GB2528434A

GB2528434A - Nicotine dosage regimen

Info

Publication number: GB2528434A
Application number: GB1411345.0A
Authority: GB
Inventors: Alex Hearn; Chris Moyses; Ritika Gupta
Original assignee: Kind Consumer Ltd
Current assignee: Kind Consumer Ltd
Priority date: 2014-06-26
Filing date: 2014-06-26
Publication date: 2016-01-27
Also published as: GB201411345D0

Abstract

An orally inhalable formulation comprising nicotine and a propellant for use in a method of relieving or preventing nicotine craving, wherein a daily dose of inhalable formulation is provided in one or more pressurized containers, wherein the inhalable formulation is for pulmonary administration using a simulated cigarette having a housing, a reservoir configured to receive and contain a charge of inhalable formulation from the pressurized container and an outlet valve, wherein the daily dose comprises a deliverable daily dose of less than 60 mg of nicotine. A simulated cigarette system comprising an orally inhalable formulation comprising nicotine and a propellant, a pressurized refill container containing the inhalable formulation, a simulated cigarette for pulmonary administration of the inhalable formulation comprising a housing, a reservoir configured to receive and contain a charge of inhalable formulation from the pressurized container, a breathe actuated valve configured to eject the formulation as droplets, wherein at least some of the droplets have a diameter of 10 Âµm or less, and wherein said refill container contains 2mg to 20mg of nicotine, wherein at least 60% of the inhalable formulation is deliverable via the pulmonary route.

Description

Nwotine DosaQe Reumteit The invention relates to dosage regimens for an inhalable formulation comprising nicotine, and to devices for delivering said dosage regimens.

The smok ng of tobacco is an addictne activlt% asoc ated w h the pleasurabic feeling Laused by rucotme, and reinforced y the habvs and r tuals ot the smoker I l'esc attributes combine to make it very difficult LO give up smoking, despite the numerous advc'-sc health eects of the carbon monwude, tar, and other combustion ptducis of tobacco it not the mcolme ascII that's harmful to health, Idther the b)-pn.dncts of tobacco smoke.

I here arc a number of \moklrg cessat oi &d cLarently on the market for use in eTectie nicotine replacement therapy (MRfl, 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, Among the various modes of NRT, nicotine inhalers most closely replicate the rituals of smoking. A class of nicotine inhalers are termed vaporizers' or 4electronic cigarettes'. Jr electronic "e"-cigarettes, as is the case in convenlional tobacco cigarettes, nicotine must be heated in order to be delivered orally to a user (to result in combustion in the ease ot'a conventional cigarette or to result in vapori.sation in the ease of an c-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-cigareUes as NB]'.

Nicotine inhalers which do not require vaporization are available on the market. These inhalers provide a nicotine formulation in a porous plug of polyethylene, for example the Nicoretie® Inhalator. Porous plug inhalers are available in 10mg or 15mg cartridges, however the delivered dose of nicotine is significantly lower than the quantity provided in

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the cartridge, This is because in normal use, much of the nicotine remains adsorbed to the polyetnylenc plug tot exam,1e, on average 4mg nicotine is ieleascc flow e 10mg cartridge following 20 thinutes of intensive use (Hukkanen ci at, Pharinacol. Rev. 2005, 57, 79). However, the distribution of delivered nicotine dose from a porous plug inhaler S cartridge is highly variable. Delivered doses range from I,3mg to 6.2mg per cartridge.

Furthermore, the nicotine release profile ftom the polyethylene plug is highly temperature dependant. The delivered dose increases by 35% for each 10°C increase in temperature.

Owing to the pharmacokine-tie profile of nicotine when delivered to a user by porous plug inhaters, inhalers of such type require a dosage regimen of up to 12 a day oFthe 10mg cartridges, or up to 6 a day of the 15mg cartridges, in order to relieve craving associated wflh nicotme nependene The ue o such hgh crength nicotire formulations at such high freqLency raes safety conLcrns Given the high sari ability of the dehvcrd n cot in dose, and its temperature dependence, there is a risk that use of a porous plug inhaler in high lemperature environments, for example atiemperatures of 37°C or more, under the dosage regimen required to relieve craving can lead to a total daily delivered dose of greater than 50mg. Such high levels of daily nicotine intake run the risk of exposing the usei to toxic o e en led a! doses ot nicotme the minima' leiha dose o nioune IS reported to he as 3ow as 30mg This nk is exacerbated n asrs with irnparcd meotine metabolism, Furthermore, the use of high and inconsistent doses of nicotine provided by porous plug inhaier.s can result in high nicotine plasma concentrations', ultimately resultng in prolonged nicotine dependence and low success in smoking cessation.

There exists a need to provide a dosing regimen for inhalable NW!' that overcomes

problem inherent in the prior art

The present invention provides improved formulations, therapeutic applications and dosage regimens ftr use in NRT. Thus, thc present invention provides a dosing regimen comprising a daily dose ofari inhalable nicotine formulation [hr use in (I) a method ol relieving or preventing nicotire craving associated with tobacco dependence in a subject, or (2) a method of relieving or preventing withdrawal symptoms associated with tobacco dependence in a subject, or (3) a method of reducing or preventing consumption of inhaled tobacco smoke in a subject, wherein the daily dose comprises a deliverable daily dose of less than 60mg of nicotine or a pharnaceul cally acceptable salt thereof In one embodiment, the invention provides an orally inhalable Ebrmulrtjon comprising nicol.ine or a pharmaceutcaily acceptable salt thereof and a propellant fOr use in a method of relieving or preventing nicotine craving associated with tobacco dependence in a subject, wherein a daily dose of inhalable fbrrnulation is provided in one or more pressurized containers, wherein the inhalable formulation is for pulmonary administration using a simulated cigarette, said simulated cigarette having a housing, a reservoir configured to receive and contain a charge oflnhaiable formulation from the prescurizcd eentamtr, anc an outlet vclve and wherein Laic daily dose of rnhalable forniulation comprises a deliverable daily dose of less than 60mg of nicotine or a pharmaceutically acceptable salt thereof Each aspect or embodiment as defined herein may he combined with any other aspect(s) or ernhodirnent(s unless clearly indicated to the contrary. hi particular any tbature indicatca s being pieferrec or advantageous ray be combined vdth any other feature oi features indicated as being preferred or advantageous.

it has been surprisingly fOund that inhalahie nicotine formulations according to the present invention deliver a highly consistent dose bf 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 administered acordiLlg co the dosing regimen of the present invention, the presently clairiic-d fcrrnuiaticns are 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 effhctive rellef of nicotine craving or withdrawa] symptoms associated with tobacco dependence using lower quantities of nicoilne than are required to achieve the same level of relief in dosage regimens ho-wa for existing orally inhalable nicotine tbrmulations.

Furthermore, the dose delivered by each inhalation of die present dosage regimen is generally uniform, and is temperature independent. Thus. it is possible to provide a dosage regimen that is sufficient to relieve or prevent nicotine cravings without exposing the user to potentially deliverable dose of nicotine in excess of 60mg per day.

In another aspect of the present invention, an orally inhalable tbrmulation is provided comprising nicotine or a pharmaceutically acceptable salt thereof and a propellant fUr use in a method of relieving or preventing withdrawal symptoms associated with tobacco dependence in a sibject wheren a daily dose of nh?hnle tormulalion is prcvid& n one o-nore pre'uriied contamers wherein the v'halaHe ormulation K br pfflmoranv administration using a simulated cigarette, said simulated cigarette having a housing, a reservoir configured to receive and contain a charge of inhatable formulation from the pressurized container, and an outlet valve, and wherein said daily dose of inhalable totmulation owpriscs a dchverablc daily dose ut less than 60 mg of nicctire or a pharmaceutically acceptable saft thereof In arotir aspect of the nreent ine ition, an or il y nhalable bormr hit or is p'ovrded comprising nicotine or a pharmaceutically acceptable sal thereof and a propellant for use in a method of reducing or preventing consumption of inhaled tobacco smoke in a subject. wherein a daily dose of inhalable formulation is provided in one or more pressurized containers, wherein the inhalable formulation is fUr pulmonary administration using a simulated cigarette, said simulated cigarette having a housing, a reservoir configured to receive arid contain a charge ofmhalahie formulation from the pressurized container, and an outlet valve, and wherein said daily dose of inhalable foimdlatron comprises a deinerable duly dose ofle,s thai 6C mg ofnicourc or a pharmaceutically acceptable salt thereof.

