WO2014093127A2 - Enhanced delivery of nicotine, thc, tobacco, cannabidiol or base alkaloid from an electronic cigarette or other vapor or smoke producing device through use of an absorption conditioning unit - Google Patents

Abstract

A method for the administration of nicotine, THC, tobacco, cannabidiol or a base alkaloid includes administering in the oral or nasal cavity an absorption conditioning unit having at least two agents selected from the group consisting of (a) a buffer agent, (b) a capturing agent, (c) a penetration agent, and (d) a thermal agent, to the mammal, and then administering by inhalation a bioactive agent selected from the group consisting of nicotine, THC, cannabidiol and a base alkaloid. The absorption conditioning unit may be in a dosage form not containing a drug. The absorption conditioning unit may create a pH in the oral cavity or nasal cavity of 7.8-10 for a period of ten minutes or more after administration, the dosage form not containing an acid and not containing a drug.

Description

ENHANCED DELIVERY OF NICOTINE, THC, TOBACCO, CANNABIDIOL OR BASE ALKALOID FROM AN ELECTRONIC CIGARETTE OR OTHER VAPOR OR SMOKE PRODUCING DEVICE THROUGH USE OF AN ABSORPTION CONDITIONING UNIT

BACKGROUND

Electronic vapor devices are increasingly popular with consumers. Such devices comprise electronic cigarettes, electronic pipes, electronic hookahs, personal vaporizers and other inhalator embodiments, both electronic and mechanical.

UBS estimates that US e-cigarette sales will reach $500 million by the end of 2012, representing 100% growth from the preceding year (See UBS Tobacco Analyst Nik Modi's May 14, 2012 report entitled "Clearing the Smoke on E-Cigarettes," the entirety of which is incorporated herein by reference). Arguably, the most well-respected tobacco analyst, Bonnie Herzog of Wells Fargo, has gone so far as to suggest in discussing Loriilard: "We remain very encouraged by blu [Lorillard's e-cigarette brand] and see huge upside potential given our belief ecigs could overtake traditional cigarettes in 10 years." See Wells Fargo Loriilard Equity Research dated October 24, 2012, the entirely of which is incorporated herein by reference. British American Tobacco Chief Financial Officer Nicandro Durante stated in an interview with the Financial Times in September 2012 that the size of the market for tobacco alternatives like the e-cigarette could account for as much as 40% of BAT's revenues (which were £15bn in 2011) in 20 years' time. "It will be sizeable in 20 years' time ... it's going to grow," he said.

Despite this rapid sales growth, it is understood that electronic cigarettes fail to deliver a steeply peaked blood plasma delivery of nicotine like the conventional cigarette does.

Still, there are good reasons for using the e-cigarette as compared with cigarettes. The level of toxicants from the electronic cigarette is a small fraction as compared with a conventional cigarette. See, e.g., John H.

Lauterbach, Murray Laugesen, James D. Ross, "Suggested protocol for estimation of harmful and potentially harmful constituents in mainstream aerosals generated by electronic delivery systems (ENDS)", SOT, San Francisco, CA, March 10-16, 2012 (http://cigtoxdoc.ehost- servicesl 13.com/sot2012poster1860aspresented.pdf) hereby incorporated by reference).

It is typically considered in the industry that electronic vapor device adoption by consumers would be enhanced by faster, improved nicotine delivery from an electronic vapor device. Thus, there is a need to improve nicotine delivery from an electronic vapor device to its user. There is in addition need for delivery improvement (faster and more efficient) in connection with the use of all vapor devices (mechanical and electronic), of any nicotine, tobacco, or marijuana actives.

SUMMARY OF THE INVENTION

The present invention relates, inter alia, to a method for the

administration of nicotine, THC, tobacco, cannabidiol, cocaine or a base alkaloid or combination thereof to a mammal, e.g., a human. The method includes administering an absorption conditioning unit, comprising at least two agents selected from the group consisting of (a) a buffer agent, (b) a capture agent, (c) a penetration agent, and (d) a thermal agent, to the mammal, and then administering by inhalation a bioactive agent selected from the group consisting of nicotine, THC, cannabidiol and a base alkaloid.

The present invention also relates to a method for the administration of nicotine, THC, cannabidiol or a base alkaloid to a mammal, including administering an absorption conditioning unit including at least at least one material that creates a pH in the oral cavity of 7.8-10 for a period of ten minutes or more after administration; and then administering by inhalation a bioactive agent selected from the group consisting of nicotine, THC, tobacco, cannabidiol and a base alkaloid.

In one aspect of the present invention, an absorption conditioning unit includes a dosage form including at least two agents selected from the group consisting of (a) a buffer agent, (b) a capture agent, (c) a penetration agent, and (d) a thermal agent, wherein said absorption conditioning unit (i) does not have an essentially acidic character, (ii) does not contain a drug, (iii) does not contain THC or other Marijuana derived active ingredient (or any base alkaloid intended as an active ingredient), and (iv) does not contain tobacco except for trace amounts in flavor. In another aspect of the present invention, an absorption conditioning unit, includes a dosage form including at least at least one material that creates a pH in the oral cavity of 7.8-10 for a period of ten minutes or more after administration, the dosage form not containing an acid and not containing a drug.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method for the oral or nasal administration of nicotine, THC, cannabidiol, cocaine or any base alkaloid to a mammal, especially to a human, and to a prior administered (and/or contemporaneously administered and/or post administered) absorption conditioning unit useful in such a method.

Nicotine inhalers are known art. For example, Pfizer markets Nicotrol^® in the United States. The Nicotrol^® inhaler consists of a mouthpiece and a plastic cartridge delivering 4 mg of nicotine from a porous plug containing 10 mg nicotine. The cartridge is inserted into the mouthpiece prior to use.

Nicotine is released when air is inhaled through the inhaler. No heating element is used - the product relies on the natural propensity of nicotine to sublime at room temperature.

Despite the inhalation-route of administration by the user of Nicotrol^®' a buccal route of absorption is described in the Nicotrol^® package insert despite the user's inhalation of nicotine from the product (the entire package insert for Nicotrol^® is incorporated herein by reference as if fully set forth).

The Nicotrol^® package insert describes its method of action: "Most of the nicotine released from the NICOTROL Inhaler is deposited in the mouth. Only a fraction of the dose released, less than 5%, reaches the lower respiratory tract. An intensive inhalation regimen (80 deep inhalations over 20 minutes) releases on the average 4 mg of nicotine content of each cartridge of which about 2 mg is systemically absorbed. Peak plasma concentrations are typically reached within 15 minutes of the end of inhalation.... Absorption of nicotine through the buccal mucosa is relatively slow and the high and rapid rise followed by the decline in nicotine arterial plasma concentrations seen with cigarette smoking are not achieved with the inhaler. After the use of the single inhaler the arterial nicotine concentrations rise slowly to an average of 6 ng/mL in contrast to those of a cigarette, which increase rapidly and reach a mean Cmax of approximately 49 ng/mL within five minutes.... Ad libitum use of the NICOTROL Inhaler typically produces nicotine plasma levels of 6-8 ng/mL, corresponding to about 1/3 of those achieved with cigarette smoking." The discrepancy between 4 mg of nicotine leaving the cartridge with just 2 mg being absorbed is noted. One source of this discrepancy is that much of the nicotine is not buccally absorbed and is swallowed where nicotine is only poorly absorbed in the Gl tract.

Now, the typical cigarette contains less than 2 mg of nicotine

(http://www.biqsixsmokes.com/Camel.shtml), yet delivers a far higher peak systemic nicotine plasma concentration (Cmax), far quicker (Tmax), than Nicotrol^® (see http://pharmrev.aspetiournals.org/content/ 57/1 /

79 T1.expansion. html which is incorporated by reference). We postulate that the more efficient delivery of nicotine from a cigarette (as compared with the Nicotrol®) is a result of enhanced motility of nicotine occurring in smoke - which results from the burning of a cigarette. This superior motility allows the nicotine to readily reach the intermediate and deep lung where the enormous surface area of the lung promotes rapid absorption (as compared with buccal delivery).

The aerosol composition from a smoked cigarette is described by

British American Tobacco at http://www.bat-science.corn/groupms/sites/bat 7awfh3.nsf/ vwPaqesWebLive/DO7AXGHN?ODendocument&SKN=1 (the entirety of which is incorporated by reference, including all links).

Now, the obvious solution to improve nicotine delivery to a human would simply be to smoke a cigarette but for the fact that it is understood that burning tobacco results in carcinogens, and it is not yet known how to effectively filter such carcinogens prior to inhalation. Such filtration is likely not possible although recent BAT sponsored studies suggest that incremental improvements in filtration may be accomplished.

Others, such as Professor Jed Rose have tried to improve nicotine delivery from inhalers by using new nicotine salts (nicotine pyruvate) and thereby obtaining faster nicotine absorption than the Nicotrol^® - though still slower (Tmax) and not as high (Cmax) as a cigarette. See http://www.eurekalert.org/pub releases/2010-02/dumc-nsc022210.php, http://tobaccofreeaz.wordpress.com/2011/05/27/new-nicotine-ciqarette-gives- rapid-lung-delivery-of-nicotine/ and US Patent Application Publication No. 2012/0006342 A1 ("Tobacco-based aerosol generation system), each of which (together with references therein) is fully incorporated herein by reference as if fully set forth.

While US Patent Application Publication No. 2012/0006342 A1 suggests the use of a gaseous carrier, the poster presentation appears to suggest no additional carrier is used. We believe nicotine pyruvate has enhanced motility that allows the nicotine to more readily reach the lung as compared with the active ingredient of NICOTROL^®.

However, Professor Rose's innovation is not directed towards use with existing electronic vapor devices such as an electronic cigarette, and poses its own challenges for commercialization and pharmacokinetic performance.

Now let us discuss the nicotine based electronic cigarette. The effluent vapor of the electronic vapor device like an e-cigarette is heavy and slow moving. Thus, it does not reach the deep lung in substantial part, akin to the NICOTROL^® device. The result is pharmacokinetic performance much closer to Nicotrol^® than to a cigarette.

Published studies on nicotine update from electronic cigarettes similarly show a substantially lower Cmax and slower Tmax for nicotine delivery than a cigarette does (See e.g. Electronic Cigarettes: Effective Nicotine Delivery After Acute Administration by Andrea Vansickei and Thomas Eissenberg, Nicotine and Tobacco Research Adances Access published February 6, 2012; Clinical Laboratory Assessment of the Abuse Liablity of an Electronic Cigarette" by Andrea Vansickei, ichaei Weaver and Thomas Eissenberg submitted 14 October 2011 to the Society for the Study of

Addiction, and available online; each of which is specifically incorporated herein by reference).

Now, it has been suggested on electronic cigarette forums (www.e- cigarette-forum.com) to enhance nicotine delivery by chewing a TUMS^® antacid by well know e-cigarette blogger "Tropical Bob" but he states that this method does not work ("I concur that e-liquid is NOT alkaline enough. I've even tried chewing Tums to lower mouth acidity and help absorption. Didn't help and messed up the flavor of the vapor. The only solution is less-acid liquid. This stuff is mostly absorbed by the mouth, according to the Health New Zealand studies, and virtually none is absorbed from the lungs. So get to work, e-liquid makers.") We demonstrate in the examples below why a

TUMS^® is ineffective. However, Tropical Bob's suggestion to focus on the e- cigarette's liquid composition is misguided.

What is however correct is that nicotine is more readily absorbed across the oral mucosa at a basic pH. The question is how to achieve this, and modifying the pH of the liquid composition in an e-cigarette will not produce substantial results.

