US 2013 O152956A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0152956A1 VOn Borstel et al. (43) Pub. Date: Jun. 20, 2013

(54) DEVICE AND METHOD FOR SIMULATING Related U.S. Application Data CHEMOSENSATION OF SMOKING (60) Provisional application No. 61/570,660, filed on Dec. 14, 2011, provisional application No. 61/651,184, (71) Applicant: SENTIENS, LLC, Charlotte, NC (US) filed on May 24, 2012 (72) Inventors: Reid von Borstel, Potomac, MD (US); Publication Classification Dennis Tan, Weddington, NC (US); (51) Int. Cl. John Siverling, Matthews, NC (US); A24F 47/00 (2006.01) Inna S. Timokhina, Potomac, MD (US) (52) U.S. Cl. CPC ...... A24F 47/002 (2013.01) USPC ...... 131A329 (73) Assignee: SENTIENS, LLC, Charlotte, NC (US) (57) ABSTRACT A device for simulating a chemosensation of Smoking (21) Appl. No.: 13/710,801 includes an outer layer, a porous medium and a chemesthetic agent. The porous medium is disposed within the outer layer. The chemesthetic agent is disposed within the porous (22) Filed: Dec. 11, 2012 medium and activates a TRP channel.

30 Patent Application Publication Jun. 20, 2013 Sheet 1 of 4 US 2013/0152956 A1

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& Patent Application Publication Jun. 20, 2013 Sheet 3 of 4 US 2013/0152956 A1

WEIGHTDECREASE PER INHALE INCIGARETTE LIKE DEVICES, INJECTED WITH FORMULA, COMPRISING TRP ACTIVATORS 1600 1400 1200 1 O O O 800 600 400 200

O 2 4 6 8 10 12 14 16 18 20 22 24 26 28 NUMBER OF DRAWS FIG. 6

EFFECT OF BENZON RESIN ON FORMULA EVAPORATION RATE INRODS 1400

1200

1 O O O -(- 0% BR O.800 H 10% BR 0.600 7, 15% BR

0.400

0.200

O.OOO O 30 60 90 120 150 180 210 TIME, MIN FIG. 7 Patent Application Publication Jun. 20, 2013 Sheet 4 of 4 US 2013/0152956 A1

EFFECT OF BENZON RESIN ON AMOUNT OF STRONG DRAWS INRODS 1400

1.200

1.000

O.800

0.600

0.400

0.200

0.000 O 5 10 15 20 25 30

NUMBER OF DRAWS -0- O% BR H 10% BR FIG. 8 15% BR US 2013/0152956 A1 Jun. 20, 2013

DEVICE AND METHOD FOR SIMULATING Some features of the Smoking experience, while acting as CHEMOSENSATION OF SMOKING non-pyrolytic delivery devices, have also been described. Other such substitutes have been described which CROSS-REFERENCE TO RELATED intend to reduce cigarette craving without delivering nicotine. APPLICATIONS Electrical devices for creating a vapor simulating smoke have also been described which typically involve heat 0001. This application claims priority to U.S. Provisional ing a solution of nicotine and flavor agents dissolved in pro App. Ser. No. 61/570,660, filed Dec. 14, 2011 and U.S. Pro pylene glycolor glycerol to produce a Smoke-like aerosol that visional App. Ser. No. 61/651,184, filed May 24, 2012, each delivers flavorings and nicotine in solvent droplets. Some of which is hereby incorporated by reference in its entirety. vaporizing devices are shaped like a cigarette, including a battery, vaporizing chamber and a reservoir for liquid, which BACKGROUND can be held in a porous Substrate. 0002 Smoking is prohibited in many locations where 0006. However, the devices described above fail to pro Smokers may spend considerable time, including work vide a non-combustible, non-electric cigarette Substitute that places, restaurants, airplanes, and hospitals. In Such settings, adequately mimics tactile, kinesthetic, organoleptic and/or the experience of craving for cigarettes can cause significant chemosensory qualities of cigarettes and cigarette Smoking discomfort and distraction. Nicotine absorption into the for relieving negative affect or mood associated with cigarette bloodstream and brain is a factor, but it is not the only or craving at times when Smoking is not possible or for use in primary factor for relief of cigarette craving, as indicated, for Supporting Smoking cessation. example, by the failure of transdermal nicotine delivery patches or other nicotine replacement therapies to have a BRIEF SUMMARY dramatic effect on Smoking cessation Success rates. Nicotine free cigarettes can reduce cigarette craving symptoms, but 0007. In one embodiment, a device for simulating they do not represent an alternative for use in environments chemosensation of Smoking includes an outer layer, a porous where Smoking is prohibited. It has been suggested that sen medium and a chemesthetic agent. The porous medium is sory effects of Smoke inhalation, and to some extent, the disposed within the outer layer. The chemesthetic agent is simple motor effects of Smoking behavior, may help to alle disposed within the porous medium and includes a Zingiber viate craving. aceae extract that activates a TRP (transient receptor poten 0003 Habituation to tactile and kinesthetic aspects of han tial) channel. dling and Smoking a cigarette contributes to reinforcement of 0008. In another embodiment, a device for simulating Smoking behavior, as do the organoleptic qualities of ciga chemosensation of Smoking includes an outer layer, a porous rette Smoke, the and other sensations in the mouth, throat medium and a chemesthetic agent. The porous medium is and respiratory tract. Sensory aspects of Smoking contribute disposed within the outer layer. The chemesthetic agent is to Smoking behavior and relief of cigarette craving both disposed within the porous medium and includes a Brassi through conditioned or learned association with nicotine caceae extract that activates a TRP channel. delivery, but also through direct “hard-wired autonomic and 0009. In another embodiment, a device for simulating sensory-metabolic reflexes independent of nicotine entry into chemosensation of Smoking includes an outer layer, a porous the brain. In particular, the characteristic airway sensation medium and a chemesthetic agent. The porous medium is caused by inhaled tobacco Smoke (sometimes referred to as disposed within the outer layer. The chemesthetic agent is “throat scratch.” “throat impact” or “throat hit) is reported as disposed within the porous medium and includes a Lami a significant component of Smoking satisfaction and espe aceae extract that activates a TRP channel. cially of relief of acute cigarette craving. Isolated reduction of 0010. In another embodiment, a device for simulating throat sensations with local anesthetics reduce the relief of chemosensation of Smoking includes an outer layer, a porous Smoking craving induced by nicotine-containing cigarette medium and a chemesthetic agent. The porous medium is Smoke; conversely, maintenance of throat Scratch while dis disposed within the outer layer. The chemesthetic agent is abling olfaction and oral taste sensation with an anesthetic disposed within the porous medium and includes a Toddalio mouthwash can alleviate the negative affect associated with ideae extract that activates a TRP channel. cigarette craving. The “throat scratch can affect perceived 0011. In another embodiment, a device for simulating taste qualities and more subtle throat and airway autonomic chemosensation of Smoking includes an outer layer, a porous sensory nerve stimulation, which can have effects beyond medium and a chemesthetic agent. The porous medium is taste sensations. The airway sensations of inhaled cigarette disposed within the outer layer. The chemesthetic agent is Smoke involve activation of receptors on sensory nerve end disposed within the porous medium and includes 1'-acetoxy ings by nicotine, other Smoke components, as well as high chavicol acetate. temperatures of Smoke. 0012. In another embodiment, a device for simulating 0004. An aerosol of citric acid or ascorbic acid has been chemosensation of Smoking includes an outer layer, a porous reported to reduce cigarette craving symptoms via irritation medium and a chemesthetic agent. The porous medium is of the throat. However, the airway sensations elicited by disposed within the outer layer. The chemesthetic agent is aerosols of these nonvolatile acids were accompanied by the disposed within the porous medium and includes 6-paradol. Sour taste sensations not associated with Smoking tobacco 0013. In another embodiment, a device for simulating and required generation of an aqueous aerosol by using a chemosensation of Smoking includes an outer layer, a porous device that did not resemble a cigarette. medium and a chemesthetic agent. The porous medium is 0005. Inhalation of vapor from oil from a disposed within the outer layer. The chemesthetic agent is plastic cigarette-like device has been reported to reduce ciga disposed within the porous medium and includes an isothio rette Smoke craving. Some cigarette Substitutes that simulate cyanate. US 2013/0152956 A1 Jun. 20, 2013

