GB2542389A

GB2542389A - Simulated cigarette

Info

Publication number: GB2542389A
Application number: GB1516507.9A
Authority: GB
Inventors: Gupta Ritika; Moyses Chris; Hearn Alex; Zaw Nyein Khine
Original assignee: Kind Consumer Ltd
Current assignee: Kind Consumer Ltd
Priority date: 2015-09-17
Filing date: 2015-09-17
Publication date: 2017-03-22
Also published as: GB201516507D0

Abstract

A simulated cigarette comprising a housing 1, a reservoir 4 of inhalable composition within the housing where the inhalable composition comprises nicotine or a pharmaceutically acceptable derivative or salt thereof, an inhalation outlet 2, for the inhalable composition, from the reservoir and leading out of the housing, and a breath-activated inhalation outlet valve 5 for controlling the flow of inhalable composition through the inhalation outlet, wherein at least one part of the simulated cigarette that comes into contact with the inhalable composition during the use comprises one or more of: polyoxymethylene, polybutylene terephthalate, polytetrafluoroethylene, ethylene propylene diene monomer rubber and a thermoplastic elastomer. The inhalable composition preferably comprises less than 50 µg/m3 of formaldehyde and/or less than 180 µg/m3 acetaldehyde and the inhalable composition may comprise one or more of monohydric alcohol and a glycol and/or glycol ether. Ideally the reservoir is pressurised and the internal walls of the reservoir may comprise polybutylene terephthalate. The reservoir may be refillable and comprise a refill valve at a refill end opposite the outlet end. The refill valve preferably comprises a refill valve element 10, a spring 11 and a cage 12.

Description

Simulated Cigarette

The invention relates to a simulated cigarette.

The smoking of tobacco is an addictive activity associated with the pleasurable feeling caused by nicotine, and reinforced by the habits and rituals of the smoker. These attributes combine to make it very difficult to give up smoking, despite the numerous adverse health effects of the carbon monoxide, tar, and other combustion products of tobacco. It is not the nicotine itself that is harmful to health, rather the by-products of tobacco smoke.

There are a number of smoking cessation aids currently on the market, such as nicotine skin patches, nicotine-containing gums, nicotine cartridges, and nicotine inhalers. These aids attempt to achieve the increase in blood nicotine content provided by tobacco smoke without the associated dangerous by-products, but do little to address the habitual aspects of cigarette smoking. Furthermore, detailed analysis of the delivery characteristics of the above smoking cessation aids has revealed a wide variation in effects in terms of speed of delivery, concentration, persistence, and bioavailability (Hukkanen etal., Pharmacol. Rev. 2005, 57, 79). Accordingly, since these aids do not provide a pharmacokinetic profile similar to that of a conventional cigarette, their use in effective nicotine replacement therapy (NRT) or as an alternative to recreational smoking of conventional cigarettes is only very limited. E-cigarettes are hand-held devices containing nicotine formulations that are vaporised by battery-powered heating elements. They are designed for the purpose of providing a nicotine containing vapour to the user, besides which they also provide smoking associated cues such as the hand-to-mouth ritual and presence of an exhaled vapour. Their worldwide increase in trial and usage has resulted in a demand for substantive safety and efficacy data by both consumers and regulatory authorities. As a result, the European Tobacco Product Directive (TPD) was revised in April 2014 to regulate nicotine containing products, including e-cigarettes. As per its guidelines, any e-cigarette product containing up to 20 mg/ml of nicotine would qualify in the TPD e-cigarette category while those with higher concentrations would require to be licenced as a pharmaceutical to be placed on the market. Among the various requirements of the revised TPD, one is the provision of a list of all ingredients contained not only in the product formulation (e-liquid) but also in the emissions resulting from their use; furthermore, these ingredients would need to be quantified as well as toxicologically assessed. Formaldehyde and other carbonyls, VOCs and tobacco specific nitrosamines have been detected in e-cigarette cartridges and vapours. One study quantified formaldehyde-releasing agents in e-cigarette vapours and concluded that if these agents were assumed to carry the same risk per unit of formaldehyde as the risk associated with inhaling gaseous formaldehyde, then long-term ‘vaping’ is associated with an incremental lifetime cancer risk that could be 5 to 15 times as high as the risk associated with long-term smoking. These compounds are understood to be released as a result of thermal decomposition of e-liquids. Formaldehyde has been identified as a known carcinogen by the International Agency for Research on Cancer (IARC) and as a probable human carcinogen by the U.S. Environmental Protection Agency (US EPA).

Simulated cigarettes that do not rely on heating the nicotine formulation are disclosed, inter alia, in WO 2014/155093 and WO2014/033437. When the nicotine formulation is dispensed from such simulated cigarettes, the levels of undesirable impurities are typically reduced in comparison to e-cigarettes. Flowever, the levels of carbonyls, such as formaldehyde, are often still undesirable.

While the components of the nicotine formulations, and the effects of heating the nicotine formulations, have both been investigated with regard to the amounts of undesirable species present in the dispensed formulations, there has been little consideration of the interaction over time of the nicotine formulation with the materials forming the simulated cigarette itself.

The present invention seeks to tackle at least some of the problems associated with the prior art or at least to provide a commercially acceptable alternative solution thereto.

In a first aspect, the present invention provides a simulated cigarette comprising: a housing; a reservoir of inhalable composition within the housing, the inhalable composition comprising nicotine or a pharmaceutically acceptable derivative or salt thereof; an inhalation outlet for the inhalable composition from the reservoir and out of the housing; and a breath-activated inhalation outlet valve for controlling the flow of inhalable composition through the inhalation outlet, wherein at least one part of the simulated cigarette that comes into contact with the inhalable composition during use comprises one or more of: polyoxymethylene, polybutylene terephthalate, polytetrafluoroethylene, ethylene propylene diene monomer rubber and a thermoplastic elastomer.

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 “polyoxymethylene” (POM) as used herein encompasses a polymer species having the following structure:

POM is also known as “acetal”, “polyacetal” and “polyformaldehyde”.

The term “polytetrafluoroethylene” (PTFE) as used herein encompasses a synthetic fluoropolymer of tetrafluoroethylene. PTFE has the following structure:

The term “thermoplastic elastomer” (TPE) encompasses a class of copolymers or a physical mix of polymers (usually a plastic and a rubber) which consist of materials with both thermoplastic and elastomeric properties. TPE is sometimes referred to as “thermoplastic rubber”.

The term “ethylene propylene diene monomer rubber” (EPDM) as used herein encompasses a terpolymer of ethylene, propylene, and a diene-component.

The term “polybutylene terephthalate” (PBT) as used herein encompasses a polymer having the following structure:

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

The term “carbonyls” as used herein may encompass organic compounds containing a carbonyl, i.e. C=0, functional group. The term may encompass, for example, the following compounds: formaldehyde, acetaldehyde, acetone, acrolein, propionaldehyde, crotonaldehyde, butan-2-one (MEK) and butyraldehyde.

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.