It is of course possible to make a less-acidic (or alkaline) liquid for use in a vapor device - however, the delivery of a less-acidic (or alkaline) condensate (i.e. the condensate that forms when the vapor cools in the mouth of the user) is challenging. Simply stated, placing buffer agents in a liquid and then vaporizing them offers little control over the pH of the condensate that forms in the mouth as well as the pH of the saliva in the mouth, which bathes the mucosa and is very important in this process. . If we add NaHC03 (sodium bicarbonate) to water: HC03-(aq) + H20 CO32-(aq) + H3O+(aq) Ka = 4.7x10-11 ; HC03-(aq) + H20 H2C03 (aq) + OH-(aq) Kb = 2.3x10-8. The solution will be alkaline. But if we vaporize the water, the vapor would not be 7.0. A complicated reaction is provoked and accelerated by the higher temperatures used to vaporize.

Similarly, it is not practicable to deliver sufficient amounts of capture agents (described below) or penetration enhancers (described below) or thermal agents (described below) via a vapor condensate (or comparable effluent from a non-vapor inhalator).

The present invention seeks to enhance the buccal delivery of nicotine (or Marijuana bioactives of any base alkaloids) from an electronic (or non- electronic) vapor (or other inhalation) device. Because of the nature of vapor effluent, there is a limit to the agents and excipients that may be employed in the composition in the vapor device that will travel with the vapor into the user's buccal cavity and oral mucosa. Similarly, absorption can be enhanced for the oropharyngial mucosa.

The present invention contemplates a separate "absorption

conditioning unit" that is placed in the user's mouth prior to and/or

contemporaneously with, the use of the electronic vapor device (or other inhalator). The present invention is not limited to the inhalation of vapor but may also be used with conventionally smoked materials (e.g. a tobacco cigarette or a medical marijuana cigarette) nor is it limited to the oral cavity or the oropharynx and it includes the nasopharnx and the nasal mucosa. The absorption conditioning unit of the present invention will enhance absorption of active ingredients contained in smoke in the oral cavity. Similarly, in the case of base alkaloids that are well absorbed in the Gl tract, like marijuana, the swallowing of ph basic compounds (including alkaline saliva produced by the dissolution of the absorption conditioning unit) will create a more basic environment in the Gl tract that will favor better Gl absorption of the actives in the Gl tract (like marijuana).

It may be desirable one or more absorption conditioning units more or less simultaneously, i.e. one in the mouth and one in the nasal cavity, particularly where the user intends to smoke or vaporize. Of course, multiple absorption conditioning units may be used in either cavity at the same time for reasons of dosing and the like, or multiple absorption conditioning units employed in serial fashion.

The absorption conditioning unit is a typically a dosage unit customarily used in the pharmaceutical and/or confection industries. The absorption conditioning unit may comprise any of following non-limitative solid or liquid examples: a tabiet, an oraiiy dissolving tablet, a chewabie tabiet, a muiti- layered tablet, a capsule, a liquid-gel, a lozenge, a thin film, a sheet, a slab, a powder, granules, a gummy, a lollipop, a suspension, a toothpaste, a chewing gum or a solution. A solution or suspension may be delivered via a spray or aerosol or like method. However, the absorption conditioning unit will preferably comprise a solid dosage unit. Chewabie dosage units are a preferred embodiment for their propensity to spread material around the mouth. Film dosage units are desirable because of small sized and their 2013/073346

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ability to be easily co-packaged with the inhalation device. For purposes of this invention, we would like to increase the amount of modified mucosal surface that is exposed to the agents contained in the absorption conditioning unit. Liquids are also good for this purpose but liquids are inevitably costly to distribute. One exception to this, and another preferred embodiment, is a liquid that is constituted by the user whereby dry or concentrated agent- materials are provided to the user who then mixes them with a liquid like for example tap water and used as a an oral gargle and/or oral swishing agent.

The emission from an electronic cigarette is a vapor - formed by heating a liquid (or primarily) liquid composition that is brought into contact with the heating element of the electronic cigarette. Said liquid composition typically comprises a vapor agent that creates a smoke-like vapor when heated (most commonly glycerin or propylene glycol), USP nicotine, water and a flavor system. Said liquid may alternatively comprise a tobacco extract together with a vapor agent (see US 2012/0145170 A1 "METHOD FOR PREPARING TOBACCO EXTRACT FOR ELECTRONIC SMOKING DEVICES" and hereby incorporated by reference). Rate of flow of the liquid composition to the heating element is typically controlled with a wick or sponge like material such that the heating element is not overwhelmed.

Drawing on the e-cigarette turns on the heating element (which can be achieved through a variety of ways in including air pressure differentials, a sound-based system and other switches).

The effluent vapor in large part forms a condensate in the mouth - it is too heavy to readily travel to the middle or deep lung. It is understood that nicotine is absorbed across mucosal surfaces (and even the skin) but absorbed very poorly in the Gi tract. Thus, to the extent condensate forms in the mouth that is in turn swallowed, the nicotine so swallowed will not reach the blood but rather will be excreted. This explains much of the discrepancy noted above for Nicotrol^® whereby 4 mg of nicotine leaves the cartridge and only 2 mg is absorbed. Loss of nicotine to salivary flow is discussed in Fuisz U.S. Patent Application Publication No. 2009/0098 92 A1 and Fuisz US Patent No. 8,241 ,661 discussing salivary flow, the content of each of which is hereby incorporated by reference in its entirety. 2013/073346

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The ability of particles to transit to the lung has been considered in the context of pulmonary drug delivery for asthma and related conditions.

"Depending on their particle size, inhaled drug particles will deposit in different regions of the lung. Particles <1 μπι are likely to reach the peripheral airways and alveoli or be exhaled, particles 1-5 pm will deposit in the large and conducting airways, while particles >5 pm will predominately deposit in the mouth and oropharynx." (Inhaler Technique and Training in People With Chronic Obstructive Pulmonary Disease and Asthma: Effects of Particle Size on Lung Deposition (CME) Toby G.D. Capstick, MRPharmS; Ian J. Clifton, MD). Of course, asthma inhalers typically employ a propellant to further help delivery the particles to the lung. E-cigarettes, personal vaporizers and nicotine inhalers do not have the benefit of propellant but rather rely on the pressure differentials created by the action of the lung itself. While there is some difference of views relative to the particle size of water contained in a water vapor, some argue that droplets in the 2-5 micron range can constitute a vapor. There is not rigid distinction between vapors and gases. Vapors are gases, that is, consist of non-associated molecules. Generally speaking, a gas is considered a vapor when its standard state at that pressure and temperature is a liquid or a solid. So, for example, gaseous water at less than 100° C is usually called a water vapor. The trick, of course, is that the partial pressure of the water vapor is less than one atmosphere. However more importantly, condensation occurs which results in sizes that are too large to operationally do much other than deposit in the mouth, oral pharynx and nasal pharynx.

We teach herein the use of a capture agent, which we define as a material that can (a) temporarily bind condensate and (b) maintain the condensate in contact with mucosal surfaces for a sustained period to enable absorption. This will allow for increased absorption of nicotine (or other actives as discussed herein). By "sustained period," we mean 0.5 to 90 minutes, preferably 3 to 10 minutes.

The capture agent is contained in the absorption conditioning unit where it is released into the mouth (or nasal cavity). Such release is 3346

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preferably controlled over a sustained period to ensure availability of the capture agent over a prolonged period.

An additional observation is important here. When a smoker smokes a cigarette, the nicotine uptake in the lung is so rapid and efficient that the loss of nicotine in effluent smoke that is exhaled cannot be seen as a negative aspect of the cigarettes essential pharmacological function. Indeed, the presence of nicotine in such exhaled smoke is has been well studied particularly in research around real or perceived second-hand smoke issues.

There is little doubt that the smoke-like vapor of the e-cigarette (and other vaporizers) is a critical component to consumer acceptance. The inventors are aware of no commercially marketed e-cigarette that does not comprise a vapor agent (glycerin is rapidly becoming the vapor agent of choice). What is interesting here is the dramatic commercial success of the e-cigarette as compared with Nicotrol^® - a product which has a comparable pharmacokinetic performance for the user. The inventors postulate that the cigarette-like experience of the e-cigarette makes the user more relaxed and patient for the slower nicotine delivery of the e-cigarette (as compared with a cigarette). Now, that observation notwithstanding, the e-cigarette would no doubt be even more successful with better nicotine delivery.

In the context of the e-cigarette and its relatively slow nicotine delivery, any nicotine in exhaled vapor is essentially lost nicotine that was actually needed to improve the product (perhaps unlike the cigarette). This is why the capture agent is so important - to capture nicotine and maintain it in buccal or sublingual (or nasal mucosa) contact for effective absorption.

The absorption conditioning unit of the present invention, may, in another embodiment, be used with non-inhaiation based products. For example, a user may use an absorption conditioning unit with a conventional smokeless tobacco product, to enhance nicotine absorption for such product (i.e. using an absorption conditioning unit together with a SNUS pouch).

Similarly, the absorption conditioning unit may be used with other solid or semi-solid orally consumed products containing base alkaloids, like a marijuana sucker, marijuana brownies, and the like. Marijuana sucker formulations are simple and absorption can be greatly improved upon through 3346

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the use of the absorption conditioning unit (for a marijuana sucker recipe, see http://www.medicaimarijuana42Qdepot.com/ cooking%20recipes/

pot%20suckers . htm , which is incorporated by reference).

When the absorption conditioning unit is used with a solid or semi-solid orally consumed product containing a base alkaloid, the capture agent serves to prolong contact of the active ingredient to the mucosa for enhanced absorption prior to swallowing. The use of an absorption conditioning unit with and distinct from a marijuana sucker is a preferred embodiment.

The absorption conditioning unit may further be employed to improve absorption from a liquid compositing containing a base alkaloid. For example, marijuana tinctures are increasingly used through vaporization, and increasingly, through administration to the buccal or oral cavity. The absorption conditioning unit may be used prior to (or simultaneously with, or after) a liquid containing a base alkaloid such as a marijuana tincture to improve absorption therefrom.

While it is possible to use an absorption conditioning unit after the underlying base alkaloid has been delivered, it is a preferred embodiment to use the absorption conditioning unit contemporaneously, or even more preferred, prior to, the administration of the underlying base alkaloid.

Film formers are, without limitation, useful as a capture agent because the condensate (from a vaporizer or smoke) may have solvent activity on condensate, on the one hand, and two, many film agents tend to have muco- adhesive properties that will help maintain the nicotine with mucosal surfaces. Likewise, sugars are useful for this purpose. Other bioadhesive agents may be useful. The film forming polymers described and/or listed in US Patent No. 7,824,588 (the contents of which are incorporated herein by reference) may be useful. The polymer may be water soluble, water swellable, water insoluble, or a combination of one or more either water soluble, water swellable or water insoluble polymers. The polymer may include cellulose or a cellulose derivative. Specific examples of useful water soluble polymers include, but are not limited to, pullulan, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium aginate, polyethylene 3346

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glycol, xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers, starch, gelatin, and combinations thereof. Specific examples of useful water insoluble polymers include, but are not limited to, ethyl cellulose,

hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate and combinations thereof.

The same capture principle may apply to active that is released from a solid, semi-solid or liquid base alkaloid containing composition, for example, a marijuana sucker that is dissolving in the mouth, or a marijuana tincture delivered to the mouth or administered nasally.

As used herein the phrase "water soluble polymer" and variants thereof refers to a polymer that is at least partially soluble in water, and desirably fully or, predominantly soluble in water, or absorbs water. Polymers that absorb water are often referred to as being water swellable polymers. The materials useful with the present invention may be water soluble or water swellable at room temperature and other temperatures, such as temperatures exceeding room temperature. Moreover, the materials may be water soluble or water swellable at pressures less than atmospheric pressure. Desirably, the water soluble polymers are water soluble or water swellable having at least 20 percent by weight water uptake. Water swellable polymers having a 25 or greater percent by weight water uptake are also useful. Films or dosage forms of the present invention formed from such water soluble polymers are desirably sufficiently water soluble to be dissolvable upon contact with bodily fluids.

