; beta-caryophyllene; liquiritin; ambrox; (E)-2-epi-beta-caryophyllene; bicyclo[7.2.0]undec-4-ene, 4,ll,ll-trimethyl-8-methylene-, (1R,4E,9S)-; (4Z)-4,ll,ll-trimethyl-8- methylidenebicyclo[7.2.0]undec-4-ene; bicyclo[7.2.0]undec-4-ene, 4,ll,ll-trimethyl-8-methylene-, (1S,4E,9R)-; isocaryophyllene; ambroxan; spatulenol; caryophyllene oxide; (-)-beta-bourbonene; oxacyclohepta
  • the ion channel is the Transient Receptor Potential cation channel, subfamily
  • TRPV1 V member 1
  • the modulator binds to the TRPV1 receptor.
  • the modulator comprises a TRPV1 agonist.
  • the TRPV1 agonist binds with one or more sites selected from Ala548, Ala568, Ala667, Asn553, Glu572, Ile571, Ile663, Leu517, Leu555, Leu664, Leu671, Met549, Phe518, Phe545, Phe593, Ser514, Thr552, Tyr513, Tyr556, and combinations thereof.
  • the TRPV1 agonist is selected from phenethyl phenylacetate; 2-propenoic acid, 3-phenyl-, 3 -pheny 1-2 -propenyl ester; theaspirane; (7R,llR)-3,7,ll,15-tetramethylhexadec-2-en-l-ol; 4-(2,5,6,6-tetramethylcyclohex-2-en-l-yl)but-3-en-2-one; cinnamyl cinnamate; alpha-irone; beta- spathulenol; spathulenol; phytol; l-penten-3-one, l-[(lR)-2,6,6-trimethyl-2-cyclohexen-l-yl]-, (IE)-; (S)- alpha-methylionone; guaiol; 3,7,1 l,15-tetramethylhexadec-2-en-l-ol;
  • the ion channel is the Transient Receptor Potential cation channel, subfamily
  • TRPV3 V member 3
  • the modulator binds to the TRPV3 receptor.
  • the modulator comprises a TRPV3 agonist.
  • the TRPV3 agonist binds with one or more sites selected from Arg693, His430, His426, His417, Leu420, Leu694, Leu429, Trp433, Thr421, and combinations thereof.
  • the TRPV3 agonist is selected from ethyl vanillin; 2,6-dimethoxyphenol; vanillin; and mixtures thereof.
  • the ion channel is the NaV1.7 sodium ion channel. Navi.7 is present at the endings of pain-sensing nerves and is usually expressed at high levels in two types of neurons: the nociceptive (pain) neurons at dorsal root ganglion (DRG) and trigeminal ganglion and sympathetic ganglion neurons, which are part of the autonomic nervous system.
  • Navi.7 has been implicated in pain signaling, and certain analgesics (e.g., the local anesthetic lidocaine) mediate their effects by electively blocking voltagegated sodium channels including Navi.7.
  • the modulator binds to the NaV1.7 channel.
  • the modulator comprises a NaV1.7 antagonist.
  • the ion channel modulator is selected from the group consisting of TRPA1 agonists, TRPA1 antagonists, TRPA1 inhibitors, TRPV1 agonists, TRPV3 agonists, TRPM8 agonists, NaV1.7 antagonists, and combinations thereof.
  • the modulator comprises at least (i) a TRPM8 agonist and a TRPV1 agonist; and (ii) a TRPA1 antagonist or a TRPA1 inhibitor. In some embodiments, the modulator comprises at least (i) a TRPM8 agonist or a TRPV1 agonist; and (ii) a TRPA1 antagonist or a TRPA1 inhibitor. In some embodiments, the modulator comprises at least (i) a TRPM8 agonist and a TRPV3 agonist; and (ii) a TRPA1 antagonist or a TRPA1 inhibitor.
  • the modulator comprises at least (i) a TRPM8 agonist or a TRPV3 agonist; and (ii) a TRPA1 antagonist or a TRPA1 inhibitor. In some embodiments, the modulator comprises (i) a TRPM1 agonist, a TRPV3 agonist and a TRPV8 agonist; and (ii) a TRPA1 antagonist or a TRPA1 inhibitor. In some embodiments, the modulator comprises at least (i) a TRPV3 agonist or a TRPV1 agonist; and (ii) a TRPA1 antagonist or a TRPA1 inhibitor.
  • the TRPA1 antagonist or a TRPA1 inhibitor has a stronger binding affinity to the TRPA1 receptor than the binding affinity of the one or more of a TRPM8 agonist, a TRPV1 agonist, and a TRPV3 agonist to their respective receptor. In some embodiments, the TRPA1 antagonist or a TRPA1 inhibitor has a stronger binding affinity to the TRPA1 receptor than the binding affinity of the TRPM8 agonist to the TRPM8 receptor. In some embodiments, the TRPA1 antagonist or a TRPA1 inhibitor has a stronger binding affinity to the TRPA1 receptor than the binding affinity of the TRPV1 agonist to the TRPV1 receptor.
  • the TRPA1 antagonist or a TRPA1 inhibitor has a stronger binding affinity to the TRPA1 receptor than the binding affinity of the TRPV3 agonist to the TRPV3 receptor. In some embodiments, the TRPA1 antagonist or a TRPA1 inhibitor has a stronger binding affinity to the TRPA1 receptor than the binding affinity of the TRPM8 agonist to the TRPM8 receptor, the TRPV1 agonist to the TRPV1 receptor and the TRPV3 agonist to the TRPV3 receptor. In some embodiments, the TRPA1 antagonist or TRPA1 inhibitor has a stronger binding affinity to the TRPA1 receptor than the binding affinity of the one or more of a TRPM8 agonist, TRPV1 agonist, and TRPV3 agonist to their respective receptor.
  • the amount of the ion channel modulator present in the composition may vary.
  • the amount of any single ion channel modulator present may vary based on the activity, potency, selectivity, and the desired effect of the modulator.
  • any single ion channel modulator may be present in the composition in an amount by weight in a range from about 0.005% to about 2%, based on the total weight of the composition. More than one modulator may be present in the composition, and each can modulate the same receptor, or may modulate different receptors.
  • the composition as described herein comprises at least one filler.
  • Fillers may fulfill multiple functions, such as enhancing certain organoleptic properties such as texture and mouthfeel, enhancing cohesiveness or compressibility of the product, and the like.
  • fillers are porous particulate materials and are cellulose-based.
  • suitable fillers are any non-tobacco plant material or derivative thereof, including cellulose materials derived from such sources.
  • cellulosic non-tobacco plant material include cereal grains (e.g., maize, oat, barley, rye, buckwheat, and the like), sugar beet (e.g., FIBREX® brand filler available from International Fiber Corporation), bran fiber, and mixtures thereof.
  • Non-limiting examples of derivatives of non-tobacco plant material include starches (e.g., from potato, wheat, rice, com), natural cellulose, and modified cellulosic materials.
  • Starch as used herein may refer to pure starch from any source, modified starch, or starch derivatives. Starch is present, typically in granular form, in almost all green plants and in various types of plant tissues and organs (e.g., seeds, leaves, rhizomes, roots, tubers, shoots, fruits, grains, and stems). Starch can vary in composition, as well as in granular shape and size. Often, starch from different sources has different chemical and physical characteristics. A specific starch can be selected for inclusion in the mixture based on the ability of the starch material to impart a specific organoleptic property to composition. Starches derived from various sources can be used.
  • starch major sources include cereal grains (e.g., rice, wheat, and maize) and root vegetables (e.g., potatoes and cassava).
  • sources of starch include acoms, arrowroot, arracacha, bananas, barley, beans (e.g., favas, lentils, mung beans, peas, chickpeas), breadfruit, buckwheat, canna, chestnuts, colacasia, katakuri, kudzu, malanga, millet, oats, oca, Polynesian arrowroot, sago, sorghum, sweet potato, quinoa, rye, tapioca, taro, tobacco, water chestnuts, and yams.
