Abstract:
A simulated cigarette comprising a housing having a generally cigarette-like shape and size; a reservoir within the housing configured to receive and contain a dose of inhalable formulation; a means for controlling the flow from the reservoir; an outlet passage from the means for controlling the flow from the reservoir to an outlet in the housing from which outlet a user inhales the formulation, wherein a deliverable daily dose of inhalable formulation is delivered by pulmonary administration using one or more of said simulated cigarette, wherein said deliverable daily dose comprises less than 60 mg of nicotine or a pharmaceutically acceptable salt thereof.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application claims benefit of United Kingdom patent application number 1416635.9, filed Sep. 19, 2014, which is herein incorporated by reference. 
       FIELD OF THE INVENTION 
       [0002]    The invention relates to a simulated cigarette for effectively delivering a safe daily dose of an inhalable formulation comprising nicotine. 
         [0003]    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. 
         [0004]    There are a number of smoking cessation aids currently on the market for use in effective nicotine replacement therapy (NRT), such as nicotine skin patches, nicotine-containing gums, nicotine cartridges, and nicotine simulated cigarettes. These aids attempt to achieve the increase in blood nicotine content provided by tobacco smoke without the associated dangerous by-products. Among the various modes of NRT, nicotine inhalers most closely replicate the rituals of smoking. A class of nicotine inhalers are termed ‘vaporizers’ or ‘electronic cigarettes’. In electronic “e”-cigarettes, as is the case in conventional tobacco cigarettes, nicotine must be heated in order to be delivered orally to a user (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. Thus, there are potential health consequences of using e-cigarettes as NRT. 
       BACKGROUND OF THE INVENTION 
     Description of the Related Art 
       [0005]    The present invention provides a simulated cigarette for use in NRT. Thus, the present invention provides a simulated cigarette comprising a housing having a generally cigarette-like shape and size; a reservoir within the housing configured to receive and contain a dose of inhalable formulation; a means for controlling the flow from the reservoir; an outlet passage from the means for controlling the flow from the reservoir to an outlet in the housing from which outlet a user inhales the formulation, wherein a deliverable daily dose of inhalable formulation is delivered by pulmonary administration using one or more of said simulated cigarette, wherein said deliverable daily dose comprises less than 60 mg of nicotine or a pharmaceutically acceptable salt thereof. 
         [0006]    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. 
         [0007]    It has been surprisingly found that the simulated cigarette according to the present invention delivers a highly consistent dose of nicotine to the user, and when used in the manner of the present invention are capable of relieving or preventing nicotine craving associated with tobacco dependence using lower doses of nicotine than in known orally inhalable NRT modes. When used according to the dosing regimen described herein, the presently claimed simulated cigarette is capable of replicating many of the rituals associated with smoking, which provides a psychological boost to the physiological effects of the administered nicotine. This enables effective relief of nicotine craving or withdrawal symptoms associated with tobacco dependence using lower quantities of nicotine than are required to achieve the same level of relief in dosage regimens known for existing orally inhalable nicotine formulations. 
         [0008]    In another aspect of the present invention, the reservoir receives said dose of inhalable formulation from a refill pack. 
         [0009]    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. 
         [0010]    The term “Dv10” as used herein refers to a droplet diameter that no more than 10% vol of the droplets in a formulation 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 formulation 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 formulation have a smaller diameter than. Dv10, Dv50 and Dv90 values may be determined using a Malvern Spraytec device. 
         [0011]    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. 
         [0012]    The term “C max ” as used herein refers to the maximum measured concentration of a compound, in this case nicotine, in the bloodstream of a subject. 
         [0013]    The term “t max ” as used herein refers to the time taken to achieve C max  from administration of the compound. 
         [0014]    The terms “patient”, “subject” and “user” are used interchangeably herein, and refer to an animal, preferably a human, to whom NRT is applied. 
         [0015]    The term “deliverable daily dose” means the cumulative amount of nicotine that is pulmonarily administered to the user over the course of a 24 hour period. According to aspects of the present invention the inhalable formulation is released from the refill pack into the reservoir of a simulated cigarette by action of a pressure gradient between the two devices. The deliverable daily dose of nicotine is the amount of nicotine that can be transferred from the refill pack to the user via iterative doses of an empty reservoir of a simulated cigarette, accounting for escape of formulation during refills. 
         [0016]    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. 