Other polymers useful as capture agents include biodegradable polymers, copolymers, block polymers and combinations thereof. Among the known useful polymers or polymer classes which meet the above criteria are: poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polydioxanoes, polyoxaiates, poly(.alpha.-esters), polyanhydrides, polyacetates, polycaprolactones, poly(orthoesters), polyamino acids, polyaminocarbonates, polyurethanes, polycarbonates, polyamides, poly(alkyl cyanoacrylates), and mixtures and copolymers thereof. Additional useful polymers include, stereopolymers of L- and D-lactic acid, copolymers of bis(p-carboxyphenoxy) propane acid and sebacic acid, sebacic acid copolymers, copolymers of caprolactone, poly(lactic acid)/poly(glycolic acid)/polyethyleneglycol copolymers, copolymers of polyurethane and (poly(lactic acid), copolymers of polyurethane and poly(lactic acid), copolymers of .alpha.-amino acids, copolymers of . alpha. - amino acids and caproic acid, copolymers of .alpha.-benzyi glutamate and polyethylene glycol, copolymers of succinate and poly(glycols),

polyphosphazene, polyhydroxy-alkanoates and mixtures thereof. Binary and ternary systems are contemplated.

Other specific polymers useful include those marketed under the Medisorb and Biodel trademarks. The Medisorb materials are marketed by the Dupont Company of Wilmington, Del. and are generically identified as a "lactide/glycolide co-polymer" containing "propanoic acid, 2-hydroxy-polymer with hydroxy-polymer with hydroxyacetic acid." Four such polymers include lactide/glycolide 100 L, believed to be 00% lactide having a melting point within the range of 338-347 ° F. (170-175° C); lactide/glycolide 100 L, believed to be 100%, glycolide having a melting point within the range of 437- 455 . (225-235° C); lactide/glycolide 85/15, believed to be 85% lactide and 15% glycolide with a melting point within the range of 338-347° F. (170-175° C); and lactide/glycolide 50/50, believed to be a copolymer of 50% lactide and 50% glycolide with a melting point within the range of 338-347° F. (170- 175° C).

The Biodel materials represent a family of various polyanhydrides which differ chemically.

The sugars and preferred combinations of/with sugars described and/or listed at US No. 5,935,600(the contents of which are incorporated herein by reference), may, without limitation, be useful as capture agents. For example, "sugars" are those substances which are based on simple crystalline mono- and di-saccharide structures, i.e., based on C5 and C6 sugar structures. "Sugars" include simple sugars, e.g., glucose, sucrose, maltose, lactose, arabinose, xylose, ribose, fructose, mannose, pentose, galactose sorbose, dextrose, and sugar alcohols, e.g., sorbitol, xylitol, mannitol, pentatol, maltitol, isomalt, sucralose and mixtures of any of these.

Maltodextrins may be used Maltodextrins include those mixtures of 46

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carbohydrates resulting from hydrolysis of a saccharide feedstock which are described as solids having a DE of up to and including 65.

Maltooligosaccharides produced by selective hydrolysis of cornstarch followed by removal of high and low molecular weight compounds may be used. The general description of maltooligosaccharides as contemplated herein is set forth in U.S. Pat. No. 5,387,431 (the contents of which are incorporated herein by reference). Polydextrose is also contemplated for use as a capture agent. Polydextrose is a non-sucrose, essentially non-nutritive carbohydrate substitute. It can be prepared through polymerization of glucose in the presence of polycarboxylic acid catalyst and polyols. Generally, polydextrose is known to be commercially available in three forms: polydextrose A and polydextrose K, which are powdered solids, and polydextrose N supplied as a 70% solution. Each of these products also contain some low molecular weight components, such as glucose, sorbitol and certain oligomers. Regarding polydextrose, Applicants incorporate herein the contents of U.S. Pat. No.

5,279,849(the contents of which are incorporated herein by reference).

The bioadhesive (and other) agents discussed and/or listed in Pranshu Tangri et a!, International Journal of Biopharmaceutics, 2011 , 2(1): 36-46 (the contents of which are incorporated herein by reference) may be used as capture agents.

Glycerin and/or propylene glycol solubility is desirable so that the capture agent will better bind the vapor (or smoke) condensate (or some or base alkaloid from a solid, semi solid or liquid composition). Preferably, materials used as capture agents are also water soluble because that they naturally wash out of the mouth without leaving unpleasant residue. The term preferably is pointedly used since non-water soluble poiymers wiii ultimately be washed out of the mouth and swallowed - just less readily.

The absorption conditioning unit may comprise a pH buffer agent (a "buffer agent"). Preferably, the buffer agent is used to raise the pH of the mouth in order to increase nicotine absorption in the buccal cavity in a manner which is based on pka and the Henderson Hasselbach equation. Preferably, the pH of the mouth is increased to 7 to 10, preferably 7.8 to 10, most preferably from 8.5 to 9.5. Preferably, the buffer agent increases the pH of 13 073346

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the oral cavity for a period of ten minutes or more after administration. The same may apply to nasal pH conditioning. As noted above, pH conditioning (or penetration enhancer spillover) of the oral cavity can have a beneficial spillover effect on the Gl tract of the user.

Buffering agents may be used to control pH, including without limitation, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, dipotassium phosphate, potassium citrate, sodium phosphate and any other such buffer system. The buffer system may be designed to dynamically control the pH of the product taking into consideration the effect of saliva during use, i.e., a dynamic buffer system. Examples of buffer systems to obtain the preferred pH include dibasic sodium phosphate and monobasic sodium phosphate. Both are FDA accepted buffer materials used and listed in the inactive ingredients list. For example, for a pH of 7, the ratio of monobasic/dibasic can be 4.6/8.6; for a pH of 7.5 the ratio of monobasic/dibasic can be 1.9/11.9; and for a pH of 8.0 the ratio of monobasic/dibasic can be 0.6/13.4. These are mathematically calculated buffer numbers and will need to be adjusted according to the other ingredients added to the formula. They also need to be adjusted for the length of time designed for the dissolution of the dosage unit on the buccal mucosa since saliva can be of a ph of about 6.8 but as it is made in larger amounts in the mouth the ph of saliva can sometimes become more basic. Thus this dynamic buffer range is adjusted in the dosage unit by the amount s of the buffer system since saliva is freshly renewable in the mouth. See Fuisz U.S. Patent Application Publication Nos. 2009/0098192 A1 and US 2011/0318390 A1 discussing dynamic buffering and incorporated herein by reference.

Alkaline buffer agents are easier to work with for sustained release pH control. Acidic agents tend to increase salivary flow which must be addressed in the formulation and practically makes formulation more difficult. The absorption conditioning unit of the present invention will generally not have an acidic character, i.e. lower the pH of water when fully dissolved therein.

The buffer agent may comprise a substantial portion of the absorption conditioning unit, including froml to 99% by mass of the dosage unit itself. 73346

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The absorption conditioning unit may comprise a penetration agent, i.e., a substance that enhances absorption through the mucosa, mucosal coating and epithelium (otherwise known (see U.S. Patent Application

Publication No. 2006/0257463 A1 , the content of which is incorporated herein by reference) as a "penetration enhancer" or "permeability enhancer"). The penetration agent may comprise but is not limited to polyethylene glycol (PEG), diethylene glycol monoethyl ether (Transcutol), 23-lauryl ether, aprotinin, azone, benzalkomin chloride, cetylperidium chloride,

cetylmethylammonium bromide, dextran sulfate, lauric acid, lauric

acid/propylene glycol, lysophosphatilcholine, menthol, methoxysalicylate, oleic acid, phosphaidylcholine, polyoxyethylene, polysorbate 80, sodium EDTA, sodium glycholated, sodium glycodeoxycholate, sodium lauryl sulfate, sodium salicylate, sodium taurocholate, sodium taurodeoxycholate, sulfoxides, and various alkyl glycosides or, as described in U.S. Patent Application

Publication No. 2006/0257463, bile salts, such as sodium deoxycholate, sodium glycodeoxycholate, sodium taurocholate and sodium glycocholate, surfactants such as sodium lauryl sulfate, polysorbate 80, laureth-9, benzalkonium chloride, cetylpyridinium chloride and polyoxyethylene monoalkyl ethers such as the BRIJ.RTM. and MYRJ.RTM. series, benzoic acids, such as sodium salicylate and methoxy salicylate, fatty acids, such as lauric acid, oleic acid, undecanoic acid and methyl oleate, fatty alcohols, such as octanol and nonanol, laurocapram, the polyols, propylene glycol and glycerin, cyclodextrins, the sulfoxides, such as dimethyl sulfoxide and dodecyl methyl sulfoxide, the terpenes, such as menthol, thymol and limonene, urea, chitosan and other natural and synthetic poiymers. Preferably, the penetration agent is a polyol, e.g., polyethylene glycol (PEG), glycerin, maltitol, sorbitol etc. or diethylene glycol monoethyl ether (Transcutol).

Thermal agents may also be employed. Heat increases blood flow which can in turn increase absorption. Physical agents may be employed - for example, in a liquid format the liquid may be pre-heated (like adding agents to water pre-heated for tea). Chemical thermal agents may be employed to provoke an exothermic reaction. T U 2013/073346

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Desirably, the absorption conditioning unit further might, but not necessarily, comprise at least one flavor for more pleasant administration. Some care must go to flavor selection so that the absorption conditioning unit is pleasant yet not disruptive to the flavor delivered by the inhalation device. Tobacco flavor may be desirable as such and not require any other flavor. Appropriate flavors can be sourced from Tobacco Technologies in Eldersburg, Maryland. In many examples, the more neutral the flavor the better so as not to interfere with the flavor of the vapor. Trace amounts of tobacco may present in flavorings, particularly for a tobacco flavored-product.

The absorption conditioning unit may further comprise effervescent agents to effect effervescence to enhance or improve absorption. Care must be taken that the acidic component of most effervescent systems does not interfere with the goal of a basic pH range.

The absorption conditioning unit may be built into the end of an electronic smoking device (or similar non-electronic inhalator, or smoking device) such that the user can remove it either with hands or mouth

immediately prior to use. In one embodiment, this can be akin to a cigar smoker "biting off' the end of a cigar, except here the user removes the absorption conditioning unit and retains it in the mouth. It may also be possible to use a flavored liquid that is dispensed, akin to the menthol "crush" systems that are currently sold but adapted for this purpose. It may also be a dissolvable tip which conditions the pH of the saliva.

It is expressly contemplated that the present invention can be used to enhance the delivery of bioactives such nicotine, THC, tobacco, cannabidiol, cocaineor a base alkaloid, or any combination thereof. The present invention can be adapted for use with marijuana/tobacco combinations. Such

combinations can involve the vaporization of tobacco and marijuana leaf, or a mixture of extracts from both materials.

The absorption conditioning unit of the present invention may be employed with suitable adaptation (e.g. optimize target buccal pH or target nasal pH) to enhance the absorption of THC (tetrahydrocannabinol), cannabidiols and other active ingredients from cannabis. While the use of marijuana remains controversial, the general trend towards decriminalization 73346

18

and even legalization is clear. Moreover, the use of medical marijuana is growing rapidly. This takes the form of marijuana leaf, marijuana extract, and marijuana active components that are delivered via approved

pharmaceuticals, like GW Pharma's Sativex^®' an oral mucosa spray.

