Nicotine composition

Abstract

An inhalable composition comprising: nicotine or a pharmaceutically acceptable derivative or salt thereof; a propellant; a monohydric alcohol; and a glycol and/or glycol ether, characterized in that the ratio of monohydric alcohol:glycol or glycol ether by weight is from 6:1 to 1:1.

Claims

1. An inhalable composition comprising: nicotine or a pharmaceutically acceptable derivative or salt thereof; at least 90% w/w of a propellant, wherein the propellant is a hydrofluorocarbon; a monohydric alcohol; and 0.1 to 1% w/w of a glycol and/or glycol ether, wherein the glycol and/or glycol ether comprises propylene glycol, wherein the ratio of monohydric alcohol:glycol or glycol ether by weight is from 3:1 to 1:1, and wherein the composition is deliverable to a user using a simulated cigarette having a non-metered valve with an inhalable droplet diameter wherein at least 50 percent of the droplets have a diameter of 5 m or less.

2. The composition of claim 1, wherein the glycol and/or glycol ether further comprises at least one of: polypropylene glycol and polyethylene glycol (PEG).

3. The composition of claim 1, wherein the monohydric alcohol is ethanol.

4. The composition of claim 3, wherein the composition comprises from 0.5 to 1.5% w/w ethanol, based on the total weight of the composition.

5. The composition of claim 1, wherein the composition further comprises a human TAS2R bitter taste receptor agonist.

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

7. The composition of claim 1, wherein when the composition is delivered to a user using a conventional metered dose inhaler the composition forms an inhalable droplet diameter wherein at least 50 percent of the droplets have a diameter smaller than 5 m.

8. The composition of claim 1, wherein when the composition is delivered to a user using a conventional metered dose inhaler the composition forms an inhalable droplet diameter wherein at least 90 percent of the droplets have a diameter smaller than 5 m.

9. The composition of claim 1, further comprising a flavour component.

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

11. The composition of claim 1, comprising from 0.001% w/w to 0.045% w/w nicotine or a pharmaceutically acceptable derivative or salt thereof, based on the total weight of the composition.

12. The composition of claim 1, comprising from 0.04% w/w to 0.07% w/w nicotine or a pharmaceutically acceptable derivative or salt thereof, based on the total weight of the composition.

13. The composition of claim 1, comprising from 0.065% w/w to 0.1% w/w nicotine or a pharmaceutically acceptable derivative or salt thereof, based on the total weight of the composition.

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

15. A pressurised container containing the composition of claim 1.

16. The pressurised container of claim 15 pressurised to a pressure of from 310.sup.5 Pa to 1.510.sup.7 Pa.

17. A simulated cigarette comprising: a housing; a pressurised reservoir of inhalable composition within the housing; an outlet for the inhalable composition from the reservoir and out of the housing, the outlet being configured to eject inhalable composition therefrom in the form of droplets, at least some of the droplets having a diameter of 10 m or less; and an outlet valve for controlling the flow of inhalable composition through the outlet, wherein the inhalable composition is according to claim 1.

18. The simulated cigarette of claim 17, wherein the outlet valve is a breath-activated valve.

19. The simulated cigarette of claim 17, further comprising a capillary plug extending from the vicinity of the outlet valve into the reservoir, filling at least 50% of the volume of the reservoir and being configured to wick the inhalable composition towards the outlet.

20. The simulated cigarette of claim 18, wherein the housing has an outlet end and an opposite end and wherein the simulated cigarette further comprises: a composition flow path for the flow of the composition from the reservoir along the flow path and out of the outlet at the outlet end of the housing; a flexible diaphragm within the housing defining an air flow path from an air inlet to an air outlet at the outlet end of the housing; a valve element movable with the diaphragm and biased by a biasing force into a position in which it closes the composition flow path; wherein suction on the outlet end causes a flow through the air flow path providing a pressure differential over the valve element thereby lifting the valve element against the biasing force to open the composition flow path; and wherein the biasing force is arranged to close the composition flow path once the suction ceases.

21. The simulated cigarette according to claim 18, wherein 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.

22. The simulated cigarette according to claim 17, further comprising a refill valve in communication with the reservoir via which the reservoir may be refilled.

23. The simulated cigarette according to claim 17, wherein 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.

24. The simulated cigarette according to claim 17, configured to eject droplets of composition therefrom in which at least 99% vol of the droplets have a diameter of less than 10 m.