0014. In another embodiment, a device for simulating kinesthetic features, and/or qualities of Smoke, Such as orga chemosensation of Smoking includes an outer layer, a porous noleptic and chemosensory qualities, involving inhalation of medium and a chemesthetic agent. The porous medium is Volatile agents activating sensory nerve ion channels, such as disposed within the outer layer. The chemesthetic agent is transient receptor potential channels and acid-sensitive ion disposed within the porous medium and includes . channels, in the respiratory tract. Additional embodiments 0015. In another embodiment, a device for simulating relate to other types of inhalation devices. chemosensation of Smoking includes an outer layer, a porous 0030 The present disclosure is generally directed to com medium and a chemesthetic agent. The porous medium is positions, apparatuses and methods for simulating the disposed within the outer layer. The chemesthetic agent is chemosensation of smoking. In some embodiments, an appa disposed within the porous medium and includes . ratus takes the form of a cigarette substitute device for alle 0016. In another embodiment, a device for simulating viating cigarette craving or Supporting Smoking cessation. chemosensation of Smoking includes an outer layer, a porous The cigarette Substitute device may comprise Volatile, Syner medium and a chemesthetic agent. The porous medium is gistic activators of transient receptor potential channels, dis disposed within the outer layer. The chemesthetic agent is persed in a porous Substrate imitating the appearance of a disposed within the porous medium and includes hydroxy-C- cigarette, and providing mimicry of the tactile, sensory and sanshool. chemosensory experiences of Smoking. 0017. In another embodiment, a device for simulating 0031. In the following discussion, cigarette smoking is chemosensation of Smoking includes an outer layer, a porous used as a generic and illustrative term to include cigarette, medium and ethanol. The ethanol is disposed within the cigar or pipe Smoking without loss of generality to Smoking in porous medium. A quantity of the ethanol dispersed within general. the porous medium is in an amount designed to perceivably 0032 Referring to FIG. 1, in some embodiments, activate TRPV1 and elicit chemesthetic sensations. improved mimicry of the experience of smoking a cigarette is 0018. In still another embodiment, a device for simulating provided by an exemplary cigarette substitute device 10 chemosensation of Smoking includes an outer layer, a porous approximately the size and shape of a conventional cigarette. medium and a chemesthetic agent. The porous medium is Volatile constituents are dispersed within a porous matrix 12 disposed within the outer layer. The chemesthetic agent is encased within a relatively nonporous, liquid impermeable disposed within the porous medium and includes a low wrapper 14 resembling the outer wrap paper of a conventional molecular weight organic acid that activates a TRP channel or cigarette. The device 10 is effective without use of applied other acid-activated ion channel on sensory nerves. heat or electrical or mechanical energy apart from suction 0019. In still another embodiment, a device for simulating applied by the user's inhalation at an end 16 of the device 10. chemosensation of Smoking includes an outer layer, a porous The end 16 may be constructed to resemble a conventional medium, a first chemesthetic agent and a second chemesthetic filter rod in appearance and/or feel. In some embodiments, a agent. The porous medium is disposed within the outer layer. filter rod is used at the end 16 of the device 10. The device 10, The first chemesthetic agent is disposed within the porous without heat, electrical power or aerosol generation, uses medium and activates a first TRP channel. The second Volatile active constituents, which in turn restrict the amount chemesthetic agentis disposed within the porous medium and of material that can be delivered versus generated aerosols or activates a second TRP channel. The second TRP channel is Smoke. Thus, cigarette-mimicking activity can be achieved of a different type than the first TRP channel. that does not require systemic absorption of nicotine or nico 0020 Related methods for manufacturing and using such tinomimetic cholinergic receptor-activating compounds. devices and for simulating chemosensation of Smoking are This principle is not restricted to cigarette-like devices, but also described. also includes Substitute cigars, pipes, and other devices used to Smoke tobacco. BRIEF DESCRIPTION OF THE DRAWINGS 0033. The principles of the present disclosure may further 0021 FIG. 1 is a perspective view of an exemplary device be applied to inhaler devices. Referring to FIG. 2, an inhaler for simulating chemosensation of Smoking. device 20 includes a housing 22 and a canister 24. The active 0022 FIG. 2 is a perspective view of an exemplary inhaler constituents are disposed as a solution in the canister 24. device. When the canister 24 is depressed into the housing 22, a 0023 FIG. 3 is an exploded schematic side view of an portion of the active constituents are released into the housing exemplary device for simulating chemosensation of smoking. 22 in a volatized form. Thus, when the user inhales from the 0024 FIG. 4 is an exploded schematic side view of an housing 22, the user receives the Volatized active constituents. exemplary embodiment of the device of FIG. 1. 0034. In one embodiment, compositions of the disclosure 0025 FIG. 5 is a schematic side view of an exemplary are delivered to the airway with an inhaler similar to those cellulose acetate tip of the device of FIG. 1. used for asthma medications or with a spray device similar to 0026 FIG. 6 is a graphical depiction of weight decrease those used for breath fresheners. 0035. The compositions of the present disclosure are also per inhalation in an exemplary embodiment. applicable for use in liquids used in electronic cigarettes or 0027 FIG. 7 is a graphical depiction of formula evapora electric vaporizers in conjunction with either an absence or tion rate in an exemplary embodiment. reduced levels of nicotine to provide an adequate simulation 0028 FIG. 8 is a graphical depiction of number of draws of the chemosensory experience of inhaling aerosols contain performula weight in an exemplary embodiment. ing nicotine as an aid to reducing dependence upon, or crav ing for, nicotine. Referring to FIG. 3, an electronic cigarette DETAILED DESCRIPTION device 30 includes a battery 32, an atomizer/vaporizer 34 and 0029 Embodiments described herein relate generally to a a cartridge 36. The active constituents are disposed as a solu device for mimicking features of smoking, such as tactile and tion in the cartridge 36. The atomizer 34 uses energy from the US 2013/0152956 A1 Jun. 20, 2013