-S -? In a tuther cmbodunent ofthc invention isa mtrod ofEclievwg or prcvcnti g n coUnt craving associated with tobacco dependence in a subject, said method comprising the step of administering to the subject an orally inhalable formulation comprising nicotine or a pharmaceutically acceptable salt thereof and a propellant, wherein a daily dose of inhalable formulation is provided in one or more pressurized containers, wherein the inhalabic formulation is for pulmonary administration using a simulated cigarette, said simulated cigarette having a housing, a reservoir configured to receive and contain a charge of inhalable formulation from the pressurized container, and an outlet valve, and wherein saiddaily dose ofinhalabie formulation comprises a deliverable daily dose of less than 60 mg of nicotine or a phannaceutically acceptable salt thereof: In a further embodiment of the invention is a method of' relieving or preventing withdrawal symptoms associated with tobacco dependence in a subject, said method comprising the step of administering to the subject an orally inhalable formulation compnsing mcotiro or a phrmaceuncal y acceptable salt thureof and a propcllant teem a daily dose of inhaløbe foiniulation is provided in one:i moie ?tessurlzed containers, wherein the inhalahleiormulation is fix pulmonary administration using a simulated cigarette, said simulated cigarette havhig a housing. a reservoir configured to receive and contain c charg. of inhalable formulahon fro 11 the presurvcu cortamer, and an outlet valve, and wherein said daily dose of inhalable formulation comprises a deliverable daily dose of less than 60 mg of nicotine or a pharmaceutically acceptable salt thereof in a further ernboditheut of the invention is a method of reducing or preventing consumption of inhaled tobacco smoke in a subject, said method comprising the step of administering to the subject an orally inhalahie formulation comprising nicotine or a pharmaceutically acceptable salt thereof and a propellant, wherein a daily dose of inhalable formulation is provided in one or more pressurized containers, wherein the inhalable formulation is for pulmonary administration using a simulated cigarette, said simulated cigarette having a housing, a reservoir configured to receive and contain a charge of inhalablë fbnnulation from the pressurized container, and an outlet valve, and wherein said daily dose ol'inhaable fbrmulation domprises a deliverable daily dose of less tian 60 mg of n ao'me or a pharnaceunca lv acceptable salt thereof The term "diameter" as used herein encompasses the largest dimension of a droplet.

Droplet diameters referred to herein may be measured using a Malvern Spraytee device.

The term "Dv 10" 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 "DvSO" as used herein refers to a droplet diameter that no more than 50 %vol of the droplets in a form uiation have a smaller diameter than. The term "Dv90" as used herein refers to a droplet diameter that no more than QO %vol of tne dropkk w a Thrmu anon have a smaller diameter than. Dv 10, DvSO and Dv90 values may he determined using a Malvern Spraytec device.

The term "nicotine free base" as used herein refers to the thrm of nicotine that pred minatcs at high p11 lev&s, e a pH levels aboc 7 The tenn "C,,J as used herein refers to the maximum measured concentration oVa compound, in this case nicotine, in the bloodstream of a subject.

I'he tenn "tmax" as used herein refers to tha time taken to achieve from administration of the compound.

The tn rn' patient" ubjeat" and user' are u\CC rnrerchangea.i y herein, and retei to an animal, preferably a human, to whom NRT is applied.

The term "deliverable daily dose" means the cumulative amount of nicotine that is pulminarily administered to the user over the course of a 24 hour period. According o aspects of the present invention the inhalable formulation is released from the pressurized container iflo 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 pressurized eotflainer to the user via iterative charges of an empty reservoir of a simulated cigarette, accounting for escape of fonrulation during retlIs.

When introducing elements of the present disclosure or the preferred embodiments(s) thereof, r e arUele a", a i", the" and sad' ate nter'ded to meal that there are one or more of the elements. The terms comprising", "including" and "having" are intended to he nclus se and mean that there tray he add lonal elements other than e listed elements.

Aeco ding to ore emhndnnuit of the pieent in'enL'on tlim total eonttrt ofn eohne or a pharmaceutically acceptable salt thereol'of the daily dose contained in the one or more pressurized containers is 0.2 mg or more and does not exceed 75mg, 70mg, 65mg, 60mg, 55mg, 50mg, 45mg, 40mg, 35mg, 30mg, 25mg, 20mg, 19mg, 18mg, 17mg, 16mg, 15mg, 14mg, 13mg, 12mg, 11mg, 10mg, 9.5mg. 9mg, 85mg, 8mg, 7.5mg, 7mg, 6.5mg, 6mg, 5.5mg, 5mg, 4.5mg 4mg, 15mg, 3mg, 2.5mg, 2mg, 1.5mg, 1mg, 0.9mg, 0.8mg, 0.7mg, 0.6mg, 0.5mg. 0.45mg. 0.4mg, 0.35mg, 0.3mg or 0.25mg.

To an embodiment ofthe invention, the deliverable daily dose of nicotine or a pharmaceutically acceptable salt thereof is at kast 60%, preferably at least 70%, more preferably at least 75% of the total dose of nicotine or pharmaceutically acceptable salt thereof contained in the inhalabie formulation provided in the one or more pressurized containers.

In an aspect of the present invention, the daily dose of inhalable formulation comprises a del vcrahk da ly dosc thai r 0 2irg or morc, and does rot txcced 60mg 55mg, 53mg 45mg, 4Oma 3nig 0mg mg, )Omg 9mg, 18mg, 17mg, 16mg, 15mg, 4rnr. 13mg, 12mg, 11mg, 10mg, 9.5mg, 9mg, 8,5mg. 8mg, 7.5mg, 7mg, 6.5mg. 6mg, 5,5mg, 5mg,

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4.5mg, 4mg, 3.5mg, 3mg, 2.5mg, 2mg, [5mg, 1mg, 0.9mg,0.Smg, 0.7mg, 0.6mg, 0.5mg, 0.45mg, 0.4mg, 015mg, 0.3mg, 0,25mg or 0.2mg. In a preferred ernbodhnenL the deliverable daily dose is 40mg or less, preferably 20mg or less, more preferably 18mg or less.

A particular advantage of formulations, devices, administration modes and regimens of the present invention is that they do not contain o produce harrnftl chemicals known to occur in tobacco smoke, which in addition to being toxic the user, can also be extremely harmful to unborn Ibetuses or breast-feeding infants, Thus, the formulations, devices, adrntni$rahon rodes and i.gmt ns descuhcd h.run provik an cffectvc ucatment or nicotine craving associated with tobacco dependence in a subject who is either pregnant ci' Lctating Accoidirgly in an embodiment of the imertion s p ovidcd the iDrmulaticns, devices, administraton modes and dosage regimens described, herein for use in a method of relieving or preventing nicotine craving associated with tobacco snoke ma pregnant subject or ma lactating sublect In an alternative embodiment of the invention is provided the formulations, devices, administration modes and dosage regimens described hereh for use in a method of relieving or preventing withdrawal symptoms associated with tobacco smoke. in a pregnant subject or in a lactating subject.

In an alternative embodiment of the invention is provided the formulations. devices, administration modes and dosage regimens described herein for use in a method of rcducing or present rig consumption of mhdled tobacco smoke in t' pregnant cublect or in a lactating subject.

in an embodiment of the invention. the subject is free to self-administer a dose that is lower man he d4 ly dose proided nerem, and the di1y cost. descnbed herem is a maximum daily dose, In an aspect of the present invention, the deliverable dose of nicotine or a pharmaceutically acceptable salt thereof' i's substa:niially temperature independent. In an embodiment ot'thc'invention, the deliverable dose remains constant across a temperature range of from about 15°C to about 50°C, preferably from about 20°C to about 30°C.

Accordingly, in anenihodiment of the invention the methods and dosage regimens of the oresent invention are adrnmstered at a temperature of 50°C 01 es, pieferably 37°C 01 kss moic prcfaraWy 30C o kas In embodiments of the present invention, a pressurized container may comprises from about 2mg to about 30mg, or about 2mg to about 25mg, or about 2mg to about 20mg, or about 3mg to about 19mg. or about 4mg to about 18mg, or about 5mg to about 17mg, or about 6mg to about 16mg, or about 7mg to about 15mg or about 8mg to about 14mg. or about 8mg to about 13mg, or about 8mg to about 12 mg, or about 8mg to about 11mg. or about 9mg to about 10mg nicotine or a pharmaceutically acceptable salt thereof. In preferred embodiments, the pressurized containermay comprise about 15mg to about 20mg, prcf'crably about 16mg to about 18mg more preferably acm l7mgto aboit 8 irn nicotine or a pharmaceutically acceptable salt thereoL In an alternative preferred embodiment, the pressurized container may comprise from about 7mg to about 14mg, ieferahly about 8mg to about 13'ig more preFerably ahut 1mg to abut 12mg nteottn.

or a pharmaceutically acceptable salt thereof. In an alternative preferred embodiment, the pressurized con'aincr tray compro.e iron about 2ni.g t abou' img prclcrably about 3mg to about 6mg, more preferably from about 4mg to about. .5Tng nicotine or a pharmaceutically acceptable salt thereof According to the present invention, the deliverable dose of nicotine or a pharmaceutically acceptable salt thereof provided by the presarized conta tier is at least 6('% peferahly at least 70%. more preibrably at least 75%, more preferably at least 78% of the total amount of nicotine or pharmaceutically acceptable salt thereof contained in. the pressurized containers.

In particularly preferred embodiments, the pressui1zed container comprises from about 16mg to about 18mg 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 -10 pharmaceutically scceptahle salt thereof contained in the pressurized container. in alternative preferred embodiments, the pressunzed container comprises from about I 1mg to about 12mg mottnL or a p1⁄4umaceuth&R acceptable salt thekeofar d pmvdes a deliverable dose of at kast 75%, preferably at [east 78% of the total amount of nicotine or pharmaceuticafly acceptable s&t thereolcontained in the pressurized container, In alternative preferred embodiments, the pressurized container comprises trom about 4mg to about 5mg 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 ntcotine or pharmaceutically acceptable salt thereof contained in the pressurized container.