The term “Cmax” as used herein refers to the maximum measured concentration of a compound, in this case nicotine, in the bloodstream of a subject.

The term “tmax” as used herein refers to the time taken to achieve Cmax from administration of the compound.

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 materials polyoxymethylene (POM), polybutylene terephthalate (PBT), polytetrafluoroethylene (PTFE), ethylene propylene diene monomer rubber (EPDM) and thermoplastic elastomers (TPE) may provide the at least one part with favourable mechanical properties, for example one or more of high stiffness, low friction and excellent dimensional stability. Such properties are particularly desirable in a simulated cigarette part. Furthermore, these materials are low cost, have high stability, and may be used to form parts via injection moulding.

The inventors have surprisingly found that, when the simulated cigarette dispenses the inhalable composition to a user, the inhalable composition comprises low levels of undesirable species such as, for example, carbonyls, typically substantially no carbonyls (in particular formaldehyde). For example, the dispensed inhalable composition may comprise less than 50 pg/m3 of formaldehyde and/or less than 180 mg/m3 acetaldehyde. Such levels are considered to be associated with the absence of adverse effects such as, for example, local irritation, respiratory sensitisation, and/or cancer. This is surprising since carbonyls, such as, for example, formaldehyde, are typical degradation products of, and/or typical leachables from, POM, PBT, PTFE, EPDM and TPE, in particular when they have been subjected to mechanical stress, for example pressure. Accordingly, the simulated cigarette may exhibit these advantages together with the advantages associated with having a part comprising one or more of POM, PBT, PTFE, EPDM and TPE, such as favourable mechanical properties.

The low levels of carbonyls are exhibited even when the inhalable formulation is contained in the simulated cigarette for at least 7 days, typically at least 10 days, more typically at least 20 days, even more typically at least 30 days.

The at least one part comprises one or more of: POM, PBT, PTFE, EPDM and TPE . The at least one part may substantially comprise, consist essentially of, or consist of one or more of these materials. The at least one part may consist of one or more of these materials together with unavoidable impurities. Typically, the surface of the at least one part comprises one or more of these materials, more typically the surface that comes into contact with the inhalable composition during use. With regard to the specific parts of the simulated cigarette discussed in more detail below, and their corresponding materials, these specific parts may also substantially comprise, consist essentially of, or consist of the corresponding materials. Likewise, the surface of the specific part may comprise the corresponding material, more typically the surface that comes into contact with the inhalable composition during use.

In some embodiments, only some of the parts that come into contact with the inhalable composition during use comprise one or more of POM, PBT, PTFE, EPDM and TPE. In other embodiments, all of the parts or parts that come into contact with the inhalable composition during use comprise one or more of POM, PBT, PTFE, EPDM and TPE .

Before the simulated cigarette is loaded with the inhalable composition, the at least one part may be washed, for example with ethanol. Alternatively, or in addition, the materials may be washed, for example with ethanol, before they are formed into the at least one part. This may serve to remove undesirable species, for example carbonyls, from the POM, PBT, PTFE, EPDM and/or TPE that may otherwise leach into the inhalable composition.

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 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 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 nicotine or a pharmaceutically acceptable derivative or salt thereof does not react unfavourably with the materials forming the at least one part (in particular POM), for example it does not react to form carbonyls, for example formaldehyde.

The simulated cigarette of the present invention may deliver the inhalable composition 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, since it mimics some of the habitual aspects of smoking.

In both conventional cigarettes and electronic “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 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. In contrast, the composition contained in the simulated cigarette of the present invention may be delivered via inhalation without the application of heat, meaning that the levels of harmful species delivered to a user are significantly reduced. Furthermore, the absence of a heating step is advantageous since it avoids the need for a power source such as a battery (in the case of an e-cigarette) or lighting means such as matches (in the case of a conventional cigarette).

As well as nicotine or a pharmaceutically acceptable derivative or salt thereof, the inhalable composition may preferably comprise one or more of a glycol and/or glycol ether, a monohydric alcohol, a propellant, menthol and a TAS2R bitter taste receptor agonist. Such species are discussed in more detail below.

The at least one part preferably comprises polyoxymethylene. Polyoxymethylene (POM) may advantageously provide the at least one part with one or more of high stiffness, low friction and excellent dimensional stability. Such properties are particularly desirable in a simulated cigarette part. Furthermore, POM is low cost, has high stability and may be used to form parts via injection moulding. When the at least one part comprises POM, the inhalable composition may comprise the low levels of undesirable species mentioned above. This is surprising since carbonyls, such as, for example, formaldehyde, are typical degradation products of POM, in particular when it has been subjected to mechanical stress, for example pressure. Accordingly, the simulated cigarette may exhibit these advantages together with the advantages associated with having a part comprising polyoxymethylene such as, for example, favourable mechanical properties, low cost, high stability and injection moldability.

Any form of POM may be used in the present invention. However, the POM is typically medical grade POM, in particular a POM containing low residual monomers and no animal products. The POM may be in the homopolymer or copolymer form. Comonomers may include, for example, dioxane and/or ethylene oxide. The POM may comprise chain end groups to resist depolymerisation such as, for example, an ether unit. The POM may exhibit one or more of the following properties: a density of from 1.3 to 1.5 g/cm3 (ISO 1183), a melt volume-flow rate (MVR) (190 °C/2.16 kg) of from 0.6 to 0.85 in3/10min (IS01133), a tensile modulus of from 400000 to 450000 psi (ISO 527-2/1A/1), a flexural modulus (73 °F) of from 380000 to 420000 psi (ISO 178), a Charpy Notched Impart Strength at -22 °F of from 2.5 to 3.5 ft-lb/in2 (ISO 179/1eA), and a Charpy Notched Impact Strength at 73 °F of from 2.5 to 3.5 ft-lb/in2 (ISO 179/1eA). A commercial example of a POM suitable for use in the present invention is HOSTAFORM® MT12U01 (TICONA).

The inhalable composition dispensed from the simulated cigarette preferably comprises less than 50 pg/m3 of formaldehyde and/or less than 180 mg/m3 acetaldehyde. As discussed above, such levels are considered to be associated with the absence of adverse effects such as, for example, local irritation, respiratory sensitisation, and/or cancer.

The inhalable composition dispensed from the simulated cigarette preferably comprises less than 50 pg/m3 of formaldehyde and/or less than 180 mg/m3 acetaldehyde even when the inhalable formulation has been present in the reservoir for at least 7 days, typically at least 10 days, more typically at least 20 days, even more typically at least 30 days. This advantageously enables the device to be filled well in advance of its intended use, which is particularly beneficial to an end user, in particular when used as an alternative to conventional cigarette smoking.

The inhalable composition preferably comprises one or more of: (i) a monohydric alcohol, and (ii) a glycol and/or glycol ether.

Monohydric alcohol has a low viscosity. Accordingly, the inhalable composition is able to form droplets of a smaller diameter. This is advantageous, since small droplets tend to be delivered to the lungs. This is discussed in more detail below.