  • modified starches are modified starches.
  • a modified starch has undergone one or more structural modifications, often designed to alter its high heat properties. Some starches have been developed by genetic modifications and are considered to be "modified” starches. Other starches are obtained and subsequently modified.
  • modified starches can be starches that have been subjected to chemical reactions, such as esterification, etherification, oxidation, depolymerization (thinning) by acid catalysis or oxidation in the presence of base, bleaching, transglycosylation and depolymerization (e.g., dextrinization in the presence of a catalyst), cross-linking, enzyme treatment, acetylation, hydroxypropylation, and/or partial hydrolysis.
  • modified starches are modified by heat treatments, such as pregelatinization, dextrinization, and/or cold-water swelling processes.
  • Certain modified starches include monostarch phosphate, distarch glycerol, distarch phosphate esterified with sodium trimetaphosphate, phosphate distarch phosphate, acetylated distarch phosphate, starch acetate esterified with acetic anhydride, starch acetate esterified with vinyl acetate, acetylated distarch adipate, acetylated distarch glycerol, hydroxypropyl starch, hydroxypropyl distarch glycerol, starch sodium octenyl succinate.
  • fillers include maltodextrin, dextrose, calcium carbonate, calcium phosphate, lactose, and sugar alcohols. Combinations of fillers can also be used.
  • the filler comprises or is a mixture of glucose and starch-derived polysaccharides.
  • One such suitable mixture of glucose and starch-derived polysaccharides is EMDEX®, available from JRS PHARMA LP, USA, 2981 Route 22, Patterson, NY 12563-2359.
  • the particulate filler is a cellulose material or cellulose derivative.
  • One particularly suitable particulate filler for use in the compositions described herein is microcrystalline cellulose ("mcc").
  • the mcc may be synthetic or semi-synthetic, or it may be obtained entirely from natural celluloses.
  • the mcc may be selected from the group consisting of AVICEL® grades PH-100, PH-102, PH- 103, PH-105, PH-112, PH-113, PH-200, PH-300, PH-302, VIVACEL® grades 101, 102, 12, 20 and EMOCEL® grades 50M and 90M, and the like, and mixtures thereof.
  • the composition comprises mcc as the particulate fdler.
  • the quantity of mcc present may vary according to the desired properties.
  • the amount of filler can vary but is typically up to about 75 percent of the composition by weight, based on the total weight of the composition.
  • a typical range of filler (e.g., mcc) within the composition can be from about 10 to about 75 percent by total weight of the composition, for example, from about 10, about 15, about 20, about 25, or about 30, to about 35, about 40, about 45, or about 50 weight percent (e.g., about 20 to about 50 weight percent or about 25 to about 45 weight percent).
  • the amount of filler is at least about 10 percent by weight, such as at least about 20 percent, or at least about 25 percent, or at least about 30 percent, or at least about 35 percent, or at least about 40 percent, based on the total weight of the composition.
  • the filler further comprises a cellulose derivative or a combination of such derivatives.
  • the composition comprises from about 1 to about 10% of the cellulose derivative by weight, based on the total weight of the composition, with certain embodiments comprising about 1 to about 5% by weight of cellulose derivative.
  • the cellulose derivative is a cellulose ether (including carboxyalkyl ethers), meaning a cellulose polymer with the hydrogen of one or more hydroxyl groups in the cellulose structure replaced with an alkyl, hydroxyalkyl, or aryl group.
  • Nonlimiting examples of such cellulose derivatives include methyl cellulose, hydroxypropyl cellulose ("HPC”), hydroxypropylmethyl cellulose (“HPMC”), hydroxy ethyl cellulose, and carboxymethyl cellulose (“CMC”).
  • the cellulose derivative is one or more of methyl cellulose, HPC, HPMC, hydroxyethyl cellulose, and CMC.
  • the cellulose derivative is HPC.
  • the composition comprises from about 1 to about 3% HPC by weight, based on the total weight of the composition.
  • the composition is less than about 60 percent by weight of water, and generally is from about 1 to about 60% by weight of water, for example, from about 5 to about 55, about 10 to about 50, about 20 to about 45, or about 25 to about 40 percent water by weight, including water amounts of at least about 5% by weight, at least about 10% by weight, at least about 15% by weight, and at least about 20% by weight.
  • the composition is less than about 10 percent by weight of water, such as about 9 weight percent or less, about 7 weight percent or less, about 5 weight percent or less, about 4 weight percent or less, about 3 weight percent or less, or about 2 weight percent or less.
  • the water content of the composition is in a range from about 0.1 weight percent to about 10 weight percent, based on the total weight of the composition.
  • the composition as disclosed herein comprises one or more organic acids.
  • organic acid refers to an organic (i.e., carbon-based) compound that is characterized by acidic properties.
  • organic acids are relatively weak acids (i.e., they do not dissociate completely in the presence of water), such as carboxylic acids (-CO2H) or sulfonic acids (-SO2OH).
  • reference to organic acid means an organic acid that is intentionally added.
  • an organic acid may be intentionally added as a specific composition ingredient as opposed to merely being inherently present as a component of another composition ingredient (e.g., the small amount of organic acid which may inherently be present in a composition ingredient, such as a tobacco material).
  • Suitable organic acids will typically have a range of lipophilicities (i.e., a polarity giving an appropriate balance of water and organic solubility).
  • lipophilicities of suitable organic acids as indicated by logP, will vary between about 1 and about 12 (more soluble in octanol than in water).
  • the organic acid has a logP value from about 1 to about 12, e.g., from about 1.0.
  • moderately lipophilic organic acids e.g., logP of from about 1.4 to about 4.5
  • produce ion pairs with nicotine which are of a polarity providing good octanol-water partitioning of the ion pair, and hence partitioning of nicotine, into octanol versus water.
  • partitioning into octanol is predictive of favorable oral availability.
  • the organic acid has a logP value from about 3.0 to about 8.0, about 10.0, or even 12.0.
  • the presence of certain solvents or solubilizing agents e.g., inclusion in the composition of glycerin or propylene glycol may be beneficial in solubilizing organic acids and the corresponding salts or ion pairs thereof with the basic amine for highly lipophilic organic acids (e.g., higher than about 4.5).
  • the organic acid is a carboxylic acid or a sulfonic acid.
  • the carboxylic acid or sulfonic acid functional group may be attached to any alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group having, for example, from one to twenty carbon atoms (C1-C20).
  • the organic acid is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl carboxylic or sulfonic acid.
  • alkyl refers to any straight chain or branched chain hydrocarbon.
  • the alkyl group may be saturated (i.e., having all sp 3 carbon atoms), or may be unsaturated (i.e., having at least one site of unsaturation).
  • unsaturated refers to the presence of a carbon-carbon, sp 2 double bond in one or more positions within the alkyl group.
  • Unsaturated alkyl groups may be mono- or polyunsaturated.
  • Representative straight chain alkyl groups include, but are not limited to, methyl, ethyl, n- propyl, n-butyl, n-pentyl, and n-hexyl.
  • Branched chain alkyl groups include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and 2-methylbutyl.
  • Representative unsaturated alkyl groups include, but are not limited to, ethylene or vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1 -pentenyl, 2-pentenyl, 3 -methyl- 1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like.
  • An alkyl group can be unsubstituted or substituted.
  • Cycloalkyl refers to a carbocyclic group, which may be mono- or bicyclic. Cycloalkyl groups include rings having 3 to 7 carbon atoms as a monocycle or 7 to 12 carbon atoms as a bicycle. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A cycloalkyl group can be unsubstituted or substituted, and may include one or more sites of unsaturation (e.g., cyclopentenyl or cyclohexenyl).
  • aryl refers to a carbocyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. An aryl group can be unsubstituted or substituted.
