WO2017046593A2

WO2017046593A2 - An inhalable composition and an inhaler

Info

Publication number: WO2017046593A2
Application number: PCT/GB2016/052885
Authority: WO
Inventors: Alex Hearn; Ritika Gupta
Original assignee: Kind Consumer Limited
Priority date: 2015-09-18
Filing date: 2016-09-15
Publication date: 2017-03-23
Also published as: GB2542404A; EP3349605A2; CN108348013A; GB2542404B; GB201516558D0; WO2017046593A3

Abstract

An inhaler comprising a reservoir of an inhalable composition, a heater to selectably volatilise at least some components of the composition, and a power source arranged to selectively supply electrical power to the heater when the user inhales from the inhaler, the inhalable composition comprising: nicotine or a pharmaceutically acceptable derivative or salt thereof, a glycol and/or glycol ether, and a propellant, wherein the propellant is present in an amount of from greater than 0 %w/w to less than 95 %w/w based on the total weight of the composition.

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 and a heating element to vaporise some of the composition as a user sucks on the end of the cigarette, the vaporised composition then being inhaled.

E-cigarettes are gaining increasing popularity as they provide an alternative to conventional smoking which eliminates the many carcinogens and toxic substances found in tobacco products.

E-cigarettes conventionally use an inhalable composition consisting of a high level of propylene glycol, glycerol, glycerin or glycol in which the nicotine (or alternative such as a flavouring) is solubilised. The high level of propylene glycol causes the composition to be viscous. This is beneficial as it can prevent unwanted evaporation of the composition out of the device and is usually contained in a cotton wadding, pad or other absorbent material. E-cigarettes generally comprise a heater or an ultrasonic atomiser which is in the vicinity of a small amount of the composition volume. Suction on the inlet end causes operation of the heater, and the substance in the vicinity of the heater is evaporated and inhaled. The relatively high viscosity of the composition ensures that the composition available to the heater is gradually replenished but generally prevents it from leaking from the absorbent material in the absence of heat.

While this is reasonably successful, there are two main drawbacks associated with electronic cigarettes. Firstly, the propylene glycol vaporises at a relatively high temperature such that this causes degradation of the composition generally used in E-cigarettes. This can lead to problems with dosage consistency and the presence of contaminants in the inhaled composition including the production of by-products such as formaldehyde, toluene and acrolein. Secondly, the E-cigarettes require relatively high power to generate the high temperature. Moreover they normally require large batteries to deliver a total dose of vaporised composition to last the user the equivalent of between 20 to 40 cigarettes worth of inhalable composition. The cigarettes have the power to dispense at least one reservoir full of composition. As this large volume is dispensed at a high temperature, a large battery is required. Additionally since larger reservoirs and batteries are used, the nicotine dosage contained in E- cigarettes is high and potentially poses safety concerns when packaged in this format.

Broadly, such E-cigarettes can be divided into three categories, namely rechargeable, refillable and disposable. Those which are rechargeable come with a mains power adaptor. This is cumbersome for a user to carry around as it cannot readily fit into a pocket which is inconvenient. The relatively long recharge time is also inconvenient if a user only remembers that the charge has run down just before they go out.

There are also refillable E-cigarettes which require disassembly of the device and the replacement of the reservoir via a cartridge, liquid or absorbent material. However these are the subject of legal restrictions in many countries due to the availability of drug compositions in unsealed containers. Moreover extra care is required in the process of replacing cartridges or material within the device, and extra 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 for a time equivalent to approximately 10-20 cigarettes, whereupon the cigarette and its container are thrown away. This is not environmentally friendly, particularly when the cigarette contains a relatively large battery and could be reused or recycled. WO2014/033437 discloses inhalable nicotine compositions that are not required to be heated in order to be delivered to an end user. While such compositions typically contain very few harmful by-products, the lack of heating, and the expansion of the propellant during delivery, typically results in the composition being delivered to an end user at a low temperature. Such a low temperature may be unpleasant, and may not adequately replicate conventional cigarette smoking.

The present invention addresses some of the above problems.

According to a first aspect, the present invention provides an inhaler comprising a reservoir of an inhalable composition, a heater to selectably volatilise at least some components of the composition, and a power source arranged to selectively supply electrical power to the heater when the user inhales from the inhaler, the inhalable composition comprising:

nicotine or a pharmaceutically acceptable derivative or salt thereof, a glycol and/or glycol ether, and

a propellant, wherein the propellant is present in an amount of from greater than 0 %w/w to less than 95 %w/w based on the total weight of the composition.

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

The term "nicotine" as used herein encompasses the compound having the following structure:

The term "diameter" as used herein encompasses the largest dimension of a droplet. Droplet diameters referred to herein may be measured using a Malvern Spraytec 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 of the droplets in a composition have a smaller diameter than. The term "Dv90" as used herein refers to a droplet diameter that no more than 90 %vol of the droplets in a composition have a smaller diameter than. Dv10, Dv50 and Dv90 values may be determined using a Malvern Spraytec device. The term "nicotine free base" as used herein refers to the form of nicotine that predominates at high pH levels, i.e. at pH levels above 7.