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 first 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 low levels of nicotine degradation products also reduce the potential for such degradation products to react unfavourably with a material of the simulated cigarette, for example the POM, and produce undesirable products, for example carbonyls.

The presence of (i) a monohydric alcohol, and (ii) a glycol and/or glycol ether in the inhalable composition does not result in the presence of high levels of undesirable species, such as carbonyls, in the dispensed compositions. This is surprising since it was previously thought that such compounds would extract carbonyls from the materials forming the at least one part (in particular POM) and/or react with the materials forming the at least one part (in particular POM) to form carbonyls as a degradation product.

Preferably the monohydric alcohol is ethanol. Ethanol has a particularly low viscosity, and is therefore particularly effective at enabling the inhalable composition to form droplets of small diameter. In addition, ethanol is cheap, relatively non-harmful and readily available. Preferably the inhalable composition comprises from 0.5 to 1.5 %w/w ethanol, preferably from 0.7 to 1.3 %w/w, more preferably from 0.9 to 1 %w/w, even more preferably about 0.95 %w/w, based on the total weight of the inhalable composition. Ethanol may be present in the inhalable composition, and in the recited amounts, without significant carbonyl formation occurring in the presence of the POM or other materials of the simulated cigarette.

The glycol and/or glycol ether may be selected from propylene glycol, polypropylene glycol and polyethylene glycol (PEG), or combinations of two or more thereof. Suitable polyethylene glycols may have a molecular mass of less than 20,000 g/mol. An example of a suitable polyethylene glycol is PEG 400. Preferably the glycol or glycol ether is propylene glycol. Propylene glycol provides the composition with a particularly desirable droplet size profile and provides enhanced solvation of excipients and reduces degradation of excipients. Preferably the inhalable composition comprises from 0.1 to 2 w/w% propylene glycol, preferably from 0.1 to 1 w/w%, more preferably from 0.2 to 0.5 %w/w, even more preferably from 0.25 to 0.4 %w/w, still even more preferably about 0.34 %w/w, based on the total weight of the inhalable composition. The inhalable composition may contain propylene glycol in the recited amounts without significant levels of carbonyls being present when the inhalable composition is dispensed from the simulated cigarette.

The reservoir is preferably pressurised, typically from 5 to 7 bar, more typically from 5.5 to 5.6 bar, even more typically about 6 bar. This may enable easy dispensing of the inhalable composition from the simulated cigarette and/or allow a larger amount of inhalable composition to be present in the simulated cigarette. When the reservoir is pressurised, the amounts of carbonyls, such as formaldehyde, contained in the dispensed inhalable composition are still typically very low, more typically substantially absent. This is surprising since formaldehyde is a typical degradation product of the materials forming the at least one part (in particular POM) when they are subjected to pressure.

The internal walls of the reservoir preferably comprise polybutylene terephthalate (PBT). The internal walls of the reservoir come into contact with the inhalable composition during use. When PBT comes into contact with the inhalable composition, it does not form significant amounts of carbonyls, typically it does not form any carbonyls (in particular formaldehyde). Accordingly, the inhalable composition that is delivered to an end user contains only low levels of carbonyls, typically substantially no carbonyls. In addition, PBT is low cost, stable and injection moldable. PBT is advantageously resistant to solvents (in particular the solvents contained in the inhalable composition), shrinks very little during forming, has low creep and is mechanically strong.

In a preferred aspect of the present invention: the housing is generally cylindrical and has a main axis; the pressurised reservoir extends along a substantial portion of the housing, and has a reservoir outlet at one end which is selectively closed by an outlet valve, the outlet valve being operable to allow the composition to flow from the reservoir outlet to the inhalation outlet; the simulated cigarette further comprises a tube with a through bore extending along a substantial portion of the reservoir from the vicinity of the reservoir outlet such that composition flows into a tube bore inlet and along the tube bore to the reservoir outlet, a tube inlet end being retained such that the axis passes through the inlet end and so that the tube bore inlet is positioned in the axial sense in the central 50% of the volume of the reservoir.

The volume of the reservoir is the free space inside the reservoir, namely the total volume that can be occupied by the composition. This volume excludes any internal features within the reservoir such as the tube wall. It does, however, include the volume of the tube bore. This volume can either be determined by calculating the volume of the various components (i.e. the internal volume of the reservoir housing minus the volume of any internal components), or can be determined by fully filling the reservoir with a liquid and measuring the volume of liquid required to do this (e.g. by determining the mass increase). By filling the reservoir with 50% of this volume and orientating the simulated cigarette with its axis vertical, the mid-point of the volume can be determined. This can be repeated with a volume of liquid which is 25% greater and 25% less respectively than the 50% volume referred to above. These two levels determine the central 50% of the volume of the reservoir as defined above. Alternatively, these positions can be calculated based on the volumes of the components.

By providing the tube bore inlet radially towards the centre of the reservoir, in a central portion of the volume in the axial sense, the tube bore inlet is in a position in which it is in the vicinity of the centroid of a body of liquid filling the reservoir such that, whatever the orientation of the cigarette, approximately 50% of the liquid can be dispensed.

Thus, it can be seen that the approach taken is different from that of, for example, DE4030257, in that the aim is to maximise the uniformity of the dosing, not to maximise the total amount of the dosing. This is achieved by retaining the inlet end of the tube in a central region of the reservoir, rather than having a flexible tube which is always biased towards the lowermost position.

The tube preferably comprises polytetrafluoroethylene (PTFE). The tube typically comes into contact with the inhalable composition during use. When PTFE comes into contact with the inhalable composition, it does not form significant amounts of undesirable species, such as, for example, carbonyls, typically it does not form any carbonyls (in particular formaldehyde). Accordingly, the inhalable composition that is delivered to an end user contains only low levels of carbonyls, typically substantially no carbonyls. In addition, PTFE is low cost, stable and injection moldable. It is also advantageously inert to the components of the inhalable composition and exhibits a low co-efficient of friction.

The tube inlet may be retained in place by the tube being rigid enough that it can support itself with the tube bore inlet in the defined position. However, preferably, the tube is a flexible tube and a support is provided to retain the inlet end in position.

The support preferably comprises POM. The support typically comes into contact with the inhalable composition during use. As discussed above, POM provides the support with a number of favourable properties, and does not result in the presence of significant levels of carbonyls in the inhalable composition delivered to a user of the simulated cigarette.

The support preferably has an outer diameter which can form an interference fit with an inner wall of the reservoir.

The support preferably has a hollow conical end portion facing the inlet end of the tube to guide the inlet end into position. This allows for a straight forward assembly process as the tube can be pushed into the reservoir so that it engages with the inner wall of the reservoir adjacent to the reservoir outlet or the outlet valve itself. The support can then be fitted into place such that the conical end portion picks up the inlet end and guides it towards the central region.

The hollow conical end portion preferably comprises polyoxymethylene. The hollow conical end portion typically comes into contact with the inhalable composition during use. As discussed above, POM provides the hollow conical end portion with a number of favourable properties, and does not result in the presence of significant levels of carbonyls in the inhalable composition delivered to a user of the simulated cigarette.