battery 32 to volatize the active constituents, which are then ings mediating sensations of pain or temperature, including delivered to a user inhaling from an end of the device 30. the pungent, hot or cool sensations elicited by specific con 0036) Devices and methods of this disclosure can also be stituents of many ingested or inhaled Substances including used to deliver tobacco extracts including nicotine, alone or in hot peppers (), black pepper (), , combination with chemosensory TRP receptor activators. In (), and (allyl ), one embodiment, nicotine is included in an ethanolic extract camphor, wintergreen, (), carbon and disposed within a porous Substrate in cigarette-like rod, ated beverages (carbon dioxide) and some air pollutants. Such that inhalation on the rod aerosolizes, nebulizes or Vola Such sensations in the oral and nasal cavities are mediated via tilizes sufficient nicotine to provide acute relief of cigarette the trigeminal nerve, and are elements of the Somatosensory craving in a tobacco Smoker, but without combustion of system, distinguishing them from olfaction and taste, tobacco or application of heat. Over time the nicotine content although chemesthesis is an integral component of character of devices can be progressively reduced in the course of a istic sensory information about foods or airborne chemicals. cessation program to provide weaning from nicotine depen In the throat, respiratory tract and lungs, chemesthetic signals dence with chemosensory agents of the disclosure replacing are transmitted to the brain via the glossopharyngeal and the airway sensation of nicotine as the actual nicotine delivery vagus nerves. Chemesthetic signals can thereby directly is diminished. affect brain activity in the Somatosensory cortex and other 0037 Chemosensory cigarette-mimetic devices and com brain regions, including appetitive circuits involved in crav positions of the disclosure may also optionally used in con ing for particular foods or other chemesthetic stimuli includ junction with other forms of nicotine replacement therapy, ing tobacco Smoke, without requiring absorption of the active including but not limited to nicotine-containing dermal agents into the bloodstream or the brain. Crossover of patches, gums, lozenges, aerosols, electronic cigarettes or chemesthetic signaling provided by compounds of the Smokeless tobacco products. In this situation, combined present disclosure with chemesthetic signaling pathways delivery of nicotine, along with use of devices and composi involved in perception and physiological responses to tions of this disclosure to provide chemosensory and tactile tobacco smoke contributes to the ability of devices and com mimicry of a cigarette, may assist in withdrawal from ciga positions of the present disclosure to reduce craving or nega rette Smoking. tive affect or mood associated with delay or withdrawal of 0038 An understanding of actions of nicotine that permit tobacco Smoke. During tobacco Smoking, chemosensory sig improvements in mimicry of its subjective and physiological nals from the respiratory tract inform the brain that smoke, effects in a non-combustible simulated cigarette is that its likely containing nicotine based on experience, has been initial perceived actions are upon sensory nerves in the res inhaled, thereby triggering alterations of activity in appetitive piratory tract. Cigarette Smoke constituents, including but not circuits involved in converting absence of central nicotinic limited to nicotine, act on sensory and autonomic afferent receptor activation into negative affect or dysphoria associ nerve terminals sending sensory information to the brain ated with cigarette craving. Activation of chemosensory neu from the mouth, throat and respiratory tract via the vagus, rons that anatomically or functionally overlap with neurons trigeminal and other cranial nerves, and induce autonomic terminating in the airways that respond to nicotine and other reflexes and effects in the central nervous system that con Smoke constituents provides signals to the brain that similarly tribute to the Subjective experience of cigarette Smoking, trigger neural reflex-mediated relief of nicotine-withdrawal including “throat Scratch, and to relief of craving, and also to dysphoria without actually delivering nicotine or potentially subjective reflex-mediated experiences such as “head rush.” toxic Smoke constituents resulting from combustion of Cigarette Smoking causes EEG changes and corresponding tobacco. Similarly, mimicry of tactile, kinesthetic, organolep subjective experiences in the brain via sensory reflexes even tic aspects of cigarette Smoking, in addition to chemosensory before nicotine is absorbed and transported to the brain. mimicry, reinforces the ability of devices and compositions of 0039. The pharmacological actions of nicotine include the present disclosure to relieve symptoms of nicotine with mediation through nicotinic cholinergic receptors in the cen drawal or cigarette craving. tral and peripheral nervous systems. According to principles 0041 Transient receptor potential ion channels are a class of the present disclosure, a class of chemosensory receptors, of receptors on sensory nerves that trigger chemesthetic nerve pharmacologically and physiologically distinct from nico activation. TRP channels mediate pungent, hot or cool sen tine-responsive cholinergic receptors can be exploited by sations of food or air constituents. TRP activation on sensory compositions and devices disclosed herein to provide mim nerve endings can induce local effects in addition to sensation icry of the sensation of inhalation of cigarette Smoke to a perse (e.g. focal vasodilatation via axon reflex) or may trigger degree sufficient to provide satisfaction and attenuation of sensory-autonomic reflexes (e.g. changes in bronchial tone, craving for nicotine-containing cigarettes without requiring coughing, Sneezing or changes in body temperature regula the use of nicotine or nicotinic cholinergic receptoragonists, tion, or Subjective sensations) mediated through the reflex which are generally toxic or malodorous. Simulation of sen arcs involving the spinal cord or brain. While TRP activation sations elicited by inhaled cigarette Smoke on nerve endings can provide warning of potentially noxious environmental or in the respiratory tract is achieved with selected volatile dietary factors, TRP stimulation can also elicit pleasure or agents acting on the chemesthetic sensory modality mediated satisfaction, as is implied by the examples of common TRP by transient receptor potential channels (“TRP channels' or, activators above. A feature of TRP activation is that chemes simply “TRP”), which are pharmacologically distinct from thetic sensations (or TRP sensations), which are generally nicotine-responsive cholinergic or acetylcholine receptors. more sensitive to temperature sensations than to Smell sensa 0040. The chemical senses comprise taste, olfaction, and tions provide less inherent discrimination between different “chemesthesis” (also known as the “common chemical agonists than is the case for olfactory sensation. Sensory sense.” or trigeminal chemosensation). Chemesthesis refers nerve endings associated with the trigeminal, glossopharyn to actions of chemicals, e.g. food constituents, on nerve end geal and vagus nerves may contain multiple types of US 2013/0152956 A1 Jun. 20, 2013