When introducing elements of the present disclosure or the preferred

embodiments(s) thereof, the articles "a", "an", "the" and "said" are intended to mean 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 be additional elements other than the listed elements.

The inhaler may deliver inhalable composition to a user in the form of an aerosol by heating the inhalable composition at a temperature warm enough to closely replicate conventional cigarette smoking, but low enough to avoid the generation of harmful by-products. The inhalable composition may be according to the second aspect of the present invention described below. The advantages and preferred features of the inhalable composition of the second aspect apply equally to the inhalable composition contained in the inhaler of the first aspect.

5

The inhalable composition preferably comprises from 0.5 to 80 % w/w propellant, more preferably from 1 to 75 % w/w propellant based on the total weight of the composition. o The inhalable composition preferably further comprises a monohydric alcohol, more preferably ethanol. The inhalable composition preferably comprises from 0.5 to 70 %w/w ethanol, more preferably from 1 to 65 %w/w ethanol, even more preferably from 15 to 62 %w/w ethanol, still even more preferably from 35 to 61 %w/w ethanol.

5

The inhalable composition may be substantially free of tobacco. Preferably, the inhalable composition is tobacco-free. As discussed above, tobacco is associated with a number of adverse effects, for example cancer. o The power source is preferably arranged to heat the heater to a temperature that will volatilise some, but not all of the components of the composition.

Because the heater is configured to heat the composition to a temperature that will volatilise some, but not all, of the components of the composition, the

5 temperatures required are less than those of the prior art. This reduces the

power requirement of the inhaler and prevents the degradation of the inhaled formulation. Thus, preferably, the heater is arranged to heat the composition to between 40 and 180°C and preferably 40°C to 100°C, even more preferably from 70 to 90°C. The ability to dispense at these temperatures is based on a

o recognition by the inventors that it is not necessary to volatilise all components of the formulation. Instead, the temperature is set at a level at which only certain components of the composition (such as ethanol) will volatilise while others (such as propylene glycol) will not.

Preferably the composition includes ethanol and the heater is arranged to heat the formulation to volatilise the majority of the ethanol.

Preferably the heater is arranged to heat the formulation not to volatilise the majority of the propylene glycol. Preferably the heater is arranged to heat the composition after it has left the reservoir. This avoids heating the composition in the reservoir itself thereby saving energy and reducing degradation of the composition.

Additionally or alternatively, other mechanisms may be employed to effect a fine aerosolisation 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 to draw air in through the side of the cigarette as a user inhales from an inhaling end, 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 is more than one such path, and preferably the paths are arranged to generate swirl around the main axis of the inhaler thereby generating further turbulence and causing greater reduction in particle size.

The airflow paths are preferably arranged to pass through a constriction in the vicinity of the outlet end of the inhaler thereby generating a Venturi effect and promoting suction of the composition out of the inhaler. The inhaler may be configured to have a through flow of air from one end to the other when the user inhales from the outlet end. However, preferably, one or both of the effect of the propellant in the reservoir and the Venturi effect provided by the airflow paths provides the motive force to expel the composition from the reservoir. The inhaler preferably further comprises an outlet valve to control the flow of inhalable composition from the reservoir and out of inhaler. The outlet valve may be any type of valve. For example, the valve may be a valve attached to the power source that operates on sensing a particular airflow. However, the outlet valve is preferably a breath-operated outlet valve.

The present invention also extends to a combination of an inhaler and a refill pack, the inhaler comprising a reservoir for an inhalable composition, a heater to selectively volatilise at least some components of the composition and at least one inhaler capacitor arranged to supply electrical power to the heater when a user inhales from the inhaler; the refill pack comprising a refill reservoir of inhalable composition and a battery coupled to a refill capacitor, and being arranged to engage with the inhaler and to refill the reservoir and recharge the inhaler capacitor from the refill capacitor Preferably, the heater is configured to heat the composition to a temperature that will volatilise some, but not all of the components of the composition.

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

Preferably the pack is arranged to fully recharge and refill the inhaler from empty in 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 compressed gas, the inhaler reservoir having a closable refill valve and the refill pack having a complementary refill valve such that engagement of the inhaler with the pack will cause the two refill valves to open thereby allowing the pressurised composition to flow into the inhaler reservoir.

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

In a second aspect the present invention provides an inhalable composition comprising:

o nicotine or a pharmaceutically acceptable derivative or salt thereof;

a propellant;

a monohydric alcohol; and

a glycol and/or glycol ether,

wherein the propellant is present in an amount of from greater than 0 %w/w to5 less than 60 %w/w based on the total weight of the composition.