  • Heteroaryl and “heterocycloalkyl” as used herein refer to an aromatic or non-aromatic ring system, respectively, in which one or more ring atoms is a heteroatom, e.g. nitrogen, oxygen, and sulfur.
  • the heteroaryl or heterocycloalkyl group comprises up to 20 carbon atoms and from 1 to 3 heteroatoms selected from N, O, and S.
  • a heteroaryl or heterocycloalkyl may be a monocycle having 3 to 7 ring members (for example, 2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, and S) or a bicycle having 7 to 10 ring members (for example, 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, and S), for example: a bicyclo[4,5], [5,5], [5,6], or [6,6] system.
  • heteroaryl groups include by way of example and not limitation, pyridyl, thiazolyl, tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H- indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-car
  • heterocycloalkyls include by way of example and not limitation, dihydroypyridyl, tetrahydropyridyl (piperidyl), tetrahydrothiophenyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, tetrahydrofnranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, piperazinyl, quinuclidinyl, and morpholinyl. Heteroaryl and heterocycloalkyl groups can be unsubstituted or substituted.
  • Substituted as used herein and as applied to any of the above alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, means that one or more hydrogen atoms are each independently replaced with a substituent.
  • a group is described as “optionally substituted,” that group can be substituted with one or more of the above substituents, independently selected for each occasion.
  • the substituent may be one or more methyl groups or one or more hydroxyl groups.
  • the organic acid is an alkyl carboxylic acid.
  • alkyl carboxylic acids include formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and the like.
  • the organic acid is an alkyl sulfonic acid.
  • alkyl sulfonic acids include propanesulfonic acid, heptanesulfonic acid, and octanesulfonic acid.
  • the alkyl carboxylic or sulfonic acid is substituted with one or more hydroxyl groups.
  • Non-limiting examples include glycolic acid, 4-hydroxybutyric acid, and lactic acid.
  • an organic acid may include more than one carboxylic acid group or more than one sulfonic acid group (e.g., two, three, or more carboxylic acid groups).
  • Non-limiting examples include oxalic acid, fumaric acid, maleic acid, and glutaric acid.
  • organic acids containing multiple carboxylic acids e.g., from two to four carboxylic acid groups
  • one or more of the carboxylic acid groups may be esterified.
  • Non-limiting examples include succinic acid monoethyl ester, monomethyl fumarate, mo no methyl or dimethyl citrate, and the like.
  • the organic acid may include more than one carboxylic acid group and one or more hydroxyl groups.
  • Non-limiting examples of such acids include tartaric acid, citric acid, and the like.
  • the organic acid is an aryl carboxylic acid or an aryl sulfonic acid.
  • aryl carboxylic and sulfonic acids include benzoic acid, toluic acids, salicylic acid, benzenesulfonic acid, and -tolucncsulfonic acid.
  • organic acids which may be useful in certain embodiments include 2-(4-isobutylphenyl)propanoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, adipic acid, ascorbic acid (L), aspartic acid (L), alphamethylbutyric acid, camphoric acid (+), camphor-10-sulfonic acid (+), cinnamic acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, furoic acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, isovaleric acid, lactobi
  • organic acid may further depend on additional properties in addition to consideration of the logP value. For example, an organic acid should be one recognized as safe for human consumption, and which has acceptable flavor, odor, volatility, stability, and the like. Determination of appropriate organic acids is within the purview of one of skill in the art.
  • the organic acid is a mono ester of a dicarboxylic acid or a poly -carboxylic acid.
  • the dicarboxylic acid is malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, maleic acid, or a combination thereof.
  • the dicarboxylic acid is succinic acid, glutaric acid, fumaric acid, maleic acid, or a combination thereof.
  • the dicarboxylic acid is succinic acid, glutaric acid, or a combination thereof.
  • the alcohol forming the mono ester of the dicarboxylic acid is a lipophilic alcohol.
  • suitable lipophilic alcohols include, but are not limited to, octanol, menthol, and tocopherol.
  • the organic acid is an octyl mono ester of a dicarboxylic acid, such as monooctyl succinate, monooctyl fumarate, or the like.
  • the organic acid is a monomenthyl ester of a dicarboxylic acid.
  • Certain menthyl esters may be desirable in oral compositions as described herein by virtue of the cooling sensation they may provide upon use of the product comprising the composition.
  • the organic acid is monomenthyl succinate, monomenthyl fumarate, monomenthyl glutarate, or a combination thereof.
  • the organic acid is a monotocopheryl ester of a dicarboxylic acid. Certain tocopheryl esters may be desirable in oral compositions as described herein by virtue of the antioxidant effects they may provide.
  • the organic acid is tocopheryl succinate, tocopheryl fumarate, tocopheryl glutarate, or a combination thereof.
  • the organic acid is a carotenoid derivative having one or more carboxylic acids.
  • Carotenoids are tetraterpenes, meaning that they are produced from 8 isoprene molecules and contain 40 carbon atoms. Accordingly, they are usually lipophilic due to the presence of long unsaturated aliphatic chains, and are generally yellow, orange, or red in color.
  • Certain carotenoid derivatives can be advantageous in oral compositions by virtue of providing both ion pairing and serving as a colorant in the composition.
  • the organic acid is 2E,4E,6E,8E,10E,12E,14E,16Z,18£)-20-methoxy- 4,8,13,17-tetramethyl-20-oxoicosa-2,4,6,8,10,12,14,16,18-nonaenoic acid (bixin) or an isomer thereof.
  • Bixin is an apocarotenoid found in annatto seeds from the achiote tree (Bixa orellana) and is the naturally occurring pigment providing the reddish orange color to annatto.
  • Bixin is soluble in fats and alcohols but insoluble in water, and is chemically unstable when isolated, converting via isomerization into the double bond isomer, trans-bixin ( -bixin), having the structure:
  • the organic acid is (2E,4E,6E,8E,10E,12E,14E,16E,18E)-4,8,13,17-tetramethylicosa- 2,4,6,8,10, 12, 14, 16, 18-nonaenedioic acid (norbixin), a water-soluble hydrolysis product of bixin having the structure:
  • more than one organic acid may be present.
  • the composition may comprise two, or three, or four, or more organic acids.
  • an organic acid contemplates mixtures of two or more organic acids.
  • the relative amounts of the multiple organic acids may vary.
  • a composition may comprise equal amounts of two, or three, or more organic acids, or may comprise different relative amounts.
  • certain organic acids e.g., citric acid or myristic acid
  • it is possible to include certain organic acids e.g., citric acid or myristic acid which have a logP value outside the desired range, when combined with other organic acids to provide the desired average logP range for the combination.
  • organic acids in the composition which have logP values outside the desired range for purposes such as, but not limited to, providing desirable organoleptic properties, stability, as flavor components, and the like.
  • certain lipophilic organic acids have undesirable flavor and or aroma characteristics which would preclude their presence as the sole organic acid (e.g., in equimolar or greater quantities relative to nicotine).
  • a combination of different organic acids may provide the desired ion pairing while the concentration of any single organic acid in the composition remains below the threshold which would be found objectionable from a sensory perspective.
  • the composition comprises an organic acid which is a monoester of a dicarboxylic acid or is a carotenoid derivative having one or more carboxylic acids as described herein above, and further comprises an additional organic acid or salt thereof.
  • the additional organic acid is benzoic acid, an alkali metal salt thereof, or a combination thereof.
  • the composition comprises an alkali metal salt of an organic acid.
  • the organic acid may be present in the composition in the form of an alkali metal salt.
  • Suitable alkali metal salts include lithium, sodium, and potassium.
  • the alkali metal is sodium or potassium.
  • the alkali metal is sodium.
  • the composition comprises an organic acid and a sodium salt of the organic acid.
  • the weight ratio of the organic acid to the sodium salt (or other alkali metal) of the organic acid is from about 0.1 to about 10, such as from about 0.1, about 0.25, about 0.3, about 0.5, about 0.75, or about 1, to about 2, about 5, or about 10.