25. The simulated cigarette according to claim 17, configured to eject droplets of composition therefrom having the following size profile: Dv 90 of less than 20 m, and/or Dv 50 of less than 5 m, and/or Dv 10 of less than 2 m.

26. The simulated cigarette according to claim 17, configured to provide a user thereof with a nicotine arterial C.sub.max of up to 15 ng/ml and/or with a t.sub.max of from 10 seconds to 20 minutes.

27. The simulated cigarette according to claim 17, configured to eject composition therefrom at a rate of from 0.5 to 3 liters per minute.

28. The simulated cigarette according to claim 17, configured to provide an inhalation resistance of from 1 to 7 kPa.

29. The simulated cigarette according to claim 17, configured to deliver nicotine to a user at a rate of from 0.01 to 0.06 mg/ml.

30. A method of manufacturing the composition of claim 1, the method comprising: preparing a pre-mixture comprising a polyhydric alcohol and a glycol or glycol ether, and optionally a TAS2R taste receptor agonist and/or flavouring component, wherein the ratio of polyhydric alcohol:glycol or glycol ether by weight is from 3:1 to 1:1; adding nicotine or a pharmaceutically acceptable derivative or salt thereof to the pre-mixture to obtain a nicotine-containing mixture; and adding a propellant to the nicotine-containing mixture.

31. A method according to claim 30, wherein the composition comprises a TAS2R taste receptor agonist and/or flavouring component, and wherein the polyhydric alcohol and glycol or glycol ether are combined before the TAS2R taste receptor agonist and/or flavouring component are added.

32. A composition comprising: nicotine or a pharmaceutically acceptable derivative or salt thereof; a monohydric alcohol; and a glycol or glycol ether, wherein the ratio of monohydric alcohol:glycol or glycol ether by weight is from 3:1 to 1:1; and saccharine, wherein the ratio of nicotine or a pharmaceutically acceptable derivative or salt thereof:saccharine by weight is from 12:1 to 5.5:1, and wherein the composition is deliverable to a user using a simulated cigarette having a non-metered valve with an inhalable droplet diameter wherein at least 50 percent of the droplets have a diameter of 5 m or less.

33. A simulated cigarette configured to provide a user thereof with a nicotine arterial C.sub.max of up to 15 ng/ml and/or with a t.sub.max of from 10 seconds to 20 minutes, comprising: a housing; a pressurised reservoir of inhalable composition within the housing; and an outlet for the inhalable composition from the reservoir and out of the housing, the outlet being configured to elect the inhalable composition therefrom in the form of droplets, at least 50 percent of the droplets have a diameter smaller than 5 m, wherein the inhalable composition comprises: nicotine or a pharmaceutically acceptable derivative or salt thereof; at least 90% w/w of a propellant, wherein the propellant is a hydrofluorocarbon; a monohydric alcohol; and 0.1 to 1% w/w of a glycol and/or glycol ether, wherein the glycol and/or glycol ether comprises propylene glycol, and wherein the ratio of monohydric alcohol:glycol or glycol ether by weight is from 3:1 to 1:1.

34. A method of treating nicotine addiction using the composition of claim 1.

35. The composition of claim 1, wherein the droplets have the following size profile: Dv 90 of less than 5 m, and/or Dv 50 of less than 0.8 m, and/or Dv 10 of less than 0.3 m.

36. The composition of claim 32, wherein the droplets have the following size profile: Dv 90 of less than 5 m, and/or Dv 50 of less than 0.8 m, and/or Dv 10 of less than 0.3 m.

Description

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

(2) FIG. 1 shows a graph of mean arterial plasma concentrations of nicotine over time for subjects administered the high, medium or low strength nicotine compositions of the first aspect of the present invention.

(3) FIG. 2 shows a graph of mean craving VAS score over time for subjects administered the high, medium or low strength nicotine compositions of the first aspect of the present invention.

(4) FIG. 3 shows plots of arterial and venous nicotine concentrations measured at intervals after inhalation of a high strength nicotine composition of the first aspect of the present invention.

(5) FIG. 4 shows plots of arterial and venous nicotine concentrations measured at intervals after inhalation of a medium strength nicotine composition of the first aspect of the present invention.

EXAMPLES

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

(7) Method of Manufacture

(8) The following starting materials were used:

(9) Saccharin (Ph. Eur)

(10) Propylene glycol (EP grade)

(11) Menthol (Ph Eur.)