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

In both conventional cigarettes and E-cigarettes, nicotine must be heated in order to be delivered to a user via inhalation (to result in combustion in the case of a conventional cigarette or to result in vaporisation, typically at a temperature of 5 from 240 to 300 °C, in the case of an E-cigarette). Such heating results in the generation of harmful by-products, such as aldehydes, ketones, nitrosamines and heavy metals, which are then also delivered to the user via inhalation. Nicotine compositions that may be delivered without being heated, for example those disclosed in WO2014/033437, may be delivered without generating such harmful o by-products. However, the absence of heating, together with the expansion of a propellant, may result in the nicotine composition being delivered to a user at low temperature. This may be unpleasant to an end user, and may not adequately replicate the feel of conventional cigarette smoking.

In contrast, the inhalable composition of the present invention may be delivered 5 to a user by heating it to a temperature of less than 300 °C, typically less than 200 °C, more typically less than 150 °C, even more typically less than 100 °C, still even 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 enough i o to replicate the feel of conventional cigarette smoking, but low enough to avoid the generation of harmful by-products. Furthermore, in contrast to conventional E-cigarettes, the lower temperatures that may be employed to deliver the inhalable composition are safer and require a smaller and/or lower powder battery.

15

Advantageously, the inhalable composition of the present invention may be delivered with a pressure of around 6 bar. This may provide the user with a favourable mouth feel, and one that more closely replicates conventional cigarette smoking.

20

Any suitable source of nicotine may be employed. For example, the nicotine may be nicotine free base, a nicotine derivative and/or a nicotine salt. Where a nicotine free base is employed, it may be employed in liquid form. Where a nicotine salt is employed, it may be employed in the form of a solution. Suitable

25 nicotine 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 and aspartic. Other nicotine salts, such as nicotine bitartrate dehydrate, may also be employed. Mixtures of two or more nicotine salts may be employed. Nicotine

3 o salts may also be in liposomal encapsulation. Such encapsulation may allow the nicotine concentration of a composition to be further increased without nicotine precipitation occurring. The glycol and/or glycol ether aids the dissolution of the nicotine or a

pharmaceutically acceptable derivative or salt thereof in the composition. This avoids the presence of precipitates of nicotine (or other additives such as saccharin, if present) in the composition, which could cause irritation when delivered to a user. In addition, the presence of glycol or glycol ether reduces the degradation of nicotine that occurs over time, thereby increasing the long-term stability or "shelf life" of the composition. For example, chromatographic analysis of the composition according to the second aspect of the present invention, after six months' storage at 40 °C, 75 % relative humidity, may indicate 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 within the

European Pharmacopoeia specifications for nicotine starting material, indicating the favourable degradation characteristics of the composition over the

composition lifetime. Notwithstanding this, the European Pharmacopoeia should not be taken as limiting in any way the allowable impurities tolerances claimed in this invention.

The monohydric alcohol may act as a solvent for the components of the inhalable composition, and may increase the stability of the inhalable composition. On heating the composition, for example to a temperature of around 80 °C, typically both the ethanol and the propellant vaporise. This may allow the inhalable 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 and glycol and/or glycol ether, being in the form of aerosolised droplets. Monohydric alcohol has a lower viscosity than glycol or glycol ether. Accordingly, the composition is able to form droplets of a smaller diameter in comparison to compositions in which the monohydric alcohol is not present. Advantageously, on inhalation, smaller droplets are more likely to be delivered to the lungs of a user. This is discussed in more detail below.

The inhalable composition comprises a propellant. Conventional E-cigarettes do not contain a propellant, since the high temperatures used in such devices enable the inhalable compositions to be completely volatalised. The presence of a propellant in the inhalable composition of the present invention may allow the inhalable composition to be aerosolised at a lower temperature. The propellant is present in an amount of from greater than 0 %w/w to less than 60 %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 inhalable composition preferably comprises from 10 to 59 %w/w propellant, more preferably from 15 to 59 %w/w propellant, even more preferably from 20 to 59 %w/w propellant, still even more preferably from 25 to 59 %w/w propellant, still even more preferably from 30 to 59 %w/w propellant, still even more preferably from 31 to 58 % w/w propellant based on the total weight of the composition. The inhalable composition may preferably comprise from 20 to 40 %w/w propellant, more preferably from 22 to 38 %w/w propellant, even more preferably from 30 to 37 %w/w propellant based on the total weight of the inhalable composition.

Alternatively, the inhalable composition may preferably comprise from 40 to 59 %w/w propellant, more preferably from 45 to 58 %w/w propellant, even more preferably from 50 to 57 %w/w propellant based on the total weight of the composition. The inhalable composition preferably comprises 59 %w/w or less, more preferably 58 %w/w or less, even more preferably 57 %w/w or less, still even more preferably 56 %w/w or less propellant based on the total weight of the composition. Higher amounts of propellant may restrict the amounts of other components that may be present in the composition, for example the monohydric alcohol or glycol and/or glycol ether. Accordingly, the beneficial effects provided by such components may be reduced. In addition, higher levels of propellant may increase the pressure at which the composition is delivered to an end user on heating, thereby resulting in an undesirable mouth feel. Lower amounts of propellant may reduce the pressure at which the inhalable composition is delivered, or may require higher heating temperatures to aerosolise the composition. Accordingly, the amount of undesirable by-products generated may be increased.