  • both an organic acid and the sodium salt thereof are added to the other components of the composition, wherein the organic acid is added in excess of the sodium salt, in equimolar quantities with the sodium salt, or as a fraction of the sodium salt.
  • the relative amounts will be determined by the desired pH of the composition, as well as the desired ionic strength.
  • the organic acid may be added in a quantity to provide a desired pH level of the composition, while the alkali metal (e.g., sodium) salt is added in a quantity to provide the desired extent of ion pairing.
  • the quantity of organic acid (i.e., the protonated form) present in the composition, relative to the alkali metal salt or conjugate base form present in the composition will vary according to the pH of the composition and the pKa of the organic acid, as well as according to the actual relative quantities initially added to the composition.
  • the amount of organic acid or alkali metal salt thereof present in the composition, relative to the basic amine (e.g., nicotine), may vary. Generally, as the concentration of the organic acid (or the conjugate base thereof) increases, the percent of basic amine (e.g., nicotine) that is ion paired with the organic acid increases. This typically increases the partitioning of the basic amine (e.g., nicotine), in the form of an ion pair, into octanol versus water as measured by the logP (the logw of the partitioning coefficient).
  • the composition comprises from about 0.05, about 0.1, about 1, about 1.5, about 2, or about 5, to about 10, about 15, or about 20 molar equivalents of the organic acid, the alkali metal salt thereof, or the combination thereof, relative to the basic amine (e.g., nicotine), calculated as the free base of the basic amine.
  • the basic amine e.g., nicotine
  • the composition comprises from about 2 to about 10, or from about 2 to about 5 molar equivalents of the organic acid, the alkali metal salt thereof, or the combination thereof, relative to the basic amine (e.g., nicotine), on a free-base basis.
  • the organic acid, the alkali metal salt thereof, or the combination thereof is present in a molar ratio with basic amine (e.g., nicotine) from about 2, about 3, about 4, or about 5, to about 6, about 7, about 8, about 9, or about 10.
  • basic amine e.g., nicotine
  • the organic acid inclusion is sufficient to provide a composition pH of from about 4.0 to about 9.0, such as from about 4.5 to about 7.0, or from about 5.5 to about 7.0, from about 4.0 to about 5.5, or from about 7.0 to about 9.0. In some embodiments, the organic acid inclusion is sufficient to provide a composition pH of from about 4.5 to about 6.5, for example, from about 4.5, about 5.0, or about 5.5, to about 6.0, or about 6.5.
  • the organic acid is provided in a quantity sufficient to provide a pH of the composition of from about 5.5 to about 6.5, for example, from about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, or about 6.0, to about 6.1, about 6.2, about 6.3, about 6.4, or about 6.5.
  • a mineral acid e.g., hydrochloric acid, sulfuric acid, phosphoric acid, or the like
  • the organic acid is added as the free acid, either neat (i.e., native solid or liquid form) or as a solution in, e.g., water, to the other composition components.
  • the alkali metal salt of the organic acid is added, either neat or as a solution in, e.g., water, to the other composition components.
  • the organic acid and the basic amine e.g., nicotine
  • the organic acid and the basic amine are combined to form a salt, either before addition to the composition, or the salt is formed within and is present in the composition as such.
  • the organic acid and basic amine e.g., nicotine
  • the organic acid and basic amine are present as individual components in the composition and form an ion pair upon contact with moisture (e.g., saliva in the mouth of the consumer).
  • the organic acid is added as the free acid, either neat (i.e., native solid or liquid form) or as a solution in, e.g., water, to the other composition components.
  • the alkali metal salt of the organic acid is added, either neat or as a solution in, e.g., water, to the other composition components.
  • the organic acid and a basic amine-containing active ingredient e.g., nicotine are combined to form a salt, either before addition to the composition, or the salt is formed within and is present in the composition as such.
  • the active ingredient comprising a basic amine functionality e.g., nicotine
  • the active ingredient comprising a basic amine functionality present in the composition can exist in multiple forms, including ion paired, in solution (i.e., fully solvated), as the free base, as a cation, as a salt, or any combination thereof.
  • the association between the active ingredient comprising a basic amine functionality and at least a portion of the organic acid or the alkali metal salt thereof is in the form of an ion pair between the active ingredient comprising a basic amine functionality and a conjugate base of the organic acid.
  • the organic acid and basic amine-containing active ingredient e.g., nicotine
  • the oral composition comprises nicotine benzoate and sodium benzoate, wherein at least a portion of the nicotine and benzoate ions present are in an ion paired form.
  • Ion pairing describes the partial association of oppositely charged ions in relatively concentrated solutions to form distinct chemical species called ion pairs.
  • the strength of the association depends on the electrostatic force of attraction between the positive and negative ions (i.e., a protonated basic amine such as nicotine, and the conjugate base of the organic acid).
  • conjugate base is meant the base resulting from deprotonation of the corresponding acid (e.g., benzoate is the conjugate base of benzoic acid).
  • benzoate is the conjugate base of benzoic acid
  • the active ingredient comprising a basic amine functionality for example nicotine
  • the conjugate base of the organic acid exist at least partially in the form of an ion pair.
  • ion pairing may minimize chemical degradation of the active ingredient comprising a basic amine functionality and/or enhance the oral availability of the active ingredient comprising a basic amine functionality (e.g., nicotine).
  • alkaline pH values e.g., such as from about 7.5 to about 9
  • certain basic amine-containing active ingredients for example nicotine
  • acidic pH values such as from about 6.5 to about 4
  • certain active ingredients for example nicotine
  • acidic pH values such as from about 6.5 to about 4
  • the extent of ion pairing in the disclosed composition may vary based on, for example, pH, the nature of the organic acid, the concentration of active ingredient comprising a basic amine functionality, the concentration of the organic acid or conjugate base of the organic acid present in the composition, the moisture content of the composition, the ionic strength of the composition, and the like.
  • ion pairing is an equilibrium process influenced by the foregoing variables. Accordingly, quantification of the extent of ion pairing is difficult or impossible by calculation or direct observation.
  • ion pairing may be demonstrated through surrogate measures, such as partitioning of the active ingredient comprising a basic amine functionality between octanol and water, or by performing membrane permeation studies of aqueous solutions of the active ingredient comprising a basic amine functionality plus organic acids and/or their conjugate bases.
  • surrogate measures such as partitioning of the active ingredient comprising a basic amine functionality between octanol and water, or by performing membrane permeation studies of aqueous solutions of the active ingredient comprising a basic amine functionality plus organic acids and/or their conjugate bases.
  • the active ingredient comprising a basic amine functionality may be nicotine or a nicotine component.
  • other active ingredients comprising a basic amine functionality are contemplated herein.
  • active ingredients as described herein below are comprised of molecules which may be categorized as basic amines. Accordingly, the ion pairing of such basic amine-containing active ingredients with an organic acid as described herein is contemplated.
  • the composition as described herein comprises a flavoring agent.
  • a flavoring agent or “flavorant” is any flavorful or aromatic substance capable of altering the sensory characteristics associated with the oral product. Examples of sensory characteristics that can be modified by the flavoring agent include taste, mouthfeel, moistness, and/or fragrance/aroma. For avoidance of doubt, such flavoring agents are different and distinct from the modulators (e.g., sensates) disclosed herein. Flavoring agents may be natural or synthetic, and the character of the flavors imparted thereby may be described, without limitation, as fresh, sweet, herbal, confectionary, floral, fruity, or spicy.
