GB2542404B

GB2542404B - An inhalable composition and an inhaler

Info

Publication number: GB2542404B
Application number: GB1516558.2A
Authority: GB
Inventors: Hearn Alex; Gupta Ritika
Original assignee: Kind Consumer Ltd
Current assignee: Kind Consumer Ltd
Priority date: 2015-09-18
Filing date: 2015-09-18
Publication date: 2019-08-14
Anticipated expiration: 2035-09-18
Also published as: GB2542404A; GB201516558D0; WO2017046593A3; WO2017046593A2; CN108348013A; EP3349605A2

Description

AN INHALABLE COMPOSITION AND AN INHALER

The present invention relates to an inhalable composition and an inhaler.

Conventional E-cigarettes have a volume of inhalable composition, a battery anda heating element to vaporise some of the composition as a user sucks on theend of the cigarette, the vaporised composition then being inhaled. E-cigarettes are gaining increasing popularity as they provide an alternative toconventional smoking which eliminates the many carcinogens and toxicsubstances found in tobacco products. E-cigarettes conventionally use an inhalable composition consisting of a highlevel of propylene glycol, glycerol, glycerin or glycol in which the nicotine (oralternative such as a flavouring) is solubilised. The high level of propylene glycolcauses the composition to be viscous. This is beneficial as it can preventunwanted evaporation of the composition out of the device and is usuallycontained in a cotton wadding, pad or other absorbent material. E-cigarettesgenerally comprise a heater or an ultrasonic atomiser which is in the vicinity of asmall amount of the composition volume. Suction on the inlet end causesoperation of the heater, and the substance in the vicinity of the heater isevaporated and inhaled. The relatively high viscosity of the composition ensuresthat the composition available to the heater is gradually replenished but generallyprevents it from leaking from the absorbent material in the absence of heat.

While this is reasonably successful, there are two main drawbacks associatedwith electronic cigarettes. Firstly, the propylene glycol vaporises at a relativelyhigh temperature such that this causes degradation of the composition generallyused in E-cigarettes. This can lead to problems with dosage consistency and thepresence of contaminants in the inhaled composition including the production ofby-products such as formaldehyde, toluene and acrolein.

Secondly, the E-cigarettes require relatively high power to generate the hightemperature. Moreover they normally require large batteries to deliver a totaldose of vaporised composition to last the user the equivalent of between 20 to 40cigarettes worth of inhalable composition. The cigarettes have the power todispense at least one reservoir full of composition. As this large volume isdispensed at a high temperature, a large battery is required. Additionally sincelarger reservoirs and batteries are used, the nicotine dosage contained in E-cigarettes is high and potentially poses safety concerns when packaged in thisformat.

Broadly, such E-cigarettes can be divided into three categories, namelyrechargeable, refillable and disposable. Those which are rechargeable comewith a mains power adaptor. This is cumbersome for a user to carry around as itcannot readily fit into a pocket which is inconvenient. The relatively longrecharge time is also inconvenient if a user only remembers that the charge hasrun down just before they go out.

There are also refillable E-cigarettes which require disassembly of the device andthe replacement of the reservoir via a cartridge, liquid or absorbent material.However these are the subject of legal restrictions in many countries due to theavailability of drug compositions in unsealed containers. Moreover extra care isrequired in the process of replacing cartridges or material within the device, andextra effort is required by the user to refill which can be cumbersome and messy,especially if composition comes in contact with the skin. A more recent development is a disposable cigarette. This is designed to last fora time equivalent to approximately 10-20 cigarettes, whereupon the cigarette andits container are thrown away. This is not environmentally friendly, particularlywhen the cigarette contains a relatively large battery and could be reused orrecycled. WO2014/033437 discloses inhalable nicotine compositions that are not requiredto be heated in order to be delivered to an end user. While such compositionstypically contain very few harmful by-products, the lack of heating, and theexpansion of the propellant during delivery, typically results in the compositionbeing delivered to an end user at a low temperature. Such a low temperaturemay be unpleasant, and may not adequately replicate conventional cigarettesmoking. W02009/001085 relates to an inhalable composition. CN201054978Yrelates to a simulated cigarette electronic apparatus. WO2015/042412 relates todevices and methods for modifying delivery devices.

The present invention addresses some of the above problems.

According to a first aspect, the present invention provides an inhalablecomposition according to claim 1.

Each aspect or embodiment as defined herein may be combined with any otheraspect(s) or embodiment(s) unless clearly indicated to the contrary. In particularany feature indicated as being preferred or advantageous may be combined withany other feature or features indicated as being preferred or advantageous.

The term “nicotine” as used herein encompasses the compound having thefollowing structure:

The term “diameter” as used herein encompasses the largest dimension of adroplet. Droplet diameters referred to herein may be measured using a MalvernSpraytec device.

The term “Dv10” as used herein refers to a droplet diameter that no more than 10%vol of the droplets in a composition have a smaller diameter than. The term“Dv50” as used herein refers to a droplet diameter that no more than 50 %vol ofthe droplets in a composition have a smaller diameter than. The term “Dv90” asused herein refers to a droplet diameter that no more than 90 %vol of the dropletsin a composition have a smaller diameter than. Dv10, Dv50 and Dv90 values maybe determined using a Malvern Spraytec device.

The term “nicotine free base” as used herein refers to the form of nicotine thatpredominates at high pH levels, i.e. at pH levels above 7.

When introducing elements of the present disclosure or the preferredembodiments(s) thereof, the articles "a", "an", "the" and "said" are intended tomean that there are one or more of the elements. The terms "comprising","including" and "having" are intended to be inclusive and mean that there may beadditional elements other than the listed elements.

The composition of the present invention may be delivered to a user via oralinhalation. Accordingly, it is effective for use in nicotine replacement therapy(NRT) or as an alternative to recreational smoking of conventional cigarettes,since it mimics some of the habitual aspects of smoking.