(12) Ethanol (100% BP, Ph. Eur.)

(13) Nicotine (Ph. Eur)

(14) HFA-134a (CPMP 1994)

(15) Starting materials were added to a mixing vessel in the following order: (i) 5.14 g saccharin, (ii) 227.0 g propylene glycol, (iii) 32.5 g menthol and (iv) 774.0 g ethanol. The mixture was then stirred at 600 rpm for 15 minutes until the menthol pellets had fully 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 for a further 10 minutes. The resultant mixture was then added to a pressure vessel which had been purged with HFA 134a. The vessel was then sealed before being cooled until the internal temperature reached 8-12 C., at which point the temperature was maintained. Approximately 40 kg of HFA-134a was then released into the vessel before magnetic stirring at 210 rpm commenced. HFA continued to be released into the vessel until a total of 80 kg had been added, at which point the composition was stirred at 210 rpm for a further 110 minutes. During the further 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 composition was dispensed into canisters.

(16) Varying the method by adding nicotine either before the saccharin had been added or before the menthol had fully dissolved resulted in precipitation of the nicotine.

(17) Stability

(18) A number of compositions were prepared with varying ratios of ethanol:propylene glycol. The stability of the compositions under various conditions was determined visually, and the results are set out in Tables 1 and 2. Compositions with ethanol:propylene glycol ratios less than 1:1 separated into two phases within a week.

(19) TABLE-US-00001 TABLE 1 Stability data for various ethanol:propylene glycol ratios. (Samples 1 and 2 are comparative examples). Composition, %, w/w Excipient Sample 1 Sample 2 Sample 3 Sample 4 Sample 5 Sample 6 Nicotine 0.0840 0.0840 0.0840 0.0840 0.0840 0.0840 Propylene glycol 1.7000 1.2750 0.8500 0.5100 0.3400 0.1700 Ethanol 0.9500 0.9500 0.9500 0.9500 0.9500 0.9500 Saccharin 0.0096 0.0096 0.0096 0.0096 0.0096 0.0096 Menthol 0.0400 0.0400 0.0400 0.0400 0.0400 0.0400 HFA 134a 97.2164 97.6414 98.0664 98.4064 98.5764 98.7464 Total 100.0000 100.0000 100.0000 100.0000 100.0000 100.0000 Ethanol:Propylene glycol 0.56:1 0.75:1 1.12:1 1.86:1 2.79:1 5.59:1 Visual appearance at t = 0 X Visual appearance at t = 1 week 2-8 C. X X Visual appearance at t = 1 week 25 C. X X Visual appearance at t = 1 week 40 C. X X Visual appearance at t = 2 week 2-8 C. X X X Visual appearance at t = 2 week 25 C. X X Visual appearance at t = 2 week 40 C. X X single phase, X2 phases.

(20) TABLE-US-00002 TABLE 2 Stability data for various ethanol:propylene glycol ratios. The term soluble indicates that no precipitates were observed. Composition, %, w/w Excipient Sample 7 Sample 8 Sample 9 Sample 10 Sample 11 Sample 12 Sample 13 Sample 14 Sample 15 Sample 16 Nicotine 0.0560 0.0560 0.0560 0.0560 0.0560 0.0560 Propylene 0.8000 0.8250 0.8500 0.8750 0.8000 0.8250 0.8500 0.8750 0.8500 0.4250 glycol Ethanol 0.9500 0.9500 0.9500 0.9500 0.9500 0.9500 0.9500 0.9500 0.9500 0.9500 Menthol 0.0050 0.0050 0.0050 0.0050 0.0050 0.0050 0.0050 0.0050 0.0500 0.0500 Saccharin 0.0400 0.0400 0.0400 0.0400 0.0400 0.0400 0.0400 0.0400 0.0058 0.0058 HFA 134a 98.1600 98.1350 98.1100 98.0850 98.1040 98.0790 98.0540 98.0290 98.0882 98.5132 Total 100.0000 100.0000 100.0000 100.0000 100.0000 100.0000 100.0000 100.0000 100.0000 100.0000 Eth:PG 1.19 1.15 1.12 1.09 1.19 1.15 1.12 1.09 1.12 2.24 Appearance Soluble Soluble Soluble Soluble Soluble Soluble Soluble Soluble Soluble Soluble
Droplet Size Profile

(21) The following composition was prepared: 0.04% w/w menthol, 0.006% w/w saccharin, 0.34% w/w propylene glycol, 0.95% w/w ethanol, 0.056% w/w nicotine, and remainder HFA-134a.