chemosensory receptors, providing a basis for chemesthetic effects of inhaled cigarette smoke sufficient to alleviate dis mimicry by chemically diverse agents. comfort or negative affect associated with cigarette craving. 0042 TRP channels can be activated by concentrations of 0047 Preferably, a TRP channel activator provides sub compounds below those that cause actual physical changes in jective and physiological mimicry of the chemosensory expe the respiratory tract, acting as sensitive sentinels of possible rience of cigarette Smoking without also providing obvious irritation or damage. TRP channel activators therefore pro sensory cues attributable to familiar, recognizable food-de vide a potential mode of action for volatile constituents to rived chemesthetic agents such as the TRP activating compo have Smoke-mimetic chemosensory or chemesthetic effects nents of black pepper, red pepper, garlic, horseradish, cinna without delivery of otherwise bioactive quantities of the sen mon, wintergreen, mint and the like, or common recognizable sory agents into the body. food acids such as acetic or citric acid. In some embodiments a complex mixture of different TRP activators is formulated, 0043. In some embodiments, a defined selection of vola which reduces individual smell and taste attributes and tile activators of TRP channels and acid sensitive ion channels is provided that, when incorporated into a cigarette-simulat increases the chemosensory effects via Synergy. ing device, provide improved chemosensory mimicry of the 0048. Furthermore, TRP channel activators for use in experience of Smoking a cigarette versus prior art cigarette compositions and devices of this disclosure preferably have substitute devices. rapid rates of onset and disappearance and do not readily desensitize their receptors to repeated stimulation so that 0044. In an exemplary cigarette substitute device, such as perceived sensation intensity disappears rapidly in the inter device 10, synergistic activity of combinations of TRP acti val between puffs and intensity does not rapidly diminish vators and modulators elicit a chemesthetic sensation. during prolonged or repeated puffing. TRPV1, for example, is a temperature-sensing TRP channel. 0049 TRP activators that may be useful for mimicry of Ethanol reduces the threshold for activation of TRPV1 by chemosensory effects of tobacco Smoke include 6-paradol heat and by TRPV1 agonists, such as extracts of Szechuan and analogs (including extracts of pepper or seeds. This is the basis for a warm sensa seeds), 1'-acetoxychavicol acetate and analogs (including tion in the mouth and throat elicited by beverages containing extracts of galangal root and compounds), ethanol: TRPV1 is activated at body temperature in the pres and analogs (including extracts of Brassica Nigra seeds), ence of ethanol, whereas higher temperatures are normally camphor and analogs (including extracts of Rosmarinus Offi needed to create sensations of warmth and heat. Acid extra cionalis leaves), Thymol and analogs (including extracts of cellular conditions, for example with a pH below about 6, also Thymus Serpullum leaves) and ethanol. TRP activators and sensitize TRPV1 to other agonists and modulators, including organic acids are preferably present in the cigarette Substitute ethanol. TRPA1, a member of the TRP family mediating heat device 10 in quantities Sufficient to provide distinct pungent sensations, is sensitized to its agonists by acidic intracellular or warm sensations in the throat and respiratory tract when pH conditions. Simultaneous sensitization of TRPV1 and inhalation or Suction similar to puffing on a cigarette is TRPA1 can thus be achieved by exposure of cells to low applied to the tip of the device. molecular weight organic acids that can readily traverse cell 0050. In some embodiments, sufficient quantities of etha membranes, preferably acids that do not have a distinctive or nol, disposed in a porous Substrate with Sufficient Surface area unmaskable odor in quantities Sufficient for contributing to and air flow characteristics (for example, 0.1 to 1.5 ml of chemosensory mimicry of cigarette smoke. Preferred low ethanol disposed in a device similar in size and shape to a molecular weight organic acids of this disclosure are car cigarette, but comprisingaporous matrix capable of retaining boxylic acids with three or fewer carbon atoms, comprising liquid ethanol encased in an ethanol-impermeable outer only carbon, oxygen and hydrogen. Suitable low molecular layer), are used to provide a concentration of ethanol vapor in weight organic acids contemplated herein include pyruvic the main airstream sufficient to elicit distinct chemesthetic acid and propionic acid. sensations of heat or burning in the mouth, throat and/or 0045 Synergistic interaction of TRP channel agonists and airways during mouth-applied Suction, delivering approxi modulators provides a unique basis for chemosensory mim mately 50 to 100 microliters of vaporized, nebulized or aero icry of inhaled cigarette Smoke achieved with limited quan Solized ethanol perpuff (i.e., an inhalation of an air Volume of tities of material that can be volatilized from a porous matrix approximately 25 to 100 ml over a time period of approxi within a device approximately the size and shape of a ciga mately 1 to 5 seconds). This is in contrast with devices used to rette via mouth-applied Suction, without heat or combustion. provide ethanol aerosol or vapor as a means to deliver ethanol 0046. An embodiment according to the present disclosure and oxygen for hedonic purposes, or for treatment of pulmo includes ethanol, optionally one or more Volatile agonists of nary edema, or cigarette-like devices containing incidental TRPA1, TRPV1, TRPV3, or TRPM8, optionally a volatile ethanol as a solvent, but in quantities and a matrix insufficient low molecular weight carboxylic acid, and optionally flavor to elicit significant chemosensation during ambient tempera and aroma agents. Another embodiment according to the ture inhalation, where the concentration of ethanol achieved present disclosure includes ethanol, one or more Volatile ago in the main airstream is below the threshold for a chemes nists of TRPA1, TRPV1, TRPV3, or TRPM8, and optionally thetic sensation Sufficient for chemosensory mimicry of flavor and aroma agents. This composition is applied to a inhaled tobacco Smoke, as this degree of chemesthetic sensa porous matrix, such as cellulosic fibers, within an imperme tion limits continued deep inhalation. able wrapper resembling the outer wrap paper of a cigarette, Exemplary Compositions that Include Constituents that Acti Such as paper coated with an impermeable ethanol-resistant vate One or More Subtype of TRP Channel film or layer. Mouth suction applied to the end of the porous 0051. In the airways, sensory cues associated with smok matrix volatilizes the constituents such that they contact the ing a cigarette are complex and include irritation of airways mouth, respiratory tract, and nasal cavity and interact to elicit by nicotine and other Smoke constituents via receptors on organoleptic and chemesthetic imitation of the sensory afferent nerves; irritation of airways by toxic components of US 2013/0152956 A1 Jun. 20, 2013 cigarette Smoke, e.g. (a major constituent of tobacco intensify the chemosensory experience and/or expand the smoke), via TRPA1 receptor and perception of warmth/heat area of sensations within the oral cavity and airways. This can associated with the process of combustion and inhalation of also enhance autonomic reflexes including but not limited to tobacco Smoke, mediated by thermo-sensing TRP receptors, bronchodilation. Table 1 provides exemplary combinations of including TRPV1 (hot sensing >42 degrees C.) and TRPV3 TRP activators that may be used in accordance with the (warm sensing 32-39 degrees C.). Compositions of the present disclosure. present disclosure can act on one, two or multiple chemosen 0054 TRP receptor activation by agonists may be deter sory receptors to provide sensory mimicry of cigarette Smoke mined using electrophysiological methods, such as whole inhalation. cell patch recordings of agonist evoked currents. Addition ally, the agonist evoked currents can be measured as changes 0052 TRPactivating agents are categorized based on TRP in cell membrane potential, and/or changes in intracellular channel subtypes affected by constituents. Blending of calcium Ca" levels, using specific fluorescent dyes. botanical extracts or constituents that activate different TRP 0055. In an exemplary method to determine activation of a channels, or which activate channels with different kinetics of specific TRP receptor subtype, e.g. TRPA1, but not TRPV1, a onset, duration, and inactivation can result in a spectrum of human embryonic kidney 293 (HEK293) cell line, which variations in sensory effects, altering the dominant locations does not express endogenous TRP receptors, is transiently or of perceived sensation (oral cavity, upper airways, lower air stably transfected with specific TRP receptor cDNA. The ways) and autonomic reflexes triggered by the sensory nerve functionality of such exogenously expressed TRP receptors is activation. then confirmed by functional assays, described above. The 0053 TRP-activating compounds or combinations thereof findings obtained with HEK293 cells, may be confirmed may be selected based on performance using sensory evalu using cultured neurons, expressing endogenous TRP recep ation. Following extensive evaluation, it was unexpectedly tors. Cell systems for Such studies may be neurons isolated discovered that an exemplary composition comprising ingre from Trigeminal ganglia, which can be obtained from rats or dients that activate more than one subtype of TRP channel can other laboratory animals. TABLE 1. Exemplary constituents that activate TRP channels Exemplary Constituents Exemplary Constituents Exemplary Constituents that that activate TRPV1 that activate TRPV3 activate TRPA1 channel channel channel and analogs, Ethanol Camphor and analogs, and botanical extracts of the and botanical extracts, of Myrtaceae subfamily, the Lamiaceae family, comprising Eugenol, including comprising Camphor, Allspice, Pimenta Dioica, including extracts of , Syzygium Aromatictim leaves, and others Rosmarinus Officinalis and other botanicals 1'-acetoxychavicol and Camphor and analogs, Eugenol and analogs, analogs, and botanical extracts, of the and botanical extracts of the and botanical extracts of the Lamiaceae family, comprising Myrtaceae subfamily, Zingiberaceae family, Camphor, comprising Eugenol, comprising 1'-acetoxychavicol, including extracts of including extracts of including extracts of Galangal Rosemary leaves, Rosmarinus Allspice, Pimenta Dioica, root, Alpinia Galanga, related Officinalis and other Clove, Syzygium and other botanicals botanicals Aromaticum and related plants Isothiocyanates and analogs, Eugenol and analogs, Thymol and analogs, and botanical extracts of the and botanical extracts of the and botanical extracts of the family, Myrtaceae subfamily, Lamiaceae family, comprising glucosinolates and comprising Eugenol, comprising Thymol, isothiocyanates, including including extracts of Allspice, including extracts of extracts of mustard seeds, Pimenta Dioica, Syzygium leaves, Thymus Serpyllum, Wasabia Japonica, Sinapis Aromaticum and related and related plants Alba, Raphantis Saivais, plants Lepidium Sativum, Nasturtium Officinale, Brassica Juncea, Brassica Nigra, Armoracia Rtisticana and related plants Hydroxy-C-sanshool and Hydroxy-C-sanshool and and analogs, analogs, analogs, and botanical extracts of the and botanical extracts, and botanical extracts, Styracaceae family, comprising Hydroxy-C- comprising Hydroxy-C- comprising Vanillin, Sanshool, including extracts of Sanshool, including extracts of including extracts of Szechuan Pepper, Xanthoxylum Szechuan Pepper, Benzoin resin, Styrax piperitum, other botanicals of Xanthoxylum piperitain, other Benzoin and other the Toddalioideae subfamily botanicals of the botanicals and other botanicals Toddalioideae subfamily and other botanicals US 2013/0152956 A1 Jun. 20, 2013

TABLE 1-continued Exemplary constituents that activate TRP channels Exemplary Constituents Exemplary Constituents Exemplary Constituents that that activate TRPV1 that activate TRPV3 activate TRPA1 channel channel channel 6-paradol and analogs, 6-paradol and analogs, Other TRPV3 activators and botanical extracts of the and botanical extracts of the Zingiberaceae family Zingiberaceae family comprising 6-paradol, comprising 6-paradol, including extracts of including extracts of Afiamontin Meieglieta, other Afiamontin Melegueta, other Afiamomum species and other Afiamomum species and botanicals other botanicals Thymol and analogs, Isothiocyanates and analogs, and botanical extracts of the and botanical extracts of the Lamiaceae family, comprising Brassicaceae family, Thymol, including extracts of comprising isothiocyanates, Thyme leaves, Thymus including extracts of mustard Serpyllum, and related plants Seeds, of Wasabia Japonica, Sinapis Alba, Raphantis Saiivus, Lepidium Sativum, Nasturtium Officinale, Brassica Jincea, Brassica Nigra, Armoracia Rusticana and related plants Other TRPA1 activators Other TRPV1 activators