Preferably the monohydric alcohol is ethanol. Ethanol has a particularly low viscosity in comparison to a glycol or glycol ether, and is therefore particularly effective at enabling the composition to form droplets of small diameter. In addition, ethanol is cheap, relatively non-harmful and readily available.

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

Preferably the glycol and/or glycol ether is selected from one or more of propylene glycol, polypropylene glycol and polyethylene glycol. Propylene glycol is particularly preferred. The glycol and/or glycol ether preferably is propylene glycol and the composition preferably comprises from 1 to 85 % w/w propylene glycol, more preferably from 2 to 40 % w/w propylene glycol, even more preferably from 3 to 38 % w/w propylene glycol based on the total weight of the composition. Lower levels of glycol and/or glycol ether may result in degradation of nicotine and/or the formation of precipitates of nicotine. Higher levels of glycol and/or glycol ether may result in the need to employ higher temperatures in order to aerosolise the composition. In a preferred embodiment, the composition comprises from 3 to 7 %w/w propylene glycol. In an alternative preferred embodiment, the composition comprises from 25 to 29 %w/w propylene glycol. The ratio by weight of monohydric alcohol to glycol and/or glycol ether is preferably from 15:1 to 1 :1 , more preferably from 13:1 to 1 .5:1 . When a nicotine composition having such a ratio of monohydric alcohol : glycol or glycol ether is 5 delivered to a user via heating, for example via the inhaler of the first aspect of the present invention described in more detail above, the composition is delivered in the form of droplets, some of which (such as, for example, at least 10 %vol) have a diameter of less than 10 μιη, typically less than 5 μιη. Typically, the majority (such as, for example, at least 50 %vol) of the droplets have a diameter0 of less than 5 μιη, 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 μιη. Advantageously, when administered to a user, droplets with a size of less than 10 μιτι 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), typically5 substantially all (such as, for example, at least 90 %w/w), of the nicotine enters the bloodstream via the pulmonary route. This means that the composition, when inhaled orally, is more able to mimic the pharmacokinetic profile of a conventional cigarette compared to nicotine compositions of the prior art. Since the

composition may be administered via oral inhalation and is able to mimic the o pharmacokinetic profile of a conventional cigarette, it is particularly effective for use in NRT or as an alternative to recreational smoking of conventional cigarettes.

Typically at least some (such as, for example, at least 10 %vol) of the droplets5 have a size of from 0.5 to 3 μιη. Such droplets may be deposited in the deep

lung, and are therefore particularly able to enter the blood stream via the pulmonary 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 μιη. Such droplets are particularly able to mimic the pharmacokinetic profile of a conventional cigarette, o since conventional cigarette smoke has a mean particle diameter in the range of from 0.4 to 0.5 μιη. The ratio of monohydric alcohol to glycol or glycol ether specified above may result in a composition with a desired combination of both long term stability (for example the composition remains as a single phase for at least a week at a temperature of 2-40 °C) and small droplet size.

In contrast to compositions of the prior art, the composition of the present invention 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 is reduced.

When the composition of the present invention is delivered to a user via the inhaler of the first aspect of the present invention described above, the droplets may exhibit the following droplet size profile:

Dv 90 of less than 20 μιη, typically less than 5 μιη, more typically less than 3, even more typically less than 2.9 μιη, and/or

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

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

This particular droplet size profile is similar to the particle size profile of tobacco smoke. Accordingly, the pharmacokinetic profile of the delivered composition closely mimics that of a conventional cigarette. In particular, delivery of the composition to a user generates an extended peak of high nicotine concentration with a short t_max, i.e. the time from first inhalation to the maximum nicotine-plasma level. As a result, the composition is highly effective for use in nicotine

replacement therapy (NRT) or as an alternative to recreational smoking of conventional cigarettes.

Preferably the composition further comprises a human TAS2R bitter taste receptor agonist. The use of a human TAS2R bitter taste receptor agonist induces bronchodilation, resulting in a reduction in the levels of delivery-related coughing. Accordingly, a user is more able to tolerate the composition since it causes very little irritation.

5 The human TAS2R bitter taste receptor agonist may be a naturally occurring compound or a synthetic compound. Examples of suitable naturally-occurring compounds include Absinthin, Aloin, Amarogentin, Andrographolide, Arborescin, Arglabin, Artemorin, Camphor, Cascarillin, Cnicin, Crispolide, Ethylpyrazine, Falcarindiol, Helicin, Humulone isomers, Limonin, Noscapine Papaverine, i o Parthenolide, Quassin, Sinigrin, and Thiamine. Examples of suitable synthetic compounds include Acesulfame K, Benzoin, Carisoprodol, Chloroquine,

Cromolyn, Dapsone, Denatonium benzoate, Dimethyl thioformamide,

Diphenhydramine, Divinylsulfoxide, Famotidine, Saccharin, Sodium benzoate, and Sodium cyclamate.