(22) The composition was inserted into nine pinch 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 3 below:

(23) TABLE-US-00003 TABLE 3 Droplet size profile. MEAN SD Dv 10 (m) 0.198758 0.010005 Dv 50 (m) 0.606342 0.094779 Dv 90 (m) 2.806378 1.063722 % vol <10 m 99.02222 0.77704
Impurities

(24) The following composition was prepared: 0.04% w/w menthol, 0.0032% w/w saccharin, 0.34% w/w propylene glycol and 0.95% w/w ethanol, 0.028% w/w nicotine, remainder HFA-134a.

(25) The composition was then inserted into a pressurised container. The percentage volume of impurities with respect to nicotine concentration was assessed chromatographically at both the time of fill and after six months. The results are set out in Table 4 below:

(26) TABLE-US-00004 TABLE 4 Stability data (inverted, 40 C./75% RH). N = 1, 2 and 3 refer to different pressurised containers from the same batch of composition. T = 6 months Impurity Initial N = 1 N = 2 N = 3 Anatabine 0.02% 0.1% 0.1% 0.1% -nicotyrine Not detected 0.2% 0.2% 0.2% Cotinine Not detected 0.2% 0.2% 0.2% Myosmine 0.02% 0.2% 0.2% 0.2% Nicotine-n-oxide Not detected 0.3% 0.3% 0.3% Nornicotine Not detected 0.1% 0.1% 0.1% Anabasine Not detected Not Not Not detected detected detected
Clinical Study

(27) This was a three-part study to determine the safety, tolerability and pharmacokinetics of orally inhaled nicotine via the Pinch valve simulated cigarette, which contained compositions according to the first aspect of the present invention.

(28) The following compositions were studied:

(29) (1) High nicotine: 0.04% w/w menthol, 0.0096% w/w saccharin, 0.34% w/w, propylene glycol, 0.95% w/w ethanol, 0.084% w/w nicotine and 98.5764% w/w HFA-134a.

(30) (2) Medium nicotine: 0.04% w/w menthol, 0.0063% w/w saccharin, 0.34% w/w propylene glycol, 0.95% w/w ethanol, 0.056% w/w nicotine and 98.6077 HFA-134a.

(31) (3) Low nicotine: 0.04% w/w menthol, 0.0032% w/w saccharin, 0.34% w/w propylene glycol, 0.95% w/w ethanol, 0.028% w/w nicotine and 98.6388% w/w HFA-134a.

(32) Part A was to assess the safety, tolerability and arterial pharmacokinetics of a single dose of orally inhaled nicotine composition via the Pinch valve simulated cigarette at the three dose levels. Part B was to assess the venous pharmacokinetics of a single dose of orally inhaled nicotine via the Pinch valve simulated cigarette. Part C was to assess the safety, tolerability and pharmacokinetics of repeat doses of orally inhaled nicotine via the Pinch valve simulated cigarette.

(33) This study was performed on male and female participants who had smoked at least ten manufactured cigarettes per day for the last year. The study was conducted in one centre in Perth, Australia, and was performed in healthy volunteers.

(34) Screening evaluations were conducted up to six weeks prior to anticipated study dosing and eligible participants enrolled in the study were re-assessed for continued study appropriateness prior to planned study dosing on Day 1. Any enrolled participants who were discontinued prior to study dosing were replaced.

(35) A minimum of sixty (60) healthy volunteers were planned for enrolment over the three parts of the study. Participants were not able to participate in more than one part of the study.

(36) Part A: This was a single blind, randomised, multi dose-level study to evaluate the tolerability and arterial pharmacokinetics of orally inhaled nicotine via the Pinch valve simulated cigarette at three doses of nicotine 0.028% w/w (low), 0.056% w/w (medium) and 0.084% w/w (high). Arterial blood sampling was required for this part of the study to investigate the rapidity of delivery to the systemic circulation. Eighteen (18) participants were enrolled into treatment group A, and were randomised to receive 2 of 3 dose levels via the Pinch valve simulated cigarette on a single study day. The nicotine dose levels were 0.028% w/w (low), 0.056% w/w (medium) and 0.084% (high).