TABLE 2 include extracts of sandalwood, redcedarwood, Vetiver, orris root, oakmoss, myrrh and others. Constituents that activate TRPM8 Exemplary Constituents that activate TRPM8 channel 0058. In one embodiment, 0.1 to 1.5 ml of ethanol dis persed in a porous or fibrous insoluble cellulosic substrate Menthol and analogs, and botanical extracts of the Lamiaceae family, encased in a relatively nonpermeable wrapper with dimen comprising menthol, sions and airflow resistance characteristics (or “draw) including extracts from Peppermint, approximating those of a cigarette is sufficient to elicit Piperita and other sources chemesthetic sensations contributing to mimicry of tobacco Citral and analogs, and botanical extracts, comprising citral, smoke inhalation. In such a device, 0.1 to 1.0 ml of pyruvic including extracts from Mandarin orange, acid, with or without concurrent inhalation of ethanol vapor Citrus Reticulate, Lemongrass, Cymbopogon (either in a parallel channel or in a mixture comprising pyru Citratus and other sources vic acid and ethanol) is sufficient to elicit chemesthetic sen Citronellal and analogs, and botanical extracts, comprising citronellal, sations contributing to mimicry of tobacco smoke inhalation. including extracts from Lemon, Citrus Limon, Note that the above specified quantities are merely exemplary Melissa, Melissa Oficinalis and other sources and accordingly this disclosure is not limited to Such specified and analogs, quantities. and botanical extracts, comprising linalool, including extracts from Bergamot, Citrus 0059 Referring to FIG. 4, an exemplary embodiment of a Bergamia, Lemon, Citrus Limon, and other device 10 includes a porous substrate 122 enclosed in a non SOUCES and analogs, porous wrapper 123 resembling the outer wrap of a cigarette. and botanical extracts, comprising linalool, The porous Substrate 122 may include a single lumen or including extracts from , Eucalyptus channel 124, or alternatively a double lumen separating the Polybractea channel 124 into a first region 126 and a second region 128, Other TRPM8 activators each comprising a porous Substrate encased within a nonpo rous wrapper, both enclosed within the outer wrapper. The double lumen structure provides for separation of volatile 0056. In some embodiments, constituents that activate constituents that may adversely affect stability if present TRPM8 are used as optional flavor components that activate together during storage or use. For example, one lumen (e.g., the cool sensing TRPM8 channel (25-28°C.) in the airways. 128) may comprise pyruvic or propionic acid, or a mixture of 0057. In some embodiments, the composition disposed in pyruvic or propionic acid and ethanol, dispersed in a porous the device 10 includes a stabilizing or fixative constituent that substrate, and the other lumen (e.g., 126) may comprise TRP reduces evaporation rate and improves stability. When added channel activators, tobacco-like flavor and aroma constitu to more volatile components, the stabilizing or fixative con ents, generally dissolved in ethanol and dispersed in a porous stituent allows the formula in the device to last longer while substrate. The lumens 126 and 128 may be arranged with a keeping its original intensity. One Suitable fixative constitu first porous substrate near a first end of the device 10 and a entis Benzoin resin. Benzoin resin or styrax resin is a balsamic second porous Substrate adjacent to the first porous Substrate resin obtained from the bark of Styrax Benzoin and other and distal from the first end of the device 10. Alternatively, the species of trees in the genus Styrax. Benzoin resin also con lumens 126 and 128 may extend for a similar length of the tains vanillin, a TRPV3 activator. Other suitable fixatives device 10 being separated in vertical or horizontal bands. In US 2013/0152956 A1 Jun. 20, 2013