  • Flavoring agents may be imitation, synthetic or natural ingredients or blends thereof. Flavoring agents may include naturally occurring flavor materials, botanicals, extracts of botanicals, synthetically obtained materials, or combinations thereof (e.g., tobacco, cannabis, licorice (liquorice), hydrangea, Japanese white bark magnolia leaf, chamomile, fenugreek, maple, matcha, Japanese mint, aniseed (anise), turmeric, Indian spices, Asian spices, herb, Wintergreen, cherry, berry, red berry, cranberry, peach, apple, orange, mango, clementine, lemon, lime, tropical fruit, papaya, rhubarb, grape, durian, dragon fruit, cucumber, blueberry, mulberry, citrus fruits, Drambuie, bourbon, scotch, whiskey, gin, tequila, rum, spearmint, peppermint, lavender, aloe vera, cardamom, celery, cascarilla, nutmeg, sandalwood,
  • Flavoring agents may be in any suitable form, for example, liquid such as an oil, solid such as a powder, or gas.
  • the flavoring agent may be provided in a spray-dried form or a liquid form.
  • a liquid flavorant is disposed (i.e., adsorbed or absorbed in or on) a porous particulate carrier, for example microcrystalline cellulose, which is then combined with the other composition ingredients.
  • the amount of flavoring agent utilized in the composition can vary, but is typically up to about 10% by weight, and certain embodiments are characterized by a flavoring agent content of at least about 0.1% by weight, such as about 0.5 to about 10%, about 1 to about 5%, or about 2 to about 4% weight, based on the total weight of the composition.
  • the composition may include one or more taste modifying agents ("taste modifiers") which may serve to mask, alter, block, or improve e.g., the flavor of a composition as described herein.
  • taste modifiers modifies one or more of bitter, sweet, salty, or sour tastes.
  • the composition comprises an active ingredient having a bitter taste, and a taste modifier which masks or blocks the perception of the bitter taste.
  • Suitable taste modifiers include, but are not limited to, gamma-amino butyric acid (GABA), adenosine monophosphate (AMP), lactisole, or a combination thereof.
  • a representative amount of taste modifier is about 0.01% by weight or more, about 0.1% by weight or more, or about 1.0% by weight or more, but will typically make up less than about 10% by weight of the total weight of the composition, (e.g., from about 0.01%, about 0.05%, about 0.1%, or about 0.5%, to about 1%, about 5%, or about 10% by weight of the total weight of the composition).
  • the composition may further comprise a salt (e.g., alkali metal salts), typically employed in an amount sufficient to provide desired sensory attributes to the composition.
  • a salt e.g., alkali metal salts
  • suitable salts include sodium chloride, potassium chloride, ammonium chloride, flour salt, and the like.
  • a representative amount of salt is about 0.5 percent by weight or more, about 1.0 percent by weight or more, or at about 1.5 percent by weight or more, but will typically make up about 10 percent or less of the total weight of the composition, or about 7.5 percent or less or about 5 percent or less (e.g., about 0.5 to about 5 percent by weight).
  • sweeteners may be added.
  • the sweeteners can be any sweetener or combination of sweeteners, in natural or artificial form, or as a combination of natural and artificial sweeteners.
  • natural sweeteners include fructose, sucrose, glucose, maltose, mannose, galactose, lactose, stevia, honey, and the like.
  • artificial sweeteners include sucralose, isomaltulose, maltodextrin, saccharin, aspartame, acesulfame K, neotame, and the like.
  • the sweetener comprises one or more sugar alcohols.
  • Sugar alcohols are polyols derived from monosaccharides or disaccharides that have a partially or fully hydrogenated form.
  • Sugar alcohols have, for example, about 4 to about 20 carbon atoms and include erythritol, arabitol, ribitol, isomalt, maltitol, dulcitol, iditol, mannitol, xylitol, lactitol, sorbitol, and combinations thereof (e.g., hydrogenated starch hydrolysates).
  • the sweetener is sucralose, acesulfame K, or a combination thereof.
  • a sweetener or combination of sweeteners may make up from about 0.01 to about 20% or more of the of the composition by weight, for example, from about 0.01 to about 0.1, from about 0.1 to about 1%, from about 1 to about 5%, from about 5 to about 10%, or from about 10 to about 20% by weight, based on the total weight of the composition.
  • a combination of sweeteners is present at a concentration of from about 0.01% to about 0.1% by weight of the composition, such as about 0.01, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, or about 0.1% by weight of the composition.
  • a combination of sweeteners is present at a concentration of from about 0.1% to about 0.5% by weight of the composition, such as about 0.1, about 0.2, about 0.3, about 0.4, or about 0.5% by weight of the composition. In some embodiments, a combination of sweeteners is present at a concentration of from about 1% to about 3% by weight of the composition.
  • the composition may comprise a binder or combination of binders to provide the desired physical attributes and physical integrity to the composition, such as a thickening or gelling agent.
  • Typical binders can be organic or inorganic, or a combination thereof.
  • Representative binders include povidone, sodium alginate, starch-based binders, pectin, carrageenan, pullulan, zein, and the like, and combinations thereof.
  • a binder may be employed in amounts sufficient to provide the desired physical attributes and physical integrity to the composition.
  • the amount of binder utilized in the composition can vary, but is typically up to about 30 weight percent, and certain embodiments are characterized by a binder content of at least about 0.1% by weight, such as about 1 to about 30% by weight, or about 5 to about 10% by weight, based on the total weight of the composition.
  • binders include a gum, for example, a natural gum.
  • a natural gum refers to polysaccharide materials of natural origin that have binding properties, and which are also useful as a thickening or gelling agents.
  • Representative natural gums derived from plants, which are typically water soluble to some degree, include xanthan gum, guar gum, gum arabic, ghatti gum, gum tragacanth, karaya gum, locust bean gum, gellan gum, and combinations thereof.
  • natural gum binder materials are typically present in an amount of up to about 5% by weight, for example, from 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, or about 1%, to about 2, about 3, about 4, or about 5% by weight, based on the total weight of the composition.
  • one or more humectants may be employed in the composition.
  • humectants include, but are not limited to, polyols such as glycerin, propylene glycol, and the like.
  • the humectant is typically provided in an amount sufficient to provide desired moisture attributes to the composition. Further, in some instances, the humectant may impart desirable flow characteristics to the composition for depositing in a mold.
  • a humectant When present, a humectant will typically make up about 5% or less of the weight of the composition (e.g., from about 0.5 to about 5% by weight). When present, a representative amount of humectant is about 0.1% to about 1% by weight, or about 1% to about 5% by weight, based on the total weight of the composition.
  • the composition of the present disclosure can comprise pH adjusters or buffering agents.
  • pH adjusters and buffering agents that can be used include, but are not limited to, metal hydroxides (e.g., alkali metal hydroxides such as sodium hydroxide and potassium hydroxide), and other alkali metal buffers such as metal carbonates (e.g., potassium carbonate or sodium carbonate), or metal bicarbonates such as sodium bicarbonate, and the like.
  • suitable buffers include alkali metals acetates, glycinates, phosphates, glycerophosphates, citrates, carbonates, hydrogen carbonates, borates, or mixtures thereof.
  • the buffering agent is typically present in an amount less than about 5 percent based on the weight of the composition, for example, from about 0.5% to about 5%, such as, e.g., from about 0.75% to about 4%, from about 0.75% to about 3%, or from about 1% to about 2% by weight, based on the total weight of the composition.
  • a colorant may be employed in amounts sufficient to provide the desired physical attributes to the composition.
  • Natural or synthetic colorants such as natural or synthetic dyes, food-grade colorants and pharmaceutical-grade colorants may be used. Examples of colorants include various dyes and pigments, such as caramel coloring and titanium dioxide. Natural colorants such as curcumin, beet juice extract, spirulina; also a variety of synthetic pigments may also be used.
  • the amount of colorant utilized in the composition can vary, but when present is typically up to about 3% by weight, such as from about 0.1%, about 0.5%, or about 1%, to about 3% by weight, based on the total weight of the composition.
  • Oral care additives such as from about 0.1%, about 0.5%, or about 1%, to about 3% by weight, based on the total weight of the composition.
  • the composition comprises an oral care ingredient (or mixture of such ingredients).