The vaporization of marijuana has also become popular but is less visible given the grey market status of marijuana. However, vaporization of marijuana is an increasingly common and accepted form of marijuana use. Indeed, Health Canada's September 2010 document on Marijuana entitled "Information for Health Care Professionals," notes the benefits of vaporization of marijuana as compared with smoking marijuana:

"Vaporization of cannabis has been explored as an alternative to smoking. The advantages of vaporization apparently include the formation of a smaller quantity of toxic by-products such as carbon monoxide, polycyclic aromatic hydrocarbons (PAHs) and tar, as well as a more efficient extraction of THC from the cannabis material (47,48,49,43,50). The subjective effects and plasma concentrations of THC are comparable to those of smoked cannabis with absorption being somewhat faster with the vaporizer (43). The vaporizer is well-tolerated, with no reported adverse effects, and is generally preferred over smoking by most subjects (43). While vaporization is amenable to self-titration (49,43), the proper use of the vaporizer for optimal

administration of medicinal cannabis has to be established in more detail (50). The amount and type of cannabis placed in the vaporizer, the vaporizing temperature and duration of vaporization, and the balloon volume are some of the parameters that can affect the delivery of THC (49). Bioequivalence of vaporization compared to smoking has not been established."

The reference to THC absorption being faster with a vaporizer is curious in view of the same document's discussion of buccal and oral routes which show that buccal absorption is relatively slow. This may be explained by the fact that the cited study employed pure THC as opposed to vaporizing marijuana plant material (or an extract therefrom).

"Following a single buccal administration of Sativex^® (four sprays of Δ⁹- THC 27mg/ml_ and CBD 25 mg/mL, totaling 10.8mg A⁹-THC and 10 mg CBD), peak plasma concentrations of both THC and CBD typically occur 6

19

within 2-4 h (55). When administered bucally, blood levels of THC and other cannabinoids are lower than those achieved by inhalation of the same dose of smoked cannabis because absorption is slower, redistribution into fatty tissue is rapid and some of the THC undergoes hepatic first-pass metabolism to 11- hydroxy-THC (55)."

"THC can be absorbed orally by ingestion of foods containing cannabis (butters, oils, brownies, cookies), teas prepared from leaves and flowering tops, or through ingestion of capsules containing THC or THC analogues. Absorption from an oral dose of 20 mg THC in a chocolate cookie was described as slow and unreliable (42), with a systemic availability of only 4 to 12% (46). While most subjects displayed peak plasma THC concentrations between 1 to 2 h, some of the 11 subjects in the study only peaked at 6 h and many had more than one peak. Consumption of cannabis-laced brownies containing 2.8% THC was associated with changes in behavior although the effects were slow to appear and variable (51). Peak effects occurred 2.5 to 3.5 h after dosing. Modest changes in pulse and blood pressure were also noted. Tea made from dried cannabis flowering tops (19.1 % THCA, 0.6% THC) has been documented, but the bioavailability of THC from such teas is likely to be smaller than that achieved by smoking (52). Only 10-20% of synthetic THC (dronabinol, Marinol®) administered in capsules with sesame oil enters the systemic circulation indicating extensive first-pass metabolism (53). The psychotropic effect or "high" occurs more quickly by the smoking than the oral route, which has been characterized by Iversen (54) as the reason "smoking is the preferred route of cannabis for many people"."

The buccal and/or sublingual use of tinctures is known (See

http:/ypatients4medicaimanju

video/marijuana-tincture/, incorporated by reference hereby).

Thus, the dynamic of marijuana vaporization is functionally comparable to tobacco/nicotine. In each case the actives are not effectively delivered to the deep lung but tend to be absorbed buccally. Marijuana is however different in that swallowed condensate is more apt to be absorbed in the Gl tract than nicotine. 13 073346

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It is important to note that while the disclosure above discussed electronic vapor devices, it will appreciated that the present invention can equally be employed with non-electronic vapor devices. Electronic - and specifically electrical devices are the most common type of vapor device.

However, vapor devices can also be "analog" like for example the butane-fired Ploom^® device or the butane fired "click-a-toke." Similarly, vapor can be generated from hookah-like devices powered by hot coals and the like. And, it is possible to have an inhaler - like Nicotrol^® - that does not use any heat source. It should be noted that it is expressly contemplated that the present invention can be used with any inhaler-like device (and not solely with a vapor device). The present invention may also be used with smoking devices (e.g. a marijuana cigarette), or with solid, semi-solid or liquid compositions (e.g. a marijuana sucker or a marijuana tincture).

Because the absorption conditioning unit does not contain tobacco or nicotine, it will generally be exempt from regulation, except where it is part of an approved pharmaceutical product (i.e. a "combination product").

References to nicotine herein include any nicotine salt, nicotine that is naturally or synthetically derived, including from tobacco or any other material.

In addition to nicotine, tobacco and marijuana, derivatives, the present invention (i.e. the absorption conditioning unit) can be readily adapted to assist with the absorption of other bioactive agents generally, and in

particular, alkaloids, especially the absorption of inhaled base alkaloids.

Preferably, base alkaloids in the form of those with pka of pH 6 or more.

Alkaloids are produced by a large variety of organisms,

including bacteria, fungi, plants, and animals, and are part of the group of natural products (also called secondary metabolites). Many alkaloids can be purified from crude extracts by acid-base extraction. Many alkaloids are toxic to other organisms. They often have pharmacological effects and are used as medications, as recreational drugs, or in entheogenic rituals.

Examples are the local anesthetic and stimulant cocaine; the

psychedelic psilocin; the stimulant caffeine; nicotine; the analgesic morphine; the antibacterial berberine; the anticancer compound vincristine; the

antihypertension agent reserpine; the cholinomimeric galatamine; the T/US2013/073346

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spasmolysis agent atropine; the vasodilator vincamine; the anti-arhythmia compound quinidine; the anti-asthma therapeutic ephedrine; and

the antimalarial drug quinine. Although alkaloids act on a diversity of metabolic systems in humans and other animals, they almost uniformly invoke a bitter taste.

Alkaloids are often divided into the following major groups: "True alkaloids", which contain nitrogen in the heterocycle and originate from amino acids. Their characteristic examples are atropine, nicotine, and morphine. This group also includes some alkaloids that besides nitrogen heterocycle contain terpene (e.g., evonine) or peptide fragments (e.g. ergotamine). This group also includes piperidine alkaloids coniine and coniceine although they do not originate from amino acids; "Protoalkaloids", which contain nitrogen and also originate from amino acids. Examples include mescaline, adrenaline and ephedrine; "Polyamine alkaloids" - derivatives of putrescine, spermidine, and spermine; "Peptide and cyclopeptide alkaloids; and "Pseudalkaloids" - alkaloid-like compounds that do not originate from amino acids. This group includes, terpene-like and steroid-like alkaloids, as well as purine-like alkaloids such as caffeine, theobromine and theophylline. Some authors classify as pseudoalkaloids such compounds such as ephedrine and cathinone. Those originate from the amino acid phenylalanine, but acquire their nitrogen atom not from the amino acid but through transamination.

In a preferred aspect of the invention, the absorption conditioning unit does not contain a "drug" as defined hereinafter.

In another preferred aspect of the invention, the absorption

conditioning unit does not contain drugs, antigenics, antibodies, tobacco, or cosmaceutieals.

In another preferred aspect of the invention, the absorption

conditioning unit does not contain any bioactive agent.

As used herein, the term "bioactive agent" shall mean any

pharmaceutical, antigenic, antibody, botanical, tobacco, food, nutraceutical, or cosmaceutical.

While the primary embodiment of the absorption conditioning unit is directed towards, primarily conditioning the oral environment for improved 3 073346

22

absorption (and in some cases secondarily conditioning the Gl tract), the present invention is expressly contemplated for use to improve absorption via nasal sites. For example, the absorption conditioning unit may comprise a liquid spray or powder that is applied to the nasal cavity prior to the nasal use of a base alkaloid such as but not limited to cocaine.

Some prominent civil libertarians have called for the decriminalization/ legalization of cocaine to follow the current decriminalization/legalization of marijuana. The nasal cavity can be conditioned for enhanced absorption prior to administration of the base alkaloid (e.g. insufflation of cocaine).

For nasal conditioning, the preferred embodiment of the absorption conditioning unit will be a liquid spray, a gel, beads, microcapsules, or a powder that can be deployed in the nasal cavity.

Conditioning the nasal cavity poses some alternative formulation issues than the oral cavity. The relative paucity of salivary secretion as compared with the oral cavity makes things easier in some respects. For example , pH control is more easily effected where there is not a heavy salivary refresh dynamic of new secretion to dilute and lower pH. On the other hand, lack of salivary flow means that dosage units that would dissolve in the oral cavity will not readily dissolve in the nasal cavity. Where a liquid is used, increased viscosity (as compared with water) and increased surface tension (as compared with water) can be used to encourage the liquid absorption conditioning unit to remain at the intended site for sustained effect including without limitation sustained pH buffering. Buffered nasal solutions for nasal irrigation are known (see http://www.sinucleanse.com/images/ parsons-1.pdf, which is fully incorporated by reference), but because the purpose of such liquids is irrigation they are intended to essentially flush out the nasal passages and operate only modestly increased basic pH ranges.

Examples of pharmaceutical bioactive agents include, but are not limited to ace inhibitors, such as Benazepril, Captopril, Enalapril, Lisinopril, Moexipril, Perindopril, Quinapril, Ramipril and Trandolapril; acne treatments, such as adapalene, azelaic acid, BenzaClin, Benzamycin, Benzoyl Peroxide, clindamycin, Duac, Erythromycin, Glycolic Acid, Isotretinoin, Sulfacetamide with sulfur, Tazarotene and Tretinoin; actinic keratosis, such as declofenac, 2013/073346

23

fluorouracil; addiction aids, such as buprenorphine, Disulfiram, Naltrexone, Suboxone and varenicline; aldosterone antagonists, such as eplerenone and spironolactone; alpha-1 adrenergic blockers, such as alfuzosin, doxazosin, prazosin, tamsulosin and terazosin; ALS agents, such as riluzole; Alzheimer's Disease medications, such as donepezil, Galantamine, rivastigmine, tacrine and memantine; anesthetics, such as dexmedetomidine, etomidate, ketamine, methohexital, pentobarbital, propofol and thiopental; angiotensin II receptor blockers, such as candesartan, eprosartan mesylate, irbesartan, losartan, olmesartan, telmisartin and valsartan; antacids, such as Aluminum hydroxide, AIOH and magnesium trisilicate; anti-arrhythmics, such as adenosine, amiodarone, Atropine, Bretylium, digoxin-lmmune Fab, disopyramide, dofetilide, epinephrine, Esmolol, flecainide, ibutilide, isoproterenol, lidocaine, mexiletine, moricizine, procainamide, propafenone, quinidine, sotalol, tocainide and verapamil; antibiotics, such as Aztreonam, TMP/SMX,

Chloramphenicol, Clindamycin, Dapsone, Daptomycin, Ertapenem,

Imipenem/cilastatin, Linezolid, Meropenem, Metronidazole, Nitrofurantoin, Quinupristin/Dalfopristin, Rifaximin, Tigecycline, Telithromycin and Tinidazole; anticholinergic acids, such as Dicyclomine, Donnatal, Flavoxate,

Glycopyrrolate, Hyoscyamine, Oxybutynin, Propantheline and Tolterodine; anticonvulsants, such as carbamazepine, clonazepam, diazepam,

ethosuximide, felbamate, fosphenytoin, gabapentin, levetiracetam,

lamotrigine, lorazepam, Oxcarbazepine, Phenobarbital, phenytoin, pregabalin, primidone, tiagabine, topiramate and valproic acid; antidepressants, such as amitriptyline, buproprion, citalopram, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, mirtazapine, nefazodone, nortriptyline, nortriptyline, sertraline, trazodone and veniafaxine; anti- diarrheals, such as dephenoxylate+atropine, Imodium and bismuth

subsalicylate; anti-emetics, such as Aprepitant, dolasetron, droperidol, granisetron, metoclopramide, ondansetron, prochlorperazine, scopolamine and trimethobenzamide; antifungals, such as Ampho B, Ampho B lipid, anidulafungin , caspofungin, Clotrimazole fluconazole, flucytosine,