In both conventional cigarettes and E-cigarettes, nicotine must be heated in orderto be delivered to a user via inhalation (to result in combustion in the case of aconventional cigarette or to result in vaporisation, typically at a temperature offrom 240 to 300 °C, in the case of an E-cigarette). Such heating results in thegeneration of harmful by-products, such as aldehydes, ketones, nitrosamines andheavy metals, which are then also delivered to the user via inhalation. Nicotine compositions that may be delivered without being heated, for example thosedisclosed in WO2014/033437, may be delivered without generating such harmfulby-products. However, the absence of heating, together with the expansion of apropellant, may result in the nicotine composition being delivered to a user at lowtemperature. This may be unpleasant to an end user, and may not adequatelyreplicate the feel of conventional cigarette smoking.

In contrast, the inhalable composition of the present invention may be deliveredto a user by heating it to a temperature of less than 300 °C, typically less than200 °C, more typically less than 150 °C, even more typically less than 100 °C, stilleven more typically from 35 to 100 °C, still even more typically from 70 to 90 °C,still even more typically from 75 to 85 °C, still even more typically about 80 °C.The inventors have surprisingly found that such temperatures are warm enoughto replicate the feel of conventional cigarette smoking, but low enough to avoidthe generation of harmful by-products. Furthermore, in contrast to conventionalE-cigarettes, the lower temperatures that may be employed to deliver theinhalable composition are safer and require a smaller and/or lower powderbattery.

Advantageously, the inhalable composition of the present invention may bedelivered with a pressure of around 6 bar. This may provide the user with afavourable mouth feel, and one that more closely replicates conventionalcigarette smoking.

Any suitable source of nicotine may be employed. For example, the nicotine maybe nicotine free base, a nicotine derivative and/or a nicotine salt. Where anicotine free base is employed, it may be employed in liquid form. Where anicotine salt is employed, it may be employed in the form of a solution. Suitablenicotine salts include salts formed of the following acids: acetic, proprionic, 1,2-butyric, methylbutyric, valeric, lauric, palmitic, tartaric, citric, malic, oxalic,benzoic, alginic, hydrochloric, chloroplatinic, silicotungstic, pyruvic, glutamic andaspartic. Other nicotine salts, such as nicotine bitartrate dehydrate, may also be employed. Mixtures of two or more nicotine salts may be employed. Nicotinesalts may also be in liposomal encapsulation. Such encapsulation may allow thenicotine concentration of a composition to be further increased without nicotineprecipitation occurring.

The glycol and/or glycol ether (i.e. propylene glycol) aids the dissolution of thenicotine or a pharmaceutically acceptable derivative or salt thereof in thecomposition. This avoids the presence of precipitates of nicotine (or otheradditives such as saccharin, if present) in the composition, which could causeirritation when delivered to a user. In addition, the presence of glycol or glycolether reduces the degradation of nicotine that occurs over time, therebyincreasing the long-term stability or “shelf life” of the composition. For example,chromatographic analysis of the composition according to the first aspect of thepresent invention, after six months’ storage at 40 °C, 75 % relative humidity, mayindicate the following impurity percentage fractions relative to nicotine fraction:anabasine at no greater than 0.3 %area; anatabine at no greater than 0.3 %area;β-nicotyrine at no greater than 0.3 %area; cotinine at no greater than 0.3 %area;myosmine at no greater than 0.3 %area; nicotine n-oxide at no greater than 0.3%area; nornicotine at no greater than 0.3 %area. These impurity limits lie withinthe European Pharmacopoeia specifications for nicotine starting material,indicating the favourable degradation characteristics of the composition over thecomposition lifetime. Notwithstanding this, the European Pharmacopoeia shouldnot be taken as limiting in any way the allowable impurities tolerances claimed inthis invention.

The monohydric alcohol (i.e. ethanol) may act as a solvent for the components ofthe inhalable composition, and may increase the stability of the inhalablecomposition. On heating the composition, for example to a temperature of around80 °C, typically both the ethanol and the propellant vaporise. This may allow theinhalable composition to be delivered to an end user in the form of an aerosol,with the propellant and monohydric alcohol functioning as the gaseous phase,and the remaining components of the composition, such as the nicotine andglycol and/or glycol ether, being in the form of aerosolised droplets. Monohydric alcohol has alower viscosity than glycol or glycol ether. Accordingly, the composition is able toform droplets of a smaller diameter in comparison to compositions in which themonohydric alcohol is not present. Advantageously, on inhalation, smallerdroplets are more likely to be delivered to the lungs of a user. This is discussed inmore detail below.

The inhalable composition comprises a propellant. Conventional E-cigarettes donot contain a propellant, since the high temperatures used in such devicesenable the inhalable compositions to be completely volatalised. The presence ofa propellant in the inhalable composition of the present invention may allow theinhalable composition to be aerosolised at a lower temperature.

The propellant is present in an amount of from greater than 0 %w/w to less than60 %w/w based on the total weight of the composition, for example from 0.5%w/w to 59.5 %w/w based on the total weight of the composition. The inhalablecomposition preferably comprises from 30 to 59 %w/w propellant, preferably from31 to 58 % w/w propellant based on the total weight of the composition. Higheramounts of propellant may restrict the amounts of other components that may bepresent in the composition, for example the monohydric alcohol or glycol and/orglycol ether. Accordingly, the beneficial effects provided by such componentsmay be reduced. In addition, higher levels of propellant may increase thepressure at which the composition is delivered to an end user on heating, therebyresulting in an undesirable mouth feel. Lower amounts of propellant may reducethe pressure at which the inhalable composition is delivered, or may requirehigher heating temperatures to aerosolise the composition. Accordingly, theamount of undesirable by-products generated may be increased.