The simulated cigarette may be a single use device. However, preferably, the reservoir is refillable and has a refill valve at a refill end opposite to the outlet end. In this case, the tube support is preferably integrated with a refill valve housing. This helps to reduce the number of components in the simulated cigarette.

The refill valve preferably comprises polyoxymethylene. The refill valve typically comes into contact with the inhalable composition during use. As discussed above, POM provides the refill valve with a number of favourable properties, and does not result in the presence of significant levels of carbonyls in the inhalable composition delivered to a user of the simulated cigarette.

In a preferred embodiment: the refill valve comprises a refill valve element, a spring and a cage, the refill valve element is operable against the action of the spring, the refill valve element and spring are retained in the cage, and the refill valve element and/or the cage comprise polyoxymethylene.

The refill valve element and/or the cage typically come into contact with the inhalable composition during use. As discussed above, POM provides the refill valve element and/or the cage with a number of favourable properties, and does not result in the presence of significant levels of carbonyls in the inhalable composition delivered to a user of the simulated cigarette.

The spring preferably comprises stainless steel, more preferably 302 stainless steel. The spring may come into contact with the inhalable composition during use. Such steels do not result in the significant formation of carbonyls. Furthermore, such materials are low cost and provide suitable mechanical properties for forming a spring.

The refill valve may further comprises a seal washer and an end cap. The seal washer preferably comprises an ethylene propylene diene monomer (EPDM) rubber and/or the end cap comprises polybutylene terephthalate (PBT). The seal washer and end cap may come into contact with the inhalable composition during use. Such materials are particularly suitable for forming the seal washer and end cap, respectively, and also do not result in the significant formation of carbonyls. EPDM exhibits satisfactory compatibility with the components of the inhalable composition.

Preferably, the tube bore inlet is positioned in the central 30% and more preferably 20% of the volume of the reservoir as this reduces variation still further.

While the tube bore inlet is in the central region of the reservoir as set out above, preferably, it is in the half of the volume furthest from the outlet. The 50%, 30% and 20% limits above allow the inlet to be 25%, 15% and 10% respectively from the centre of the reservoir. Given the desire to have the inlet towards the end opposite to the outlet end, the preferred range may be lower towards the outlet than the opposite end. It may, for example, be preferred to have the inlet with 15% of the centre of the volume towards the outlet end and 25% of the volume towards the opposite end. This allows a greater volume to be inhaled in the more common “tip-down” configuration, but is still sufficiently close to the centre that undue variation of the dosage is avoided.

The inhalation outlet valve is preferably biased closed by a resilient member and is supported by a flexible diaphragm, and an air flow path is provided through the cigarette such that suction on the outlet end causes the air flow to create a pressure on the diaphragm sufficient to lift the inhalation outlet valve against the action of the resilient member and open the inhalation outlet valve.

The tube is preferably relatively long and extends for at least 60% of the length of the cigarette. The bore is preferably less than 1 mm. Tubes with at least a portion of different internal diameters can be used in order to vary the dosage that the cigarette is able to dispense. Previously, the dosage was varied by varying the size of an outlet orifice downstream of the outlet valve, but this also changes the particle size. By using the bore to control the dosage, this can be done without compromising the particle size.

The inhalation outlet is preferably configured to eject inhalable composition therefrom in the form of droplets, at least some of the droplets having a diameter of 10 pm or less, preferably less than 5 pm. Typically, the majority (such as, for example, at least 50 %vol) of the droplets have a diameter of 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 10 pm 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), typically 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 inhalable composition, when inhaled orally, is more able to mimic the pharmacokinetic profile of a conventional cigarette compared to conventional nicotine compositions. Since the composition may be administered via oral inhalation and is able to mimic the pharmacokinetic profile of a conventional cigarette, the simulated cigarette is particularly effective for use in NRT or as an alternative to recreational smoking of conventional cigarettes.

The inhalation outlet is preferably configured to eject droplets of inhalable composition therefrom in which at least 99 %vol of the droplets have a diameter of less than 10 pm.

The inhalation outlet is preferably configured to eject droplets of inhalable composition therefrom having the following size profile:

Dv 90 of less than 20 pm, preferably less than 5 pm, more preferably less than 3, even more preferably less than 2.9 pm and/or

Dv 50 of less than 5 pm, preferably less than 0.8 pm, more preferably less than 0.7 pm, even more preferably less than 0.6 pm and/or

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

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 tmax, i.e. the time from first inhalation to the maximum nicotine-plasma level. As a result, the simulated cigarette is highly effective for use in nicotine replacement therapy (NRT) or as an alternative to recreational smoking of conventional cigarettes.

In a preferred embodiment, the housing preferably has an outlet end and an opposite end and the simulated cigarette preferably further comprises: a composition flow path for the flow of the composition from the reservoir along the flow path and out of the inhalation outlet at the outlet end of the housing; a flexible diaphragm within the housing defining an air flow path from an air inlet to an air outlet at the outlet end of the housing; a valve element movable with the diaphragm and biased by a biasing force into a position in which it closes the composition flow path; wherein suction on the outlet end causes a flow through the air flow path providing a pressure differential over the valve element thereby lifting the valve element against the biasing force to open the composition flow path; and wherein the biasing force is arranged to close the composition flow path once the suction ceases.

The breath-activated inhalation outlet valve is preferably a non-metered valve between the inhalation outlet and the reservoir, the breath-activated inhalation outlet valve comprising a flow path extending from the reservoir to the outlet end, at least a portion of the flow path being a deformable tube, and a clamping member which pinches the deformable tube closed when no suction force is applied to the device and releases the tube to open the flow path when suction is applied at the inhalation outlet, to provide uninterrupted flow from the reservoir to the inhalation outlet.

The deformable tube preferably comprises a thermoplastic elastomer (TPE). The deformable tube typically comes into contact with the inhalable composition during use. When the deformable tube comprises TPE, it does not result in the significant formation of carbonyls. In addition, TPE exhibits particularly favourable mechanical properties for use as the deformable tube. In contrast to, for example, thermoset polymers, thermoplastics relatively easy to use in manufacturing, for example, by injection molding. TPEs show advantages typical of both rubbery materials and plastic materials.

The size of the reservoir, the pressure within the reservoir and the size of the inhalation outlet at its narrowest point are preferably arranged so that, when the outlet valve is fully opened, the reservoir will discharge in less than 30 seconds.

The simulated cigarette is preferably configured to provide a user thereof with a nicotine arterial Cmax of up to 15 ng/ml and/or with a tmax of from 10 seconds to 20 minutes. The Cmax is preferably from 2 to 10 ng/ml, or even from 4 to 8 ng/ml.

Cmax values greater than about 2 ng/ml provide a user with a “head rush” as experienced when smoking a conventional cigarette. Such Rvalues are close to those exhibited by conventional cigarettes. Accordingly, the simulated cigarette of the present invention more closely mimics the pharmacokinetic profile of a conventional cigarette, and is therefore particularly effective for use in NRT or as an alternative to recreational smoking of conventional cigarettes.