The one or more pressurized containers may consist of the number of pressurized containers ncccssaiy fr d cehered daik dose of nhakbie forniuLtion acordmg o 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 pressurized containers. in an alternative preferred embodiment, the pressurized containers comprise from about 2mg to about 7mg nicotine or a pharmaceutically acceptable salt thereof; arid the delivered daily dose of inhalahie. formulation is provided in five pressurized containers, or alternatively in four pressurized containers.

In an embodiment of the present invention, the prbssurized container comprises from about S charges to about 40 charges, wherein a charge is an amount of inhalable fbrrnulation necessary to fill the reservoir ofa simulated cigarette. in a preferred embodiment the pressurized container comprises from about 10 charges to about 35 charges, or about iS charges to about 30 charges, or about 17 charges to about 25 charges of inhalabie tbrmulation. In a preferred embodiment the pressurized container comprises approximately 20 charges of inhalabie formulation, In one embodiment of the present invenUon each charge comprises approximately 0, img I mg nicotine or a pharmaceutically acceptable salt thereof; or approximately 0.2mg- 0.9mg, or approxinuitely 0.3mg-0.Srng, or approximately 0,3mg-0.7mg, or approximat&y -1 1 - 0.4mg-0.ómg, or approximately 0.4mg-05mg, or approximately 0.4-06mg nicotine or a pharmaceutically acceptable salt thereof hi a preitrred embodiment each charge compnses appwximatels 0 (thrng 069mg mcut ne or a phsmaccutllv acceptable salt thereof or approximately 0,43mg-GAS mg nicotine or a pharmaceutically acceptable salt thereof, or approximately 0.2 img-0.23 ijicotine or a pharmaceutically acceptable salt thereof in one embodiment of the present invention, the first charge administered to a simulated cigartic mc iding to th pesert meruon coniprie es nuotire than the seond tnd subsequent charges, Thus, in an embodiment ot'the invention, the flrst charge comprises less than approximately I rng nicotine or a pharmaceutically acceptable salt thereof preferablq ess than apptoxcrnateiy 043 mg, more preferably approxlmatcl\ 0 02-03 mg Ir these enibodirr ent the second and subseqLent crarges may comprise appw'urnately 0.1mg-i rig nicotine or a pharmaceutically acceptable salt thereof; or approximately 0.2mg-0.9mg, or approximately 0.3mg-0.Smg, or approximately 0.3mg-0.7mg, or approximately 04mg-06rng, or approximately OAi g-0.Smg, or approximately 0,4- 0.6mg nicotine or a pharmaceutically acceptable salt thereof; provided that the nicotine content oithe first charge is less than the second and subsequent charges. In a preferred embodiment the first charge comprises less nicotine or a pharmaceutically acceptable salt thereof than the second and subsequent charges, wherein the second and subsequent charges compnce approxunatel> 0 6ôrng-0 69mg nmcot!ne r a phaimaceuca1y acceptable ah thereof, ot approxm&ly 0 4mg-0 45 rug mcotine or a phurniaceu' ufflv acceptable 4lt thereof, ci appioxiniatcly 02 Inig-0 23 notmne or a pharmaceucicully acceptable salt thereof in a preferred embodiment of the invention, each charge contains approximately 5-15 mhalations, preternbly approximately 6 12 inralations mere preferably approxirratel 7-inhalations, mote preferably about 8 inhalations or about 9 inhalations. In a preferred embodiment each charge is consumed at a rate of approximately one inhalation per 0.05 minutes to one inhalation per 2 minutes, preferably approximately one iihalation per 0.1 12 -minutes to one inhalation per minutes, preferably approximately one inhalation per 0.2 minutes to one iiihaltion per 0.5 minutes, more preferably approximately one mtralation pc" 0'S minutes In a pretrred embodimern ofthc invnuon each hargc s consumcd over a period otup to 10 minutes. or up toó minutes, or up to 5 minutes, and preftrably up to 4 minutes. more preferably up to 3 minutes and more preferably up to 2 minutes.

In preferred embodiments of the invention, the orally inhalable formulation comprises: nicotine or a pharmaceutically acceptable derivative or salt thereof a propellant; a monohydric alcohol; and a glycol and/or g1yco ether, characterised in that the ratio of monohvdric alcohol glycol and/or glycol ether by weight is from 6:1 to 1:1.

The glycol and/or glycol ether aids the dissolution of the nicotine or a phantiaceinically acceptable derivative or salt thereof in the formulation, This avoids the presence of precipitates of nicotine (or other additives such as saccharin, if present) in the formuPation, which could cause in'itation when deliveed 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 formulation.

Morohydnc alcohol has a lower uscosity than a glycol or glycol ether Acordmg1s the formulation is aile to toun dioplets of a smaller dia'r eler ir cornpansor to 1orrrulaions in which the monohydric alcohol is not present. The present inventors have surprisingly found that the ratio ofmonohvdrie alcohol to alycol or lycol ether specified above results in a formulation with a desired combination of both long term stability (for example the forinulatcn remains rs a single ohase lot at least a weck at a Temperature of 2-40°C) and small droplet size. -. 13

Advantageously, wheil a nicotine formulation having such a ratio of monohydric alcohol glycol or glycol ether is delierecI to a user via r conventional pm ssuriscd neW ed dose mhakE (pMDJ tbc L rmulatk ii is delivu cd m the form)t droplets some o v.hich (such as, for example at least 10 °e\o1) have a diametei oflcss than 10 i. in tpically less than 5 inn 3 %pLaliy, the mapn y (suh as, to" example, at least 50 %vol) of the dropleb have a diameter of less than 5 trn, typically substantiallSi all (such as, for example., at least 90 %voi, or even at least 95 %vol) of the droplets have a diameter of less than 5 sm.

Advantageously, when administered orally, droplets with a size of less than 10 itm tend to be deposited in toe ungs, iathei tlwn fur example, the oiopliarynx Acordi igly, at least some (such as, for example, at least 10 %w!w, typically substantially all (such as, kr example, at least 90 %w/w), of the nicoirne enters the bloodstream via the pulmonary route I his nicars that the formulanon, when mh4lcd orally s more able to m mi the pharmacokinene profile of a conventional cigarette compared to nicotine tbrmulations of the prior art. Since the formulation may be administered orally and is able to mimic the pharmacokinetie profile of a conventional cigarette, it is particularly effective for use in NiU' or as an alternative to recreational smoking Of conventional cigarettes, Typically at least sonic (such as, for example, at least 10 %vol) of the droplets have a size of' from 0,.5 to 3 tni. Such droplets may he deposited in the deep lung, and are therefOre particularly able to enter the blood stream via the nulmonary route. Typically at least some (such as, for example, at least 10 %vol) of' the droplets have a diameter of from 0.4 toO 5 im Such droplets aie tiarticuarly aale to n-mn. the pharmacWreuc profile of 4 corventional cigarc4te since wnvcntional eigai ette smoke hes a nean part dc din rter in the range of from 0.4 to 0.5 pm.

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 urn, typically less than 5 tin, morn typically less than 3, even more typically less than 2.9 L, and/or D.c 0 of less that 6 jim, t>pcally ks than 0 8 jim, inont typically less than 0 7 jim, even more typically less than 0.6 urn, and/or 6 Dv 10 of ksc than 2 rn, 1> peaIly lcs than 0 3 p in moi e typia1ly less than 025 pm, even more typically less than 0,2 urn.

Ibis part cular droplet size profile s smilar o the paita.le size profile of tobacco smoke Accordingly, the pharmacokinetic proftie of the delivered formulation closely mimics that of a conventional cigarette. In particular, delivery of the fbrrnulation to a user generates an extended peak of high nicotine concentration with a short 4,, i.e. the lime from first inhalation to the maximum mcomepIasm4 level As a rcsult thc forr ulaion is highiy effective ibr use in NRT and is capable of effectively relieving nicotine craving associated with tobacco dependence or withdrawal symptoms associated with cobacco dependence at lower deli verable doses ot nicoti ie than other oiallv mhalable n'odes of NRT.

Any suitable source of' nicotine may he employed. For example, the nicotine may he nicotine free base, a nicotine derivative and/or a nicotine salt. Where a nicotine free base is erployed, it may oc crnploved in *iqmd form Wheic a nicotme salt s empoyed, it may be employed in the form of a solution. Suitable nicotine salts include salts formed of the followmg acids cettc, proprtoni, l,2hutynL, iethylhutynt.., vakri, launc palnutie taane, ethic4 make oxalie berzoic, alwic, iywoehlonc, chloroplatmic silieoungstie pyruv:, glutarne and asparne Other nicotine salts such M nicotine hitartrate 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 nary allow the nicotine concentration of a formulation to he further increased without nicotine precipitation occurring. As used herein the weight of nicotine or a pharmaceutically acceptable sail thereof refers to the freebase form of nicotine, --15 Therefbre, when a nicotine salt is emphyed, the molar equivalent to the free-base weight should be calculated, As dheused abon, the rano of monohdnc alcohol glyco or glycol ethet by weght results in a combination of both stabffity and a desired droplet size profile. Preferably the ratio of monohydric alcohol glycol or glycoi ether by weight is from 5:! lo 1,5:1, preferably from 4:1 to 2:1, more preferably from 3:1 to 25:1, even more preferably about n The glycol and/or glyeol ether may be selected from propylene glycoL polypropylene glycol and polyethylene glycol (PEG), or combinations of two or more thereof Suitably polyethylene g]ycols may have a molecular mass of less than 20,000 a/mo!. An example o"a uitabk pohethlenc glycol is PFG 400 Prefrab y vie lycol or glyco' ether is propylene glycol. Propylene giyeol provides the ibrmn!ation with a particularly desirable droplet size profile and provides enhanced solvation of excipients and reduces degradation of e'upients Preferably the tbnnulation comprisos from 0 1 to 2 sYw% propylene glycol, preferably from 0. Ito i w/w%, more preferably from 0.2 to 0.5 %w/w, even rno'e preferably from 025 to 04 °4../w st Il even more prefcahly abot 0 34 %w/w, based on the total weight of the formulation, Propylene gycol is known to he safe for human consumption, however ii has been reported Chat prolonged exposure to high lcvcls of mhakd piop lcne glycol can result in decrcascs in whitc bloou cell count This in an embodiment of the present invention, the one or more pressurized containers comprise a delrverab e dady aose ot propylene glyco' of less than I 000mg, n eferabl) less than 500mg, more preferably less than 200mg, and more preferably less than 150mg.