The monohydric alcohol is ethanol. Ethanol has a particularly low viscosity incomparison to a glycol or glycol ether, and is therefore particularly effective atenabling the composition to form droplets of small diameter. In addition, ethanolis cheap, relatively non-harmful and readily available.

The inhalable composition comprises from 15 to 75 % w/w ethanol, preferablyfrom 30 to 70 % w/w ethanol, more preferably from 35 to 65 % w/w ethanol, evenmore preferably from 38 to 62 % w/w ethanol based on the total weight of thecomposition. Lower levels of ethanol may decrease the stability of thecomposition, and may require higher levels of (typically higher cost) propellant toachieve aerosolisation at a given temperature. Higher levels of ethanol mayrequire higher temperatures to achieve aerosolisation. In one preferredembodiment, the composition comprises from 30 to 40 % w/w ethanol. In analternative preferred embodiment, the composition comprises from 50 to 55%w/w ethanol.

The glycol and/or glycol ether is propylene glycol. The composition comprisesfrom 1 to 40 % w/w propylene glycol, preferably from 2 to 40 % w/w propyleneglycol, more preferably from 3 to 38 % w/w propylene glycol based on the totalweight of the composition. Lower levels of glycol and/or glycol ether may result indegradation of nicotine and/or the formation of precipitates of nicotine. Higherlevels of glycol and/or glycol ether may result in the need to employ highertemperatures in order to aerosolise the composition. In a preferred embodiment,the composition comprises from 3 to 7 %w/w propylene glycol. In an alternativepreferred embodiment, the composition comprises from 25 to 29 %w/w propyleneglycol.

The ratio by weight of monohydric alcohol (i.e. ethanol) to glycol and/or glycolether (i.e. propylene) is preferably from 15:1 to 1:1, more preferably from 13:1 to1.5:1. When a nicotine composition having such a ratio of monohydric alcohol:glycol or glycol ether is delivered to a user via heating, for example via the inhalerof the third aspect of the present invention described in more detail below, thecomposition is delivered in the form of droplets, some of which (such as, forexample, at least 10 %vol) have a diameter of less than 10 pm, typically less than5 pm. Typically, the majority (such as, for example, at least 50 %vol) of the droplets have a diameterof less than 5 pm, typically substantially all (such as, for example, at least 90%vol, or even at least 95 %vol) of the droplets have a diameter of less than 5 pm.Advantageously, when administered to a user, droplets with a size of less than 10pm tend to be deposited in the lungs, rather than, for example, the oropharynx.Accordingly, at least some (such as, for example, at least 10 %w/w), typicallysubstantially all (such as, for example, at least 90 %w/w), of the nicotine entersthe bloodstream via the pulmonary route. This means that the composition, wheninhaled orally, is more able to mimic the pharmacokinetic profile of a conventionalcigarette compared to nicotine compositions of the prior art. Since thecomposition may be administered via oral inhalation and is able to mimic thepharmacokinetic profile of a conventional cigarette, it is particularly effective foruse in NRT or as an alternative to recreational smoking of conventionalcigarettes.

Typically at least some (such as, for example, at least 10 %vol) of the dropletshave a size of from 0.5 to 3 pm. Such droplets may be deposited in the deeplung, and are therefore particularly able to enter the blood stream via thepulmonary route. Typically at least some (such as, for example, at least 10 %vol)of the droplets have a diameter of from 0.4 to 0.5 pm. Such droplets areparticularly able to mimic the pharmacokinetic profile of a conventional cigarette,since conventional cigarette smoke has a mean particle diameter in the range offrom 0.4 to 0.5 pm.

The ratio of monohydric alcohol to glycol or glycol ether specified above mayresult in a composition with a desired combination of both long term stability (forexample the composition remains as a single phase for at least a week at atemperature of 2-40 SC) and small droplet size.

In contrast to compositions of the prior art, the composition of the presentinvention is able to form small diameter droplets without the use of organic acids.

Accordingly, the level of irritation experienced by a user of the compositions isreduced.

When the composition of the present invention is delivered to a user via theinhaler of the third aspect of the present invention described below, the dropletsmay exhibit the following droplet size profile:

Dv 90 of less than 20 pm, typically less than 5 pm, more typically less than3, even more typically less than 2.9 pm, and/or

Dv 50 of less than 6 pm, typically less than 0.8 pm, more typically lessthan 0.7 pm, even more typically less than 0.6 pm, and/or

Dv 10 of less than 2 pm, typically less than 0.3 pm, more typically lessthan 0.25 pm, even more typically less than 0.2 pm.

This particular droplet size profile is similar to the particle size profile of tobaccosmoke. Accordingly, the pharmacokinetic profile of the delivered compositionclosely mimics that of a conventional cigarette. In particular, delivery of thecomposition to a user generates an extended peak of high nicotine concentrationwith a short tmax, i-θ- the time from first inhalation to the maximum nicotine-plasmalevel. As a result, the composition is highly effective for use in nicotinereplacement therapy (NRT) or as an alternative to recreational smoking ofconventional cigarettes.

Preferably the composition further comprises a human TAS2R bitter tastereceptor agonist. The use of a human TAS2R bitter taste receptor agonistinduces bronchodilation, resulting in a reduction in the levels of delivery-relatedcoughing. Accordingly, a user is more able to tolerate the composition since itcauses very little irritation.

The human TAS2R bitter taste receptor agonist may be a naturally occurringcompound or a synthetic compound. Examples of suitable naturally-occurringcompounds include Absinthin, Aloin, Amarogentin, Andrographolide, Arborescin,

Arglabin, Artemorin, Camphor, Cascarillin, Cnicin, Crispolide, Ethylpyrazine,Falcarindiol, Helicin, Humulone isomers, Limonin, Noscapine Papaverine,Parthenolide, Quassin, Sinigrin, and Thiamine. Examples of suitable syntheticcompounds include Acesulfame K, Benzoin, Carisoprodol, Chloroquine,Cromolyn, Dapsone, Denatonium benzoate, Dimethyl thioformamide,Diphenhydramine, Divinylsulfoxide, Famotidine, Saccharin, Sodium benzoate,and Sodium cyclamate.