Preferably the simulated cigarette is configured to eject composition therefrom at a rate of from 0.5 to 3 litres per minute. This rate is similar to the rate smoke is ejected from a conventional cigarette. Preferably the simulated cigarette is configured to provide an inhalation resistance of from 1 to 7 kPa, preferably about 4 kPa. This inhalation resistance is similar to that provided by a conventional cigarette. When the simulated cigarette is configured to have the above ejection rate and/or inhalation resistance, preferably the simulated cigarette is configured to deliver nicotine to a user at a rate of from 0.01 to 0.06 mg/ml. This is less than a conventional cigarette. However, since the habitual aspects of smoking have been mimicked by the above ejection rate and inhalation resistance, a user will experience the same level of satisfaction with a lower level of inhaled nicotine in comparison to conventional smoking cessation aids.

The inhalable composition preferably further comprises: a glycol and/or glycol ether; a propellant; and a monohydric alcohol, wherein the ratio of monohydric alcohol: glycol or glycol ether by weight is from 6:1 to 1:1.

Such compositions, together with their method of manufacture, are discussed in more detail in WO2014/033437, the disclosure of which is herein incorporated by reference. Advantageously, when the compositions are brought into contact with POM, PBT, EPDM, PFTE and/or TPE, it does not result in the presence of significant amounts of carbonyls in the dispensed inhalable composition.

Monohydric alcohol has a lower viscosity than a glycol or glycol ether. Accordingly, the inhalable composition is able to form droplets of a smaller diameter in comparison to compositions in which the monohydric alcohol is not present. The present inventors have surprisingly found that the ratio of monohydric alcohol to glycol or glycol ether specified above results 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 QC) and small droplet size.

Advantageously, when a nicotine composition having such a ratio of monohydric alcohol: glycol or glycol ether is delivered to a user via the simulated cigarette of the present invention, 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 pm, typically less than 5 pm. Typically, the majority (such as, for example, at least 50 %vol) of the droplets have a diameter of 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 10 pm 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), typically 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 pharmacokinetic profile of a conventional cigarette, the simulated cigarette 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 droplets have a size of from 0.5 to 3 pm. 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 pm. Such droplets are particularly able to mimic the pharmacokinetic profile of a conventional cigarette, since conventional cigarette smoke has a mean particle diameter in the range of from 0.4 to 0.5 pm.

The inhalable composition 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 inhalable composition is delivered to a user via the simulated cigarette of the present invention, the droplets may exhibit the following droplet size profile:

Dv 90 of less than 20 pm, typically less than 5 pm, more typically less than 3, 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 less than 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 less than 0.25 pm, even more typically less than 0.2 pm.

Preferably the ratio of monohydric alcohol : glycol or glycol ether by weight is from 5:1 to 1.5:1, preferably from 4:1 to 2:1, more preferably from 3:1 to 2.5:1, even more preferably about 2.8:1.

Examples of particular glycols and/or glycol ethers, and their %w/w values, may be as discussed above. Examples of particular monohydric alcohols, and their %w/w values, may be as discussed above. 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 inhalable composition to form droplets of small diameter.

Preferably the inhalable 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 inhalable composition since it causes very little irritation.

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, 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.

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 inhalable composition, is readily available and provides the composition with a desirable taste profile. Preferably the ratio of nicotine or a pharmaceutically acceptable derivative or salt thereof: saccharin by weight is from 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 an inhalable composition with an unacceptable tolerability. Higher levels of saccharin result in an acceptable tolerability but are disfavoured since saccharin they may lead to precipitates of saccharin forming in the inhalable composition, which may cause irritation when the inhalable composition is administered to a user or blockage when the inhalable composition is incorporated into a simulated cigarette. Such ratios also provide the inhalable composition with an optimised taste profile. Saccharin may be present in the inhalable composition, and in the recited amounts, without significant carbonyl formation occurring in the presence of the POM or other materials of the simulated cigarette. While saccharin contains a C=0 bond, it is not considered an undesirable “carbonyl” in the inhalable compositions.

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 inhalable composition may comprise at least 60 %w/w propellant, preferably from 90 to 99.5 %w/w, preferably from 96 to 99 %w/w, more preferably from 98 to 99 %w/w, based on the total weight of the inhalable composition. The propellant is preferably liquefied.

Such propellants may be present in the inhalable composition, and in the recited amounts, without significant carbonyl formation occurring in the presence of the POM or other materials of the simulated cigarette.

The inhalable 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 C10 alkenols, preferably C5 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, 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-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 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 inhalable composition. Such flavour components may be present in the inhalable composition, and in the recited amounts, without significant carbonyl formation occurring in the presence of the POM or other materials of the simulated cigarette.

Preferably, the levels of mineral acids and/or chlorine contained in the inhalable composition are kept to a minimum, more preferably the inhalable composition is substantially free of mineral acids and/or chlorine. The presence on mineral acids and/or chlorine may result in degradation of the materials forming the at least one part (in particular POM).

The inhalable 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 %w/w to 0.03 %w/w, most preferably about 0.028 %w/w, based on the total weight of the inhalable composition. Such an inhalable composition provides similar effects to a “low strength” nicotine cigarette. In addition, such recited amounts of nicotine or a pharmaceutically acceptable derviative or salt thereof do not result in significant carbonyl formation occurring in the presence of the POM or other materials of the simulated cigarette.

The inhalable composition may comprise from 0.04 %w/w to 0.07 %w/w nicotine or a 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 inhalable composition. Such an inhalable composition provides similar effects to a “medium strength” nicotine cigarette. In addition, such recited amounts of nicotine or a pharmaceutically acceptable derviative or salt thereof do not result in significant carbonyl formation occurring in the presence of the POM or other materials of the simulated cigarette.

The inhalable 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 inhalable composition. Such an inhalable composition provides similar effects to a “high strength” nicotine cigarette. In addition, such recited amounts of nicotine or a pharmaceutically acceptable derviative or salt thereof do not result in significant carbonyl formation occurring in the presence of the POM or other materials of the simulated cigarette. A particularly preferred composition comprises, based on the total weight of the inhalable composition: from 0.03 to 0.05 %w/w menthol, preferably about 0.04 %w/w, from 0.25 to 0.4 %w/w propylene glycol, preferably about 0.34 %w/w, from 0.9 to 1 %w/w ethanol, preferably about 0.95 %w/w, saccharin, and either: (i) from 0.025 %w/w to 0.03 %w/w nicotine or a pharmaceutically acceptable derivative or salt thereof, preferably about 0.028 %w/w, or (ii) from 0.054 %w/w to 0.058 %w/w nicotine or a pharmaceutically acceptable derivative or salt thereof, preferably about 0.056 %w/w, or (iii) from 0.08 %w/w to 0.088 %w/w nicotine or a pharmaceutically acceptable derivative or salt thereof, preferably about 0.084 %w/w, the balance being HFA-134a, wherein the ratio of nicotine to saccharin by weight is from 9.5:1 to 8:1, preferably about 8.75:1. Such an inhalable composition exhibits a particularly desirable combination of the above-described advantages.