yet another alternative, the lumens 126 and 128 may be ingredients in liquefied form, in one embodiment dissolved in arranged concentrically with a first central porous Substrate propylene glycol or glycerine, for release upon heating from and a second Surrounding porous Substrate. The lumens 126 within a cartridge, to be used, for example, in electronic and 128 may be separated by a Substantially non-porous or cigarettes or vaporizing devices for generation of a Smoke liquid impermeable barrier to provide separation between like aerosol with enhanced chemosensory mimicry of constituents disposed in the lumens 126 and 128 respectively. tobacco Smoke. 0060. In a single lumen construction, the pyruvic acid and 0069. Several variations of device 10 are contemplated ethanol mixture may be separated from the TRP channel herein, including but not limited to single channel configura activators by applying the two distinct mixtures in separate tions comprising ethanol dispersed in a porous Substrate, with alternating bands on the porous Substrate with barrier sections TRP-active agents or extracts dissolved in the ethanol, e.g.: between the bands. Additional embodiments having three or 0070 1) Cigarette-like rod loaded with an ethanolic more lumens are also contemplated. extract of a non-tobacco botanical material comprising con 0061 An untreated region 130 may be included at a sec stituents that activate TRPA1. ond end 132 of the device 10, which is subjected to mouth 0.071) 2) Cigarette-like rod loaded with a sufficient quan applied suction by a user. The untreated region 130 may be tity, such as 0.1 to 1.5 ml, of ethanol to sufficiently activate untreated cellulose. In some embodiments, the untreated TRPV1, or to potentiate TRPV1 activation by other agonists, region 130 may be a filter plug. In some embodiments, the to elicit chemesthetic sensations. untreated region 130 may be a cellulose acetate tip with a 0072 3) Cigarette-like rod loaded with an ethanolic micro capsule (discussed in more detail with respect to FIG. extract of a non-tobacco botanical material comprising con 5). Stituents that activate TRPV3. 0062. The region 130 and part of the channel 124 may be 0073 4) Cigarette-like rod loaded with an ethanolic covered with a wrap 134. The wrap 134 enhances visual extract of a botanical material comprising constituents that similarity between the device 10 and a cigarette. A portion activate TRPA1 and TRPV1. 136 of the wrap 134 may include trade dress for identifying 0074 5) Cigarette-like rod loaded with an ethanolic the device 10 or the maker thereof. extract of a botanical material comprising constituents that 0063. In an embodiment, the device 10 may have a length activate TRPA1 and TRPV3. of approximately 100 mm and a diameter of approximately 0075 6) Cigarette-like rod loaded with an ethanolic 7.9 mm in diameter. The channel 124 may be approximately extract of a botanical material containing constituents that 80 mm in length and the region 30 may be approximately 20 activate TRPV1 and TRPV3. mm in length. The wrap 134 may be approximately 30 mm in 0076 7) Cigarette-like rod loaded with an ethanolic length. extract of a botanical material comprising constituents that 0064 Referring to FIG. 5, the region 130a is an exemplary activate TRPA1, TRPV1 and TRPV3. cellulose acetate tip with a micro capsule 140. Such as a micro (0077. Further embodiments of the device 10 may include bead. The micro capsule 140 may be of various sizes such as two (2) channels, e.g.: 3.5-5 mm in diameter and may provide for a formula booster 0078 1) a first channel comprising a volatile organic acid containing one or more TRP activating ingredients of the dispersed in a porous substrate, with the pH at or lower than present disclosure or menthol additives. In some embodi the pKa of the acid; and ments including a micro capsule for a formula booster, the 0079 a second channel comprising a TRPA1 activator micro capsule may be approximately 5.5 mm in diameter. In dispersed in a porous Substrate, optionally as a solution in Some embodiments including a micro capsule for a menthol ethanol. additive, the micro capsule may be approximately 3.5 mm in 0080 2) a first channel comprising pyruvic acid dispersed diameter. The micro capsule 140 may be arranged with its in a porous Substrate, optionally a mixture of pyruvic acid and center at approximately 15 mm from the second end 132. ethanol; and 0065. A preferred porous substrate for high-speed manu I0081 a second channel comprising 6-paradol dispersed in facturing is cellulose paper of the type used in manufacturing a porous Substrate, optionally as a solution in ethanol. paper cigarette filter rods on a conventional rod-making I0082 3) a first channel comprising pyruvic acid dispersed machine, though any stable, porous material including but not in a porous Substrate, optionally a mixture of pyruvic acid and limited to polypropylene, polyethylene, polyester, or rayon ethanol; and may be used. 0083 a second channel comprising galangal acetate or an 0066. A suitable nonporous wrapper for the individual analog dispersed in a porous Substrate, optionally as a solu lumens or channels or for the outer wrapper may be conven tion in ethanol. tional outer wrap paper used in cigarette manufacturing, but I0084. 4) a first channel comprising pyruvic acid dispersed coated on the inside with a Substantially nonporous layer of in a porous Substrate, optionally a mixture of pyruvic acid and polyvinylacetate or otherwise laminated with a substantially ethanol; and nonporous flexible plastic material. I0085 a second channel comprising ethanol dispersed in a 0067. An alternate embodiment may utilize a porous sub porous Substrate. strate material with TRPactivators dispersed on the substrate, I0086. The foregoing exemplary composition may be fur combined with an acetate cellulose tip that has pyruvic acid, ther described with respect to several specific implementa or other constituents disclosed herein, or flavorings agents tions. It is to be appreciated that such specific implementa Such as menthol, encapsulated in a preferably 4-5 mm bead tions are exemplary in nature. positioned in the center of the tip (for example, as shown in FIG. 5). Example 1 0068 Another alternative embodiment may combine I0087 An extract of Aframomum Melegueta seeds was pre chemosensory activating ingredients along with stabilizing pared by pulverizing the seeds in an electric coffee grinder US 2013/0152956 A1 Jun. 20, 2013 and adding three grams of the pulverized seeds to 20 ml of approximately one half of the diameter of a cigarette with its ethanol. After periodic shaking and sitting overnight, 0.4 ml internal lumen filled with crimped filter rod paper; and 2) a of the ethanolic extract was introduced via a syringe and 3.25 inch long thin walled polyethylene tube approximately needle into a cigarette-like rod including crimped porous the diameter of a cigarette into which the 3.0 long lower filter rod paper with a nonporous overwrap. Inhalation from diameter tube was inserted, with the gap between the tubes one end of the rod in the manner of someone Smoking a filled with crimped filter rod paper, thus forming a tube within cigarette provided a warm chemesthetic sensation mimicking a tube. Pyruvic acid (0.2 ml) was injected into the inner tube, the throat Scratch associated with Smoking a standard com and ethanol (0.6 ml) was injected into the space between the bustible cigarette. The sensation was of greater intensity than inner and outer tubes. In separate similarly-constructed that elicited by the equivalent volume of ethanol alone. devices, ethanol extracts of galangal root powder or pulver ized Aframomum Melegueta seeds as described in Examples Example 2 1 and 2 were used instead of plain ethanol. Mouth-applied Suction provided a chemesthetic sensation providing satisfac 0088 An extract of galangal root powder was prepared by tory mimicry of the chemosensory experience of inhaling adding three grams of root powder to 20 ml of ethanol. After tobacco smoke. The addition of tobacco flavoring to the etha periodic shaking and sitting overnight, 0.4 ml of the ethanolic nol (or to the corresponding ethanol extract of galangal root or extract was introduced via a syringe and needle into a ciga Aframomum Melegueta seeds) further enhanced the mimicry rette-like rod including crimped porous paper with a nonpo of the total olfactory, taste and chemesthetic experience of rous overwrap. Inhalation from one end of the rod in the inhaling tobacco smoke. The outer tube was covered with a manner of someone Smoking a cigarette provided a warm cigarette paper overwrap and the tip was covered with the chemesthetic sensation mimicking the throat Scratch associ cork paper overwrap of a standard cigarette filter to provide ated with Smoking a standard combustible cigarette. The sen visual mimicry of a cigarette. The exemplary device provides sation was of greater intensity than that elicited by the equiva tactile, kinesthetic, olfactory, taste and chemosensory mim lent volume of ethanol alone. icry of a standard cigarette. Example 3 Example 7 I0089. Ethanol (0.1 to 1.6 ml by 0.1 or 0.2 ml increments) was introduced via a syringe and needle into a set of cigarette 0093 Aframomum Melegueta seeds (3 grams) were pull like rods including crimped porous paper with a nonporous Verized and extracted with 20 ml of 95% ethanol for 1 hour at overwrap. Inhalation from one end of the rod in the manner of room temperature. The Supernatant was decanted and evapo someone Smoking a cigarette provided a warm chemesthetic rated to dryness under an air stream. The resultant beige sensation mimicking the throat Scratch associated with Smok colored material was dissolved in 10 ml of a nicotine-free ing a standard combustible cigarette. The intensity of the electronic cigarette liquid comprising propylene glycol with chemesthetic sensation and its durability with repeated puff flavor and fragrance additives. The extract was loaded into an ing increased dose-dependently. empty electronic cigarette cartridge and affixed to the body of an electronic cigarette, which contained a battery and an Example 4 airflow-activated switch and provided current to the heating coil within the cartridge element when Suction simulating 0090 Pyruvic acid (0.1 to 1.0 ml by 0.1 or 0.2 ml incre Smoking was applied to the opening of the cartridge. The ments) was introduced via a syringe and needle into a set of nicotine-free liquid without the extract of Aframomum cigarette-like rods including crimped porous paper with a Melegueta seeds provided very little throat orchest sensation nonporous overwrap. Inhalation from one end of the rod in the characteristic of Smoking nicotine-containing cigarettes. The manner of someone Smoking a cigarette provided a warm nicotine-free electronic cigarette liquid containing an extract chemesthetic sensation mimicking the throat Scratch associ of Aframomum Melegueta seeds provided a strong throat and ated with Smoking a standard combustible cigarette. The chest sensation simulating that elicited by standard cigarette intensity of the chemesthetic sensation and its durability with Smoke or electronic cigarette liquid containing nicotine. repeated puffing increased dose-dependently. Example 5 Example 8 0091. A 1: 1 (v/v) mixture of pyruvic acid and ethanol (0.1 0094 5 grams of Carbopol980 polyacrylate was dispersed to 1.0 ml by 0.1 or 0.2 ml increments) was introduced via a in 500 ml 95% ethanol in a blender by gradual addition over Syringe and needle into a set of cigarette-like rods including 10 minutes followed by blending for a further 5 minutes. The crimped porous paper with a nonporous overwrap. Inhalation Carbopol-ethanol dispersion was stirred overnight on a mag from one end of the rod in the manner of someone Smoking a netic stirrer. A 100 ml aliquot was poured into a beaker, 0.1 ml cigarette provided a warm chemesthetic sensation mimicking triethanolamine dissolved in 1 ml glycerol was added to the the throat Scratch associated with Smoking a standard com 100 ml portion of the dispersion while stifling continuously. bustible cigarette. The intensity of the chemesthetic sensation The dispersion became a uniform slightly viscous solution, suitable for mixing with ethanolic extracts of TRP activators and its durability with repeated puffing increased dose-de and flavor constituents prior to application into cigarette-like pendently. The sensation was more intense than that obtained rods including a porous matrix encased in a relatively imper with equivalent Volumes of ethanol alone. meable wrapper. Other carbomer variants and other ethoxy Example 6 lated amine neutralizing agents, preferably with an alkyl or a nonpolar moiety, are optionally used for preparing an ethan 0092. A dual lumen cigarette-like device was constructed, olic gel to reduce the rate of evaporation of ethanol and the including 1) a 3.0 inch long thin-walled polyethylene tube extent of its seepage in the porous matrix of a device. US 2013/0152956 A1 Jun. 20, 2013