Preferably the human TAS2R bitter taste receptor agonist is saccharin. Saccharinis particularly effective as a human TAS2R bitter taste receptor agonist, may bereadily dissolved in the composition, is readily available and provides thecomposition with a desirable taste profile. Preferably the ratio of nicotine or apharmaceutically acceptable derivative or salt thereof: saccharin by weight isfrom 12:1 to 5.5:1, preferably from 11:1 to 6:1, more preferably from 10:1 to 7:1,even more preferably from 9.5:1 to 8:1, even more preferably about 8.75:1.Lower levels of saccharin result in a composition with an unacceptabletolerability. Higher levels of saccharin result in an acceptable tolerability but aredisfavoured since they may lead to precipitates of saccharin forming in thecomposition, which may cause irritation when the composition is administered toa user or blockage when the composition is incorporated into an inhaler or asimulated cigarette. Such ratios also provide the composition with an optimisedtaste profile.

The inhalable composition may comprise additional components, for exampleone or more of theobromine and vitamin C. Such additional components aretypically present in an amount less than 1 %w/w, for example from 0.0001 to 1%w/w, or from 0.001 to 0.1 %w/w based on the total weight of the composition.

The propellant may be a hydrofluorocarbon, preferably a hydrofluoroalkane, evenmore preferably 1,1,2,2-tetrafluoroethane (HFA-134a) or 1,1,1,2,3,3-heptafluoropropane (HFC-227). Such compounds are particularly effective aspropellants and have no adverse effect on the body.

The composition may further comprise a flavour component. Nicotine has a bitter,long lasting taste which can often elicit a burning taste sensation. The use of aflavour component may mask this taste. Suitable flavour components include theflavour components typically added to tobacco products. Examples includecarotenoid products, alkenols, aldehydes, esters and delta-lactone flavourconstituents. Suitable carotenoid products include beta ionone, alpha ionone,beta-damascone, beta-damascenone, oxo-edulan I, oxo-edulan II, theaspirone,4-oxo-beta-ionone, 3-oxo-alpha-ionone, dihydroactinodiolide, 4-oxoisophorone,safranal, beta-cyclocitral. Suitable alkenols include C4 to C10 alkenols, preferablyC5 to C8 alkenols. Specific examples include: cis-2-Penten-1-ol, cis-2-Hexen-1-ol, trans-2-Hexen-1-ol, trans-2-Hexen-1-ol, cis-3-Hexen-1-ol, trans-3-Hexen-1-ol,trans-2-Hepten-1-ol, cis-3-Hepten-1-ol, trans-3-Hepten-1-ol, cis-4-Hepten-1-ol,trans-2-Octen-1-ol, cis-3-Octen-1-ol, cis-5-Octen-1-ol, 1-Octen-3-ol and 3-Octen-2-ol. Suitable aldehydes include benzaldehyde, glucose and cinnamaldehyde.Suitable esters include allyl hexanoate, benzyl acetate, bornyl acetate, butylbutyrate, ethyl butyrate, ethyl hexanoate, ethyl cinnamate, ethyl formate, ethylheptanoate, ethyl isovalerate, ethyl lactate, ethyl nonanoate, ethyl valerate,geranyl acetate, geranyl butyrate, isobutyl acetate, isobutyl formate, isoamylacetate, isopropyl acetate, linalyl acetate, linalyl butyrate, linalyl formate, methylacetate, methyl anthranilate, methyl benzoate, methyl benzyl acetate, methylbutyrate, methyl cinnamate, methyl pentanoate, methyl phenyl acetate, methylsalicylate (oil of Wintergreen), nonyl caprylate, octyl acetate, octyl butyrate, amylacetate (pentyl acetate), pentyl hexanoate, pentyl pentanoate, propyl ethanoate,propyl isobutyrate, terpenyl butyrate, ethyl formate, ethyl acetate, ethylpropionate, ethyl butyrate, ethyl valerate, ethyl hexanoate, ethyl heptanoate, ethyloctanoate, ethyl nonanoate, ethyl decanoate, ethyl dodecanoate, ethyl myristate,ethyl palmitate. Suitable delta-lactone flavour constituents include delta-Hexalactone, delta-Octalactone, delta-Nonalactone, delta-Decalactone, delta-Undecalactone, delta-Dodecalactone, Massoia lactone, Jasmine lactone and 6-Pentyl-alpha-pyrone. Flavour components may serve to mask the taste ofnicotine, which is unpleasant.

The flavour component is preferably menthol and/or vanillin. The presence ofmenthol, together with the saccharin, reduces the irritation experienced by a user.Preferably the composition comprises up to 0.1 %w/w menthol, preferably from0.01 %w/w to 0.08 %w/w, more preferably from 0.02 %w/w to 0.06 %w/w, evenmore preferably from 0.03 %w/w to 0.05 %w/w, still even more preferably about0.04 %w/w, based on the total weight of the composition.

The composition may comprise from 0.001 %w/w to 0.045 %w/w nicotine or apharmaceutically acceptable derviative or salt thereof, preferably from 0.01 %w/wto 0.045 %w/w, more preferably from 0.015 %w/w to 0.04 %w/w, even morepreferably from 0.02 %w/w to 0.035 %w/w, still even more preferably from 0.025%w/w to 0.03 %w/w, most preferably about 0.028 %w/w, based on the totalweight of the composition. Such a composition provides similar effects to a “lowstrength” nicotine cigarette.