15

Preferably the human TAS2R bitter taste receptor agonist is saccharin. Saccharin is particularly effective as a human TAS2R bitter taste receptor agonist, may be readily dissolved in the composition, is readily available and provides the composition with a desirable taste profile. Preferably the ratio of nicotine or a

2 o pharmaceutically acceptable derivative or salt thereof : saccharin by weight is from 12:1 to 5.5:1 , preferably from 1 1 :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 unacceptable

tolerability. Higher levels of saccharin result in an acceptable tolerability but are

25 disfavoured since they may lead to precipitates of saccharin forming in the

composition, which may cause irritation when the composition is administered to a user or blockage when the composition is incorporated into an inhaler or a simulated cigarette. Such ratios also provide the composition with an optimised taste profile.

30

The inhalable composition may comprise additional components, for example one or more of theobromine and vitamin C. Such additional components are typically 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, even more preferably 1 ,1 ,2,2-tetrafluoroethane (HFA-134a) or 1 ,1 ,1 ,2,3,3- heptafluoropropane (HFC-227). Such compounds are particularly effective as propellants 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 a flavour component may mask this taste. Suitable flavour components include the flavour components typically added to tobacco products. Examples include carotenoid products, alkenols, aldehydes, esters and delta-lactone flavour constituents. 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 C-io alkenols, preferably C5 to Cs 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, butyl butyrate, ethyl butyrate, ethyl hexanoate, ethyl cinnamate, ethyl formate, ethyl heptanoate, ethyl isovalerate, ethyl lactate, ethyl nonanoate, ethyl valerate, geranyl acetate, geranyl butyrate, isobutyl acetate, isobutyl formate, isoamyl acetate, isopropyl acetate, linalyl acetate, linalyl butyrate, linalyl formate, methyl acetate, methyl anthranilate, methyl benzoate, methyl benzyl acetate, methyl butyrate, methyl cinnamate, methyl pentanoate, methyl phenyl acetate, methyl salicylate (oil of wintergreen), nonyl caprylate, octyl acetate, octyl butyrate, amyl acetate (pentyl acetate), pentyl hexanoate, pentyl pentanoate, propyl ethanoate, propyl isobutyrate, terpenyl butyrate, ethyl formate, ethyl acetate, ethyl propionate, ethyl butyrate, ethyl valerate, ethyl hexanoate, ethyl heptanoate, ethyl octanoate, 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- 5 Undecalactone, delta-Dodecalactone, Massoia lactone, Jasmine lactone and 6- Pentyl-alpha-pyrone. Flavour components may serve to mask the taste of nicotine, which is unpleasant.

The flavour component is preferably menthol and/or vanillin. The presence of i o menthol, together with the saccharin, reduces the irritation experienced by a user.

Preferably the composition comprises up to 0.1 %w/w menthol, preferably from 0.01 %w/w to 0.08 %w/w, more preferably from 0.02 %w/w to 0.06 %w/w, even more preferably from 0.03 %w/w to 0.05 %w/w, still even more preferably about 0.04 %w/w, based on the total weight of the composition.

15

The composition may comprise from 0.001 %w/w to 0.045 %w/w nicotine or a pharmaceutically acceptable derviative or salt thereof, preferably from 0.01 %w/w to 0.045 %w/w, more preferably from 0.015 %w/w to 0.04 %w/w, even more preferably from 0.02 %w/w to 0.035 %w/w, still even more preferably from 0.025 2 0 %w/w to 0.03 %w/w, most preferably about 0.028 %w/w, based on the total

weight of the composition. Such a composition provides similar effects to a "low strength" nicotine cigarette.

The composition may comprise from 0.04 %w/w to 0.07 %w/w nicotine or a

25 pharmaceutically 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 more preferably from 0.054 %w/w to 0.058 %w/w, still even more preferably about 0.056 %w/w, based on the total weight of the composition. Such a composition provides similar effects to a "medium strength" nicotine cigarette.

3 0

The composition may comprise from 0.065 %w/w to 0.1 %w/w nicotine or a pharmaceutically acceptable derivative or salt thereof, preferably from 0.07 %w/w to 0.095 %w/w, more preferably from 0.075 %w/w to 0.09 %w/w, even more preferably 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 provides similar effects to a "high strength" nicotine cigarette.

A particularly preferred composition comprises, based on the total weight 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.

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

from 30 to 40 %w/w propellant,

from 55 to 65 % w/w ethanol, and

from 3 to 15 %w/w propylene glycol.

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 after heating to only a low temperature, for example around 80 °C. Accordingly, the composition may provide a combination of satisfactory mouth feel and low levels 5 of harmful by-products.

from 50 to 57 %w/w propellant,

0 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 after heating to only a low temperature, for example around 80 °C. Accordingly, the5 composition may provide a combination of satisfactory mouth feel and low levels of harmful by-products.

The composition is preferably substantially free of tobacco, preferably the composition is tobacco free. Tobacco is associated with a number of adverse o effects, for example cancer.