Example 9 extracts using a slurry extraction procedure as described in 0095 500 grams of a mixture of powdered Aframomum Example 9. The constituents were combined using the ratios Melegueta seeds, mustard seeds, Szechuan peppercorns and listed in Table 4 below. galangal root, rosemary leaves and optionally allspice, in relative percentage ranges as indicated in Examples 10, 11 TABLE 4 and 12, was added to an 8 liter cylindrical glass vessel. 2.5 Compositions including constituents that activate multiple liters of ethanol were added to the vessel, and a concave lid TRP channels was placed on top and sealed with plastic adhesive tape around the lid joint. The vessel was placed in a double boiler Active filled with water, and a 2 liter stainless steel canister of ice was Botanical chemical component TRP channel % by weight placed on top, in the convex lid. The water was heated to 85 Szechuan Pepper Hydroxy-a- TRPA1 15-25% Sanshool TRPV1 degrees C. for 60 minutes. The extract was then allowed to Yellow Mustard isothiocyanate TRPA1 15-25% cool to room temperature and filtered through a cloth and a 75 Afiamomum 6-paradol TRPA1 15-25% micron nylon mesh. Thymol and Benzoin resin were added to Meiegueta TRPV1 the extract in relative percentages as indicated below in Galangal 1'-acetoxychavicol TRPA1 15-25% Rosemary Camphor TRPV1 10-15% Examples 10, 11 and 12 and applied to devices of this disclo TRPV3 sure in a volume of 1 ml per rod. Thymol Thymol TRPA1 O.2-0.4% TRPV3 Example 10 Benzoin Resin Resin, vanillin TRPV3 10-15% 0096 Constituents, that activate TRPA1, TRPV1 and TRPV3 channels, listed in Table 1, were obtained as botanical (0099. The formula from Table 4 (1.5 ml per rod) was extracts, using a slurry extraction procedure as described in introduced via a syringe and needle into a set of cigarette-like Example 9. The constituents were combined using the ratios rods including crimped porous paper with a nonporous over listed in Table 3 below. wrap. Inhalation from one end of the rod in the manner of someone Smoking a cigarette provided a chemesthetic sensa TABLE 3 tion of heat/warmth and deep throat Scratch mimicking sen Compositions including constituents that activate multiple sations associated with Smoking a standard combustible ciga TRP channels rette. The sensation was significantly more intense than that obtained with equivalent Volumes of ethanol alone, or any Active single constituent alone, Suggesting Synergistic action. Botanical chemical component TRP channel % by weight Szechuan Pepper Hydroxy-a- TRPA 5-10% Example 12 Sanshool TRPV Allspice Eugenol TRPA 5-10% 01.00 Constituents that activate TRPA1, TRPV1 and TRPV TRPV3 channels, listed in Table 1, were obtained as botanical TRPV3 TRPM8 extracts, using a slurry extraction procedure as described in Afiamomum 6-paradol TRPA 15-25% Example 9. The constituents were combined using the ratios Meiegueta TRPV listed in Table 5 below. Galangal 1'-acetoxychavicol TRPA 30-50% Rosemary Camphor TRPV 5-10% TRPV3 TABLE 5 Thymol Thymol TRPA O.2-0.4% TRPV3 Compositions including constituents that activate multiple Mustard seed Isothionates TRPA 5-10% TRP channels TRPV Benzoin Resin Resin, vanillin TRPV3 10-15% Active Botanical chemical component TRP channel % by weight Szechuan Pepper Hydroxy-a- TRPA 15-25% 0097. The formula from Table 3 (1.5 ml per rod) was Sanshool TRPV introduced via a syringe and needle into a set of cigarette-like Yellow Mustard Benzyl- TRPA 5-10% rods including crimped porous paper with a nonporous over isothiocyanate Allspice Eugenol TRPA 5-10% wrap. Inhalation from one end of the rod in the manner of TRPV someone Smoking a cigarette provided a chemesthetic sensa TRPV3 tion of heat/warmth and deep throat Scratch mimicking sen TRPM8 sations associated with Smoking a standard combustible ciga Afiamomum 6-paradol TRPA 15-25% Meiegueta TRPV rette. The sensation was significantly more intense than that Galangal 1'-acetoxychavicol TRPA 15-25% obtained with equivalent Volumes of ethanol alone, or any Rosemary Camphor TRPV 10-15%% single constituent alone, Suggesting Synergistic action. As TRPV3 shown in FIG. 6, after eachinhale, the weight of cigarette-like Thymol Thymol TRPA O.2-0.4% rods was measured, revealing that each inhale absorbed 20-40 TRPV3 mg of volatile formula. This configuration of the device per Benzoin Resin Resin, vanillin TRPV3 10-15% mitted at least 25 strong draws, before intensity decreased. 0101. The formula from Table 5 (1.5 ml per rod) was Example 11 introduced via a syringe and needle into a set of cigarette-like 0098 Constituents that activate TRPA1, TRPV1 and rods including crimped porous paper with a nonporous over TRPV3 channels, listed in Table 1, were obtained as botanical wrap. Inhalation from one end of the rod in the manner of US 2013/0152956 A1 Jun. 20, 2013 someone Smoking a cigarette provided a chemesthetic sensa Example 15 tion of heat/warmth and deep throat Scratch mimicking sen 0112 A mixture of powdered Aframomum Melegueta sations associated with Smoking a standard combustible ciga seeds, mustard seeds, Szechuan peppercorns, galangal root, rette. The sensation was significantly more intense than that dried rosemary leaves, dried thyme leaves and optionally obtained with equivalent Volumes of ethanol alone, or any allspice, in relative percentage ranges as indicated in single constituent alone, Suggesting Synergistic action. Examples 10, 11 and 12, were combined with 95% ethanol at 1:1 ratio (w/v) and incubated at room temperature for 30-60 Example 13 minutes, followed by separation of herbal slurry from the 0102 Benzoin resin powder (such as that available from extract, using a French press device. The resulting ethanolic bulk herb suppliers) was subjected to the following extraction extract containing active TRPsensation agents can be used as procedure: a constituent of ethanolic TRP extracts, optionally also com 0103 1. Carrier oil (e.g. Canola oil) was incubated in 70° prising flavoring agents, for loading cigarette-like devices. C. water bath for 10 min. 0113. It will be appreciated that the described exemplary 0104 2. 1 part benzoin resin was mixed with 1.1 part of botanical constituents are not limiting and the described pre-warmed carrier oil (weight/volume) and incubated for 1 chemesthetic agents include equivalents such as Synthetic hour at 70° C. water bath or until fully dissolved, with peri alternatives. It will also be appreciated that description of odic mixing. constituents in compositions as by weight or by Volume is 0105 3. The homogenous thick mixture was combined merely exemplary and is not limiting. Constituents may be with 2 parts of ethanol and incubated for 1 hour at 70° C. measured using any of a variety of available methods. followed by 1 hour at room temperature. 0114. In addition, it will be appreciated that the above 0106 4. Three distinct layers were formed: a layer of resin described devices and compositions are not limited to ciga particles (bottom), a layerofoil (middle), and a layer of sticky rette-like rods, but are also applicable to other devices such as ethanol extract (top). inhalers that may be used to deliver the volatile constituent(s). 0107 5. The top layer was collected as Benzoin resin Also, it will be appreciated that the above described devices extract. The extract had a brown color, was slightly viscous, are applicable to applications beyond Smoking Substitution and was highly sticky and aromatic. and Smoking cessation. 0108 Cigarette-like devices, similar to the ones from 0115 For example, in addition to providing mimicry of Examples 10-12 were injected with 1.5 ml of formula con chemosensations similar to tobacco Smoke for providing Sup taining 0%, 10% and 15% of Benzoin resin extract. As shown port from smoking cessation or increasing the duration of in FIG. 7, formula evaporation rate was evaluated by measur time free of negative affect between cigarettes, the described ing the weight of rods, left unprotected in the open air, over a devices and compositions are useful for providing sensory period of time. cues associated with alcoholic beverages. TRP channel acti 0109 The addition of Benzoin resin (BR) significantly Vation by ethanol provides the burning sensation of strong reduced formula evaporation rate in cigarette-like rods. The alcoholic beverages that contributes to reinforcement of difference between 10% BRand 15% BR (see FIG.5) was not habitual drinking behavior. Mutations in TRP channels alter significant. alcohol preference behavior in experimental animals. In one embodiment, an alcoholic beverage, such as cognac, whisky, 0110 Cigarette-like devices, similar to the ones from or a liqueur, is diluted with ethanol in a ratio in the range of Examples 10-12 were injected with 1.5 ml of formula con 0.5:1 to 2:1, and 0.5 to 2.0 ml of the diluted beverage is loaded taining 0%, 10% and 15% of Benzoin resin extract. Inhalation into a device of the disclosure. Inhalation through the rod from one end of the rod in the manner of someone Smoking a results in a strong warm alcohol TRP sensation with minimal cigarette provided a chemesthetic sensation of heat/warmth actual delivery of ethanol along with the characteristic flavor and deep throat Scratch mimicking sensations associated with elements of the particular alcoholic beverage. Alcoholic bev Smoking a standard combustible cigarette. As shown in FIG. erages with a relatively low alcohol concentration Such as 8, after each inhale, the weight of cigarette-like rods was wine are preferably concentrated by freezing at -20 degrees measured and recorded. For each formula, the measurements C. or lower. A portion of the water freezes and the alcohol were conducted until it was determined that the intensity of a containing fraction is poured off and used in a device of this chemesthetic sensation of heat/warmth and deep throat disclosure, optionally after addition of ethanol to further scratch started to decrease. The addition of BR increased the increase Volatility. Alternatively, ethanol incorporating con number of strong draws in cigarette-like rods from 15 to at centrated aroma and flavor extracts or components derived least 25. from or resembling alcoholic beverages is loaded into a Example 14 device of this disclosure. 0116. As another example, devices and compositions con 0111. An 8 liter cold-finger extraction apparatus was templated herein can also be used for delivery of aromatic loaded with 500 ml 95% ethanol. A suspended filter basket agents useful for clearing airways in people with colds, contained 100 grams of a powdered product TRP source including menthol, camphor, thyme oil, eucalyptus oil or (separately, Aframomum Melegueta seeds, galangal root, eucalyptol, providing delivery of airway-clearing aromatic mustard seeds, or rosemary leaves; additional TRP source agents directly to the throat rather than via nostrils as occurs materials are extracted similarly) beneath the tip of the ice with nasal tubes or ointments applied around the opening of chilled cold finger. The apparatus was heated in a 190 degree the nasal passages. F. water bath for 6 hours. The resulting ethanolic extract 0117. While various embodiments in accordance with the containing active TRP sensation agents can be used as a disclosed principles have been described above, it should be constituent of ethanolic TRP extracts, optionally also com understood that they have been presented by way of example prising flavoring agents, for loading cigarette-like devices. only, and are not limiting. Thus, the breadth and scope of the US 2013/0152956 A1 Jun. 20, 2013