Preferably the monohydric alcohol is ethanol. Ethanol has a particularly low viscosity in comparison to a giyco or giyeol ether, and is theef0re particularly effective at enabling the forn,ui&ion to form droplets of small diameter, In addition, ethanol is cheap, relatively non-harmful and readily available, Preferably the formulation comprises from 0.5 to 1.5 %w/w ethanol, preferably from 0.7 to 13 %w/w, more preferably from 09 to I Ltj* %w/w. even more preferably about 0.93 %wiw, based on the total weight of the formulation.

heferably tre fornmlaton flirthercompnes a h..iman IAS2R h fler tastc receptor agonist The use of a human FAS2R htter taIe reccptor ag. nit indue bronc oailaton, resulting in a reduction in the levels of deliveryrelatcd coughing. Accordingly, a user is more able to tolerate the formulation since It causes very little irritation.

The human TAS2R hitter taste receptor agonist may he a naturally occurring compound or a synthetic compound. Examples of suitable naturally-occurring compounds include Absinthin, Alo:n. Amaro'.entiu. Andrographohde, Arborescin, Arglabin, Arteinorin, Camphor, Cascarillin, Cnicin, Crispolide, Ethylpyrazine, Falcarindiol, HeRein, 1-lumulone isomers, Limonin. Noscapine Papaverine, Parthenolide, Quassin, Sinigrin, and I hiairnne Lxamp es of suitable synthetic compounds include A.esuilame K. Btnzom, Carisoprodol, Chioroquine, Cromolyn, Dapsone, Denatoniurn bcnzoate, Dimethyl hioturmcrmde, D nhenliyeram me, D vin Isu foxuie I-' smoudi ne, Sacc5a' ti, Sodium benzoate, and Sodium cyclamate.

Prefrrahly the human TAS2E. hitter taste receptor agonist is saccharin. Saccharin is particularly effective as a human TAS2R bitter taste receptor agonist, may be readily dIssolved in the formulation, is readily available and provides the formulation with a desirable taste profile. Preferably the ratio of nicotine or a phannaeeu cally acceptable derivativeorsaltthereof: saccharinby weightis from 12:1 to 5.5:1. preferablyfrom 11:1 to 6:1, more prctèrably from 10: Ito 7:1, even more preferably from 9.5:1 to 8:1, even more preferably about 8.75:1, Lower levels of saccharin result in a formulation with an unacceptable tolerability, Higher levels of saccharin result in an acceptable tolerability but are disfavoured since they may lead to precipitates of saccharin Forming in the forniulation, which may cause irritation when the formulation is administered to a user or blockage when the formulation is incorporated into a simulated cigarette. Such ratios also provide the formulation with an opumised taste profile, 17 -The propellant may be a hydrotluorocarbon, preferably a hydrofluoroalkane, even more preferably I, 1,2,2-tetratluoroediane (HFAI 34a) or 14, 1,2,3.3-heptafluoropropane (HFC 227). Such compounds are particularly effective as propellants and have no adverse effect on the body.

The formulation may comprise at Least 60 %w/w propellant, preferably from 90 to 99,5 %wfw, preferably from 96 to 99 %w/w, more preferably from 9S to 99 %w/w. based on the total weight of the formulation, The propellant is preferably liquefied.

The formulation may further comprise a flavour component. Nicotine has a hitter, 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, akiehydes, esters and delta-lactone flavour constituents. Suitable carotenod products include beta boone, alpha ionone, heta-damascone, beta-darnascenone, oxo-.

edulan I, oxo-edulan II, theaspirohe, 4-oxo-beta-lonorie, 3-oxo-alpha-ionone, dthydroaLtmodlol tie 4-cxo sophorore, s,1frend, bets-cyc locitral uitaole alkcnols mdude ( t' C10 alkenols, pictuahiv C to C a1knoh SpeutL examni s mt Jude us- 2-Pentcn-i-ol, cis-2-Hexen-I-ol, trans-2-l-lexen-I-.ol, trans2-Hexen-.i-ol, cis-3-I-lexen--l-- ol, lrans-3-Hexen-i-oi, trans-2-Hepten-Iol, cis-34-lepten-i-ol, trans-3-Hepten-1-ol, cis- 4-Hepteii-I-ol, trans-2-Octen-i-ol, cis-3-Octen-l -ol, cis-5-Octen-1-oL, I -Octen-3-ol and 3-Octen-2-ol. Suitable aldehydes include benzaldehyde, glucose and cinnamaldehyde.

Suitable esters include ally! hexanoate, benzyl acetate, bornyl acetate, butyl hutyrate, ethyl butyrate, ethyl hexanoate, ethyl cinnamate, ethyl formate, ethyl heptanoate, ethyl isovalerate, ethyl lactate, ethyl nonanoate. ethyl valerate, geranyl acetate, geranyl hutyrate, isobutyl acetate, isohutyl forrnae, isoamyl acetate, isopropy! acetate, linalyl acetate, linalyl butyrate, linalyl formate, methyl acetate, methyl anthranilate, methyl henzoate, methyl benzyl acetate, methyl butyrate. methyl cinnamate. methyl pentanoate, methyl phenyl acetate, methyl salicylate (oil ofwintergreen), nonyl caprylate, octyl -. 18 acetate, octyl buryrate, amyl acetate (pentyl acetate), pentyl hexanoate, pentyl pentanoate, propyl ethanoate, propyl isobutyrate, terpenyl hutyrate, ethyl thrmate, ethyl acetate, ethyl pioponate, ethyl butyrte, eti v1 va crate eth) hexanoate, ethyl heptanoate, et \i oeanctc eths] nonuno4te, cthJ dectnodte ethyl dodetanate, ethyl mvn4ate, ethyl nalnut4e Sitahle dckaiaetoie flavour ort tuents include 4]LHexaladone, 4 ha- Octaluetone, delta-y onrx]actone, deita-Decalactone. delta4Jndec&actone, delta-Dodecalactone, Massola lactone, Jasmine iactone and 6-Pentyl-aipha-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. Ikeftrahly the formulation comprises up to 0.1 %w/w menthol, preferably from 0.01 %w/w to 0,08 %wiw, more preferably From 0.02 %w/w to 0.06 %w/w, even more preferably from 0M3 %w/w to 0.05 %w/w, still even more preferably about 004 %w/w, based on the total weight of the formulation.

The formulation may comprise from 0.301 ?/n'w to 0.045 %w/w nicotine or a pharmaceutically acceptable derviative or salt thereot preferably from 0.01 %w!w to 0.045 %w/w, mote preferably from 3.015 %w/w to 0.04 %wlw, even more preferably from 0.02 %w/w to 0,035 %w/w, still even more preferably from 0,025 %w/w to 003 %w/w, most preferably about 0.028 %w/w, based on the total weight of the formulation.

Such a formulation provides similar eiTeet.s to a "low strength" nicotine cigarette.

The tbrmulation may comprise from 0.04 %wi\v 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 formulation. Such a formulation provides similar effects to a "medium strength" nicotine cigarette.

The formu1Monthay&rprise from Q065 %wiwtoOi %WtWflItOtihCtta pkarmaceutiSlly acçp derivadve Qr $It bereof, prdetàbIy fltm 0S7 %wM' to O.ø5 %wjw, more preferably from 0407$ %wlw to 0409 %w/w, even more preferably from.. %*v flP8S4w/w,*tllevqn pyfemblydbouttO84 %w/w, base&on the teSt weight ae çp144. a1,b a provideitilir effectsto a *enéth" nk4n.

A Pad[Oui* Mf.d P!!$ai 9fl!P$e!t 4 ffif *óht of the from tfl.Qff%wj4 men9*,prefór,ly about 044 %wt*, from 0 2s tø 04 %wtw propylene glycol, preferabty about 0.34 Vow/*, torn oc 1 %sv7:etIiwø1, pfesya$j 0s5: %Ww; sacahat1n and effliet $ Mm O4wiw to Os[%wiw nh otine ra;pnaceutàfl'acceptabIe dedvativeur sajtther ptfbabty tO.O8mr to &öt9SSwnk*1ne oraphartnaeeuticatlyaceeptaSe deriS or sait h pntàablp' Wu fl:%wJw pr ($11) fnn DM0 3w t b TMwituSâe"or a phannaMIca* uceptabièf ddei* salt iheteof, prefembiy about 0. 084 %w/w, tbe:tatanecbeing H -U4a whoreinThe ratio onicoéinetosaceharin byweght1s from 9ii tt&!, pnfe abt%abou &l5t 1. Suchi fotrnulatk e*hlbttsa paul y deshaWe :afic oftheabde Pt*pabl' tht ilventtontentte. the totat a &mob4rk&eohot:nd glycol afld/O &iJ ethe Is teThan 35 %*&, pperetabIy ka Sit 6 34wi*nton pi ctabt' ft 041 %w/it:23 %wtw based tuhatigMvIsine Ottht*nfldetloi.