       SUMMARY OF THE INVENTION 
       [0017]    The present invention provides a simulated cigarette, comprising:
       a housing having a generally cigarette-like shape and size;   a reservoir within the housing configured to receive and contain a dose of inhalable formulation;   a means for controlling the flow from the reservoir; and   an outlet passage from the means for controlling the flow from the reservoir to an outlet in the housing from which outlet a user inhales the formulation, wherein a deliverable daily dose of inhalable formulation is delivered by pulmonary administration using one or more of said simulated cigarettes, wherein said deliverable daily dose comprises less than 60 mg of nicotine or a pharmaceutically acceptable salt thereof.       
 
         [0022]    In an embodiment of the invention, the reservoir receives said dose of inhalable formulation from one or more refill packs, such that the deliverable daily dose is contained in said one or more refill packs. 
         [0023]    According to one embodiment of the present invention, the total content of nicotine or a pharmaceutically acceptable salt thereof of the daily dose contained in the one or more refill packs is 0.2 mg or more and does not exceed 75 mg, 70 mg, 65 mg, 60 mg, 55 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, 19 mg, 18 mg, 17 mg, 16 mg, 15 mg, 14 mg, 13 mg, 12 mg, 11 mg, 10 mg, 9.5 mg, 9 mg, 8.5 mg, 8 mg, 7.5 mg, 7 mg, 6.5 mg, 6 mg, 5.5 mg, 5 mg, 4.5 mg 4 mg, 3.5 mg, 3 mg, 2.5 mg, 2 mg, 1.5 mg, 1 mg, 0.9 mg, 0.8 mg, 0.7 mg, 0.6 mg, 0.5 mg, 0.45 mg, 0.4 mg, 0.35 mg, 0.3 mg or 0.25 mg. 
         [0024]    In an embodiment of the invention, the deliverable daily dose of nicotine or a pharmaceutically acceptable salt thereof is at least 60%, preferably at least 70%, more preferably at least 75% of the total dose of nicotine or pharmaceutically acceptable salt thereof contained in the inhalable formulation provided in the one or more refill packs. 
         [0025]    In an aspect of the present invention, the daily dose of inhalable formulation comprises a deliverable daily dose that is 0.2 mg or more, and does not exceed 60 mg, 55 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, 19 mg, 18 mg, 17 mg, 16 mg, 15 mg, 14 mg, 13 mg, 12 mg, 11 mg, 10 mg, 9.5 mg, 9 mg, 8.5 mg, 8 mg, 7.5 mg, 7 mg, 6.5 mg, 6 mg, 5.5 mg, 5 mg, 4.5 mg, 4 mg, 3.5 mg, 3 mg, 2.5 mg, 2 mg, 1.5 mg, 1 mg, 0.9 mg, 0.8 mg, 0.7 mg, 0.6 mg, 0.5 mg, 0.45 mg, 0.4 mg, 0.35 mg, 0.3 mg, 0.25 mg or 0.2 mg. In a preferred embodiment, the deliverable daily dose is 40 mg or less, preferably 20 mg or less, more preferably 18 mg or less. 
         [0026]    In some embodiments when using the simulated cigarette of the present invention the subject is free to self-administer a dose that is lower than the daily dose provided herein, and the daily dose described herein is a maximum daily dose. 
         [0027]    In an aspect of the present invention, the simulated cigarette delivers a deliverable dose of nicotine or a pharmaceutically acceptable salt thereof which is substantially temperature independent. In an embodiment of the invention, the simulated cigarette delivers a deliverable dose which is constant across a temperature range of from about 15° C. to about 200° C., preferably about 15° C. to about 180° C., more preferably from about 20° C. to about 80° C. Accordingly, in an embodiment of the invention the methods and dosage regimens of the present invention are administered at a temperature of 50° C. or less, preferably 37° C. or less, more preferably 30° C. or less. Alternatively, the formulation is heated to a temperature of under 180° C. using a heating element comprised in the housing, such that some or all components of the formulation are volatilized. Preferably the formulation is heated to 80° C. 