Preferably the total solvent content, i.e. the total content of monohydric alcohol and glycol and/or glycol ether, is less than 35 %w/w, preferably less than 6 %w/w, more preferably from 0.1 %w/w to 2.5 %w/w, based on the weight volume of the inhalable composition. Reducing the total solvent content of the inhalable composition reduces its viscosity, meaning it is more able to form more favourable droplet sizes.

Preferably the inhalable 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, the inhalable composition comprises substantially no nicotinic acid. The presence of nicotinic acid may result in the formation of precipitates in the inhalable composition.

The inhalable compositions may “consist of” the components recited above. The inhalable compositions may “consist of” the components recited above together with any unavoidable impurities.

The present invention is described by way of example in relation to the following non-limiting figures.

Figure 1 is an axial cross section through an embodiment of the simulated cigarette;

Figure 2 is a view similar to Figure 1 in a “tip-down” configuration;

Figure 3 is a view similar to Figures 1 and 2 in a “tip-up” configuration;

Figure 4 is an axial cross section showing the right hand portion of Figure 1 in greater detail; and

Figure 5 is an end view of the tube support.

Figure 6 is an exploded view of an embodiment of the simulated cigarette.

The basic arrangement of the simulated cigarette is as described in WO2011/107737, the disclosure of which is herein incorporated by reference. Thus, the simulated cigarette has a generally cylindrical shape and is approximately the size of a cigarette. It has a housing 1 with an outlet end 2 and a refill end 3 with a reservoir 4 occupying the majority of the internal space. The reservoir 4 contains an inhalable composition (not shown for clarity) comprising nicotine or a pharmaceutically acceptable derivative or salt thereof At the outlet end 2 is an outlet valve 5 with a valve element 6 in the form of a tooth which pinches a resilient tube 7 in order to close the tube. The tube 7 may be formed of TPE. The outlet valve 5 further comprises a vane which cooperates with a diaphragm 8 to open the valve element 6 against the action of a spring 9 when a user sucks on the outlet end 2 as described in WO2011/107737 and in greater detail in WO 2014/033438, the disclosures of which are herein incorporated by reference.

At the opposite end of the reservoir 4 is the refill valve element 10 which is essentially a check valve which is openable against the action of a second spring 11. This is the subject of co-pending application 1305486.1. The second spring 11 and refill valve element 10 are retained in a cage 12 which has a number of openings 13 such that the space within the cage 12 forms part of the reservoir 4. The refill valve element 10 and/or the cage 12 may be formed of POM. The second spring 11 may be formed of stainless steel, for example 302 stainless steel.

Also within the reservoir 4 is a flexible tube 20 with an internal bore 21. The flexible tube 20 may be formed of PTFE. The bore 21 has an outlet 22 located adjacent to the end of the resilient tube 7 and can be placed against or is sealed to the wall 23 of the reservoir 4 in the vicinity of the outlet end so that the composition can only reach the outlet valve 5 via the bore 21. As is apparent from the drawings, it can be either the side wall or the end wall of the tube 20 that seal with the wall 23 of the reservoir or the end of the tube 7, but it is preferably both.

It will also be apparent from the drawings that the right hand side of the resilient tube 7 between the valve element 6 and the tube 20 is also a part of the reservoir. The wall 23 of the reservoir 4 may be formed of PBT.

At the inlet end 25 of the tube 20, the bore 21 has an inlet 26 which is supported by a support 30 so that the inlet end 25, and preferably the inlet 26 of the bore 21 is on the main axis X of the housing 1 as shown in Figure 4.

The support 30 abuts against the valve cage 12 at the end of the support 30 closest to the refill end 3. The support 30 and valve cage 12 may be made as a single component. The support 30 may be formed of POM. At the opposite end, the support 30 has a conical face 31 facing towards the outlet end 2. The outer diameter 32 of this end has a diameter corresponding to the internal diameter of the reservoir 4 at this point so that the support 30 is an interference fit within the reservoir 4. Four openings 34 as shown in Figure 5 allow the liquid in the reservoir to freely pass the support 30 to gain access to the inlet 26.

To assemble the cigarette, the tube 20 is inserted into the reservoir 4 until it reaches the position show in Fig. 1 in which the outlet 22 seals with the wall 23. The support 30 is then inserted from the same end and the conical face 31 picks up the inlet end 25 and guides it into a central region as shown in the drawings. The conical region 31 extends into a cylindrical region 35 which maintains the inlet end 25 of the tube 20 in the central region. The end of the tube may be tightly held in this position, or may be free to move a small amount which is immaterial to its ability to function. Even if it is tightly held, the openings 34 allow liquid in the reservoir to reach the inlet 26 of the bore 21.

It will be appreciated from the drawings and from the above explanation that the shape of the reservoir 4 is complex. The right hand portion has a generally cylindrical configuration occupying the majority of the diameter of the device while the left hand portion of the reservoir may just be the internal bore 21 of the tube, or there may be a portion of the reservoir on either side of this tube. Further, in the right hand portion, the volume of the reservoir is reduced by the inlet end portion of the tube 20, the support 30, the valve cage 12, the second spring 11 and the portion of the refill valve element 10 which is within the reservoir. Thus, while the volume of the reservoir 4 can be determined by measuring these components, it may be simpler to determine this experimentally.

With reference to Fig. 6, in some embodiments the simulated cigarette may include a seal washer 100 and an end cap 200 disposed on the filling valve 10. For a preferred embodiment, the materials of the components of the simulated cigarette that come into contact with the inhalable composition during use are summarised in Table 1 below:

Table 1 - Summary of materials forming components coming into contact with inhalable composition in use. (*Denotes components that have only partial contact with the inhalable composition.)

The operation of the device will now be described with reference to Figs. 1 to 3.

When a user sucks on the outlet end 2, the outlet valve 5 opens as previously described. Provided that the inlet 26 of the bore 21 is below the level L of the liquid in the reservoir, the liquid will travel along the bore 21 and will be atomised downstream of the outlet valve element 6 to create a plume for inhalation. Figs. 1 to 3 show the centroid C of a body of liquid filling the reservoir 4. The inlet 26 of the bore 21 is in the vicinity of the centroid. In this specific example shown in Fig. 1, it is displaced by 1,3mm from the centroid C towards the refill end 3. In the horizontal orientation shown in Fig. 1, all of the liquid above the level L which represents approximately 50% of the total liquid in the reservoir can be inhaled from the cigarette. When the cigarette is in the tip-down configuration shown in Fig. 2, as the inlet 26 is displaced from the centroid C as described above, slightly more liquid is available than it is in Fig. 1. Conversely, in the tip-up configuration, slightly less liquid is available for inhalation. In a different arrangement, the inlet 26 is at the centroid C, so that there is essentially no variation in dispensing between the three positions. The current preference is for a slight displacement of the inlet 26 towards the refill end from the centroid C as shown as this causes slightly more liquid to be dispensed in the more common tip-down orientation.