RSuclng'theiotal::solvem totheibmwtatiofl Suces its vIsco*ymeaning:tt Is 3G inote abktoToth nibS f4bUWtôlótt -20 -Preferably the formulation comprises less than 0,01 %w/w nicotirile acid, inure preferably ess than 0.005 %wlw, even more preThrablv less than 0.001 %w/w niectinic acid, based on the total weight of the formulation. Most preferably, the formulation comprises substantially no mcotmic acid! The presence of nitotinic acid may result in the formation of precipitates in the formulation.

The formulations of the first aspect may "consist of' the components recited above. The fhrmulations of the first aspect may "consist of" the components recited above together with any unavoidable irnpu cs The formulflion may' conht essert ally.. ftc components recited above along with any component that has no material effect on the function of the formulation, In a further aspect, the present invention provides a pressurised container containing the formu1ation fox usc in the methods here'i descr bed The pressurised container of the further aspect of the present invention may be used to release a gaseous flow of the nicotine formulation to a user. For example, the pressurised container may be provided with means for delk'ering the contents of the container to the lungs of a user, The pressurised container of the present invention may he used to release the formulation to a usci without r'e need Ui a separate,curce of energy For example, the farmulatton may he released without requiring the heating of substrates, combustion of material or a battery powered electric current, As discussed above, this can result in a reduction in the levels of harmfiul by-products delivered 10 a user, The presunscd contain&r of ftc prcsnt ins-ent on may take the form of a prcssur sed camter for example a presu ked aluminium canister P'e LctflISt' may be fulls recyclable and/or reusable. The canister may be refilled as required by a vending :z.

machine or a larger container containing the desired tbmiulation under a high pressure gradient. in one embodirnem, the canister is a AW5052 aluminium canister, The pressurised container may be capable of dispensing the formulation as a mixtUre of aeosohsed droplets Preferao y, tie imxttue has a partI e site distrihuttun tha is s mini to tobacco smoke. The mixture may have the appearance of a vapour or smoke.

The pressurised container may he pressurised to a pressure of from 3 x It? Pa to 1.5 x 1 o Pa, preferably from 5 x IO Pato 2 x 106 Pa, more preferably from 5.5 x IO Pato x 106 Pa, even more preferably at about 6 x o Pa.

The pressurised container may be used to re-till a simulated cigarette, in particular the simulated cigarette of the an aspect of the present. invention described below.

The pressurised container contents may comprise from Ito 18 mg nicotine, preferably about 17 8 rng nicotine, from 7 to 9 rug mentho], pretera1y about 8 76 nig menthol, from I to 3 rug saccham in preferably about 1 963 m s&uhu in from 68 to 72 mg piopylent glycol pid'eraby about 69 rug ppykrc g1yol, from 190 to 200 nig ethanol, preferably about 194.2 rug ethanol; and from 1 8 to 22 g HFA-I 34a, preferably about 20.15 g 1-IFA-134a, Alternatively, the pressurised container contents may comprise from 10 to 12mg nicotine, preferably about 11.45 mg nicotine; from 7 to 9mg menthol, preferably about 8.176 mg menthol; from 1.1 to L4 rug saccharin, prel'brably about 1.288 mg sacchann horn 68 to 72 rug propylene glycol orelerably about 695mg Prop) lemie glcol; from 190 to 200mg ethanol, preferably about 194.2mg ethanol; from 18 to 228 HFA'.134a, preferably and about 20.16 g HFA-134a. Alternatively, the pressurised container contents may comprise from 5 to 7 rug nicotine, preferably about 5.73 mg nicotine; from 7 to 9mg menthol, prefbrahly about 8.176mg menthol; from 0.5 to 0.8mg saccharin, preferably about 0.654mg saccharin; fmm 68 to 72 rug propylene giycol, preferably about 69.5 mg propylene glyeol; from 190 1o 200 rug ethanol, preferably about 194.2 rug ethanol; and from 18 to 22 g HFA-i 34a, preferably about 20.16 g HFA134a.

----

Alternatively, the pressurised container contents may comprise about from 7 to 9 mg menthol, preferably 8176 mg menthol; from 0.1 to 0.3 mg saccharin, petirably about 0204 mg achann, horn 68 1072 mg prolene glyc>l, referah1v about 6° 5 mg propylene glycol; from 190 to 200mg ethanol, preferably about 194.2mg ethanol; and from 18 to 22 g HFA-134a, preferably about 2017 g HFAl34a.

The pressurised container may be used to refiH a simulated cigarette. Such a "relill" container may comprise from 0.6 to 0.7 rng nicotine, preferably about 0,672 mg nicotine; from 0.2 to 0.4 rug menthol, preferably about 0.32 rug menthol; from 0.07 to 0.09 rug saccharin, preferably about 0,077 mg saccharin; from 2.5 to 2.9 rug propylene glycol, preferably about 2.72 mg propylene glycol; from 7 to 9 mg ethanol, preferably ahoat 7.6 mg ethanol; and from 760 to 800 rug HFA-l3a, preferably about 788,6 mgHFA-134a.

Alternatively, such a re4ili may comprise from 0.4 to 0.5 mg rilcotine, preferably about 0.448 mg nicotine; from 0,2. to 0.4 rug menthol, preferably about 0,32mg menthol; horn 0.04 to 0.06 rug saccharin, preferably about 0,051 mg saccharin; from 2.5 to 2.9 rug prrpylene glycol, prefcrably a5out 2 72 nig pro >1ene glyLol, Porn 7 to 9mg ethanol, preferably about 7.6 mg ethanol; and horn 760 to 800 nlg HFA-1 34a, preferably about 788.9mg HFA-l34a, Alternatively, each refill rna comprise from 0.1 to 0.3 rug nicotine, preferably about 3224 rig mcotue tr in 02 to 04 iw menthol, pielerably anout 032 mg mcnthol, from 0 01 to 003 sav'arin, preerahh' about 0 026mg sacclnnn, from 2 5 to 29 rrg propylene gly...ol, preferably dbout 2 72mg prop) lene glycol from 7 t 9 ng ethanol, pieterably about 76mg etharol, and hon 760 to 800 ng HFA-l 3-la, prcfcraoly about /89 mg!IFA-134a Altemaflvely, such a re-fill may comprist. fk.m 02 to 04mg menthol, preferably about 0.32 mg menthol, from 0.007 ma to 0,009 rug saccharin, preferably about 0.008 nig saccharin, from 2.5 to 2.9 mg propylene glycol, preferably ahiut 2 72 rug propylene glycol, trom 7 to 9 ug ethauol, peferably about 7 6 tog ethanol, and from 760 to 800mg FIFA434a, preferably about 789.4mg HFA-134a, The nicotine in the pressurised container contents described above may, of course, be substituted with a pharmaceutically acceptable d4rivatve or salt thereof n In a further aspect, the present invention provides a simulated cigarette device, also referred to herein as a simulated cigarette, comprising: a housing; a pressuriséd reservoir of inhalable formulationwithin the housing; an outlet for the inhalable formulation from the reservoir and out of the housing, the outlet being configured to eject inh&ahle fbrmfflation therefrom in the form of droplets, at kaY some ot the droplets hauig a diameter ol ID xm oi less ard an outlet valve for controDling the flow of inhalahie formulation through the outlet.

wherein the inhalable formulation is according to the first aspect.

For example, the outlet may he configured to eject inhalable formulation therefrom in the form of droplets, at least I %vol of the droplets having a diameter of 10 pm or less.

Prefuabl the rnalonty of lie dronkts (sat,h as tor exalnpe at east 50 °/cvol) have a diameter of 10 pm or less, more preferably substantially aU of the droplets (such as, for example, at least 50 %s'ol) have a diameter of 1 (1 inn or less, Preferably at least sonic of the droplets (such as, for example, at least I %vol) have a diameter of' 5 pm or less, preftrably the majority of the droplets (such as, for example, at least 50 %voi) have a diameter of 5 pm or less, more j,refbrabiy substamially all of the droplets (such as, For example, at least 90 %vol) have a diameter of S im or less Preferably the outlet valve is a breath-activated valve, Preferably the simulated cigarette l'urther comprises a capillary phig extending from the vie mt> at the ovtlet valve ntn the rec,,rveIr filling at lca 50 % of the volume of he reservoir and being configured to wick the inhalable formulation towards the outlet, Preferably the simttlated cigarette has a breathactivated valve and the housing has an owlet end and an opposite end and the simulated cigarette further comprises: -24 a formulation flow path for the flow of the formulation from the reservoir along the flow pato aid ou of the outbt et the.iudet one of the housmg, a tiexihic dnmhrctgm within the huu.ing dtfi'ung ar atr Vow ptth from a" an inlet to an air outlet at the outlet end of the housing; a valve element movable with the diaphragm and biased by a biasing three 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.