         [0028]    In embodiments of the present invention, a refill pack may comprises from about 2 mg to about 30 mg, or about 2 mg to about 25 mg, or about 2 mg to about 20 mg, or about 3 mg to about 19 mg, or about 4 mg to about 18 mg, or about 5 mg to about 17 mg, or about 6 mg to about 16 mg, or about 7 mg to about 15 mg or about 8 mg to about 14 mg, or about 8 mg to about 13 mg, or about 8 mg to about 12 mg, or about 8 mg to about 11 mg, or about 9 mg to about 10 mg nicotine or a pharmaceutically acceptable salt thereof. In preferred embodiments, the refill pack may comprise about 15 mg to about 20 mg, preferably about 16 mg to about 18 mg, more preferably about 17 mg to about 18 mg nicotine or a pharmaceutically acceptable salt thereof. In an alternative preferred embodiment, the refill pack may comprise from about 7 mg to about 14 mg, preferably about 8 mg to about 13 mg, more preferably about 11 mg to about 12 mg nicotine or a pharmaceutically acceptable salt thereof. In an alternative preferred embodiment, the refill pack may comprise from about 2 mg to about 7 mg, preferably about 3 mg to about 6 mg, more preferably from about 4 mg to about 5 mg nicotine or a pharmaceutically acceptable salt thereof. 
         [0029]    According to the present invention, the deliverable dose of nicotine or a pharmaceutically acceptable salt thereof provided by the refill pack is at least 60%, preferably at least 70%, more preferably at least 75%, more preferably at least 78% of the total amount of nicotine or pharmaceutically acceptable salt thereof contained in the refill packs. 
         [0030]    In particularly preferred embodiments, the refill pack comprises from about 16 mg to about 18 mg nicotine or a pharmaceutically acceptable salt thereof and provides a deliverable dose of at least 75%, preferably at least 78% of the total amount of nicotine or pharmaceutically acceptable salt thereof contained in the refill pack. In alternative preferred embodiments, the refill pack comprises from about 11 mg to about 12 mg nicotine or a pharmaceutically acceptable salt thereof and provides a deliverable dose of at least 75%, preferably at least 78% of the total amount of nicotine or pharmaceutically acceptable salt thereof contained in the refill pack. In alternative preferred embodiments, the refill pack comprises from about 4 mg to about 5 mg nicotine or a pharmaceutically acceptable salt thereof and provides a deliverable dose of at least 75%, preferably at least 78% of the total amount of nicotine or pharmaceutically acceptable salt thereof contained in the refill pack. 
         [0031]    The one or more refill packs may consist of the number of refill packs necessary for a delivered daily dose of inhalable formulation according to the present invention. In a preferred embodiment of the invention, the total nicotine content is such that the delivered daily dose of the present invention is provided in two refill packs. In an alternative preferred embodiment, the refill packs comprise from about 2 mg to about 7 mg nicotine or a pharmaceutically acceptable salt thereof, and the delivered daily dose of inhalable formulation is provided in five refill packs, or alternatively in four refill packs. 
         [0032]    In an embodiment of the present invention, the refill pack comprises from about 5 doses to about 40 doses, wherein a dose is an amount of inhalable formulation necessary to fill the reservoir of a simulated cigarette. In a preferred embodiment the refill pack comprises from about 10 doses to about 35 doses, or about 15 doses to about 30 doses, or about 17 doses to about 25 doses of inhalable formulation. In a preferred embodiment the refill pack comprises approximately 20 doses of inhalable formulation. 
         [0033]    In one embodiment of the present invention each dose comprises approximately 0.1 mg-1 mg nicotine or a pharmaceutically acceptable salt thereof, or approximately 0.2 mg-0.9 mg, or approximately 0.3 mg-0.8 mg, or approximately 0.3 mg-0.7 mg, or approximately 0.4 mg-0.6 mg, or approximately 0.4 mg-0.5 mg, or approximately 0.4-0.6 mg nicotine or a pharmaceutically acceptable salt thereof In a preferred embodiment each dose comprises approximately 0.66 mg-0.69 mg nicotine or a pharmaceutically acceptable salt thereof, or approximately 0.43 mg-0.45 mg nicotine or a pharmaceutically acceptable salt thereof, or approximately 0.21 mg-0.23 nicotine or a pharmaceutically acceptable salt thereof. 
         [0034]    In one embodiment of the present invention, the first dose administered to a simulated cigarette according to the present invention comprises less nicotine than the second and subsequent doses. Thus, in an embodiment of the invention, the first dose comprises less than approximately 1 mg nicotine or a pharmaceutically acceptable salt thereof, preferably less than approximately 0.43 mg, more preferably approximately 0.02-0.3 mg. In these embodiments, the second and subsequent doses may comprise approximately 0.1 mg-1 mg nicotine or a pharmaceutically acceptable salt thereof, or approximately 0.2 mg-0.9 mg, or approximately 0.3 mg-0.8 mg, or approximately 0.3 mg-0.7 mg, or approximately 0.4 mg-0.6 mg, or approximately 0.4 mg-0.5 mg, or approximately 0.4-0.6 mg nicotine or a pharmaceutically acceptable salt thereof, provided that the nicotine content of the first dose is less than the second and subsequent doses. In a preferred embodiment the first dose comprises less nicotine or a pharmaceutically acceptable salt thereof than the second and subsequent doses, wherein the second and subsequent doses comprise approximately 0.66 mg-0.69 mg nicotine or a pharmaceutically acceptable salt thereof, or approximately 0.43 mg-0.45 mg nicotine or a pharmaceutically acceptable salt thereof, or approximately 0.21 mg-0.23 nicotine or a pharmaceutically acceptable salt thereof. 