  • Oral care ingredients provide the ability to inhibit tooth decay or loss, inhibit gum disease, relieve mouth pain, whiten teeth, or otherwise inhibit tooth staining, elicit salivary stimulation, inhibit breath malodor, freshen breath, or the like.
  • effective amounts of ingredients such as thyme oil, eucalyptus oil and zinc (e.g., such as the ingredients of formulations commercially available as ZYTEX® from Discus Dental) can be incorporated into the composition.
  • ingredients that can be incorporated in desired effective amounts within the present composition can include those that are incorporated within the types of oral care compositions set forth in Takahashi et al., Oral Microbiology and Immunology, 19(1), 61-64 (2004); U.S. Pat. No. 6,083,527 to Thistle; and US Pat. Appl. Pub. Nos. 2006/0210488 to Jakubowski and 2006/02228308 to Cummins et al.
  • Other exemplary ingredients of tobacco containing-formulation include those contained in formulations marketed as MALTISORB® by Roquette and DENTIZYME® by NatraRx.
  • a representative amount of oral care additive is at least about 1%, often at least about 3%, and frequently at least about 5% of the total dry weight of the effervescent composition.
  • the amount of oral care additive within the effervescent composition will not typically exceed about 30%, often will not exceed about 25%, and frequently will not exceed about 20%, of the total dry weight of the effervescent composition.
  • a flow aid can also be added to the composition in order to enhance flowability of the composition.
  • the composition e.g., melt and chew forms
  • Exemplary flow aids include microcrystalline cellulose, silica, polyethylene glycol, stearic acid, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, carnauba wax, and combinations thereof.
  • the flow aid is sodium stearyl fumarate.
  • a representative amount of flow aid may make up at least about 0.5 percent or at least about 1 percent, of the total dry weight of the composition.
  • the amount of flow aid within the composition will not exceed about 5 percent, and frequently will not exceed about 3 percent, of the total dry weight of the composition.
  • additives can be included in the disclosed composition.
  • the composition can be processed, blended, formulated, combined and/or mixed with other materials or ingredients.
  • the additives can be artificial or can be obtained or derived from herbal or biological sources.
  • further types of additives include thickening or gelling agents (e.g., fish gelatin), emulsifiers, preservatives (e.g., potassium sorbate and the like), disintegration aids, or combinations thereof. See, for example, those representative components, combination of components, relative amounts of those components, and manners and methods for employing those components, set forth in US Pat. No. 9,237,769 to Mua et al., US Pat. No. 7,861,728 to Holton, Jr.
  • Typical inclusion ranges for such additional additives can vary depending on the nature and function of the additive and the intended effect on the final composition, with an example range of up to about 10% by weight, based on total weight of the composition (e.g., about 0.1 to about 5% by weight).
  • additives can be employed together (e.g., as additive formulations) or separately (e.g., individual additive components can be added at different stages involved in the preparation of the final mixture).
  • aforementioned types of additives may be encapsulated as provided in the final product or composition.
  • Example encapsulated additives are described, for example, in WO2010/132444 to Atchley, which has been previously incorporated by reference herein.
  • any one or more of the filler, tobacco material, other composition components, and the overall composition described herein can be described as a particulate material.
  • the term "particulate” refers to a material in the form of a plurality of individual particles, some of which can be in the form of an agglomerate of multiple particles, wherein the particles have an average length to width ratio less than 2:1, such as less than 1.5:1, such as about 1:1.
  • the particles of a particulate material can be described as substantially spherical or granular.
  • the particle size of a particulate material may be measured by sieve analysis.
  • sieve analysis is a method used to measure the particle size distribution of a particulate material.
  • sieve analysis involves a nested column of sieves which comprise screens, preferably in the form of wire mesh cloths. A pre-weighed sample may be introduced into the top or uppermost sieve in the column, which has the largest screen openings or mesh size (i.e. the largest pore diameter of the sieve). Each lower sieve in the column has progressively smaller screen openings or mesh sizes than the sieve above.
  • a receiver portion to collect any particles having a particle size smaller than the screen opening size or mesh size of the bottom or lowermost sieve in the column (which has the smallest screen opening or mesh size).
  • the column of sieves may be placed on or in a mechanical agitator.
  • the agitator causes the vibration of each of the sieves in the column.
  • the mechanical agitator may be activated for a pre-determined period of time in order to ensure that all particles are collected in the correct sieve.
  • the column of sieves is agitated for a period of time from 0.5 minutes to 10 minutes, such as from 1 minute to 10 minutes, such as from 1 minute to 5 minutes, such as for approximately 3 minutes.
  • the screen opening sizes or mesh sizes for each sieve in the column used for sieve analysis may be selected based on the granularity or known maximum/minimum particle sizes of the sample to be analysed.
  • a column of sieves may be used for sieve analysis, wherein the column comprises from 2 to 20 sieves, such as from 5 to 15 sieves.
  • a column of sieves may be used for sieve analysis, wherein the column comprises 10 sieves.
  • the largest screen opening or mesh sizes of the sieves used for sieve analysis may be 1000 pm, such as 500 pm, such as 400 pm, such as 300 pm.
  • any particulate material referenced herein can be characterized as having at least 50% by weight of particles with a particle size as measured by sieve analysis of no greater than about 1000 pm, such as no greater than about 500 pm, such as no greater than about 400 pm, such as no greater than about 350 pm, such as no greater than about 300 pm.
  • at least 60% by weight of the particles of any particulate material referenced herein have a particle size as measured by sieve analysis of no greater than about 1000 pm, such as no greater than about 500 pm, such as no greater than about 400 pm, such as no greater than about 350 pm, such as no greater than about 300 pm.
  • At least 70% by weight of the particles of any particulate material referenced herein have a particle size as measured by sieve analysis of no greater than about 1000 pm, such as no greater than about 500 pm, such as no greater than about 400 pm, such as no greater than about 350 pm, such as no greater than about 300 pm. In some embodiments, at least 80% by weight of the particles of any particulate material referenced herein have a particle size as measured by sieve analysis of no greater than about 1000 pm, such as no greater than about 500 pm, such as no greater than about 400 pm, such as no greater than about 350 pm, such as no greater than about 300 pm.
  • At least 90% by weight of the particles of any particulate material referenced herein have a particle size as measured by sieve analysis of no greater than about 1000 pm, such as no greater than about 500 pm, such as no greater than about 400 pm, such as no greater than about 350 pm, such as no greater than about 300 pm. In some embodiments, at least 95% by weight of the particles of any particulate material referenced herein have a particle size as measured by sieve analysis of no greater than about 1000 pm, such as no greater than about 500 pm, such as no greater than about 400 pm, such as no greater than about 350 pm, such as no greater than about 300 pm.
  • At least 99% by weight of the particles of any particulate material referenced herein have a particle size as measured by sieve analysis of no greater than about 1000 pm, such as no greater than about 500 pm, such as no greater than about 400 pm, such as no greater than about 350 pm, such as no greater than about 300 pm. In some embodiments, approximately 100% by weight of the particles of any particulate material referenced herein have a particle size as measured by sieve analysis of no greater than about 1000 pm, such as no greater than about 500 pm, such as no greater than about 400 pm, such as no greater than about 350 pm, such as no greater than about 300 pm.
  • At least 50% by weight, such as at least 60% by weight, such as at least 70% by weight, such as at least 80% by weight, such as at least 90% by weight, such as at least 95% by weight, such as at least 99% by weight of the particles of any particulate material referenced herein have a particle size as measured by sieve analysis of from about 0.01 gm to about 1000 gm, such as from about 0.05 gm to about 750 gm, such as from about 0.1 gm to about 500 gm, such as from about 0.25 gm to about 500 gm.