Preferably the composition comprises less than 0.01 %w/w nicotinic acid, more preferably less than 0.005 %w/w, even more preferably less than 0.001 %w/w nicotinic acid, based on the total weight of the composition. Most preferably, the5 composition comprises substantially no nicotinic acid. The presence of nicotinic acid may result in the formation of precipitates in the composition.

The compositions of the second aspect may "consist of" the components recited above. The compositions of the second aspect may "consist of the components o recited above together with any unavoidable impurities. In a third aspect, the present invention provides a pressurised container containing the composition of the second aspect.

The pressurised container of the third aspect of the present invention may be used to release a gaseous flow of the nicotine composition of the second aspect to a user. For example, the pressurised container may be provided with means for delivering 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. The pressurised container may be used to deliver an unmetered dose of nicotine to the user. This may be advantageous over prior art methods of NRT, such as conventional inhalers, nasal sprays, lozenges and patches currently on the market, because it can allow autonomy in nicotine replacement regulation, where there the user can regulate the amount of compositional nicotine he or she wishes to inhale. In addition, the pressurised container can be used as an alternative to recreational smoking of conventional cigarettes.

The pressurised container of the present invention may take the form of a pressurised canister, for example, a pressurised aluminium canister. The canister may be fully recyclable and/or reusable. The canister may be refilled as required by a vending machine or a larger container containing the desired composition under a high pressure gradient. In one embodiment, the canister is a AW5052 aluminium canister.

The pressurised container may be a simulated cigarette or inhaler.

The pressurised container may be capable of dispensing the composition as a mixture of aerosolised droplets. Preferably, the mixture has a particle size distribution that is similar to tobacco smoke. The mixture may have the appearance of a vapour or smoke. The pressurised container may be pressurised to a pressure of from 3 x 10⁵ Pa to 1 .5 x 10⁷ Pa, preferably from 5 x 10⁵ Pa to 2 x 10⁶ Pa, more preferably from 5.5 x 10⁵ 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 first aspect of the present invention described above.

Examples

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

Inhalable compositions were prepared as set out in Table 1 .

Table 1 - Inhalable compositions 1 -7. The %w/w values are approximate, since each composition also contained approximately 0.056 %w/w nicotine. Using the inhaler of the present invention, compositions 1 -3 were suitable to be aerosolised at a temperature of around 40 °C, compositions 4-6 were suitable to be aerosolised at a temperature of around 80 °C, and composition 7 was suitable to be aerosolised at a temperature of around 175 °C. An example of a combination of an inhaler and refill pack will now be described with 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 cylindrical configuration the approximate size of a cigarette.

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

Within the housing 1 is a reservoir 2 of inhalable composition. The reservoir 2 has an outlet 3, flow from which is controlled by a ball valve 4 which is opened by an 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 breath operated valve such as that disclosed in WO 201 1/015825 and WO

2014/033438. Downstream of the ball valve 4 is a heater 6. This is made of any highly efficient conductive material, preferably fibreglass, and has an internal pathway 7 along its central axis for the passage of composition. The heating element 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 a length of 5 to 50mm. There may be more than one capacitor provided. Fig. 1 also shows an optional battery 9 which will charge the capacitor 8. However, the current preference is for no battery to be present. The capacitor 8 is connected to the heater 6 by a wire 10. Circuitry 1 1 is provided to control the operation of the inhaler. The inhaler has an inhaling end 12 and a refill end 13. The inhaling end is provided with an outlet orifice 14 which is in communication with the internal pathway 7 from the heater. Surrounding the heater 6 in the vicinity of the inhaling end 12 are a number of air paths 15 as shown in Fig. 1 . In practice, there may be a number of air paths arranged around the axis, but there are preferably 2 to 4 such passages. These are angled with respect to the main axis of the inhaler as shown. They are also be offset with respect to the axis such they general swirl of the air about the main axis. In particular, the air paths 15 are configured to generate a Venturi effect causing suction in the internal pathway 7 of the heater 6 when 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 which opens against the action of a spring 17 which biases the valve closed onto a refill nozzle 18. The refill valve 16 is connected to the reservoir 2 by a refill conduit 19 which extends past the capacitor 8 to provide fluid communication between the refill nozzle 18 and the reservoir 2. A pair of electrical contacts 20 with exposed ends 21 are arranged to provide an electrical connection from the refill end 13 to the opposite terminals of the capacitor 8.

When a user inhales from the inhaling end 12, air flow is detected by a sensor switch (not shown) in the air flow path 15 triggering the current flow from the capacitor 8 to the heater 6 in order to heat the composition. The composition comprises ethanol (boiling point 78.4°C), nicotine (boiling point 247°C), propylene glycol (boiling point 188°C) and HFA (boiling point -26°C). Thus, by heating the composition to a temperature of under 180°C, all but the nicotine and propylene glycolene are volatilised. Preferably the composition is heated to 80°C which will comprise the ethanol but not the propylene glycol. The result of this heating is a mixture 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, for example, 6 bar if a propellant is used, leaves the reservoir along the internal pathway 7 assisted by the suction force generated by the airflow in the air paths

15. This airflow also serves to break up the composition ensuring that the plume emitted from the outlet orifice 4 has a fine aerosolisation that promotes higher pulmonary deposition.