         [0035]    In a preferred embodiment of the invention, each dose contains approximately 5-inhalations, preferably approximately 6-12 inhalations, more preferably approximately 7-10 inhalations, more preferably about 8 inhalations or about 9 inhalations. In a preferred embodiment each dose is consumed at a rate of approximately one inhalation per 0.05 minutes to one inhalation per 2 minutes, preferably approximately one inhalation per 0.1 minutes to one inhalation per 1 minutes, preferably approximately one inhalation per 0.2 minutes to one inhalation per 0.5 minutes, more preferably approximately one inhalation per 0.25 minutes. In a preferred embodiment of the invention each dose is consumed over a period of up to 10 minutes, or up to 6 minutes, or up to 5 minutes, and preferably up to 4 minutes, more preferably up to 3 minutes and more preferably up to 2 minutes. 
         [0036]    Typically at least some (such as, for example, at least 10% vol) of the droplets have a size of from 0.5 to 3 μm. 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 μm. 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 μm. 
         [0037]    When the formulation of the present invention is delivered to a user via one of the simulated cigarettes described below, the droplets may exhibit the following droplet size profile:
       Dv 90 of less than 20 μm, typically less than 5 μm, more typically less than 3, even more typically less than 2.9 μm; and/or   Dv 50 of less than 6 μm, typically less than 0.8 μm, more typically less than 0.7 μm, even more typically less than 0.6 μm, and/or;   Dv 10 of less than 2 μm, typically less than 0.3 μm, more typically less than 0.25 μm, even more typically less than 0.2 μm.       
 
         [0041]    This particular droplet size profile is similar to the particle size profile of tobacco smoke. Accordingly, the pharmacokinetic profile of the delivered formulation closely mimics that of a conventional cigarette. In particular, delivery of the formulation 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 formulation is highly effective for use in NRT and is capable of effectively relieving nicotine craving associated with tobacco dependence or withdrawal symptoms associated with tobacco dependence at lower deliverable doses of nicotine than other orally inhalable modes of NRT. 
         [0042]    In a further aspect, the refill pack may comprise a pressurised container containing the formulation to refill the reservoir of the simulated cigarette with the inhalable formulation. 
         [0043]    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 formulation under a high pressure gradient. In one embodiment, the canister is an AW5052 aluminium canister. 
         [0044]    The pressurised container may be capable of dispensing the formulation 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. 
         [0045]    The pressurised container may be pressurised to a pressure of from 3×10 5  Pa to 1.5×10 7  Pa, preferably from 5×10 5  Pa to 2×10 6  Pa, more preferably from 5.5×10 5  Pa to 1×10 6  Pa, even more preferably at about 6×10 5  Pa. 
         [0046]    Preferably the simulated cigarette is configured to eject droplets of formulation therefrom in which at least 97% vol of the droplets have a diameter of less than 10 μm, preferably at least 98% vol, more preferably at least 98.5% vol, even more preferably at least 99% vol. Droplets of diameter less than 10 μm are deposited in the lungs, meaning that a pharmacokinetic profile similar to that of a conventional cigarette is provided. 
         [0047]    Preferably the simulated cigarette is configured to eject droplets of formulation therefrom having the following size profile:
       Dv 90 of less than 20 μm, preferably less than 5 μm, more preferably less than 3 μm, even more preferably less than 2.9 μm; and/or   Dv 50 of less than 6 μm, preferably less than 0.8 μm, more preferably less than 0.7 μm, even more preferably less than 0.6 μm; and/or   Dv 10 of less than 2 μm, preferably less than 0.3 μm, more preferably less than 0.25 μm, even more preferably less than 0.2 μm.       