Once the cigarette reaches the liquid level position L shown in Figs. 1 to 3 with the reservoir approximately half full, no further liquid can be inhaled and the cigarette is then refilled via the refill valve 10.

The invention will now be further described with reference to the following nonlimiting example.

Example 1

Samples

The test samples were Voke® 0.45mg inhaler products that comprise a refillable device and a pressurised canister containing nicotine formulation. The Voke® inhaler products are as shown in Figs. 1 to 6 discussed above. Each canister provides the device with approximately 20 charges of formulation (a solution of nicotine (0.056% w/w) comprising ethanol and propylene glycol as the cosolvents, HFA propellant and menthol and saccharin as flavouring excipients).

For the purpose of this testing, 15 inhalers were prepared as follows: - Batch 1: Five Voke® devices were charged with formulation and tested immediately - Batch 2: Five Voke® devices were charged with formulation and allowed to rest for 1 hour before being tested - Batch 3: Five Voke® devices were charged with formulation and allowed to rest for 24 hours before being tested

Apparatus and Procedure A linear smoking machine was used to extract aerosols from the Voke® devices. Actuation of the devices was enabled using a 67 mL volume, square wave puff profile. Each actuation lasted 1.5 seconds and puffs were extracted at intervals of 30 seconds. The puffing regime consisted of a single block of eight puffs that resulted in the extraction of one complete charge from a device (0.45mg nicotine). The aerosol generated with each puff, over 8 puffs, was collected in 30 mL of 2,4-dinitrophenylhydrazine (DNPH) derivatisation solution. The DNPFI aerosol extract solution was allowed to sit for five minutes before continuing with sample preparation. The solution was then filtered via a 0.2pm nylon microfilter.

0.4 mL of the filtered DNPH aerosol extract solution and 0.6 mL of 0.2% Trizma base solution were transferred to an autosampler vial for analysis using UHPLC. The column used for analysis was Waters Acquity BEH C18 UHPLC column (100 x 2.1 mm; 1.7pm) with UV detection at 365nm. Results were obtained using a mobile phase gradient consisting of 300ml acetonitrile, 620 ml H20, 70ml THF and 10ml IPA (A) and 650ml acetonitrile, 270ml H20, 70ml THF and 10ml IPA (B). The flow rate was set at 0.4 mL/min. This method was validated for Limits of Detection (LOD) and Limits of Quantification (LOQ).

Sample analysis comprised of the following steps: 1. Calibration standard was run as a system check with a separation of each analyte with no valley to be >10% 2. Standards were run. Calibration curves were checked for linearity (correlation coefficient (R2) >0.99) 3. Samples were analysed A calibration check standard was typically analysed after every puff block. The calculated values for the check standards were to be within 15% of its nominal value.

Calculations

The results were per block of puffs i.e. pg/8 puffs. Any carbonyls found in the blank were subtracted from the measured amounts in samples.

Aliquot vol (ml)

Results were recorded to the nearest 0.01 pg.

Results

No carbonyls were detected in 13 of the 15 samples tested. Acetaldehyde was detected in 2 samples, one tested immediately after charging and the other tested 1 hour after sampling; however, both samples contained the analyte in quantities below its LOQ (3.18 pg/ml).

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

Claims:

1. A simulated cigarette comprising: a housing; a reservoir of inhalable composition within the housing, the inhalable composition comprising nicotine or a pharmaceutically acceptable derivative or salt thereof; an inhalation outlet for the inhalable composition from the reservoir and out of the housing; and a breath-activated inhalation outlet valve for controlling the flow of inhalable composition through the inhalation outlet, wherein at least one part of the simulated cigarette that comes into contact with the inhalable composition during use comprises one of more of: polyoxymethylene, polybutylene terephthalate, polytetrafluoroethylene, ethylene propylene diene monomer rubber and a thermoplastic elastomer.

2. The simulated cigarette of claim 1, wherein the at least one part comprises polyoxymethylene.

3. The simulated cigarette of claim 1 or claim 2, wherein inhalable composition dispensed from the simulated cigarette comprises less than 50 gg/m3 of formaldehyde and/or less than 180 mg/m3 acetaldehyde.

4. The simulated cigarette of claim 3, wherein inhalable composition dispensed from the simulated cigarette comprises less than 50 pg/m3 of formaldehyde and/or less than 180 mg/m3 acetaldehyde even when the inhalable formulation has been present in the reservoir for at least 7 days, typically at least 10 days, more typically at least 20 days, even more typically at least 30 days.

5. The simulated cigarette of any preceding claims, wherein the inhalable composition comprises one or more of: (i) a monohydric alcohol, and (ii) a glycol and/or glycol ether.

6. The simulated cigarette of any preceding claim, wherein the reservoir is pressurised.

7. The simulated cigarette of claim 6, wherein the internal walls of the reservoir comprise polybutylene terephthalate.

8. The simulated cigarette of claim 6 or claim 7, wherein: the housing is generally cylindrical and has a main axis; the pressurised reservoir extends along a substantial portion of the housing, and has a reservoir outlet at one end which is selectively closed by an outlet valve, the outlet valve being operable to allow the composition to flow from the reservoir outlet to the inhalation outlet; the simulated cigarette further comprises a tube with a through bore extending along a substantial portion of the reservoir from the vicinity of the reservoir outlet such that composition flows into a tube bore inlet and along the tube bore to the reservoir outlet, a tube inlet end being retained such that the axis passes through the inlet end and so that the tube bore inlet is positioned in the axial sense in the central 50% of the volume of the reservoir.

9. The simulated cigarette of claim 8, wherein the tube comprises polytetrafluoroethylene.

10. The simulated cigarette of claim 8 or claim 9, wherein the tube is a flexible tube and a support is provided to retain the inlet end in position, the support comprising polyoxymethylene.

11. The simulated cigarette of claim 10, wherein the support has an outer diameter which can form an interference fit with an inner wall of the reservoir.

12. The simulated cigarette of claim 10 or claim 11, wherein the support preferably has a hollow conical end portion facing the inlet end of the tube to guide the inlet end into position.

13. The simulated cigarette of claim 12, wherein the hollow conical end portion comprises polyoxymethylene.

14. The simulated cigarette of any of claims 8 to 13, wherein the reservoir is refillable and has a refill valve at a refill end opposite to the outlet end.

15. The simulated cigarette of claim 14, wherein the refill valve comprises polyoxymethylene.

16. The simulated cigarette of claim 14 or claim 15, wherein: the refill valve comprises a refill valve element, a spring and a cage, the refill valve element is operable against the action of the spring, the refill valve element and spring are retained in the cage, and the refill valve element and/or the cage comprise polyoxymethylene.

17. The simulated cigarette of claim 16, wherein the spring comprises stainless steel, preferably 302 stainless steel.

18. The simulated cigarette of claim 16 or claim 17, wherein the refill valve further comprises a seal washer and an end cap, and wherein the seal washer comprises an ethylene propylene diene monomer rubber and/or the end cap comprises polybutylene terephthalate.