Griseofulvin, Itraconazole, ketoconazole, Micafungin, nystatin, Posaconazole, terbinafine, voriconazole, butenafine, ciclopirox, clotrimazole, enconazole, 3346

24

ketoconazole, Miconazole, naftifine, nystatin, oxiconazole terbinafine and Tolnaftate; anti-hepatitis, such as adefovir, entecavir, lamivudine,

peginterferon alfa-2a, peginterferon alfa-2b, Rebetron and ribavirin; anti- herpetic agents, such as Acyclovir, famciclovir, valacyclovir, acyclovir, docosanol and penciclovir; antihistamines, such as cetirizine, desloratadine, fexofenadine, loratadine, chlorpheniramine, clemastine, cyproheptadine, dimenhydrinate, diphenhydramine, hydroxzine and promethazine; anti- hypertension, such as Benazepril & HCTZ, Captopril & HCTZ, Enalapril & HCTZ, Lisinopril & HCTZ, Moexipril & HCTZ, Losartan & HCTZ, Valsartan & HCTZ, Atenolol & chlorthalidone, Bisoprolol & HCTZ, Metoprolol & HCTZ, Nadolol & bendroflumethazide, Propranolol & HCTZ, Timolol & HCTZ,

Amlodipine & benazepril, Verapamil & trandolapril, Amiloride & HCTZ,

Spironolactone & HCTZ, Triamterene & HCTZ, Clonidine & chlorthalidone, Hydralazine & HCTZ, Methyldopa & HCTZ and Prazosin & polythiazide; anti- hypertensives, such as Aliskiren, Aliskiren, epoprostenol, fenoldopam, hydralazine, minoxidil, nitroprusside, phentolamine and treprostinil; anti- influenza agents, such as amantadine, oseltamivir phosphate, rimantadine and zanamivir; anti-malarials/anti-protozoals/amebicides, such as

Atovaquone, Chloroquine, lodoquinol, Mefloquine, Primaquine,

Pyrimethamine, Pyrimethamine -Sulfadoxine and Quinine Sulfate; anti-platelet agents, such as abciximab, dipyridamole/ASA, anagrelide, cilostazol, clopidogrel, dipyridamole, eptifabatide, ticlopidine and tirofiban;

antipsychotics, such as aripiprazole, chlorpromazine, Clozapine,

fluphenazine, haloperidol, loxapine, molindone, olanzepine, perphenazine, pimozide, quetiapine, risperidone, thioridazine, thiothixine, trifluoperazine, ziprasidone and Lithium; antispasmotics, such as Dicyclomine, Donnatai Extentabs, Propantheline, Simethicone, hyoscyamine, Librax, tegaserod and Bellergal-S; anti-tussives/expectorants, such as Benzonatate and guaifenesin; atopic dermatitis medications, such as pimecrolimus and tacrolimus;

benzodiazepines and non-benzodiazepine sedatives, such as alprazolam, buspirone, chlordiazepoxide, chlorazepate, clonazepam, diazepam, estazolam, eszcpiclone, flurazepam, lorazepam, midazolam, Oxazepam, ramelteon, temazepam, triazolam, zaieplon and Zolpidem; beta blockers, such 2013/073346

25

as atenolol, betaxolol, bisoprolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, pindolol, propranolol, sotalol and timolol; bile acid sequestrants, such as cholestyramine, colesevelam and colestipol; bisphosphonates, such as alendronate, etidronate, pamidronate, risedronate, tiludronate and Zoledronic acid, Raloxifene and Teriparatide; bladder spasm medications, such as flavoxate.hyoscyamine, darifenacin, oxybutynin, solifenacin, tolterodine and trospium; benign prostatic hypertrophy medications, such as alfuzosin, doxazosin, dutasteride, finasteride, tamsulosin and terazosin; burn

preparations, such as mafenide acetate and silver sulfadiazine; calcium channel blockers, such as amlodipine, bepridil, diltiazem, felodipine, isradipine, nicardipine, nifedipine and nisoldipine; calcium supplements, such as Calcium and Hypocalcemia; cephalosporins, such as Cefadroxil, Cefazolin, Cephradine, Cephalexin, Cefaclor, Cefotetan.Cefoxitin, Cefprozii, Cefuroxime, Cefuroxime, loracarbef, Cefdinir, Cefixime, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime and Cefepime; colony stimulating factors, such as darbepoietin alfa, erythropoietin, filgrastim, oprelvekin, pegfilgrastim and sargramostim; corticosteroids, such as

Budesonide, cortisone acetate, dexamethasone, fludrocortisones,

hydrocortisone, methylprednisolone and prednisone; corticosteroids Intra- articular, such as Depo-Medrol and Triamcinolone Acetonide; cystitis, such as pentosan polysulfate, Bethanecol and Alum irrigation; decongestants, such as Phenylephrine and Pseudoephedrine; anti-diabetic agents, such as acarbose, Miglitol and metformin, Avandamet.RTM., Glucovance, Metaglip, Metaglip, rosiglitazone, osiglitazone, repaglinide, Chlorpropamide, glimepiride, glyburide, glipizide, Tolazamide, Tolbutamide, Glucagon, extenatide and pramiintide; direct thrombin inhibitors, such as argatroban, Bivaiirudin and lepirudin; disease modifying agents, such as adalimumab, anakinra, auranofin, azathioprine, etanercept, hydroxychloroquine, infliximab,

leflunomide, methotrexate and sulfasalazine; diuretics, such as

Acetazolamide, Amiloride, Amiloride and HCTZ Bendroflumethiazide,

Bumetanide, Chlorothiazide, Chlorthalidone, Dichlorphenamide, Eplenerone, Ethacrynic acid, Furosemide, Hydrochlorothiazide, HCTZ/Triampterene, Hydroflumethiazide, Indapamide, Methazolamide, Methyclothiazide, 2013/073346

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Methyclothiazide, Metolazone, Polythiazide, Spironolactone, Spironolactone, HCTZ Torsemide, Trichlormethiazide and Triamterene; endocrine agents, such as bromoc cinacalcet cosyntropin, riptine, cabergoline, calcitonin, desmopressin, Leuprolide, octreotide and vasopressin; erectile dysfunction agents, such as Sildenafil, tadalafil, vardenafil; fever medications, such as allopurinol, antihistamines, azathioprine, barbiturates, carbamazepine, cephalosporins, cimetidine, folic acid, hydralazine, hydroxyurea, ibuprofen, isoniazid, methyldopa, nitrofurantoin, penicillins, phenytoin, phenytoin, procainamide, prophylthiouracil, quinidine, streptomycin sulfonamides, sulindac, triamterene and vancomycin; fibrates, such as clofibrate, fenofibrat and gemfibrozil; fluoroquinolones, such as Ciprofloxacin, Gatifloxacin,

Levofloxacin, Moxifloxacin, Norfloxacin and Ofloxacin; gastrointestinal agents, such as Alosetron, infliximab, Mesalamine, misoprostol, Neomycin,

octreotidev, osalazine, Orlistat, sucralafate, Sulfasalazine and vasopressin; gout treatments, such as allopurinol, colchicine, probenecid, Rasburicase and sulfinpyrazone; H2 receptor blockers, such as cimetidine, famotidine, nizatidine and ranitidine; aAnti-herpetic agents, such as Acyclovir, famciclovir, valacyclovir, acyclovir, docosanol and penciclovir; hypertensive urgency, such as Captopri!, Clonidine and Labetalol; hypertensive emergency, such as Enalaprilat, Esmolol, Fenoldopam mesylate, Hydralazine, Labetalol,

Nicardipine, Nitroglycerin and Sodium nitroprusside; hemorrhoidal

preparations, such as Anusol HC, Anusol Suppository, Dibucaine, pramoxine 1%, Proctofoam-HC and Analpram-HC; inflammatory bowel disease agents, such as balsalazide, budesonide, infliximab, mesalamine, olsalazine and sulfasalazine; Interferon, such as Interferon Alfa-2A, Interferon Alfa-2b, interferon Aifa-2b and Ribavirin combo Pack, interferon Aifa-N3, interferon Beta-1A, Interferon Beta-1 B (Betaseron); intermittent claudication, such as cilostazol and pentoxifylline; immunizations, such as Comvax, diphtheria- tetanus toxoid, Hepatitis A vaccine, Hepatitis B vaccine, Influenza vaccine, Fluzone, Lyme disease vaccine, PNEUMOVAX* 23; laxatives, such as

Bisacodyl, Cascara, Docusate, Fleet Phospho-Soda, Glycerin, Lacalutose, lubiprostone, Magnesium citrate, Magnesium hydroxide-MOM, Mineral Oil, Pericolace, Psyllium and Senna; low molecular weight heparins, such as 13 073346

27

dalteparin, danaparoid, enoxaparin, tinzaparin, fondaparinux; macrolides, such as Azithromycin, Clarithromycin and Erythromycin; magnesium, such as magnesium salt; migraine treatments, such as almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan, Cafergot.RTM., Cafergot.RTM., dihydroergotamine and Midrin.RTM.; mouth and lip

treatments, such as amlexanox, Benzocaine, carbamide, peroxide, Kenalog in Orabase.RTM., Phenol, chlorhexidine gluconate, clotrimazole, Nystatin, Penciclovir, docosanol, Gelclair, lidocaine viscous, BMX Cocktail, Pilocarpine and Artificial saliva; multiple sclerosis treatments, such as glatiramer, interferon beta-1A and interferon beta-1 B; muscle relaxants, such as baclofen, carisprodol, cyclobenzaprine, cyclobenzaprine, Diazepam,

Metaxalone, Methocarbamol, Orphenadrine; nasal preparations, such as azelastine, beclomethasone, budesonide, cromolyn, desmopressin acetate, flunisolide, fluticasone, Ipratropium bromide, mometasone, oxymetazoline, phenylephrine, Saline nasal spray, Sumatriptan, triamcinolone and

Zolmitriptan; urology treatments, such as Belladonna and opium, flavoxate, hyoscyamine, hyoscyamine, oxybutynin, solifenacin, tolterodine and trospium; neuromuscular blockers, such as Atracurium, Cisatracurium, doxacurium, mivacurium, pancuronium, Rocuronium, Succinylcholine, vecuronium,

Mivacurium, Rapacuronium, Rocuronium, Succinylcholine, Atracurium,

Cisatracurium, Pancuronium, Vecuronium, Doxacurium, Pipecuronium and Tubocurarine; nitrates, such as Isosorbide dinitrate, Isosorbide mononitrate, Nitroglycerin ointment, Nitrobid and Nitroglycerin transdermal; NSAID's, such as Arthrotec, diclofenac, Etodolac, indomethacin, Ketorolac, Sulindac, Tolmentin Diflunisal Salsalate Meloxicam, piroxicam, Nabumetone

Flurbiprofen, ibupropen, Ketoprofen, Naproxen, Oxaprozin, celecoxib, Rofecoxib and Valdecoxib; ophthalmic agents, such as, proparacaine, tetracaine, Ciprofloxacin, Erythromycin, Gentamcyin, levofloxacin,

levofloxacin, norfloxacin, Ofloxacin, Polysporin.RTM., Polytrim,

Sulfacetamide, Tobramycin, Blephamide.RTM., Blephamide.RTM.,

Maxitrol.RTM., Pred G.RTM. and TobraDex.RTM., Dexamethasone,

Fluorometholone, Loteprednol, Prednisone, Rimexolone, azelastine,

Cromolyn sodium, emedastine, Epinastine, Ketotifen Fumarate Ophthalmic 13 073346

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Solution 0.025%, Levocabastine, Lodoxamide tromethamine, Naphazoline, Naphcon-A.RTM., nedocromil, Olopatadine, pemirolast, Betaxolol, Betaxolol, Levobunolol, Timolol, Brinzolamide, Dorzolamide, Pilocarpine, bimatoprost, Latanoprost, travoprost, unoprostone, Apraclonidine, Brimonidine,