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 defon-nable 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 ref rred to hereinuIter as a "pinch valve" simulated eiarette Preferably the simulated cigarette further comprises a re-flu valve in comTnumcMion with the reservoir via wInch the reservoir may he refilled. The simulated cigarette may be re-filled from a pressUrized container according to the second aspect of the present invention.

Preferably the cize 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.

-

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 urn, prekrably at least 98 %vol, more prefeby r least 98 5 0/ovol ever mew piefeiab y at least 99 %vo Droplets of diameter less than 10 pm are deposited in the lungs, meaning that a pharmacokinctic profile similar to that of a conventional cigarette is provided.

Pielerahlv the stnmlated eAgarettc is configured to eject droplets of formulat on therefrom having the following size profile: Dv 90 of less than 20 urn, prefrably less than 5 pm, more preferably ess than 3 pm, eve!) more preferably less than 2,9 urn, and/or Dv 50 of less than 6 pm, preferably less than 0.8 pm, more preferably less than 07 run, 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.

Accordingly, in one embodiment, the simulated cigarette is configured to eject droplets with the following size profile: Dv 90<20 pm, Dv 50<6 pm and Dv 10<2 pm; preidrably with the following size profile: Dv 90<5 pm, Dv 50< 08 urn and Dv 10< 0.3 pm; more preferably with the following size profile: Dv 90 <3 pm, Dv 50<07 pm and Dv 10 <0.25 pm; even more preferably with the following size profile: Dv 90 <2.9 pin, Dv 50<0.6 pm and Dv 10 <0.2 pm, Such a profile is sun lar to that of a convenional cigalette mean ng that the pharmacok.inetic profile provided closely mimics that of a conventional cigarette.

The simulated cigarette may provide a user with a nicotine arterial C, of up to 15 ng/nil, typically from 2 to 10 ngiml, or even from 4 toS ng/rni. Cmax values greater than about 2 ng/ml provide a user with a "head rush" as experienced when smoking a conventional cigarette. 26 --

the strulated cigarette iay provice t iese C,, values vith a i, of ftc n 10 seconds to minutes, typically from 5 minutes to 15 minutes, often about 12 minutes, Compared to simulated cigarette devices of the tirior art, such tnm, values are closer to those exhibited by conventional cigarettes. Accordingly, the present mvennon mote closely mimics the pharniacokinetic profile of a conventional cigaretic, and is therefbre particularly effective ftn' use in NRT or as an alternative to recreational smoking of conventional cigarettes.

Preferably the simifiated 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 inhalaton resistance of from Ito 7 kPa, preferably about 4 kPa. This inhalation resistance is simdai to that pruvided by a corventional cigare1te \Vhen the srn'ulaed cgaiette 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 0.0 ito 0.06 mg/mI Ibis bless th4n. conventional vigarctte However nce the hatunial aspects 04 smoking have been mimicked by the above ejection rate and inhalation resistance, a user will experience the same]evei of satisfaction with a lower level of inhaled nicotine in comparison to conventional smoking cessation aids.

In a yet fiwther aspect, the present invention provides a method of manufacturing the formulation of the present invention, the method comprisinw preparing a pre-mixture comprising a polyhydrie alcohol and a glycol and/or glycol ether, and optionally a TAS2R taste recepthr agonist and/or flavouring agent, wherein the ratio of polyhydric alcohol: glyeol or glycol ether by weight is from 6:1 to hI: adding nicotine or a phannaceutically acceptable derivative or salt thereof to the premixture to obtain a nicotinecontaining mixture: and adding a propellant to the nicotine'containing mixture.

-27 -If the nicotine is added beibre the polyhydric alcohol and glycol or glycol ether are combined, then precipitation of nicotine may occur, Likewise, if the formulation comprises other components, such as a flavouring component or a TAS2R taste receptor agonist, then these componenis should he uUy mixed into the premixture hefbre the nicotine is added in order to avoid precipitation of nicotine. In particular, it has been found that when The formulation comprises menthol, the menthol should he fully dissolved into the pre-inixture before the nicotine is added in order to avoid precipitation of nicotine.

When the formulation is to include a TAS2R taste receptor agonist ttndior a flavouring co nponent, prefer'hiy the polyhydric alcohol and &ycol or yLol cther arc combined before the TAS2R taste receptor agonist and/or a flavouring component are added. This avoids precipitation of the flavouring component or TAS2R taste receptor agonist.

In an ernhodunent of the pre'er t rn%entlon, the imiiated cigarette is configured to provide a user thereof with a nicotine venous of up to IS ug/mi and/or with a t,, of from 10 seconds to 20 minutes.

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

Fhures Figure 1 shows the mean plasma nicotine concentrations over time by treatment from the investigation in Part B. Figure 2 shows the mean pasrna nicotine coneentratimis onr time by treatment from the investigation in Part D. Figure 3: Mean craving VAS scores over time by treaunent in Part B Figure 4t Mean craving \5 scores over time by treatment in Part D *Differe.nee between the novel nicotine inh&er device 045 mg and Nicorette® Inhahitor (.10 mg) is significant (p=OOi) tDifference between the novel nicotine inhaler device 067 mg and Nicorette® inhalator (10 mg) is significant (p=O. (ii) SF means standard error, VAS means visual analogue scale -29

Examples

Sections of these examples are reproduced from a manuscript endtk.d "Evaluation of Pharmacoknetics, ua'mg and smokmg urges when u"g a ravel ricoune nhjer device" submitted for pualicat'on in Nicotme and Rh'to Rescarch ManusLnp II) NFR-20 13-621 Ri The invention wilt now be described with reference to thefl roI1ong non-limiting

examples.

Method of manufacftwe The thilowirig starting materials were used to prepare the ibrmulation used in the present

examples:

Saccharin fth, Eur) Propylene glycoi (EP grade) Menthol (Ph But.) Ethanol (100% HP, Ph. Fur,) Nicotine (Ph. Eur) 1-IFA-134a (CPMP 1994) Starting materials were added to a mixing vessel in the following order: (i) 5.14 g saccharin, (a) 227 0 g propylene glycol, (w) 32 5 g ruerthol and (iv) 774 0 g etl'aiol The mixture was then stirred at 600 rpm for 15 minutes until the menthol peflets had ftEly dissolved and a clear liquid was observed. 45.6 g of nicotine was then added to the mixture and stirring was continued at 600 rpm tor a further 10 minutes. The resultant mixture was then added to a pressure vessel which had been nurged with HFA 1 34a. The vessel was then sealed before being cooled until the internal temperature reached 8-12 CC, at which point the temperature was maintained, Approximately 40 kg of HFA-1 34a was -30 then rcaei nra Lh. vcsscl before mdgnet c tirnng at 210 rpm commenced HF& contiw cc to be released into the sLssel until a total of 30kg had been added, at which porn tic forrnulatn as suned it "10 ipm lb a turthei 110 rnmutes During the tudher stirring, the pressure was controlled to ensure that it did not exceed 4.5 bar and that the final pressure was between 3-4 bar, After stirring, the fbrmulation was dispensed into canisters, Varying the method by adding nicotine either before the saccharin had been added or betbre the meinho had Fully dissolved resulted in precipitation of the nicotine.

etsizerofilc The following formulation was prepared: "6 004 %w'w menthol 0.006 %w/w saccharin.

0.34 %wtw propylene glycol, 0.95 %w!w ethahol, 0.056 %w/w nicotine, and remainder HFA-134a.

The formulation was inserted into nine phich valve simulated cigarettes. Five doses were emitted from each device and the droplet size profile of each was measured using a Malvern Spraytec device. The results are set out in Table I below: Dv 10 (Lrn 0 198758 jO uMO5 Dv 50 (run) 0 Q9.779 Dv 9O(tm) 2 80o37S fI 063722 % * Q9 022221 077/04 Table I -Droplet size profile.

hiipurities The following formulation was prepared: 004 %w/w menthol, 0.0032 %wfw saccharin, 034 %w/w propylene glycol and 0.95 %w/w ethanol.

0.028 %w/w nicoline, enaindet HF 1⁄2-J34a The fbnm.ilation was then inserted into a pressurised container. The percentage volume of HflpL flues w h repett to ii cotme conceivralion was assessed thronatcgi ap:calIy at both the time of fiB and after six months, The results are set our in Fable 2 below: 32 --Impurity Initial I = a rnonth' -N I N-2 jN=3 Annabae i002% 0 1% 011⁄4 0 1% 1-nctyr re Not detceted 0 "% 02% 0 % Co'mme Noideteted 0 2% 0 2% 0 2% Myosmme 002% 0 2% 0 2% 0 2% Ncetme:n.,.ide hot deteced 0 3% 03V0 0 % Norniconne Not detected U P10 01%0I% Arnthasne Nddcted \otdetcckd No detected Not deocted Table 2-Stability data (inverted, 40°J/75% RU). N I, 2 and 3 refer to different pressurised containers from the same batch of fhrrnulation, calj es qgghun Part B: A random ised, open-label, single-blind, three-way crossover study to determine the venous PTC of orally inhaled nicotine at Iwo dose levels: 0.45 mg and 0.67 mg. The 045 ing dose co"re5ponds to one charge of the fo'riulation piepaed Eo the d'oplct oze study in a simulated cigarette as described herein. The 0.67 mg dose corresponds to one charge of a higher strength formulation in a simulated cigarette according to a preferred embodiment of the invention (herein referred to as the device of the present invention), wherein the formulation prepared for the droplet size study is prepared using 0.084 %w/w nicotine, The dosages of the present invention were compared with the Nicorette® inhalator (10 mg).