The composition may comprise from 0.04 %w/w to 0.07 %w/w nicotine or apharmaceutically acceptable derivative or salt thereof, preferably from 0.045%w/w to 0.065 %w/w, more preferably from 0.05 %w/w to 0.06 %w/w, even morepreferably from 0.054 %w/w to 0.058 %w/w, still even more preferably about0.056 %w/w, based on the total weight of the composition. Such a compositionprovides similar effects to a “medium strength” nicotine cigarette.

The composition may comprise from 0.065 %w/w to 0.1 %w/w nicotine or apharmaceutically acceptable derivative or salt thereof, preferably from 0.07 %w/wto 0.095 %w/w, more preferably from 0.075 %w/w to 0.09 %w/w, even morepreferably from 0.08 %w/w to 0.088 %w/w, still even more preferably about 0.084%w/w, based on the total weight of the composition. Such a composition providessimilar effects to a “high strength” nicotine cigarette. A particularly preferred composition comprises, based on the total weight of thecomposition: from 3 to 58 %w/w propellant, from 38 to 62 % w/w ethanol, and from 2 to 38 %w/w propylene glycol.

Such a composition may be delivered to a user in the form of an aerosol afterheating to only a low temperature, for example around 80 °C. Accordingly, thecomposition may provide a combination of satisfactory mouth feel and low levelsof harmful by-products. A particularly preferred composition comprises, based on the total weight of thecomposition: from 30 to 40 %w/w propellant, from 55 to 65 % w/w ethanol, and from 3 to 15 %w/w propylene glycol.

Such a composition may be delivered to a user in the form of an aerosol afterheating to only a low temperature, for example around 80 °C. Accordingly, thecomposition may provide a combination of satisfactory mouth feel and low levelsof harmful by-products. A particularly preferred composition comprises, based on the total weight of thecomposition: from 30 to 40 %w/w propellant, from 35 to 45 % w/w ethanol, and from 22 to 32 %w/w propylene glycol.

Such a composition may be delivered to a user in the form of an aerosol afterheating to only a low temperature, for example around 80 °C. Accordingly, thecomposition may provide a combination of satisfactory mouth feel and low levelsof harmful by-products. A particularly preferred composition comprises, based on the total weight of thecomposition: from 50 to 57 %w/w propellant, from 35 to 45 % w/w ethanol, and from 22 to 32 %w/w propylene glycol.

Such a composition may be delivered to a user in the form of an aerosol afterheating to only a low temperature, for example around 80 °C. Accordingly, thecomposition may provide a combination of satisfactory mouth feel and low levelsof harmful by-products.

The composition is preferably substantially free of tobacco, preferably thecomposition is tobacco free. Tobacco is associated with a number of adverseeffects, for example cancer.

Preferably the composition comprises less than 0.01 %w/w nicotinic acid, morepreferably less than 0.005 %w/w, even more preferably less than 0.001 %w/wnicotinic acid, based on the total weight of the composition. Most preferably, thecomposition comprises substantially no nicotinic acid. The presence of nicotinicacid may result in the formation of precipitates in the composition.

The compositions of the first aspect may “consist of” the components recitedabove. The compositions of the first aspect may “consist of” the componentsrecited above together with any unavoidable impurities.

In a second aspect, the present invention provides a pressurised containercontaining the composition of the first aspect.

The pressurised container of the second aspect of the present invention may beused to release a gaseous flow of the nicotine composition of the first aspect to auser. For example, the pressurised container may be provided with means fordelivering the contents of the container to the lungs of a user. Such means may take the form of a button, trigger or breath-activated mechanism. Thepressurised container may be used to deliver an unmetered dose of nicotine tothe user. This may be advantageous over prior art methods of NRT, such asconventional inhalers, nasal sprays, lozenges and patches currently on themarket, because it can allow autonomy in nicotine replacement regulation, wherethere the user can regulate the amount of compositional nicotine he or shewishes to inhale. In addition, the pressurised container can be used as analternative to recreational smoking of conventional cigarettes.

The pressurised container of the present invention may take the form of apressurised canister, for example, a pressurised aluminium canister. Thecanister may be fully recyclable and/or reusable. The canister may be refilled asrequired by a vending machine or a larger container containing the desiredcomposition under a high pressure gradient. In one embodiment, the canister isa AW5052 aluminium canister.

The pressurised container may be a simulated cigarette or inhaler.

The pressurised container may be capable of dispensing the composition as amixture of aerosolised droplets. Preferably, the mixture has a particle sizedistribution that is similar to tobacco smoke. The mixture may have theappearance of a vapour or smoke.

The pressurised container may be pressurised to a pressure of from 3 x 105 Pa to1.5 x 107 Pa, preferably from 5 x 105 Pa to 2 x 106 Pa, more preferably from 5.5 x105 Pa to 1 x 106 Pa, even more preferably at about 6 x 105 Pa.

The pressurised container may be used to re-fill an inhaler or simulated cigarette,in particular the inhaler of the third aspect of the present invention describedbelow.

In a third aspect, the present invention provides an inhaler comprising a reservoirof an inhalable composition, a heater to selectably volatilise at least somecomponents of the composition, and a power source arranged to selectivelysupply electrical power to the heater when the user inhales from the inhaler, theinhalable composition is according to the first aspect.

The inhaler may deliver inhalable composition to a user in the form of an aerosolby heating the inhalable composition at a temperature warm enough to closelyreplicate conventional cigarette smoking, but low enough to avoid the generationof harmful by-products.

The inhalable composition is according to the first aspect of the present invention.The advantages and preferred features of the inhalable composition of the firstaspect apply equally to the inhalable composition contained in the inhaler of thethird aspect.

The inhalable composition may be substantially free of tobacco. Preferably, theinhalable composition is tobacco-free. As discussed above, tobacco is associatedwith a number of adverse effects, for example cancer.

The power source is preferably arranged to heat the heater to a temperature thatwill volatilise some, but not all of the components of the composition.