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

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

The power supply 32 comprises a capacitor 34 which is charged from the battery 35 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 is connected by a refill duct 41 to a refill valve 42 beneath the inhaler port 31 . The refill valve 42 is a ball valve which is biased closed by a spring and which is opened, in use, by the refill nozzle 18 of the inhaler which presses downwardly on the refill valve 42.

A release spring 43 is provided in the housing 30 underneath the inhaler recess 31 . This spring will push the inhaler away from the refilling position to a storage position when the refilling process is complete. This may be done, for example, by releasing the inhaler when a certain priority is detected which indicates that the refill operation is complete.

When the reservoir 2 is depleted of composition, the inhaler is inserted into the housing 30 in the orientation as shown in Fig. 2 and downward pressure is applied to overcome the release spring 42. The refill nozzle 18 opens the refill valve 42 such that the pressure in the reservoir 33 is sufficient to lift the refill valve 16 in the inhaler thereby allowing composition to flow along the refill conduit 19 and link to the reservoir 2. The refill operation is automatically terminated as described 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 electrical contacts 20 make contact with inner 44 and outer 45 charging plate rings in the housing 30 which are electrically coupled to the capacitor 43. This causes the inhaler capacitor 8 to be recharged simultaneously with the refill. The recharge circuit is shown in Fig. 3.

The foregoing detailed description has been provided by way of explanation and illustration, and is not intended to limit the scope of the appended claims. Many variations in the presently preferred embodiments illustrated herein will be apparent to one of ordinary skill in the art, and remain within the scope of the appended claims and their equivalents.

Claims

1 . An inhaler comprising a reservoir of an inhalable composition, a heater to selectably volatilise at least some components of the composition, and a power

5 source arranged to selectively supply electrical power to the heater when the user inhales from the inhaler, the inhalable composition comprising:

a propellant, wherein the propellant is present in an amount of from

i o greater than 0 %w/w to less than 95 %w/w based on the total weight of the

composition.

2. The inhaler of claim 1 , wherein the inhalable composition comprises from 0.5 to 80 % w/w propellant, preferably from 1 to 75 % w/w propellant based on

15 the total weight of the composition.

3. The inhaler of claim 1 or claim 2, wherein the inhalable composition further comprises a monohydric alcohol, preferably ethanol.

2 0 4. The inhaler of any of claims 1 to 3, wherein the composition is

substantially free of tobacco, preferably the composition is tobacco free.

5. The inhaler of any of claims 1 to 4, wherein the power source is arranged to heat the heater to a temperature that will volatilise some, but not all of the

25 components of the composition.

6. The inhaler of any of claims 1 to 5, wherein the heater is arranged to heat the composition to between 40 and 180°C.

3 0 7. The inhaler of claim 6, wherein the heater is arranged to heat the

composition to between 40 and 100°C.

8. The inhaler of any of claims 1 to 7, wherein the composition includes ethanol and the heater is arranged to heat the formulation to volatilise the majority of the ethanol.

5 9. The inhaler of any of claims 1 to 8, wherein the heater is arranged to heat the formulation not to volatilise the majority of the propylene glycol.

10. The inhaler of any of claims 1 to 9, wherein the heater is arranged to heat the composition after it has left the reservoir.

0

1 1 . The inhaler of any of claims 1 to 10, further comprising at least one airflow path arranged to draw air in through the side of the cigarette as a user inhales from an inhaling end, and impinge on the composition leaving the heater at the inhaling end.

5

12. The inhaler of claim 1 1 , wherein there is more than one path and wherein the paths are arranged to generate swirl around the main axis of the inhaler.

13. The inhaler of any of claim 1 1 or claim 12, wherein there is more than one 0 path and wherein the airflow paths are arranged to pass through a constriction in the vicinity of the outlet end of the inhaler thereby generating a Venturi effect and promoting suction of the composition out of the inhaler.

14. The inhaler of any of claims 1 to 13, wherein the inhaler is a simulated 5 cigarette.

15. The inhaler of any of claims 1 to 14, wherein the reservoir is pressurised.

16. The inhaler of any of claims 1 to 15, further comprising an outlet valve to o control the flow of inhalable composition from the reservoir and out of inhaler.

17. The inhaler of claim 16, wherein the outlet valve is a breath-operated outlet valve.

18. A combination of an inhaler and a refill pack, the inhaler comprising a

5 reservoir for an inhalable composition, a heater to selectively volatilise at least some components of the composition and at least one inhaler capacitor arranged to supply electrical power to the heater when a user inhales from the inhaler; the refill pack comprising a refill reservoir of inhalable composition and a battery coupled to a refill capacitor, and being arranged to engage with the inhaler and to0 refill the reservoir and recharge the inhaler capacitor from the refill capacitor, the inhalable composition comprising:

a propellant, wherein the propellant is present in an amount of from

5 greater than 0 %w/w to less than 95 %w/w based on the total weight of the

inhalable composition.