19. The simulated cigarette of any of claims 10 to 18, wherein the support is integrated with a refill valve housing.

20. The simulated cigarette of any of claims 8 to 19, wherein the tube bore inlet is positioned in the central 30% and preferably the central 20% of the volume of the reservoir.

21. The simulated cigarette of any of claims 8 to 20, wherein the tube bore inlet is in the half of the volume furthest from the outlet.

22. The simulated cigarette of any of claims 8 to 21, wherein the inhalation outlet valve is biased closed by a resilient member and is supported by a flexible diaphragm, and an air flow path is provided through the cigarette such that suction on the outlet end causes the air flow to create a pressure on the diaphragm sufficient to lift the outlet valve against the action of the resilient member and open the outlet valve.

23. A simulated cigarette of any of claim 8 to 22, wherein the tube extends for at least 60% of the length of the cigarette.

24. A simulated cigarette of any of claims 8 to 23, wherein the internal diameter of the bore is less than 1 mm.

25. The simulated cigarette of any preceding claim, wherein the inhalation outlet is configured to eject inhalable composition therefrom in the form of droplets, at least some of the droplets having a diameter of 10 pm or less

26. The simulated cigarette of any of claim 25, wherein the inhalable outlet is configured to eject droplets of composition therefrom in which at least 99 %vol of the droplets have a diameter of less than 10 pm.

27. The simulated cigarette of claim 26, wherein the inhalable outlet is configured to eject droplets of composition therefrom having the following size profile: Dv 90 of less than 20 pm, and/or Dv 50 of less than 5 pm, and/or Dv 10 of less than 2 pm.

28. The simulated cigarette of any preceding claim, wherein the housing has an outlet end and an opposite end and wherein the simulated cigarette further comprises: a composition flow path for the flow of the composition from the reservoir along the flow path and out of the inhalation outlet at the outlet end of the housing; a flexible diaphragm within the housing defining an air flow path from an air inlet to an air outlet at the outlet end of the housing; a valve element movable with the diaphragm and biased by a biasing force into a position in which it closes the composition flow path; wherein suction on the outlet end causes a flow through the air flow path providing a pressure differential over the valve element thereby lifting the valve element against the biasing force to open the composition flow path; and wherein the biasing force is arranged to close the composition flow path once the suction ceases.

29. The simulated cigarette of claim 28 wherein the breath-activated inhalation outlet valve is a non-metered valve between the inhalation outlet and the reservoir, the breath-activated inhalation outlet valve comprising a flow path extending from the reservoir to the outlet end, at least a portion of the flow path being a deformable tube, and a clamping member which pinches the deformable tube closed when no suction force is applied to the device and releases the tube to open the flow path when suction is applied at the inhalation outlet, to provide uninterrupted flow from the reservoir to the inhalation outlet.

30. The simulated cigarette of claim 29, wherein the deformable tube comprises a thermoplastic elastomer.

31. The simulated cigarette of any preceding claim, wherein the size of the reservoir, the pressure within the reservoir and the size of the inhalation outlet at its narrowest point are arranged so that, when the outlet valve is fully opened, the reservoir will discharge in less than 30 seconds.

32. The simulated cigarette of any preceding claim configured to provide a user thereof with a nicotine arterial Cmax of up to 15 ng/ml and/or with a tmax of from 10 seconds to 20 minutes.

33. The simulated cigarette of any preceding claim configured to eject composition therefrom at a rate of from 0.5 to 3 litres per minute.

34. The simulated cigarette of any preceding claim configured to provide an inhalation resistance of from 1 to 7 kPa.

35. The simulated cigarette of any preceding claim configured to deliver nicotine to a user at a rate of from 0.01 to 0.06 mg/ml.

36. The simulated cigarette of any preceding claim, wherein the inhalable composition further comprises: a glycol and/or glycol ether; a propellant; and a monohydric alcohol, wherein the ratio of monohydric alcohol: glycol or glycol ether by weight is from 6:1 to 1:1.

37. The simulated cigarette of claim 36 wherein the ratio of monohydric alcohol: glycol or glycol ether by weight is from 5:1 to 1.5:1.

38. The simulated cigarette according to claim 33 or claim 34, wherein the glycol and/or glycol ether is selected from propylene glycol, polypropylene glycol and polyethylene glycol (PEG), or combinations of two or more thereof.

39. The simulated cigarette of claim 38 wherein the inhalable composition comprises from 0.1 to 2 w/w% propylene glycol, based on the total weight of the inhalable composition.

40. The simulated cigarette of any of claims 36 to 39, wherein the monohydric alcohol is ethanol.

41. The simulated cigarette of claim 40, wherein the inhalable composition comprises from 0.5 to 1.5 %w/w ethanol, based on the total weight of the inhalable composition.

42. The simulated cigarette of any preceding claim, wherein the inhalable composition further comprises a human TAS2R bitter taste receptor agonist, preferably wherein the human TAS2R bitter taste receptor agonist is saccharin.

43. The simulated cigarette of any preceding claim, wherein the inhalable 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.

44. The simulated cigarette of any of claims 36 to 43, wherein the propellant is a hydrofluorocarbon.

45. The simulated cigarette of any of claims 36 to 44 comprising at least 60 %w/w propellant, based on the total weight of the composition.

46. The simulated cigarette any preceding claim, wherein the inhalable composition further comprises a flavour component, preferably menthol and/or vanillin.

47. The simulated cigarette of claim 46, wherein the inhalable composition comprises up to 0.1 %w/w menthol, based on the total weight of the inhalable composition.

48. The simulated cigarette of any preceding claim, wherein the inhalable composition comprises 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 inhalable composition.

49. The simulated cigarette of any of claims 1 to 47, wherein the inhalable composition comprises 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 inhalable composition.

50. The simulated cigarette of any of claims 1 to 47, wherein the inhalable composition comprises from 0.065 %w/w to 0.1 %w/w nicotine or a pharmaceutically acceptable derivative or salt thereof, based on the total weight of the inhalable composition.

51. The simulated cigarette of any preceding claim, wherein the inhalable composition comprises, based on the total weight of the inhalable composition: from 0.03 to 0.05 %w/w menthol, from 0.25 to 0.4 %w/w propylene glycol, from 0.9 to 1 %w/w ethanol, saccharin, and either: (i) from 0.025 %w/w to 0.03 %w/w nicotine or a pharmaceutically acceptable derivative or salt thereof, or (ii) from 0.054 %w/w to 0.058 %w/w nicotine or a pharmaceutically acceptable derivative or salt thereof, or (iii) from 0.08 %w/w to 0.088 %w/w nicotine or a pharmaceutically acceptable derivative or salt thereof, the balance being HFA-134a, wherein the ratio of nicotine or a pharmaceutically acceptable derivative or salt thereof to saccharin is from 9.5:1 to 8:1 %w/w.