I'air 1) A randornised open-Lbe two-s ay cre.s ver study o dde' r ne the s enus Nv of orally inhaled nicotine at one dose level (0.45 mg) delivered as for Part B via a nicotine inhaler system ofthe present invention compared with the Nicorette® Inhalator (10 tug), -33 -Particinants Healthy volunteers (male or female) aged 18-55 years were eligible to participate if they had smoked at least 10 manufactured cigarettes per day for the last year. and smoked their first cigarette within 1 hour of waking. All participants had an expired carbon monoxide level of at least 10 ppm at screening and were required to abstain from smoking for 12 hours prior to their scheduled dosing time.

Participants were excluded if they had a known or suspected history of hypersensitivity to nicotine or any other component of the inhaler or Nicorette® inhalator. Participants were also excluded if they had a history of confirmed chronic and/or serious pulmonary disease, including asthma, or chronic obstructwe pulnionary disease, a history of myocardial infarction or cerebrovascular accident. other clinically significant cardiac or renal conditions, or any eolniorbidity that could place them at risk or interfere with the interpretation of the study data.

Study treatment Participants were familiarized with the use of the inhaler device of the present invention (hereinafter "the inhaler device") using a placebo fbnnuiation on the day prior to receiving active treatment, The piaeebo formulation was identical to the active fonnulation with the exception of nicotine. Study participants were blinded to the dose of nicotine administered in each part of the study. Participants inhaled the contents of one charge of the device of the present invention in a similar way to a cigarette. All participants were instructed to inhale the dose at the same rate of one inhalation every 15 seconds over ?pproxlrrately 2 rnmutes (i e eight inhalahons n total) Tre tine particle dose yc5 lim has a specifkaton et 60 05 tg for a torrnlatior concentration of 0.056% w1w nicotine (he.

to 68% of the nicotine dose). The nicotine dose contained in 0.8 g of formulation (a single dose/refill of the device of the present invention) is estimated to be 045 mg and 0.67 rug for the 0.056% w/w and 0.084% w/\v concentrations, respectively The -34 -Nicorette® inhalator (10mg) is an orally inhaled NRT product and was selected as the comparator bet ause it wa the closest available 1resentauon to the innaler deice Participants took one inhalation of the Nicorette® inhalator (10 mg) every 15 seconds, taking no longer than 20 minutes (i.e. 80 inhalations) to complete the dose, in Ene with the regimen described in the prescribing information (McNeil Products Limited. 2010), The available nicotine dose per cartridge of Nicorette® inhalator (10 rng) is estimated to be 4 mg but is temperature dependent (McNeil Products Limited, 2010). The time at which participants started to take the first inhalation of the test product was recorded as the dose time (NO), in Part B, each participant received a single dose. of nicotine on three consecutive days, at dose levels of 0.45mg and 0.67mg via the novel nicotine inhaler device, and a single dose via the Nicorette® Inhalator (10 trig).

in Part D, each participant received a single dose of nicotine via the novel nicotine inhaler device (045 mg) and a single dose of nicotine viaThe Nicorette® Inhalator (10 mc,) on two cusecutive days For e deice ofthe p eert mwenticn, Pail B tested the first refill, whereas Part D examinLd the tourtli refill During the earty stages of the 4udy, it wa noLd that th quantity of nicotine delivered via the novel inhakr device for the first dose (be. one complete refill) tended to be only approximately 70% that of subsequent doses. In Part D of the study, the fourth refill of the device of the present invention was investigated by filling and flushing the device thiee times, u'ng a pump (Cole-Pannt) a Criucal I low ControHer (Model TPK) and the Dose Uniformity Samphng Apparatus, Administration of the Nicorette® Inhalator (10 mg) was identical in both study parts.

Stiidil assessments FK analysis PR assessment was the primary outcome measure for this study. For both Parts B and D, --35 venous blood samples were collected 5 nunutes (±1 minute) pre-dose and at 2, -4, 7, tO minutes (±1 minute), 15, 20, 30, 40, 50, 60 minutes (±2 minutes) and 120, ISO, 240 and 300 ninnIes (5 mirutes) post_dose (i e horn the start of inhalatonI fcu the measurement at plasma nicotine concentration by a liqmd chromatography with tandem mass spectrometry method The nietl'od as va idated tar linear y, precision and accjracj Quality control samples at concentrations of 10, 7.5 and 37,5 ng!ml, as well as 37.5 ng1ml i scd as ddute quality control tar sampLs of low vo ume (diluted ui 2) were to determine inter-and intra-precision and biter-and intra-aceuracy, The nican inter-run accuracy was within 1% and precision was within 5%. Derived PK parameters were summarized separately by device and dose level.

Efficacy Efficacy was evaluated by assessing the impact of the test devices on craving satiation and smoking urges, mid their effect on aspects of nicotine withdrawal, using: 1. a visual analogue scle (VAS) to assess the level of craving of the. subject based on their response to the question, How strong is your craving for cigarettes?' on a scale of 0 (no craving) to 10 (strong craving), This assessment was made prel dose and at 4, 20, 40, 60, 120, 180, 240 and 300 minutes from the start of dosing. in Part D, additional assessments were made at 2 and 10 minutes from the start of dosing.

2, the Questionnaire of Smoking Urges (QSUlBrief) (Ca; Tiffany, & Christen. 2001) to assess the level ofc"avu g ana smolang uq'e based on II e responses a! participants to statements on a scale of I (strongiy disagree) to 7 (strongly agree). These assessments were made preldose and at 20. 40. 60. 120, 180, 240 and 300 minutes horn the start ot dosmg Component sco"es were determmeL for the aesire' and anticipation' subscates. Results of the anticipation' component score of the QSU-Brief were used as a measure of nicotine craving. Sèiy

Safety and tolerability of the device of the present invention and Nicorette® inhalator were compared. Local tolerability was an assessnient of the contact area of the device of the present invention or Nicorette® Inhalator with the participants lips. Participants were asked how the device felt in their mouth or lips, which were also assessed visually. 1'oerability was an assessment of symptoms resulting from the oral inhalation from the inhaiers, Any symptoms that were reported as worse than pnor o dosmg were reordcd as auvcrw events iAF') Abs were ascertained by neutral questioning and their incidence and nature were recorded and aleo rated by the c'4igator a not relatea' possibly related probaly iclated' and cL flnitcly re[ated to the test product Phs-sical examinaUon end monitoring I vital signs (blood pressure, heart rate, respiration rate and temperature) were also conducted.

For both Parts B and I), assessments of local tolerability and vital sigjts were pertbrmed at 20 minutes pre-dose. Post-dose assessments measured after the start of dosing comprised: local tolerability at 4 and 20 minutes; physical examination at 300 minutes; and vita] signs and AEs. SAEs and concomitant medicine at 4, 20, 40, 60.

120. 180, 240 and 300 mInutes. All partipants were contacted by telephone (9±2 days) following the study end and any AEs, SAEs and concomitant medicines were recorded.

l'reatmenti emergent AEs (TEAEs) were evaluated from the start of dosing of the test product until the safety telephone follow-up call.

Participants were included in the PLC population if they received all of the planned doses of rdcotinc, Participants were included in the safety intent-to--treat population if they recen 0 te dose of njcotine St8tNt1al m41 ses wv-c conducted using SASt Vrsion 9.2.

-37 --FTC analysis Plasm-a concentrations of nicotine were measured over time and derived PK parameters were summarized by device and dose level separat&y for both Parts B and D of the study.

The PK parameters determined were the mean maxunurn plasma nicotine concentration (c), the mean time to maximum plasma nicotine concentration (Twax), and the mean area under the plasma concentration-time curve (AUC), from time zero to the end of' the sample collection period (AUCon and from time zero to the time of the last quantifiable concentration AUCiasi, following administration of nicotine using either device, Comparative analysis between both dose levels of the novel nicotine inhaler device and the Nicorette® inhalator (10 mg) was perfbrrned using an analysis of variance (ANOVA) with logarithmic transformation of Cmax and AUC values. Differences ofp:O. 05 were considered significant. P1K analysis was conducted using PhoenixTM WinNonlin® Vers4' 62. Ecacy

Craving measures and the QSU-I3rief total and component scores were summarized, over time by device and dose level in both study Parts B and D. A paired Student's i-ks! was used to analyze the difference in mean craving VAS and QSU-Brief scores by device and timepoint. Craving was also assessed from the area under the VAS score--time curve, where a lower craving AUC equates to a better craving reduction. Comparative analysis heteen both dose leqeIs of the noel nicotine rhJer dtvae and the Ncore1te® inhalator (10mg) of cffieacy was performed using an ANOVA with logarithmic transformation oIAUC.