19. The combination of claim 18, wherein the heater is configured to heat the composition to a temperature that will volatilise some, but not all of the

o components of the composition.

20. The combination of to claim 19, wherein the heater is arranged to heat the composition to between 40 and 180°C. 5

21 . The combination of claim 20, wherein the heater is arranged to heat the composition to between 40 and 100°C.

22. The combination of any of claims 18 to 21 , wherein the pack is arranged to fully recharge and refill the inhaler from empty in less than 30 seconds and0 preferably less than 10 seconds.

23. The combination of any of claims 18 to 22, wherein the battery is non- rechargeable.

24. The combination of any of claims 18 to 23, wherein the refill reservoir is pressurised with the propellant or a compressed gas, the inhaler reservoir having a closable refill valve and the refill pack having a complementary refill valve such that engagement of the inhaler with the pack will cause the two refill valves to open thereby allowing the pressurised composition to flow into the inhaler reservoir.

25. The combination of any of claims 18 to 24, wherein the refill pack is configured such that it will automatically terminate the refill and recharge operations.

26. An inhalable composition comprising:

nicotine or a pharmaceutically acceptable derivative or salt thereof;

a propellant;

a monohydric alcohol; and

a glycol and/or glycol ether,

wherein the propellant is present in an amount of from greater than 0 % w/w to less than 60 %w/w based on the total weight of the composition.

27. The inhalable composition of claim 26, comprising from 10 to 59 %w/w propellant, preferably from 30 to 59 %w/w propellant, more preferably from 31 to 58 % w/w propellant based on the total weight of the composition.

28. The inhalable composition of claim 26 or claim 27, wherein the monohydric alcohol is ethanol.

29. The inhalable composition of claim 28, comprising from 15 to 75 % w/w ethanol, preferably from 30 to 70 % w/w ethanol, more preferably from 35 to 65 % w/w ethanol, even more preferably from 38 to 62 % w/w ethanol based on the total weight of the composition.

30. The inhalable composition of any preceding claim, wherein the glycol 5 and/or glycol ether is selected from one or more of propylene glycol,

polypropylene glycol and polyethylene glycol.

31 . The inhalable composition of claim 30, wherein the glycol and/or glycol ether is propylene glycol and the composition comprises from 1 to 85 % w/w0 propylene glycol, preferably from 2 to 40 % w/w propylene glycol, more preferably from 3 to 38 % w/w propylene glycol based on the total weight of the composition.

32. The inhalable composition of any preceding claim, wherein the ratio by weight of monohydric alcohol to glycol and/or glycol ether is from 15:1 to 1 : 1 .5

33. The composition of any preceding claim wherein the composition further comprises a human TAS2R bitter taste receptor agonist, preferably wherein the human TAS2R bitter taste receptor agonist is saccharin. o

34. The composition of any preceding claim wherein the composition further comprises saccharin and wherein the ratio of nicotine or a pharmaceutically acceptable derivative or salt thereof : saccharin by weight is from 12:1 to 5.5:1 .

35. The composition of any preceding claim wherein the propellant is a

5 hydrofluorocarbon.

36. The composition of any preceding claim further comprising a flavour component, preferably menthol and/or vanillin. 0

37. The composition of claim 36 wherein the composition comprises up to 0.1 %w/w menthol, based on the total weight of the composition.

38. The composition of any preceding claim comprising from 0.001 %w/w to 0.045 %w/w nicotine or a pharmaceutically acceptable derivative or salt thereof, based on the total weight of the composition.

5 39. The composition of any of claims 26 - 37 comprising from 0.04 %w/w to 0.07 %w/w nicotine or a pharmaceutically acceptable derivative or salt thereof, based on the total weight of the composition.

40. The composition of any of claims 26 - 37 comprising from 0.065 %w/w too 0.1 %w/w nicotine or a pharmaceutically acceptable derivative or salt thereof, based on the total weight of the composition.

41 . The composition of any preceding claim comprising, based on the total weight of the composition:

5 from 3 to 58 %w/w propellant,

from 38 to 62 % w/w ethanol, and

from 2 to 38 %w/w propylene glycol.

42. The composition of any of claims 26 to 40 comprising, based on the total o weight 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. 5

43. The composition of any of claims 26 to 40 comprising, based on the total weight 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.

0

44. The composition of any of claims 26 to 40 comprising, based on the total weight 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.

45. The composition of any preceding claim, wherein the composition is substantially free of tobacco, preferably the composition is tobacco free.

46. A pressurised container containing the composition of any of claims 26 - 45.

47. The pressurised container of claim 46 pressurised to a pressure of from 3 x 10⁵ Pa to 1 .5 x 10⁷ Pa.

48. The inhaler of any of claims 1 - 17, wherein the inhalable composition is according to any of claims 26 to 45.