invention(s) should not be limited by any of the above-de approximately 5-10% by weight Szechuan pepper extract, scribed exemplary embodiments, but should be defined only 5-10% by weight mustard seed extract, approximately in accordance with the claims and their equivalents issuing 5-10% by weight allspice extract, approximately from this disclosure. Furthermore, the above advantages and 15-25% by weight Aframomum Melegueta extract, features are provided in described embodiments, but shall not approximately 30-50% by weight galangal extract, limit the application of Such issued claims to processes and approximately 5-10% by weight rosemary extract, and structures accomplishing any or all of the above advantages. approximately 0.2-0.4% by volume thymol solution: 0118. Additionally, the section headings herein are pro approximately 15-25% by weight Szechuan pepper vided for consistency with the suggestions under 37 C.F.R. extract, approximately 15-25% by weight mustard 1.77 or otherwise to provide organizational cues. These head extract, approximately 15-25% by weight Aframomum ings shall not limit or characterize the invention(s) set out in Melegueta extract, approximately 15-25% by weight any claims that may issue from this disclosure. Specifically galangal extract, approximately 10-15% by weight rose and by way of example, a description of a technology in the mary extract, and approximately 0.2-0.4% by volume “Background is not to be construed as an admission that thymol solution; and technology is prior art to any invention(s) in this disclosure. approximately 15-25% by weight Szechuan pepper Neither is the "Summary' to be considered as a characteriza extract, approximately 5-10% by weight mustard tion of the invention(s) set forth in issued claims. Further extract, approximately 5-10% allspice extract, approxi more, any reference in this disclosure to “invention' in the mately 15-25% by weight Aframomum Melegueta singular should not be used to argue that there is only a single extract, approximately 15-25% by weight galangal point of novelty in this disclosure. Multiple inventions may be extract, approximately 10-15% by weight rosemary set forth according to the limitations of the multiple claims extract, and approximately 0.2-0.4% by volume thymol issuing from this disclosure, and Such claims accordingly Solution. define the invention(s), and their equivalents, that are pro 14. The device according to claim 1, wherein the agent tected thereby. In all instances, the scope of such claims shall includes approximately 10-15% by weight benzoin resin be considered on their own merits in light of this disclosure, eXtract. but should not be constrained by the headings set forth herein. 15. A device for simulating a chemosensation of Smoking, What is claimed is: comprising: 1. A device for simulating a chemosensation of Smoking, an outer layer, comprising: a porous medium disposed within the outer layer, and an outer layer, a chemesthetic agent that activates a TRP channel disposed a porous medium disposed within the outer layer, and within the porous medium, the chemesthetic agent a chemesthetic agent that activates a TRP channel disposed including at least one of 6-paradol, isothiocyanate, within the porous medium, the chemesthetic agent hydroxy-C-sanshool. 1'-acetoxychavicol, camphor, including at least one of Zingiberaceae extract, Brassi eugenol and thymol. caceae extract, Toddalioidae extract and Lamiaceae 16. The device according to claim 15, wherein the agent is eXtract. disposed in an ethanol-based solution within the porous 2. The device according to claim 1, wherein the agent is medium. disposed in an ethanol-based solution within the porous 17. The device according to claim 16, wherein the ethanol medium. based solution includes a stabilizing constituent that includes 3. The device according to claim 2, wherein the ethanol at least one of a Benzoin resin from the Styracaceae family, based solution includes a stabilizing constituent that includes sandalwood, redcedarwood, Vetiver, orris root, oakmoss and at least one of a Benzoin resin from the Styracaceae family, myrrh. sandalwood, redcedarwood, Vetiver, orris root, oakmoss and 18. The device according to claim 15, wherein the agent myrrh. activates a TRP channel that is a TRP receptor that imparts a 4. The device according to claim 1, wherein the TRP chan chemesthetic sensation. nel is a TRP receptor that imparts a chemesthetic sensation. 19. The device according to claim 15, wherein the agent is 5. The device according to claim 1, wherein the device is Volatized when Suction is applied to the porous medium. sized and shaped to mimic a cigarette. 20. The device according to claim 15, wherein the TRP 6. The device according to claim 1, wherein the agent is a channel is one or more of TRPV1, TRPA1, TRPV3 and Volatile agent. TRPM8. 7. The device according to claim 1, wherein the agent is 21. The device according to claim 15, wherein the agent Volatized when Suction is applied to the porous medium. includes 6-paradol. 8. The device according to claim 1, wherein the TRP chan 22. The device according to claim 15, wherein the agent nel is one or more of TRPV1, TRPA1, TRPV3 and TRPM8 includes 1'-acetoxychavicol. 9. The device according to claim 1, wherein the agent 23. The device according to claim 15, wherein the agent includes Zingiberaceae extract. includes isothiocyanate. 10. The device according to claim 1, wherein the agent 24. The device according to claim 15, wherein the agent includes Brassicaceae extract. includes hydroxy-C-sanshool. 11. The device according to claim 1, wherein the agent 25. The device according to claim 15, wherein the agent includes Toddalioidae extract. includes camphor. 12. The device according to claim 1, wherein the agent 26. The device according to claim 15, wherein the agent includes Lamiaceae extract. includes thymol. 13. The device according to claim 1, wherein the agent 27. The device according to claim 15, wherein the agent includes at least one of the following: includes at least one of the following: US 2013/0152956 A1 Jun. 20, 2013 12

approximately 5-10% by volume hydroxy-C-sanshool solution, approximately 15-25%. 1'-acetoxychavicol solution, 5-10% by volume isothiocyanates solution, solution, approximately 10-15% by volume camphor approximately 5-10% by volume eugenol solution, solution, and approximately 0.2-0.4% by volume thy approximately 15-25% by volume 6-paradol solution, mol solution. approximately 30-50% by volume 1'-acetoxychavicol 28. The device according to claim 15, wherein the agent solution, approximately 5-10% by volume camphor includes a stabilizing constituent of approximately 5-15% by solution, and approximately 0.2-0.4% by volume thy Volume. mol Solution; 29. A device for simulating a chemosensation of Smoking, approximately 15-25% by volume hydroxy-C-sanshool comprising: solution, approximately 15-25% by volume isothiocy an outer layer, anate solution, approximately 15-25% by volume a porous medium disposed within the outer layer, and 6-paradol solution, approximately 15-25% by volume 1'-acetoxychavicol solution, approximately 10-15% by ethanol disposed within the porous medium, wherein Volume camphor Solution, and approximately 0.2-0.4% a quantity of the ethanol dispersed within the porous by volume thymol solution; and medium is in an amount sufficient to activate TRPV1 approximately 15-25% by volume hydroxy-C-sanshool and elicit chemesthetic sensations. solution, approximately 5-10% by volume isothiocyan 30. The device according to claim 29, wherein the quantity ate solution, approximately 5-10% by volume eugenol is approximately 0.1 to 1.5 ml. solution, approximately 15-25% by volume 6-paradol k k k k k