  • At least 50% by weight, such as at least 60% by weight, such as at least 70% by weight, such as at least 80% by weight, such as at least 90% by weight, such as at least 95% by weight, such as at least 99% by weight of the particles of any particulate material referenced herein have a particle size as measured by sieve analysis of from about 10 pm to about 400 pm, such as from about 50 pm to about 350 pm, such as from about 100 pm to about 350 pm, such as from about 200 pm to about 300 pm.
  • the various components of the mixture may vary. As such, the overall mixture of various components with e.g., powdered mixture components may be relatively uniform in nature.
  • the components noted above which may be in liquid or dry solid form, can be admixed in a pretreatment step prior to mixture with any remaining components of the mixture, or simply mixed together with all other liquid or dry ingredients.
  • the various components of the mixture may be contacted, combined, or mixed together using any mixing technique or equipment known in the art. Any mixing method that brings the mixture ingredients into intimate contact can be used, such as a mixing apparatus featuring an impeller or other stmcture capable of agitation.
  • mixing equipment examples include casing drums, conditioning cylinders or drums, liquid spray apparatus, conical-type blenders, ribbon blenders, mixers available as FKM130, FKM600, FKM1200, FKM2000 and FKM3000 from Littleford Day, Inc., Plough Share types of mixer cylinders, Hobart mixers, and the like. See also, for example, the types of methodologies set forth in US Pat. Nos. 4,148,325 to Solomon et al.; 6,510,855 to Korte et al.; and 6,834,654 to Williams, each of which is incorporated herein by reference. Manners and methods for formulating mixtures will be apparent to those skilled in the art. See, for example, the types of methodologies set forth in US Pat. No.
  • the compositions may be prepared such that the composition mixture may be used in a starchless molding process or a starch-based molding process.
  • Example types of molds that may be used in a production process include, for example, starch molds, starchless molds, pectin molds, plastic tray molds, silicone tray molds, metallic tray molds, neoprene tray molds, and the like.
  • composition configured for oral use.
  • the term "configured for oral use” as used herein means that the composition is provided in a form such that during use, saliva in the mouth of the user causes one or more of the components of the composition (e.g., basic amine, flavoring agents and/or active ingredients) to pass into the mouth of the user.
  • the components of the composition e.g., basic amine, flavoring agents and/or active ingredients
  • the composition is adapted to deliver components to a user through mucous membranes in the user's mouth, the user's digestive system, or both, and, in some instances, said component is a nicotine component or an active ingredient (including, but not limited to, for example, nicotine, a stimulant, vitamin, amino acid, botanical, or a combination thereof) that can be absorbed through the mucous membranes in the mouth or absorbed through the digestive tract when the product is used.
  • a nicotine component or an active ingredient including, but not limited to, for example, nicotine, a stimulant, vitamin, amino acid, botanical, or a combination thereof
  • compositions configured for oral use as described herein may take various forms, including gels, pastilles, gums, chews, melts, tablets, lozenges, granules, powders, and pouches. Gels can be soft or hard. Certain compositions of the disclosure are in the form of solids. Certain compositions can exhibit, for example, one or more of the following characteristics: crispy, granular, chewy, syrupy, pasty, fluffy, smooth, and/or creamy.
  • the desired textural property can be selected from the group consisting of adhesiveness, cohesiveness, density, dryness, fracturability, graininess, gumminess, hardness, heaviness, moisture absorption, moisture release, mouthcoating, roughness, slipperiness, smoothness, viscosity, wetness, and combinations thereof.
  • compositions of the present disclosure may be dissolvable.
  • dissolvable refers to compositions having aqueous-soluble components that interact with moisture in the oral cavity and enter into solution, thereby causing gradual consumption of the composition.
  • the dissolvable composition is capable of lasting in the user’s mouth for a given period of time until it completely dissolves. Dissolution rates can vary over a wide range, from about 1 minute or less to about 60 minutes.
  • fast release compositions typically dissolve and/or release the desired component(s) (e.g., active ingredient, flavor, and the like) in about 2 minutes or less, often about 1 minute or less (e.g., about 50 seconds or less, about 40 seconds or less, about 30 seconds or less, or about 20 seconds or less).
  • Dissolution can occur by any means, such as melting, mechanical disruption (e.g., chewing), enzymatic or other chemical degradation, or by disruption of the interaction between the components of the composition.
  • the products do not dissolve during the product’s residence in the user’s mouth.
  • compositions as disclosed herein can be formed into a variety of shapes, including pills, tablets, spheres, strips, fdms, sheets, coins, cubes, beads, ovoids, obloids, cylinders, bean-shaped, sticks, or rods.
  • Cross-sectional shapes of the composition can vary, and example cross-sectional shapes include circles, squares, ovals, rectangles, and the like. Such shapes can be formed in a variety of manners using equipment such as moving belts, nips, extruders, granulation devices, compaction devices, and the like.
  • compositions configured for oral use are in the form of pastilles.
  • the term "pastille” refers to a dissolvable oral composition made by solidifying a liquid or gel composition so that the final composition is a somewhat hardened solid gel. The rigidity of the gel is highly variable.
  • a pastille product may alternatively be referred to as a soft lozenge.
  • the pastille products of the disclosure are characterized by sufficient cohesiveness to withstand light chewing action in the oral cavity without rapidly disintegrating.
  • the pastille products of the disclosure typically do not exhibit a highly deformable chewing quality as found in conventional chewing gum.
  • the products disclosed herein may be in the form of a dissolvable lozenge product configured for oral use.
  • Example lozenge-type products of the invention have the form of a lozenge, tablet, microtab, or other tablet-type product. See, for example, the types of nicotine-containing lozenges, lozenge formulations, lozenge formats and configurations, lozenge characteristics and techniques for formulating or manufacturing lozenges set forth in US Pat. Nos. 4,967,773 to Shaw; 5,110,605 to Acharya; 5,733,574 to Dam; 6,280,761 to Santus; 6,676,959 to Andersson et al.; 6,248,760 to Wilhelmsen; and 7,374,779; US Pat. Pub. Nos.
  • Lozenge products are generally described as "hard” and are distinguished in this manner from soft lozenges (i.e., pastilles).
  • Hard lozenges are mixtures of sugars and/or carbohydrates in an amorphous state. Although they are made from aqueous syrups, the water, which is initially present, evaporates as the syrup is boiled during processing so that the moisture content in the finished product is very low, such as 0.5% to 1.5% by weight.
  • the temperature of the melt generally must reach the hard crack stage, with an example temperature range of 149° to 154°C.
  • the composition can be chewable, meaning the composition has a mild resilience or "bounce" upon chewing, and possesses a desirable degree of malleability.
  • a composition in chewable form may be entirely dissolving or may be in the form of a non-dissolving gum in which only certain components (e.g., active ingredients, flavor, sweetener) dissolve, leaving behind a non-dissolving matrix.
  • Chewable embodiments generally include a binder, such as a natural gum or pectin.
  • the composition in chewable form comprises pectin and an organic acid, along with one or more sugar alcohols in an amount by weight of at least 50%, based on the total weight of the composition. Generally, the pectin is present in an amount of from about 1 to about 3% by weight, based on the total weight of the composition.
  • the composition can be meltable as discussed, for example, in US Patent App. Pub. No. 2012/0037175 to Cantrell et al., incorporated by reference herein in its entirety.
  • “melt,” “melting,” and “meltable” refer to the ability of the composition to change from a solid state to a liquid state. That is, melting occurs when a substance (e.g., a composition as disclosed herein) changes from solid to liquid, usually by the application of heat.
  • the application of heat in regard to a composition as disclosed herein is provided by the internal temperature of a user's mouth.
  • meltable compositions refers to a composition that is capable of liquefying in the mouth of the user as the composition changes phase from solid to liquid and is intended to distinguish compositions that merely disintegrate in the oral cavity through loss of cohesiveness within the composition that merely dissolve in the oral cavity as aqueous- soluble components of the composition interact with moisture.
  • meltable compositions comprise a lipid as described herein above.