 
         [0051]    Accordingly, in one embodiment, the simulated cigarette is configured to eject droplets with the following size profile: Dv 90&lt;20 μm, Dv 50&lt;6 μm and Dv 10&lt;2 μm; preferably with the following size profile: Dv 90&lt;5 μm, Dv 50&lt;0.8 μm and Dv 10&lt;0.3 μm; more preferably with the following size profile: Dv 90&lt;3 μm, Dv 50&lt;0.7 μm and Dv 10&lt;0.25 μm; even more preferably with the following size profile: Dv 90&lt;2.9 μm, Dv 50&lt;0.6 μm and Dv 10&lt;0.2 μm. 
         [0052]    Such a size profile is similar to that of a conventional cigarette, meaning that the pharmacokinetic profile provided closely mimics that of a conventional cigarette. 
         [0053]    The simulated cigarette may provide a user with a nicotine arterial C max  of up to 15 ng/ml, typically from 2 to 10 ng/ml, or even from 4 to 8 ng/ml. C max  values greater than about 2 ng/ml provide a user with a “head rush” as experienced when smoking a conventional cigarette. 
         [0054]    The simulated cigarette may provide these C max  values with a t max  of from 10 seconds to 20 minutes, typically from 5 minutes to 15 minutes, often about 12 minutes. Compared to simulated cigarette devices of the prior art, such t max  values are closer to those exhibited by conventional cigarettes. Accordingly, 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. 
         [0055]    Preferably the simulated cigarette is configured to eject formulation 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. 
         [0056]    In an embodiment of the present invention, the simulated cigarette is configured to provide a user thereof with a nicotine venous C max  of up to 15 ng/ml and/or with a t max  of from 10 seconds to 20 minutes. 
         [0057]    In one embodiment, the inhalable composition comprises a propellant. In another embodiment, the inhalable composition comprises a solvent. In a preferred embodiment the solvent comprises a monohydric alcohol; and a glycol and/or glycol ether, characterised in that the ratio of monohydric alcohol:glycol and/or glycol ether by weight is from 6:1 to 1:1. 
         [0058]    In a preferred embodiment, the inhalable composition comprises nicotine or a pharmaceutically acceptable derivative or salt thereof;
       a propellant;   a monohydric alcohol; and   a glycol and/or glycol ether, characterised in that the ratio of monohydric alcohol:glycol and/or glycol ether by weight is from 6:1 to 1:1.       
 
         [0062]    A particularly preferred formulation comprises, based on the total weight of the formulation:
       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.   
               
 
         [0069]    In an embodiment of the invention, the outlet passage is preferably a breath-activated valve. 
         [0070]    In some embodiments the simulated cigarette has a breath-activated valve and the housing has an outlet end and an opposite end and the simulated cigarette further comprises:
       a formulation flow path for the flow of the formulation from the reservoir along the flow path and out of the 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; and   a valve element movable with the diaphragm and biased by a biasing force into a position in which it closes the formulation 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 formulation flow path; and   
           wherein the biasing force is arranged to close the formulation flow path once the suction ceases.       
 
         [0076]    Preferably the simulated cigarette has a breath-activated valve and the breath-activated valve is a non-metered valve between the outlet and the reservoir, the breath-activated 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 outlet, to provide uninterrupted flow from the reservoir to the outlet. This simulated cigarette is referred to hereinafter as a “pinch valve” simulated cigarette. 
         [0077]    Preferably the simulated cigarette further comprises a re-fill valve in communication with the reservoir via which the reservoir may be refilled. The simulated cigarette may be re-filled from a refill pack according to a further aspect of the present invention. 
         [0078]    Preferably the size of the reservoir, the pressure within the reservoir and the size of the 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. 
         [0079]    In an embodiment of the invention, the simulated cigarette comprises a heating element and/or vibrating transducer to selectively volatilize at least some components of the formulation, and a power source arranged to supply electrical power to the heater and/or vibrating transducer when the user inhales from the simulated cigarette. The heater is preferably configured to heat the formulation to a temperature that will volatilise some, but not all, of the components of the formulation. This means that the temperatures required are less than those of the prior art. This further reduces the power requirement of the simulated cigarette and prevents the degradation of the inhaled formulation. Thus, preferably, the heater is arranged to heat the formulation to between 40 and 180° C. and preferably 40° C. to 100° C. The ability to dispense at these temperatures is based on a 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 formulation will volatilise. 
         [0080]    Additionally or alternatively, other mechanisms may be employed to effect a fine aerosolisation of the non-volatilised formulation components. For example, the formulation may include a propellant to increase the pressure in the reservoir resulting in improved aerosolisation. 