The number of participants in Parts B and LI was sufficient to demonstrate equivalence at a strular' .nargm c 20% w th 8O°o poe 104 ig t c two sided S'o tests approaci, assuming an underlying intra-subject coefficient of variation of 15%, The quantity of nicotine inhaled from the device of the present invention by each participant was calculawd 38 --front the weight of formulation emitted by the device and the target nicotine concentration of the formulation,

RESULTS

Stndy population A total of 24 participants were randornised for Part B and a further 24 for Part D of the study. Mean ages of participants were 28.6 years (Part B) and 29.7 years (Part D), and 58% (Part B) and 54% (Part C)) were male. Pan B

Al] 24 participants in Part B received a sing]e dose from the Nicorerte® Inhalator (10 mg, but only 23 received a single dose of each of two dose levels of the novel nicotine inhaler device as one parttcipant withdrew because of study restrictions. The mean (standard deviation) weights of formulation inhaled from the device of the present invention were 0.9472 g (020Mg) and 0,8610 g(C3005g), corresponding to 0.5304mg and 0.7232 mg nicotine from the device of the present invention 0.45 mg and 0.47 mg, respectively. There were no withdrawals resulting from AEs.

Par? 1) All 24 participants in Part D received single doses of the device of the present invention 0.45 mg and the Nicorette® Inhalator (10 ñg). The mean (standard deviation) weight of formulation inhaled from the device of the present invention in Part D Was 0,7074 g (0.3028 g, corresponding to 0.396 1 rug nicotine. sis

Mavimzern plasma concentrallon in Part B, the mean venous plasma nicotine concentration increased following administration of all three trealments. The mean venous plasma Cma following administration of the inhalation device 0,45 mg and 0.67mg was 3.28 ng/m! and 3.92 39 -ng'ml, respectively see Table 3). The mean cr, following administration oIthe Nicorette' inhalator (10mg) was 6.57 ng/ml (Table 3).

Results for Part D were similar to those for Part B, with the Nicorefle® Inhalator 0mg) producing a higher, but InteL peak than the device of the present invention, The mean Ca following administration of the device of the present invention 045 rug and Nicorette® Inhalator (10mg) was 3.52 ng!ml and 763 ng/ml, respectively (Table 3).

i7me to C,,,, The nican nicotine Cm calculated in Part [3 was higher tollowlng administration of the Nicorettet Inhalator (10 mg) than either dose from the device of the present invention (fable 3). However, the for the Nicorette® Inhalator (I 0 nig) was longer than for the device of the present invention of either strength (38.0 minutes vs 18.7 and 19.2 minutes [device ofthe nresent invention 0.45 mg and 0.67 mg, respectively] in Pail B, and 36.3 ruin' tes v 21 0 minutes [dev e of the present rnvernon 045 mg] in Part D) (I abic 3j Mean plasma nicotine concentrations over time by treatment for Parts B and D are shown in Figures 1 and 2, Aea under the co"cenfrcvon-vme cWVC In Part 13, the mean AUC was higher for the Nicorette® inhalator (10 mg than it the inhalation device of either strength. Similar results were seen in Part D (Table 1).

Coniparison of the reIatie hioavai ability of mcotsne Det\een treatments n both Parts B and D indicated that the device of the present invention produced significantly lower C. AtJCi and AUC, and a significantly shorter Trn< than the Nicorette® inhalator (10 mg)(Table 1), Analysis of the AUC0 from both Parts B and D confirmed the early delivery of higher amounts of nicotine from the device of the present invention compared with the Nicorette® Inhalator (10 mg. -40

Efficacy Cravi,w MS scores Mean craving scores assessed by the lAS were lower (higher craving relief) for the device of the present invention than the Nicorette® Inhalator 0mg) at the majority of timepoints in both Parts B lFigure 3) and I) (Figure 4). In Part B, the lowest score was at minutes for both the device of the present invention 0,45 rug and the Nicorette® inhalator (10 mg, and at 4 minutes for the device of the present invention 067 mg (Figure 3). In Part D, the lowest mean craving lAS score was at 20 minutes thr the device of the present invention 0.45 mg and at 40 minutes for the Nicorette® Inhalator 10 rug) (Figure 4).

A comparison of the mean craving lAS scores showed that, in Part B, nican scores were lower (higher craving relict) thr the device of the present invention GAS rug than for the Nicorette® inhalator (10 rug) at. 7 of the 8 post-dose tiinepoints and that this difference reachen statistical s gn flcnce at Ire ISO-and 240-minure tin'epoins Jigure Mean scores were lower fbr the device of the present invention 0.67 rug than 1 a the Nicorette® lnha'ator (10 rug) n 6 of 8 post! dose turepoints, reaching statist c.d signi 3cance at the I 80-mint e timepoint ftiguc 3) In Part 9, mean scores were icwer br the device of the present invention 0.45 mg than thr the Nicorette® Inhalator (10mg) at all TO post-dose rhnepoints, differences reaching sigiiiilcance at the 2-, 4-, and 10-minute timepoints (Figure 4).

A UC fir craving VAS scons in both Parts B and D, the mean AUG was lower (indicating greater craving relic!) for the device of the present invention than the Nicorette® inhalator (10 mg). in Part B, the mean (standard deviation) AUG fOr craving lAS score was kwest for the device of the present invention (lAS tug (1356.3 [789.4] crntmin), iblidwed by the device of the present invention 0.67mg (1431.6 [769.0] cmmin. The greatest AUG was calculated for the Nicorette® inhalator (10 rug) (1 5663 [6204] cmmin), In Part B, the mean AUC for --41 craving VAS score was lower for the device of the present invention 0.45mg (i20&5 1724.4] cmthhn), than for the Nicorette® inhalator (10mg) (1402.3 [8152] ern*min).

A statistical comparison of craving AVC between fteatments showed that in Part B, the AUC For the device of the present invention 0.45 trig was significantly lower than for the ocorettet Innalator 0 mg) cp-M 029), m Part D the MiC for thc deiee of the present invention 0.45 trig was lower than that tbr the Nicorette® Inhalator (10 trig) and 4ppoahcd stgtisuj signiicane (p=O 059) Tnese results scggest thit greater relief of craving is achieved with both the medmm and high doses or the devtce of the present invention than with the Nicorette® Inhalator (10mg).

QSU-Brlef score For both parts, the mean QSU-Brief total scores were reduced (indicating craving re1ie1 at the time of first measurement (20 minutes) for all treatment groups; simi]ar patterns were seen for each of the QSU-Brief cohiponent scores for anticipation' and desire'.

A treatment comparison of mean QSU-Brief scores showed that in Part B, total scores were statistically significantly lower for the device of the present invention 0.45 mg, than for the NieoretteX Inhalatoi (10 rng at 120 180 aid 240 mautes potIdose (1 p 0 1L5 In Part D, total scores were lower for the device of the present invention, atihough none of the differences were statistically significant o>0.05), Sqfty in Part B. a total of 87 TEARs were reported by 23/24(96%) participants. Of these, 79 were considered related to the study medication. Most T[iAEs were mild in nawre. Two lFAls ieie moderate, one otw9 cli ns iclated to study medicaticn (local nuiibnecs, which was reported 4 minutes after administration of the inhalator and resolved within 15 minutes), There was one report of mild numbness 20 minutes post-dose with the device of the present invention 0,67 rug. For both the devke of the present invention and Nieorette Innalator n-id tmghng was the noct commonly reported oeal tolerability symptom * In Part D. a total of 61 TEAEs were repcntd by 22t24 (92%) participants. Of these, 19 reported a total of 5OTEAEs that were considered related to the study medication and all were mild. For both the device of the present invention and inhalator, mild tingling was the most commonly reported local tolerability symptom.

All AEs seen in Parts B and D were mild or moderate in nature and none were reported as severe. There were no serious AEs or deaths throughout the study, and no participants discontinued treatment because of an ALL. Overall, the most common AEs were oral naresthesia, throat irritation, headache and oral hypoesthesia, In terms of local tolerability, the most common local An reported by participants in both parts of the study was tingling of the mouth/lips.

There were no clinically significant changes in mean vital signs over time fix the duration.

of the study, 43 --Partf3(N=24 ParDN 24) Nicorefl® Inh4latrnn mnhalanon N coretteQt) InMiaflon lnhaicr De ice-045 De ice-0 b7 nhaler De cc-04" mg mg mg C,< ngml 6688 Jzs4 JJ5 3915(1 e40) + 7628(4 718 3519(1 375) (2.965) Tmax minute', 38OP8) iaiTee Th2t11 8 3C3(124 210(135) 9777 43C 8 273 8) 545 3(334 4) 99l b 4 (2989) mm*ngjlrl kUCd, 9577 4533(2590) 6630 rä22 1 13026 + 4 2 (28i6) min*ngirrl 487 1) (5845) 135'99) l84(l13 22Y132 142(138) 173(130) mrn*n/irl Table 3. Summary of pharinacokinetic parameters by treatment Data are mean (standard deviation) All novel inhaler pharmacokinetic parameters except AUC were sign ificantly different from the reference product (Nicorette® Inhalator) cpco.05).

"N-23 forPa'tB AUC, area under the plasma concentration versus time curve [torn time 0 to the end of the sample collechoii period; AUCiat area under the plasma concentration time curve from time 0 to the lime of the last quaiitifiahle concentralion; AUC0..0 area under the plasma concentration time curve from time 0 to 10 minutes; Crc!, maxinlum plasma concentration; time to maximum concentration. 44 -

The foregoing detailed description has been provided by way of explanation and UlusLrgtion, and is not intended to ilinit the scope of the appended claims. Many variations in the presently preferred embodiments illustra ed herein will be apoartnt to one of ordinary skill in the art, arid remain within the scope of the tppended claims and their equh'alents.