  • the composition in meltable form comprises a lipid in an amount of from about 35 to about 50% by weight, based on the total weight of the composition, and a sugar alcohol in an amount of from about 35 to about 55% by weight, based on the total weight of the composition.
  • the sugar alcohol is isomalt, erythritol, sorbitol, arabitol, ribitol, maltitol, dulcitol, iditol, mannitol, xylitol, lactitol, or a combination thereof. In some embodiments, the sugar alcohol is isomalt.
  • the composition is in the form of a compressed or molded pellet.
  • Example pellet weights range from about 250 mg to about 1500 mg, such as about 250 mg to about 700 mg, or from about 700 mg to about 1500 mg.
  • the pellet can have any of a variety of shapes, including traditional pill or tablet shapes.
  • the composition in tablet form comprises a glucose-polysaccharide blend and a sugar alcohol.
  • the glucose-polysaccharide blend is present in an amount of from about 35 to about 50% by weight, based on the total weight of the composition; and the sugar alcohol is present in an amount of from about 30 to about 45% by weight, based on the total weight of the composition.
  • the sugar alcohol is isomalt, erythritol, sorbitol, arabitol, ribitol, maltitol, dulcitol, iditol, mannitol, xylitol, lactitol, or a combination thereof. In some embodiments, the sugar alcohol is isomalt.
  • the composition of the present disclosure is disposed within a moisture- permeable container (e.g., a water-permeable pouch).
  • a moisture- permeable container e.g., a water-permeable pouch
  • the composition enclosed in the pouch may be in any desired form.
  • the composition is in granular form.
  • Such compositions in the water- permeable pouch format are typically used by placing one pouch containing the composition in the mouth of a human subject/user.
  • the pouch is placed somewhere in the oral cavity of the user, for example under the lips, in the same way as moist snuff products are generally used.
  • the pouch preferably is not chewed or swallowed unless the pouch composition or materials are ingestible (e.g., dissolvable or dispersable) as described herein below.
  • the components of the composition therein e.g., flavoring agents and/or nicotine
  • the pouch may be removed from the mouth of the human subject for disposal.
  • oral products provided herein may be in the form of center-filled pastilles or lozenges, for example, such that the interior (or at least a portion) of the product has one or more different organoleptic properties (e.g., texture, mouthfeel, taste, etc.) from the outer surface thereof (or other portion thereof).
  • Such center-filled pastille or lozenge formulations may include a liquid and/or a gel and/or a meltable and/or a chewable and/or a gummy and/or an effervescent center-filling that is surrounded by a harder outer shell that can be associated with pastille-type or lozenge products as described herein.
  • the center-filling may be described as having less rigidity and/or increased softness compared to the outer shell.
  • the center-filling may or may not include an active ingredient therein.
  • both the outer shell and the center-filling formulations may include an active ingredient so as to provide an extended release of the active ingredient therefrom.
  • at least the outer shell formulation includes a pastille formulation as described herein above.
  • both the outer shell formulation and the center-filling formulation may comprise a pastille formulation as described herein having similar or different organoleptic properties.
  • the composition as disclosed herein and any other components noted above are combined within a moisture-permeable packet or pouch that acts as a container for use of the composition to provide a pouched product configured for oral use.
  • Certain embodiments of the disclosure will be described with reference to the accompanying drawing, and these described embodiments involve snus-type products having an outer pouch and containing a mixture as described herein.
  • the pouched products of the present disclosure can include the composition in other forms.
  • the mixture/construction of such packets or pouches, such as the container pouch 102 in the embodiment illustrated in the drawing may be varied. Referring to the drawing, there is shown a first embodiment of a pouched product 100.
  • the pouched product 100 includes a moisture-permeable container in the form of a pouch 102, which contains a material 104 comprising a composition as described herein.
  • Suitable packets, pouches or containers of the type used for the manufacture of smokeless tobacco products are available under the tradenames CatchDry, Ettan, General, Granit, Goteborgs Rape, Grovsnus White, Metropol Kaktus, Mocca Anis, Mocca Mint, Mocca Wintergreen, Kicks, Probe, Prince, Skruf and TreAnkrare.
  • the mixture may be contained in pouches and packaged, in a manner and using the types of components used for the manufacture of conventional snus types of products.
  • the pouch provides a liquid- permeable container of a type that may be considered to be similar in character to the mesh-like type of material that is used for the construction of a tea bag. Components of the mixture readily diffuse through the pouch and into the mouth of the user.
  • Non-limiting examples of suitable types of pouches are set forth in, for example, US Pat. Nos. 5,167,244 to Kjerstad and 8,931,493 to Sebastian et al.; as well as US Patent App. Pub. Nos. 2016/0000140 to Sebastian et al.; 2016/0073689 to Sebastian et al.; 2016/0157515 to Chapman et al.; and 2016/0192703 to Sebastian et al., each of which are incorporated herein by reference.
  • Pouches can be provided as individual pouches, or a plurality of pouches (e.g., 2, 4, 5, 10, 12, 15, 20, 25 or 30 pouches) can be connected or linked together (e.g., in an end-to-end manner) such that a single pouch or individual portion can be readily removed for use from a one-piece strand or matrix of pouches.
  • a plurality of pouches e.g., 2, 4, 5, 10, 12, 15, 20, 25 or 30 pouches
  • An example pouch 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.
  • 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 each 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.
  • pouch materials 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).
  • Preferred 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.
  • each product unit for example, a pouch
  • the weight of the composition within each pouch is at least about 50 mg, for example, from about 50 mg to about 1 gram, from about 100 to 800 about mg, or from about 200 to about 700 mg. In some smaller embodiments, the weight of the composition within each pouch may be from about 100 to about 300 mg. For a larger embodiment, the weight of the composition within each pouch may be from about 300 mg to about 700 mg.
  • other components can be contained within each pouch. For example, at least one flavored strip, piece or sheet of flavored water dispersible or water-soluble material (e.g., a breath-freshening edible film type of material) may be disposed within each pouch along with or without at least one capsule.
  • Such strips or sheets may be folded or crumpled in order to be readily incorporated within the pouch. See, for example, the types of materials and technologies set forth in US Pat. Nos. 6,887,307 to Scott et al. and 6,923,981 to Leung et al.; and The EFSA Journal (2004) 85, 1-32; which are incorporated herein by reference.
  • a pouched product as described herein can be packaged within any suitable inner packaging material and/or outer container. See also, for example, the various types of containers for smokeless types of products that are set forth in US Pat. Nos. 7,014,039 to Henson et al.; 7,537,110 to Kutsch et al.; 7,584,843 to Kutsch et al.; 8,397,945 to Gelardi et al., D592,956 to Thiellier; D594,154 to Patel et al.; and D625,178 to Bailey et al.; US Pat. Pub. Nos.
  • Example 1 Pouched product comprising nicotine and an ion channel modulator
  • An oral pouched product containing nicotine and an ion channel modulator is prepared.
  • a filler and nicotine source e.g., nicotine benzoate solution
  • an ion channel modulator sodium chloride, a sweetener, deionized water, and optionally sodium benzoate
  • the composition is transferred to a pouch filler, and the oral pouched product fabricated by adding the pouch filler contents into a non-woven fleece and heat sealing the fleece. Water is added to the pouch to give the desired moisture content.
  • the nicotine content of each pouch, in the form of nicotine benzoate is about 6.0 mg on a free base nicotine basis.

Abstract

L'invention concerne une composition conçue pour une utilisation orale, la composition comprenant au moins un principe actif, un modulateur de canal ionique qui se lie à un ou plusieurs récepteurs choisis parmi TRPA1, TRPV1, TRPV3, TRPM8, NaV1.7, et des combinaisons de ceux-ci ; et au moins une charge.
PCT/IB2023/056478 2022-06-24 2023-06-22 Composition orale comprenant un modulateur de récepteur WO2023248187A1 (fr)

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