         [0081]    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 formulation 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 simulated cigarette thereby generating further turbulence and causing greater reduction in particle size. 
         [0082]    The airflow paths are preferably arranged to pass through a constriction in the vicinity of the outlet end of the simulated cigarette thereby generating a Venturi effect and promoting suction of the formulation out of the simulated cigarette. The simulated cigarette may be configured to have a throughflow 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 formulation from the reservoir. 
         [0083]    The present invention also extends to a combination of a simulated cigarette and a refill pack, the simulated cigarette comprising a reservoir for an inhalable composition, a heating element to selectively volatilise at least some components of the composition and at least one simulated cigarette capacitor arranged to supply electrical power to the heater when a user inhales from the simulated cigarette; 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 simulated cigarette and to refill the reservoir and recharge the simulated cigarette capacitor from the refill capacitor, wherein the heater is configured to heat the composition to a temperature that will volatilise some, but not all of the components of the composition, wherein a deliverable daily dose of inhalable composition is contained in one or more refill pack and is delivered by pulmonary administration using one or more of said simulated cigarette, wherein said deliverable daily dose comprises less than 60 mg of nicotine or a pharmaceutically acceptable salt thereof. 
         [0084]    The simulated cigarette of this combination may have any of the preferred features referred to herein. Preferably the pack is arranged to fully recharge and refill the simulated cigarette from empty in less than 30 seconds and preferably less than 10 seconds. 
         [0085]    The battery may be rechargable, but is preferably non-rechargable. Preferably, the refill reservoir is pressurised with a propellant or a compressed gas, the simulated cigarette reservoir having a closable refill valve and the refill pack having a complementary refill valve such that engagement of the simulated cigarette with the pack will cause the two refill valves to open thereby allowing the pressurised composition to flow into the simulated cigarette reservoir. The refill pack is preferably configured such that it will automatically terminate the refill and recharge operations. 
         [0086]    Preferably, the refill reservoir is pressurised with a propellant or a compressed gas, the simulated cigarette reservoir having a closable refill valve and the refill pack having a complementary refill valve such that engagement of the simulated cigarette with the pack will cause the two refill valves to open thereby allowing the pressurised composition to flow into the simulated cigarette reservoir. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0087]    The refill pack is preferably configured such that it will automatically terminate the refill and recharge operations. An example of a combination of a simulated cigarette and refill pack will now be described with reference to the accompanying drawings, in which: 
           [0088]      FIG. 1  is a schematic cross-section of a simulated cigarette. 
           [0089]      FIG. 2  is a schematic cross-section of a simulated cigarette within a refill pack. 
           [0090]      FIG. 3  is a circuit diagram for the recharging operation. 
       
    
    
     DETAILED DESCRIPTION 
       [0091]    The simulated cigarette is in the form of a simulated cigarette having a generally cylindrical configuration the approximate size of a cigarette. The simulated cigarette 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. 
         [0092]    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 2011/015825 and WO 2014/033438. 
         [0093]    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 6 mm to 10 mm and a length of 5 to 50 mm. 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  11  is provided to control the operation of the simulated cigarette. 
         [0094]    The simulated cigarette 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 simulated cigarette as shown. They may also be offset with respect to the axis such they generate a swirl of the air about the main axis. In particular, the air paths 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 . 
         [0095]    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. 
         [0096]    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. 
         [0097]    The refill pack will now be described by reference to  FIG. 2 . This shows the simulated cigarette 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. 
         [0098]    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 simulated cigarette, a power supply  32  and a composition refill  33 . These are connected across the base of the housing  30  as described below. 
         [0099]    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 . 
         [0100]    The bottom end of the reservoir is connected by a refill duct  41  to a refill valve  42  beneath the simulated cigarette 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 simulated cigarette which presses downwardly on the refill valve  42 . 
         [0101]    A release spring  43  is provided in the housing  30  underneath the simulated cigarette recess  31 . This spring will push the simulated cigarette away from the refilling position to a storage position when the refilling process is complete. This may be done, for example, by releasing the simulated cigarette when a certain priority is detected which indicates that the refill operation is complete. 
         [0102]    When the reservoir  2  is depleted of composition, the simulated cigarette 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 simulated cigarette  25  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 simulated cigarette to the storage position. 
         [0103]    At the same time as the simulated cigarette 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 simulated cigarette capacitor  8  to be recharged simultaneously with the refill. The recharge circuit is shown in  FIG. 3 .