Cosopt.RTM. and Cosopt.RTM., Atropine, Cyclopentolate, Homatropine, Phenylephrine, Phenylephrine, Diclofenac, Flurbiprofen and Ketorolac; ear (otic) preparations, such as Auralgan.RTM., carbamide peroxide,

CIPRODEX.RTML, Ciprofloxacin and hydrocortisone, Cortisporin.RTM., Ofloxacin, Triethanolamine and Vosol Otic.RTM.; opiates, such as Codeine Fentanyl Hydrocodone Hydrocodone, Meperidine Methadone, morhphine, xycodone, Propoxyphene, Darvon.RTM., Fioricet, Fiorinal, Soma compound, Tramadol, Anexsia, Darvocet, Darvon Compound, Lorcet, Lortab, Percocet, Percodan, Roxicet, Tylenol with Codeine, Tylox, Vicodin, Wygesic,

Buprenorphene, Butorphanol, Dezocine, Nalbuphine, Pentazocine,

Nalmefene Naloxone, Suboxone.RTM. and Ziconotide; parkinson's disease treatments, such as amantadine, benztropine, bromocriptine, entacapone, pergolide, pramipexole, ropinirole, selegiline, Sinemet.RTM., tolcapone and trihexyphenidyl; PCA--Patient Controlled Analgesia, such as Fentanyl, Hydromorphone, Meperidine and Morphine; penicillin's, such as Ampicillin, Ampicillin/sulbactam, Amoxicillin, Amoxicillin/Clavulanate, Cloxacillin,

Dicloxacillin, Nafcillin, Penicillin G, Penicillin VK, Piperacillin,

Piperacillin/Tazobactamm, Ticarcillin, and Ticarcillin/Clavulanate; phosphate supplementation, such as, K-Phos.RTM. Neutral Tablets, K-PHOS.RTM. ORIGINAL, Neutra-Phos.RTM.; potassium supplementation, such as K-LOR, Klor-Con.RTM., Potassium depletion; prostate cancer medications, such as bicalutamide, fiutamide, gosereiin, ieuprolide and niiutamide; proton pump inhibitor's, such as esomeprazole, Lansoprazole, Omeprazole, Pantoprazole and Rabeprazole Sodium; psoriasis medications, such as acitretin, aiefacept, Anthralin, Calcipotriene, efalizumab and Tazarotene; renal failure

medications, such as Aluminum Hydroxide, Calcium acetate, Calcitriol, Doxercalciferol, Ferric Sodium Gluconate, paricalcitol and sevelamer;

pulmonary medications, such as ipratropium, tiotropium, albuterol, bitolterol, levalbuterol, pirbuterol, metaproterenol, formoterol, salmeterol, Advair.RTM., 13 073346

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Symbicort.RTM., beclomethasone, budesonide, flunisolide, fluticasone, Mometasone furoate, triamcinolone, montelukast Singulair.RTM., zafirlukast, cromolyn sodium, nedocromil, acetylcysteine and aminophylline/theophylline; disease modifying agents, such as adalimumab, anakinra, auranofin, azathioprine, etanercept, hydroxychloroquine, infliximab, leflunomide, methotrexate and sulfasalazine; HMG COA reductase inhibitors, such as Atorvastatin, Fluvastatin, Lovastatin, Pravastatin, Rosuvastatin, Simvastatin, Advicor.RTM., Vytorin.RTM. and ezetimibe; stimulants, such as atomoxetine, benzphetamine, Caffeine, dexmethylphenidate, Dextroamphetamine, diethylpropion, Methylphenidate, Modafinil, Pemoline, phendimetrizine, phentermine and sibutramine; tetracyclines such as Doxycycline, Minocycline andTetracycline; thrombolytic agents such as Alteplase; anti-thyroid agents such as methimazole and propylthiouracil; toxicology related medications such as acetylcysteine, Charcoal, deferoxamine, digoxin immune fab, flumazenil, fomepizole, methylene blue, naloxone, sodium polystyrene sulfonate and Sorbitol; anti-mycobacterial agents such as Ethambutol, Isoniazid, Pyrazinamide, rifabutin, Rifamate, Rifampin, Rifapentine and Rifater; topical products such as Alitretinoin, Becaplermin, Calamine, Capsaicin, Doxepin, lidocaine/prilocaine, fluorouracil, Masoprocol,

Pimecrolimus, Selenium sulfide and Tacrolimus; topical anti-viral agents such as acyclovir, docosanol, imiquimod, penciclovir, podofilox and podophyllin; topical antibacterials such as bacitracin, metronidazole, mupirocin, bacitracin/neomycin/polymyxin, bacitracin/polymyxin and silver sulfadiazine; topical antifungals such as butenafine, ciclopirox, clotrimazole, econazole, ketoconazole, miconazole, naftifine, nystatin, oxiconazole, terbinafine and toinaftate; topical anti-parasitic agents such as Crotamiton, Lindane,

Permethrin, pyrethrins and piperonyi butoxide; topical burn preparations such as mafenide acetate and silver sulfadiazine; topical corticosteroids such as Aclometasone diproprionate, Desonide, Flucinolone acetonide,

Hydrocortisone, Betamethasone dipropionate, betamethasone valerate, clocortolone pivalate, desoximetasone, fluocinolone acetonide,

flurandrenolide, fluticasone propionate, Chydrocortisone butyrate,

hydrocortisone valerate, mometasone furoate, prednicarbate, triamcinolone, 13 073346

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amcinonide, augmented betamethasone dipropionate, betamethasone dipropionate, desoximetasone, diflorasone diacetate, fluocinolone acetonide, fluocinonide, halcinonide, clobetasol propionate, diflorasone diacetate and halobetasol propionate; urology medications such as pentosan polysulfate, Bethanecol and phenazopyridine; vaginal preparations such as clindamycin, metronidazole, butoconazole, clotrimazole, miconazole, terconazole and tioconazole; vasodilators such as Fenoldopam mesylate, Hydralazine,

Nesiritide, Nicardipine, Nitroglycerin, and Sodium Nitroprusside; and vasopressors and inotropes such as Dobutamine, Dopamine, Epinephrine, inamrinone, Milrinone, Norepinephrine, Phenylephrine, and Vasopressin.

Examples of food or nutraceutical bioactive agents include, but are not limited to, constituents in foods or dietary supplements that are responsible for changes in health status, such as components of plants, especially fruits and vegetables, e.g., soy which contains isoflavones and phytoestrogens, tomatoes which contain lycopene that may have anticancer properties, berries such as blueberries and raspberries which contain flavonoids like

anthocyanins that may act as antioxidants, green tea which contains epigallocatechin gallate (EGCG) that may have anticancer properties, resveratrol from red grape products as an antioxidant, soluble dietary fiber products, such as psyllium seed husk for reducing hypercholesterolemia, broccoli (sulforaphane) as a cancer preventative, and soy or clover

(isoflavonoids) to improve arterial health.

Examples of antigen bioactive agents include, but are not limited to exogenous antigens, endogenous antigens, autoantigens and tumor antigens. Exogenous antigens are antigens that have entered the body from the outside, for example by inhalation, ingestion, or injection. By endocytosis or phagocytosis, these antigens are taken into the antigen-presenting cells (APCs) and processed into fragments. APCs then present the fragments to T helper cells (CD4⁺) by the use of class II histocompatibility molecules on their surface. Some T cells are specific for the peptide.MHC complex. They become activated and start to secrete cytokines. Cytokines are substances that can activate cytotoxic T lymphocytes (CTL), antibody-secreting B cells, macrophages, and other particles. Endogenous antigens are antigens that T U 2013/073346

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have been generated within the ceil, as a result of normal cell metabolism, or because of viral or intracellular bacterial infection. The fragments are then presented on the cell surface in the complex with MHC class I molecules. If activated cytotoxic CD8⁺T cells recognize them, the T cells begin to secrete various toxins that cause the lysis or apoptosis of the infected cell. In order to keep the cytotoxic cells from killing cells just for presenting self-proteins, self- reactive T cells are deleted from the repertoire as a result of tolerance (also known as negative selection). They include xenogenic (heterologous), autologous and idiotypic or allogenic (homologous) antigens. An autoantigen is usually a normal protein or complex of proteins (and sometimes DNA or RNA) that is recognized by the immune system of patients suffering from a specific autoimmune disease. These antigens should, under normal conditions, not be the target of the immune system, but, due to mainly genetic and environmental factors, the normal immunological tolerance for such an antigen has been lost in these patients. Tumor antigens or Neoantigens are those antigens that are presented by MHC I or MHC II molecules on the surface of tumor cells. These antigens can sometimes be presented by tumor cells and never by the normal ones. In this case, they are called tumor- specific antigens (TSAs) and, in general, result from a tumor-specific mutation. More common are antigens that are presented by tumor cells and normal cells, and they are called tumor-associated antigens (TAAs). Cytotoxic T lymphocytes that recognize these antigens may be able to destroy the tumor cells before they proliferate or metastasize. Tumor antigens can also be on the surface of the tumor in the form of, for example, a mutated receptor, in which case they will be recognized by B cells.

Examples of botanical bioactive agents include, but are not limited to PMI-004 (advanced botanical formulation for type II diabetes that represents a multi-mechanism bioactive that: 1) in adipocytes increases adiponectin secretion, 2) in the liver lowers PEPCK expression, and 3) in muscle cells increases cellular signaling through the insulin receptor pathway, increasing glucose uptake, glycogen synthase, and glycogen accumulation), PMI-005 (botanical bioactive, derived from a common vegetable, that inhibits gene expression of a variety of pro-inflammatory cytokines (including a-TNF, i-NOS, U 2013/073346

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IL-1 b, and COX-2) that are currently undergoing a human clinical trial in osteoarthritis may also may have utility in the management of severe/life threatening inflammatory conditions, such as in the management of the septic patient), PMI-006 (botanical bioactive, derived from a spice, that inhibits a range of inflammation-related enzymes (including a-TNF and COX-2) and also possesses range of novel bioactivities related to both lipid and glucose metabolism (RXR receptors)), PMI-007 (a powerful, centrally acting, botanical appetite suppressor which acts via a unique central pathway in the nutrient- sensing hypothalamic neurons by increasing ATP content/production, possesses potent anorectic activity without typical CNS appetite suppressor side effects and pre-clinical data for which has shown that the agent suppresses both appetite and reduces weight in animal models, while there is supporting clinical evidence of human efficacy), P I-008 (botanical bioactive, derived from an agricultural waste processing stream, that blocks fat accumulation/absorption and promotes weight loss via interaction with a variety of lipases including PL, LPL, and HSL), and PMI-016 (a powerful, plant-derived anabolic/ergogenic agent, with no androgenic side effects; could be used in a range of human muscle wasting disorders, including those associated with both cancer and AIDS, as well as general aging (sarcopenia); has been shown to induce protein synthesis in muscle cells (similar to IGF) and promote a reduction in protein degradation, while it has also been shown to increase growth hormone gene transcription and decrease in ubiquitin protein ligase gene transcription; and shows no binding to testosterone receptor in contrast to anabolic steroids). Examples of botanical bioactive agents also include tobacco and all tobacco extracts, as well as nicotine itself.

In the present application, we define "drug" as it is defined in The Food, Drug and Cosmetic Act, which defines a drug as follows. "The term "drug" means (A) articles recognized in the official United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles U 2013/073346

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intended for use as a component of any article specified in clause (A), (B), or (C). A food or dietary supplement for which a claim, subject to sections

343(r)(1)(B) and 343(r)(3) of this title or sections 343(r)(1)(B) and 343(r)(5)(D) of this title, is made in accordance with the requirements of section 343(r) of this title is not a drug solely because the label or the labeling contains such a claim. A food, dietary ingredient, or dietary supplement for which a truthful and not misleading statement is made in accordance with section 343(r)(6) of this title is not a drug under clause (C) solely because the label or the labeling contains such a statement." The definitions contained in the Food, Drug and Cosmetic Act as amended and in effect from time to time are hereby incorporated by reference as if fully set forth herein.