Because the heater is configured to heat the composition to a temperature thatwill volatilise some, but not all, of the components of the composition, thetemperatures required are less than those of the prior art. This reduces thepower requirement of the inhaler and prevents the degradation of the inhaledformulation. Thus, preferably, the heater is arranged to heat the composition tobetween 40 and 180°C and preferably 40°C to 100°C, even more preferably from70 to 90°C. The ability to dispense at these temperatures is based on arecognition by the inventors that it is not necessary to volatilise all components ofthe formulation. Instead, the temperature is set at a level at which only certaincomponents of the composition (such as ethanol) will volatilise while others (suchas propylene glycol) will not.

Preferably the heater is arranged to heat the formulation to volatilise the majorityof the ethanol.

Preferably the heater is arranged to heat the formulation not to volatilise themajority of the propylene glycol.

Preferably the heater is arranged to heat the composition after it has left thereservoir. This avoids heating the composition in the reservoir itself therebysaving energy and reducing degradation of the composition.

Additionally or alternatively, other mechanisms may be employed to effect a fineaerosolisation of the non-volatilised formulation components. The reservoir may be pressurised, for example due to the presence of the propellant, such as HFA,to increase the pressure in the reservoir resulting in improved aerosolisation.

The inhaler may have any configuration but is preferably a simulated cigarette.

Additionally or alternatively there may be at least one airflow path arranged todraw air in through the side of the cigarette as a user inhales from an inhalingend, and impinge on the composition leaving the heater at the inhaling end.Such airflow will reduce the mean particle size of the plume. Preferably there ismore than one such path, and preferably the paths are arranged to generate swirlaround the main axis of the inhaler thereby generating further turbulence andcausing greater reduction in particle size.

The airflow paths are preferably arranged to pass through a constriction in thevicinity of the outlet end of the inhaler thereby generating a Venturi effect andpromoting suction of the composition out of the inhaler. The inhaler may beconfigured to have a through flow of air from one end to the other when the userinhales from the outlet end. However, preferably, one or both of the effect of thepropellant in the reservoir and the Venturi effect provided by the airflow pathsprovides the motive force to expel the composition from the reservoir.

The inhaler preferably further comprises an outlet valve to control the flow ofinhalable composition from the reservoir and out of inhaler. The outlet valve maybe any type of valve. For example, the valve may be a valve attached to thepower source that operates on sensing a particular airflow. However, the outletvalve is preferably a breath-operated outlet valve.

The present invention also extends to a combination of an inhaler and a refillpack, the inhaler comprising a reservoir for an inhalable composition, a heater toselectively volatilise at least some components of the composition and at leastone inhaler capacitor arranged to supply electrical power to the heater when auser inhales from the inhaler; the refill pack comprising a refill reservoir of inhalable composition and a battery coupled to a refill capacitor, and beingarranged to engage with the inhaler and to refill the reservoir and recharge theinhaler capacitor from the refill capacitor, the inhalable composition beingaccording to the first aspect.

Preferably, the heater is configured to heat the composition to a temperature thatwill volatilise some, but not all of the components of the composition.

The inhaler and/or inhalable composition of this combination may have any of thepreferred features referred to above.

Preferably the pack is arranged to fully recharge and refill the inhaler from emptyin less than 30 seconds and preferably less than 10 seconds.

The battery may be rechargeable, but is preferably non-rechargeable.

Preferably, the refill reservoir is pressurised with the propellant or a compressedgas, the inhaler reservoir having a closable refill valve and the refill pack having acomplementary refill valve such that engagement of the inhaler with the pack willcause the two refill valves to open thereby allowing the pressurised compositionto flow into the inhaler reservoir.

The refill pack is preferably configured such that it will automatically terminate therefill and recharge operations.

Examples

The invention will now be described with reference to the following non-limitingexamples.

Inhalable compositions were prepared as set out in Table 1.

Table 1 - Inhalable compositions 1-7 (compositions 2, 3 and 7 are referenceexamples). The %w/w values are approximate, since each composition alsocontained approximately 0.056 %w/w nicotine.

Using the inhaler of the present invention, compositions 1-3 were suitable to beaerosolised at a temperature of around 40 °C, compositions 4-6 were suitable tobe aerosolised at a temperature of around 80 °C, and composition 7 was suitableto be aerosolised at a temperature of around 175 °C.

An example of a combination of an inhaler and refill pack will now be describedwith reference to the accompanying drawings, in which:

Fig. 1 is a schematic cross-section of an inhaler;

Fig. 2 is a schematic cross-section of an inhaler within a refill pack; and

Fig. 3 is a circuit diagram for the recharging operation.

The inhaler is in the form of a simulated cigarette having a generally cylindricalconfiguration the approximate size of a cigarette.

The inhaler has a cylindrical housing 1 which may be in one or more parts. Thehousing may be wrapped with a paper-like wrap to provide a more realisticcigarette-like appearance and feel.

Within the housing 1 is a reservoir 2 of inhalable composition. The reservoir 2has an outlet 3, flow from which is controlled by a ball valve 4 which is opened byan electromagnetic actuator against the action of a spring 5 which biases the ball

valve 4 onto the outlet 3. As an alternative, the outlet valve may be a breathoperated valve such as that disclosed in WO 2011/015825 and WO2014/033438. Downstream of the ball valve 4 is a heater 6. This is made of anyhighly efficient conductive material, preferably fibreglass, and has an internalpathway 7 along its central axis for the passage of composition. The heatingelement 6 is powered by a super capacitor 8 (also known as an ultra-capacitor).A suitable capacitor is sold by Maxwell Technologies as part of the HC series.This preferably has a capacity of 3-7 F and a diameter of 6mm to 10mm and alength of 5 to 50mm. There may be more than one capacitor provided. Fig. 1also shows an optional battery 9 which will charge the capacitor 8. However, thecurrent preference is for no battery to be present. The capacitor 8 is connectedto the heater 6 by a wire 10. Circuitry 11 is provided to control the operation ofthe inhaler.