Typical confection formulations are not suitable in connection with the present invention. Foremost, confection formulations are typically acidic to provoke additional salivary response. This is good for a juicy candy but is the opposite pH direction to promote nicotine absorption.

The absorption conditioning unit of the present invention can be packaged and sold in a kit together with vapor devices and vapor

compositions (or smoking devices). Vapor compositions can be any form of nicotine, tobacco, marijuana or base alkaloid suitable for vaporization. The vapor device can be components useful for doing so - as simple as a candle or other basic heat source, conventional e-cigarette components, or other personal vaporizer.

The absorption conditioning unit can be adapted for aural and ophthalmic use, i.e. to enhance absorption of base alkaloids to the ear or eye.

The advantageous results of the present invention are evident from the following examples.

Example A (Soft Lozenge)

A soft lozenge was made comprising 300 mg of sodium bicarbonate together with carbowax sentry PEG 1450. The resulting lozenge weighted approximately one gram, had harmless taste and was easily chewable.

The lozenge of this example was provided to a healthy female volunteer, and the pH of her saliva was measured at intervals over a period of ten minutes. 2013/073346

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The tO saliva pH was 6.8; t1 was 8.3; t3 was 8.3; t5 was 8.3 and t10 was 8.1.

For this and the other examples, pH measurements were taken using a Horiba compact portable meter.

Example B (Liquid and Nicotine Delivery)

A healthy male volunteer experienced with nicotine placed

approximately 400 mg of sodium bicarbonate in a hot tea cup, and stirred the liquid.

The volunteer took several strong draws on a commercially available Nicotrol^® inhaler (10 mg/cartridge, marketed by Pfizer). The volunteer noted a mild throat burn sensation - attributable to nicotine absorption.

The volunteer then took three sips of the hot beverage, and used the same Nicotrol^® inhaler again. The volunteer noted a burn sensation throughout the mouth including the roof of the mouth. The user noted the sensation was comparable to the throat sensation. The user felt the nicotine delivery was much stronger.

The same health male volunteer repeated the same experiment this time, except that a tobacco-based e-cigarette from Discreet^®. The volunteer noted a similar improvement in nicotine delivery.

This same experiment was repeated with room temperature water (and

Nicotrol^®) While still being highly effective, it was observed that the heated water seemed to provoke stronger nicotine absorption which may be attributed to thermal effects.

Example C (Liquid)

A liquid was prepared by adding the following ingredients in the foiiowing order; Sodium bicarbonate (NaHC-03) 3.35 g; tablet salt 0.315 g; tap water 16.1 g; and glycerin 11.38 g of glycerin.

The liquid of this example was provided to a healthy female volunteer (one ½ teaspoon was swirled in the mouth without swallowing), and the pH of her saliva was measured at intervals over a period of ten minutes.

The TO pH was 6.5; T1 was 8.5; T3 was 8.7; T4 was 8.2; T8 was 7.5 and T10 was 7.6. 2013/073346

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Example D (Liquid)

Example D employed the same ingredients as Example C but they were mixed in a different order. Glycerin was added first, then solids, mixed together and then water added. The solution was mixed and ½ teaspoon swirled in the mouth without swallowing, and the pH of her saliva was measured at intervals over a period of ten minutes.

The TO pH was 6.5; T1 was 8.4; T2 was 8.5; T3 was 7.9; T5 was 7.9; T7 was 7.5 and T10 was 7.3.

Example E (Non Aqueous Liquid)

This example used the same ingredients as the preceding Examples C and D but eliminated water. A solution was made with three grams of sodium bicarbonate, 6 grams of glycerin and no water. To test the solution, a health female volunteer swished it in the mouth and expectorated.

pH was measured over ten minutes with the following results.

T1 was 8.2; T2 was 8.7; T3 was 8.6; T4 was 8.6; T5 was 8.6; T7 was

8.0 and T10 was 7.2.

Example F (Propylene Glycol)

The following formulation as made: 3 grams glycerin; 1 gram propylene glycol; and 1.5 grams sodium bicarbonate. The solution was mixed and ½ teaspoon was swirled in mouth without swallowing.

TO pH was 6.5 and T1 as 7.2. Because of disagreeable taste, the test was ended after T1 timepoint.

Example G (Xantham)

Xantham was selected as a capture agent in view of its mucoadhesive properties. As an additional benefit it is relatively insensitive to pH.

Prepared a high viscosity gum by dispersing xantham in glycerin first and then introducing the xantham/glycerin blend to water to hydrate. The composition was 60 ml glyverin, 120 ml water and 1 gram modified xantham. All components were mixed at room temperature yielding a consistent viscosity. One drop 00% pure wintergreen essential oil was added.

To test the xantham composition orally, xantham/glycerin/water gel were blended with baking soda by volume at 2:1 liquid/powder. A ½ teaspoon was taken orally, without swallowing and swirled in mouth for 2013/073346

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several seconds. The following pH measurements were taken over a ten minute period.

TO was 6.5; T1 was 8.4; T2 was 8.4; T3 was 8.6.; T4 was 8.4; T5 was 8.4; T6 was 8.4; T7 was 8.4; T8 was 8.4; T9 was 8.1 and T10 was 8.2.

The experiment was repeated by the same volunteer after thirty minutes and several mouth rinses to demonstrate reproducibility.

TO was 6.6; T1 was 8.1 ; T2 was 8.3; T3 was 8.3; T4 was 8.5; T5 was 8.5; T6 was 8.5; T7 was 8.4; T8 was 8.3; T9 was 8.3 and T10 was 8.1.

Xantham seems to have delayed the release of the sodium bicarbonate increasing the timescale for pH>8.0. This suggests a film delivery of sodium bicarbonate.

Example H (Listerine^® Film)

Sandwich pouches of Listerine^® film as a capture agent with 200 mg of sodium bicarbonate were made and tested.

As a baseline, pH was measured over a ten minute period with a

Listerine^® film only.

TO was 6.2; T1 was 6.3; T2 was 6.6; T8 was 6.7 and T10 was 6.5. Listerine^® film pouch with 0.2g sodium bicarbonate was tested by a healthy female volunteer (1 15 lbs).

TO was 6.5; T1 was 8.5; T3 was 8.7; T5 was 8.7; T8 was 8.5 and T10 was 8.5.

The product was pleasant to the taste.

The sodium bicarbonate was reduced to 0.1 grams and used by second tester (180 lb male).

The pH results over six minutes were as follows.

TO was 6.5; T1 was 8.0; T2 was 8.2; T4 was 8.0 and To was 7.5.

The experiment was repeated with a the same 1 15 lb female as tester and 0.2 grams of sodium bicarbonate in a single Listerine^® film (the single film was wrapped around the sodium bicarbonate). The pH results over ten minutes were was follows.

TO was 6.2; T1 was 8.0; T2 was 8.7; T3 was 8.7; T5 was 8.7 and T10 was 8.4. 13 073346

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The process was repeated for the 115lb female with the same formulation (i.e., 0.2 grams baking soda in a single Listerine^® film). The pH results over ten minutes were as follows:

TO was 6.2; T1 was 8.0; T2 was 8.7; T3 was 8.7; T5 was 8.6; and T10 was 8.2.

Thus, results appear to be dependent on subject weight. We then made 0.3 gram sodium bicarbonate/2 Listerine^® film pouches for the 180 lb male.

The pH results over ten minutes were as follows.

TO was at 6.4; T1 was at 8.1 ; T2 was at 8.6; T3 was at 8.6; T4 was at

8.4; T7 was at 8.4; T9 was at 8.1 and T10 was at 7.7.

Thus the male subjected required 0.3 grams for 180 lbs of body mass as compared with 0.2 grams for 115 lbs.

Example l

In considering acid/base for CO2 generation in the mouth, we

considered two commercial products were considered - Alka Seltzer^®

(anhydrous citric acid) and Briosch^® (tartaric acid).

We added Alka Seltzer^® Original, two tabs, to a 200 ml bottle of water and measured pH over give minutes.

TO was 7.35; T1 was 6.23; T2 was 6.35; T4 was 6.14 and T5 was 6.57.

Briosch^® was used with 200 ml of water at the recommended dosage and the pH was measured over ten minutes as follows.

TO was 6.81 ; T(10s) was 4.41 ; T(30s) was 4.95; T1 was 5.45; T4 was 5.47; T6 was 5.52 and T10 was 5.52.

The Briosch^® was more acidic than the Alka Seltzer^®.

Next a dry powder blend of 1 :2 citric acid/sodium bicarbonate blend was tested orally by our 115 lb female volunteer. pH was measured as follows.

TO was at 6.4; t(30s) was at 2.9; T1 was at 3.8; T2 was at 5.4; T3 was at 6.5 and T4 was at 6.5. While a very low initial pH was achieved, washout was very rapid and the mix generated a high volume of saliva.

Example J (Other Commercial Products including TU S^®). 3346

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Several commercial products were tested using pH papers and a simple procedure as follows. First, rinse mouth with water. Second, wait for 1 minute. Third, take pH of saliva. Fourth, put tablet in mouth for one minute and discard it. Fifth, measure pH as a function of time.

With Turns^®' pH was normal at one minute and the test was

discontinued. With CVS^® Chewable Antacid tablets (childrens) (testing two tabs), pH at one minute was 7.

Example K (Capture of Condensate Using a Polymer)

Two squares were cut of identical surface area (1 by 1 inch) - one from paper and one from an HPC-extruded film sourced from Fuisz LLC of Miami, Florida (containing approximately 2/3's hpc by weight). The two squares were weighted, and then were held above a steaming cup of tap water for approximately forty-five seconds. After thirty seconds the samples were weighed again, demonstrating that HPC film captured approximately 20 mg of water whereas the paper captured just 5 mg.

Example L (Soft Chew)

A soft chew was prepared with the following composition: 6 grams of sodium bicarbonate (29%); 11 grams of Carbowax 1450 (54%); 1 gram of HPMC (5%); 1 gram of powdered sugar (5%); 1 gram of glycerin (5%); 0.5 ml mint extract (2%); and 1 drop of red food coloring.

The resulting soft chew was tested together with Nicotrol^® by a healthy volunteer and found to be quite effective for improving nicotine delivery.

Example M (Gummy Preparation))

A gummy was prepared with the following composition: 6 grams of sodium bicarbonate (14%); 20 grams of glycerin (47%); 12 grams of water (28%); 4 grams of unfiavored geiatin (9%); 1 g of corn syrup (2%) and 1 drop of red food coloring.

Example N (Gummy with Marijuana Cigarette)

The gummy of example M was used by a healthy male volunteer while smoking a marijuana cigarette. The user reported feeling "high" much faster than normal, and characterized the experience as like using marijuana "at volume 10."

Example O (Gummy with Marijuana Vaporizer) 3346

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The gummy of example M was used by a healthy male volunteer while vaporizing marijuana. The user reported more rapid and powerful effects from the marijuana as compared with his typical experience when vaporizing marijuana.

Example P (Gummy with solid tobacco composition/SNUS)

The gummy of example M was used by a health male volunteer while using a pouch of Marlboro® SNUS. The user placed the gummy in the cheek on the same side of the mouth as the SNUS pouch. The user waited several hours and repeated the use of the Marlboro® SNUS pouch. The user perceived better nicotine absorption when the SNUS pouch was used together with gummy of example M.

Example Q (Nasal Absorption Conditioning Unit)

The purpose of this example was to provide an absorption conditioning unit for nasal use, including a buffer agent, a capturing agent and a

penetration agent. Additionally, we intended to use increased viscosity to better retain the absorption conditioning unit in the nasal cavity to thereby sustain the conditioning effect.

Our premise was that the nasal cavity is less efficient than the oral cavity in pH maintenance and the best route for a buffer agent would likely be an alkaline pH buffer solution. We considered two compounds of choice: sodium carbonate (Na₂CO₃) and sodium bicarbonate (NaHCO₃).

The bicarbonate buffer is a well know physiological buffer. The carbonate/bicarbonate volume ratio can be adjusted to produce buffers in the pH range shown in the following table:

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Table 1 : Sodium Carbonate/Sodium Bicarbonate Buffer Compositions and pH

Na₂C0₃ · 10H₂O, 286.2; 0.1M-solution contains 28.62 g/l.

NaHC0₃, Mw_t 84.0; 0.1M-solution contains 8.40 g/l. x ml 0. M-Na₂CO₃ and y ml 0.1 M-NaHCO₃ mixed.

The pH values are listed at both 20 and 37°C based on .1M solutions of each compound. Based on these results, we selected the 30-70 ratio and 50-50 ratio for initial trials for the nasal spray since they represented the upper range of pH and likely to be the most difficult to thicken effectively.

Our first problem was the actual measurement of nasal pH for pre- and post- alkaline nasal spray administration. We could not generate enough volume for repeatable measurements under any circumstances. Best approach was to adopt the criteria used in US Patent 6,187,332 (EP

1 ,183,009) (each of which is hereby incorporated by reference in the entirety) for simulating conditions of a runny nose: "In this test a given volume of the preparation is mixed at room temperature with three times that volume of Dulbecco's phosphate buffered saline (pH 7.4)(sold by Fisher Scientific- currently Pittsburgh, Pa.). The pH of the resulting solution is tested and the test is passed if the resulting solution has a pH below 6.0. "

Our pH criterion is different but the approach is considered useful. A

Dulbecco phosphate buffer saline solution (DPBS) was purchased and used for all compositions at the 1X, 2X and 3X dilution. A typical composition for DPBS is provided below: Dulbecco's phosphate-buffered saline (Dulbecco's PBS): 2.7 mM KCI; 1.5 mM KH₂P0₄; 136.9 mM NaCI; and 8.9 mM Na₂HPO₄ ^«7H₂O

The pH of DBPS measured at 22°C to be 7.0. Experimental solutions are summarized below:

5 Table 2: Experimental buffer solution compositions and pH values at 22-23°C

Sodium bicarbonate was sourced from Church and Dwight (Arm and

Hammer); Sodium Carbonate was sourced from Fisher BioReagents.

10 For the desired alkalinity, sodium bicarbonate will be insufficient and a proportion of sodium carbonate will be needed to raise the pH of the nasal spray.

We briefly reviewed the technical and patent literature and looked at the compositions of OTC nasal wash/sprays and purchased several products 15 to evaluate.

Composition of Shop-Rite Saline Nasal Spray (1.5 fl oz (44 ml): Active: .65% Sodium Chloride Inactives: Benzalkonium Chloride, Disodium

Phosphate, Phenylcarbinol, Monosodium Phosphate, Water

This product had a Poor quality sprayer and spray pattern, and very 20 poor dose control per spray.

pH of the product: 7.2 (22°C) (Lot 3044 Exp 02/ 6) (1X pH = 7.2) (2X pH = 7.1) (3X pH = 7.1).

Repeated measurements with identical results: 3X pH = 7.1. Second product evaluated is NeilMed Saline Spray Nasal Wash for sinus and cold relief. Ingredients are listed as UPS Grade Water, USP

Sodium Chloride (.9 mg/ml), USP Sodium Bicarbonate (0.5 to 1 .0 mg/ml) to neutralize pH. Three spray tips are included for large volume rinse tip, medium stream tip and ultra gentle mist tip. Nasal wash in packaged in a aerosol container.

pH of the product: 7.7 (22°C) (Lot NM452 Exp2016-03) (1X pH = 7.0) (2X pH = 7.0) (3X pH = 7.0). We repeated measurements with identical results: 3X pH = 7.0.

Both products appear to neutralize pH - as cited on their labels. They are neutral pH nasal sprays and washes.

Began preparation of alkaline sodium carbonate and sodium

bicarbonate buffers as potential nasal sprays.

50ml Na₂CO₃/50ml Na₂HC0₃): .1 M carbonate/bicarbonate buffer - pH = 10.0 (25°C)

Results of 1X, 2X and 2X DPBS buffer test: (1 x pH = 10.0) (2x pH = 10.0) (3x pH = 10.0).

This was a very nice result. Maintains pH with dilution (DPBS) simulating nasal discharge. Repeated with new solutions. 3X dilution pH = 10.0.

Sodium carbonate solution: .1 M, pH = 1 1 .5 (25°C) tested in DPBS buffer test: (1X pH = 10.9) (2x pH = 10.8) (3x pH = 10.6).

With a 30/70 volume ratio of carbonate/bicarbonate, pH measured to be 9.9 (1 x pH = 9.8) (2x pH = 9.7))(3x pH = 9.8). This works well to

maintaining pH.

Took the above buffer and added 10mi more of the .1 M sodium bicarbonate solution to reduce buffer pH. Measured pH to be 9.5. Diluted now in buffer power test with DPBS: (1x pH = 9.5) (2x pH = 9.4) (3x pH = 9.4).

We prepared additional buffers with 30/70 carbonate/bicarbonate - with objective of thickening with methyl cellulose, HPMC with and without added PG.

New Solutions: .1 M Sodium Carbonate - pH 1 1 .3, . Sodium

Bicarbonate - pH = 8.1 3346

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Buffer at 30/70 volume ratio (Carbonate/Bicarbonate) pH = 9.9.

We prepared 2% Methyl Cellulose (Acros Organics), .5% Propylene Glycol, 97.5% Buffer solution to increase viscosity. Measured viscosity in parallel plates in the shear rate range of 0-25 s^"1 and solution is Newtonian with viscosity of 140 mPa.s or cps at 24°C.

Sample is aerated from the stirring bar but clears upon standing to a slightly cloudy fluid.

We prepared 1 % HPMC (Dow F50), 1 % PG and 98% Buffer (pH9.9) with good thickening and clear solution. Measured viscosity in parallel plates in the shear rate range of 0-50 s^"1 and solution is Newtonian with viscosity of 8-10 mPa.s or cps at 24°C.

Completed buffer power test for the two thickened solutions to be sure that the pH was maintained in dilution with DPBS. Results are provided below.

2% methyl cellulose thickened buffer: (OX pH = 9.9) (1X pH = 9.8) (2X pH = 9.8)(3X pH = 9.8).

1 % HPMC thickened buffer: (OX pH = 9.9) (1X pH = 9.8) (2X pH = 9.8) (3X pH = 9.8).

This showed no change In buffer capacity with thickeners or enhancers or capture agents..

Prepared 10/90 volume ratio buffer of sodium carbonate/sodium bicarbonate - pH 9.4. Worked through buffer power test: (1X pH = 9.4) (2X pH = 9.4) (3X pH = 9.4). We had good results at this level.

Made an additional sodium bicarbonate solution, approximately .1 M solution, pH = 8.1.

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= 7.5) (3X pH = 7.5).

Repeated with one more solution of sodium bicarbonate, , .1 M solution, pH = 8.1. (1X pH = 7.7)(2X pH = 7.5) (3X pH = 7.5).

These experiments are summarized in Table 2.

Claims

We Claim:

1. A method for the administration of nicotine, THC, cannabidiol or a base alkaloid to a mammal, comprising:

administering an absorption conditioning unit in the oral or nasal cavity, comprising at least two agents selected from the group consisting of (a) a buffer agent, (b) a capturing agent, (c) a penetration agent, and (d) a thermal agent, to the mammal; and

administering by inhalation a bioactive agent selected from the group consisting of nicotine, THC, tobacco, cannabidiol and a base alkaloid.

2. The method according to claim 1 , wherein the absorption conditioning unit does not contain a bioactive.

3. The method according to claim 1 , wherein the absorption conditioning unit does not contain a drug.

4. The method according to claim 3, wherein the absorption conditioning unit does not contain an acid.

5. The method according to claim 1 , wherein the absorption conditioning unit does not contain an acid.

6. The method according to claim , wherein the absorption conditioning unit includes at least the buffer agent.

7. The method according to claim 1 , wherein the absorption conditioning unit includes at least the capturing agent, and the capturing agent has mucoadhesive properties.

8. The method according to claim 1 , wherein the bioactive agent is a base alkaloid comprising cocaine.

9. A method for the administration of nicotine, THC, cannabidiol, cocaine or abase alkaloid to a mammal, comprising:

administering an absorption conditioning unit including at least at least one material that creates a pH in the oral cavity of 7.8-10 for a period of ten minutes or more after administration; and

administering by inhalation a bioactive agent selected from the group consisting of nicotine, THC, tobacco, cannabidiol and a base alkaloid.

10. The method according to claim 9, wherein the absorption conditioning unit does not contain a bioactive.

11. The method according to claim 9, wherein the absorption conditioning unit does not contain an acid.

12. The method according to claim 9, wherein the absorption conditioning unit does not contain a drug.

13. The method according to claim 9, wherein the absorption conditioning unit includes at least a buffer agent.

14. The method according to claim 9, wherein the absorption conditioning unit includes at least a capturing agent having mucoadhesive properties.

15. The method according to claim 9, wherein the bioactive agent is a base alkaloid comprising cocaine.

16. An absorption conditioning unit, comprising a dosage form including at least two agents selected from the group consisting of (a) a buffer agent, (b) a capturing agent, (c) a penetration agent, and (d) a thermal agent, wherein said absorption conditioning unit (i) does not have an essentially acidic character, (ii) does not contain a drug, (iii) does not contain THC or other Marijuana derived active ingredient, and (iv) does not contain tobacco except for trace amounts in flavor.

17. The absorption conditioning unit according to claim 16, wherein the absorption conditioning unit does not contain an acid.

18. The absorption conditioning unit according to claim 16, wherein the absorption conditioning unit includes at least the buffer agent.

19. The absorption conditioning unit according to claim 18, wherein the buffer agent is configured to create a pH in the oral cavity of 7.8-10 for a period of ten minutes or more after administration

20. The absorption conditioning unit according to claim 16, wherein the absorption conditioning unit includes at least the capturing agent, and the capturing agent has mucoadhesive properties.

21. An absorption conditioning unit, comprising a dosage form including at least at least one material that creates a pH in the oral cavity of 7.8-10 for a period of ten minutes or more after administration, the dosage form not containing an acid and not containing a drug.

22. The absorption conditioning unit according to claim 21 , wherein the absorption conditioning unit includes at least a capturing agent.

23. The absorption conditioning unit according to claim 22, wherein the capturing agent has mucoadhesive properties.

24. A method for the administration of nicotine, THC, cannabidiol, or base alkaloid to a mammal, comprising:

administering an absorption conditioning unit in the nasal cavity, comprising at least two agents selected from the group consisting of (a) a buffer agent, (b) a capturing agent, (c) a penetration agent, and (d) a thermal agent, to the mammal; and separately administering a bioactive agent in the nasal cavity selected from the group consisting of nicotine, THC, tobacco, cannabidiol, and a base alkaloid.

25. The method according to claim 24, wherein the bioactive agent is a base alkaloid comprising cocaine.

26. A method for the administration of nicotine, THC, cannabidiol or a base alkaloid to a mammal, comprising:

administering an absorption conditioning unit in the oral cavity, comprising at least two agents selected from the group consisting of (a) a buffer agent, (b) a capturing agent, (c) a penetration agent, and (d) a thermal agent, to the mammal; and

separately administering a bioactive agent selected from the group consisting of nicotine, THC, tobacco, cannabidiol and a base alkaloid, where such bioactive agent is contained in a solid, semi-solid or liquid based dosage form.

27. The method according to claim 26, wherein the bioactive agent is a base alkaloid comprising cocaine.