The inhaler has an inhaling end 12 and a refill end 13. The inhaling end isprovided with an outlet orifice 14 which is in communication with the internalpathway 7 from the heater. Surrounding the heater 6 in the vicinity of the inhalingend 12 are a number of air paths 15 as shown in Fig. 1. In practice, there may bea number of air paths arranged around the axis, but there are preferably 2 to 4such passages. These are angled with respect to the main axis of the inhaler asshown. They are also be offset with respect to the axis such they general swirl ofthe air about the main axis. In particular, the air paths 15 are configured togenerate a Venturi effect causing suction in the internal pathway 7 of the heater 6when a user inhales from the inhaling end 12.

The refill end is provided with a refill valve 16 in the form of a ball valve whichopens against the action of a spring 17 which biases the valve closed onto a refillnozzle 18. The refill valve 16 is connected to the reservoir 2 by a refill conduit 19which extends past the capacitor 8 to provide fluid communication between therefill nozzle 18 and the reservoir 2. A pair of electrical contacts 20 with exposedends 21 are arranged to provide an electrical connection from the refill end 13 tothe opposite terminals of the capacitor 8.

When a user inhales from the inhaling end 12, air flow is detected by a sensorswitch (not shown) in the air flow path 15 triggering the current flow from thecapacitor 8 to the heater 6 in order to heat the composition. The compositioncomprises ethanol (boiling point 78.4°C), nicotine (boiling point 247°C), propyleneglycol (boiling point 188°C) and HFA (boiling point -26°C). Thus, by heating thecomposition to a temperature of under 180°C, all but the nicotine and propyleneglycolene are volatilised. Preferably the composition is heated to 80°C which willcomprise the ethanol but not the propylene glycol. The result of this heating is amixture of non-volatilised liquid formation and vapour.

At the same time, the ball valve 4 is opened by the electromagnetic actuator.Thus, the composition in the reservoir 2, which may be pressurised to, forexample, 6 bar if a propellant is used, leaves the reservoir along the internalpathway 7 assisted by the suction force generated by the airflow in the air paths15. This airflow also serves to break up the composition ensuring that the plumeemitted from the outlet orifice 4 has a fine aerosolisation that promotes higherpulmonary deposition.

The refill pack will now be described by reference to Fig. 2. This shows theinhaler of Fig. 1 inserted into the refill pack with the refill end 13 lowermost. Therefill pack is approximately the size and shape of a standard cigarette pack butcan have any configuration.

The refill pack comprises a housing 30 and is broadly divided into three sectionsnamely, from left to right (in Fig. 2), a storage port 31 to receive the inhaler, apower supply 32 and a composition refill 33. These are connected across thebase of the housing 30 as described below.

The power supply 32 comprises a capacitor 34 which is charged from the battery35 as shown in Fig. 3. Control circuitry 36 is retained in place by a screw cap 37.The reservoir 33 is pressurised by a plunger 38 which is biased downwardly by a spring 39 held in place by a screw cap 40. The bottom end of the reservoir isconnected by a refill duct 41 to a refill valve 42 beneath the inhaler port 31. Therefill valve 42 is a ball valve which is biased closed by a spring and which isopened, in use, by the refill nozzle 18 of the inhaler which presses downwardlyon the refill valve 42. A release spring 43 is provided in the housing 30 underneath the inhaler recess31. This spring will push the inhaler away from the refilling position to a storageposition when the refilling process is complete. This may be done, for example,by releasing the inhaler when a certain priority is detected which indicates thatthe refill operation is complete.

When the reservoir 2 is depleted of composition, the inhaler is inserted into thehousing 30 in the orientation as shown in Fig. 2 and downward pressure isapplied to overcome the release spring 42. The refill nozzle 18 opens the refillvalve 42 such that the pressure in the reservoir 33 is sufficient to lift the refillvalve 16 in the inhaler thereby allowing composition to flow along the refill conduit19 and link to the reservoir 2. The refill operation is automatically terminated asdescribed above and the release spring urges the inhaler to the storage position.

At the same time as the inhaler is being refilled, the ends 21 of the electricalcontacts 20 make contact with inner 44 and outer 45 charging plate rings in thehousing 30 which are electrically coupled to the capacitor 43. This causes theinhaler capacitor 8 to be recharged simultaneously with the refill. The rechargecircuit is shown in Fig. 3.

The foregoing detailed description has been provided by way of explanation andillustration, and is not intended to limit the scope of the appended claims.

Claims

1. An inhalable composition comprising: nicotine or a pharmaceutically acceptable derivative or salt thereof; a propellant; from 15 to 75 %w/w ethanol based on the total weight of the composition;and from 1 to 40 %w/w propylene glycol based on the total weight of thecomposition, wherein the propellant is present in an amount of from greater than 0 % w/w toless than 60 %w/w based on the total weight of the composition.

2. The inhalable composition of claim 1, comprising from 30 to 59 %w/wpropellant, preferably from 31 to 58 % w/w propellant based on the total weight ofthe composition.

3. The inhalable composition of claim 1 or claim 2, comprising from 30 to 70% w/w ethanol, preferably from 35 to 65 % w/w ethanol, more preferably from 38to 62 % w/w ethanol based on the total weight of the composition.

4. The inhalable composition of any preceding claim, wherein thecomposition comprises 2 to 40 % w/w propylene glycol, preferably from 3 to 38 %w/w propylene glycol based on the total weight of the composition.

5. The inhalable composition of any preceding claim, wherein the ratio byweight of ethanol to propylene glycol is from 15:1 to 1:1.

6. The composition of any preceding claim wherein the composition furthercomprises a human TAS2R bitter taste receptor agonist, preferably wherein thehuman TAS2R bitter taste receptor agonist is saccharin.

7. The composition of any of claims 1 to 5 wherein the composition furthercomprises saccharin and wherein the ratio of nicotine or a pharmaceuticallyacceptable derivative or salt thereof: saccharin by weight is from 12:1 to 5.5:1.

8. The composition of any preceding claim wherein the propellant is ahydrofluorocarbon.

9. The composition of any preceding claim further comprising a flavourcomponent, preferably menthol and/or vanillin.

10. The composition of claim 9 wherein the composition comprises up to 0.1%w/w menthol, based on the total weight of the composition.

11. The composition of any preceding claim comprising from 0.001 %w/w to0.045 %w/w nicotine or a pharmaceutically acceptable derivative or salt thereof,based on the total weight of the composition.

12. The composition of any of claims 1-10 comprising from 0.04 %w/w to0.07 %w/w nicotine or a pharmaceutically acceptable derivative or salt thereof,based on the total weight of the composition.

13. The composition of any of claims 1-10 comprising from 0.065 %w/w to0.1 %w/w nicotine or a pharmaceutically acceptable derivative or salt thereof,based on the total weight of the composition.

14. The composition of any preceding claim comprising, based on the totalweight of the composition: from 3 to 58 %w/w propellant, from 38 to 62 % w/w ethanol, and from 2 to 38 %w/w propylene glycol.

15. The composition of any of claims 1 to 13 comprising, based on the totalweight of the composition: from 30 to 40 %w/w propellant, from 55 to 65 % w/w ethanol, and from 3 to 15 %w/w propylene glycol.

16. The composition of any of claims 1 to 13 comprising, based on the totalweight of the composition: from 30 to 40 %w/w propellant, from 35 to 45 % w/w ethanol, and from 22 to 32 %w/w propylene glycol.

17. The composition of any of claims 1 to 13 comprising, based on the totalweight of the composition: from 50 to 57 %w/w propellant, from 35 to 45 % w/w ethanol, and from 22 to 32 %w/w propylene glycol.

18. The composition of any preceding claim, wherein the composition issubstantially free of tobacco, preferably the composition is tobacco free.

19. A pressurised container containing the composition of any of claims 1 - 18.

20. The pressurised container of claim 19 pressurised to a pressure of from 3 x 105 Pa to 1.5 x 107 Pa.

21. An inhaler comprising a reservoir of an inhalable composition, a heater toselectably volatilise at least some components of the composition, and a powersource arranged to selectively supply electrical power to the heater when a userinhales from the inhaler, the inhalable composition being according to any ofclaims 1 to 18.

22. The inhaler of claim 21, wherein the power source is arranged to heat theheater to a temperature that will volatilise some, but not all of the components ofthe composition.

23. The inhaler of claim 21 or claim 22, wherein the heater is arranged to heatthe composition to between 40 and 180°C.

24. The inhaler of claim 23, wherein the heater is arranged to heat thecomposition to between 40 and 100°C.

25. The inhaler of any of claims 21 to 24, wherein the heater is arranged toheat the formulation to volatilise the majority of the ethanol.

26. The inhaler of any of claims 21 to 25, wherein the heater is arranged toheat the formulation not to volatilise the majority of the propylene glycol.

27. The inhaler of any of claims 21 to 26, wherein the heater is arranged toheat the composition after it has left the reservoir.

28. The inhaler of any of claims 21 to 27, further comprising at least oneairflow path arranged to draw air in through a side of the inhaler as the userinhales from an inhaling end, and impinge on the composition leaving the heaterat the inhaling end.

29. The inhaler of claim 28, wherein there is more than one path and whereinthe paths are arranged to generate swirl around a main axis of the inhaler.

30. The inhaler of any of claim 28 or claim 29, wherein there is more than onepath and wherein the airflow paths are arranged to pass through a constriction inthe vicinity of the outlet end of the inhaler thereby generating a Venturi effect andpromoting suction of the composition out of the inhaler.

31. The inhaler of any of claims 21 to 30, wherein the inhaler is a simulatedcigarette.

32. The inhaler of any of claims 21 to 31, wherein the reservoir is pressurised.

33. The inhaler of any of claims 21 to 32, further comprising an outlet valve tocontrol the flow of inhalable composition from the reservoir and out of the inhaler.

34. The inhaler of claim 33, wherein the outlet valve is a breath-operatedoutlet valve.

35. A combination of an inhaler and a refill pack, the inhaler comprisinga reservoir for an inhalable composition, a heater to selectively volatilise at leastsome components of the composition and at least one inhaler capacitor arrangedto supply electrical power to the heater when a user inhales from the inhaler; therefill pack comprising a refill reservoir of inhalable composition and a batterycoupled to a refill capacitor, and being arranged to engage with the inhaler and torefill the reservoir and recharge the inhaler capacitor from the refill capacitor, theinhalable composition being according to any of claims 1 to 18.

36. The combination of claim 35, wherein the heater is configured to heat thecomposition to a temperature that will volatilise some, but not all of thecomponents of the composition.

37. The combination of to claim 36, wherein the heater is arranged to heat thecomposition to between 40 and 180°C.

38. The combination of claim 37, wherein the heater is arranged to heat thecomposition to between 40 and 100°C.

39. The combination of any of claims 35 to 38, wherein the pack is arranged tofully recharge and refill the inhaler from empty in less than 30 seconds andpreferably less than 10 seconds.

40. The combination of any of claims 35 to 39, wherein the battery is non-rechargeable.

41. The combination of any of claims 35 to 40, wherein the refill reservoir ispressurised with the propellant or a compressed gas, the inhaler reservoir havinga closable refill valve and the refill pack having a complementary refill valve suchthat engagement of the inhaler with the pack will cause the two refill valves toopen thereby allowing the pressurised composition to flow into the inhalerreservoir.

42. The combination of any of claims 35 to 41, wherein the refill pack isconfigured such that it will automatically terminate the refill and rechargeoperations.