(37) The eighteen (18) participants were randomized into three groups with each containing six participants. One group received the low nicotine dose followed by the medium nicotine dose; one group received the low nicotine dose followed by the high nicotine dose; and one group received the medium nicotine dose followed by the high nicotine dose. The first dosing took place at approximately 8 am, and the second at approximately 1.30 pm. This was to ensure that circulating nicotine concentrations from the first dose had reached baseline levels through excretion before the second dose was inhaled. Participants were blinded to the dose level of the orally inhaled nicotine via Pinch valve simulated cigarette they were to be receiving.

(38) At the end of Part A, the pharmacokinetics, safety and tolerability data obtained from Part A were reviewed to determine which two of the three dose levels studied were to be used in Part B.

(39) Part B: This was an open label/single blind, randomised, 3-way crossover study to evaluate the venous pharmacokinetics of two dose levels of orally inhaled nicotine via the Pinch valve simulated cigarette. Participants were blinded to the nicotine dose level of the Pinch valve simulated cigarette they received.

(40) Twenty four (24) participants were enrolled into treatment group B. Each participant attended the clinical trial unit confined for three consecutive days to receive one complete refill of Pinch valve simulated cigarette at one nicotine dose level on one day, one complete refill of Pinch valve simulated cigarette at a second nicotine dose level on a second day and one treatment of a conventional nicotine Inhaler (10 mg) on a third day. The order in which treatment was to be received was randomised.

(41) At the end of Part B, the pharmacokinetics, safety and tolerability data obtained from Parts A and B were reviewed to determine which one of the two dose levels studied was to be used in Part C.

(42) Part C: This was an open label study to evaluate the tolerability and venous pharmacokinetics of repeat doses of orally inhaled nicotine via the Pinch valve simulated cigarette at one dose level of nicotine.

(43) Eighteen (18) participants were enrolled into treatment group C. Each participant received repeat doses of nicotine over the period of one day. All participants received the same dose of nicotine via the Pinch valve simulated cigarette. One complete refill of Pinch valve simulated cigarette was inhaled every hour for 12 hours. The first dosing took place at approximately 8 am.

(44) Study Population:

(45) TABLE-US-00005 TABLE 5 Study population. Part A Part B Part C Parameter Statistic (N = 18) (N = 24) (N = 18) Gender Male n (%) 10 14 13 Female n (%) 8 10 5 Age (Years) N 18 24 18 Mean 33.7 28.6 32.7 SD 9.2 7.9 9.1 Median 35.0 26.0 32.0 Min 21 21 21 Max 53 53 52 Race Asian n (%) 1 3 2 Caucasian n (%) 17 20 16 Other: Mixed race n (%) 1
Pharmacokinetic Data:

(46) Pharmacokinetic data are illustrated in FIG. 1 and are listed in Table 6. From FIG. 1 it can be seen that the arterial sampling times were sufficient to clearly define the pharmacokinetic profile and in particular to define the plasma nicotine C.sub.max. All timings are taken from the start of inhalation which took approximately 2 minutes to complete. The first sampling time point at +2 minutes already reveals uptake of nicotine into arterial blood. For example for the 0.056% w/w strength the mean arterial nicotine concentration had risen from zero pre-dose to 2.06 ng/ml at 2 minutes, i.e. already at more than half the eventual C.sub.max. From this it can be inferred that plasma nicotine was rising rapidly during the process of inhalation. The mean maximum nicotine concentrations were 2.11, 3.73 and 4.38 ng/ml at the low, medium and high strengths respectively and the corresponding t.sub.max were 10.2, 7.3 and 6.5 minutes after the start of inhalation.

(47) The generation of arterial pharmacokinetic data is not without some technical difficulties in terms of vascular access but in this part of the study the arterial data is valuable in demonstrating the rapidity with which nicotine reaches the arterial circulation. Since the composition is inhaled orally, one conclusion that follows is that this speed of nicotine delivery indicates that there is a degree of pulmonary delivery since oromucosal delivery, such as that provided by a conventional nicotine inhalator, is very much slower.

(48) TABLE-US-00006 TABLE 6 Pharmacokinetic data (arterial concentration). AUC.sub.all refers to area under the curve. AUC.sub.all C.sub.max (ng/mL) t.sub.max (min) (min * ng/ml) Std Std Std Treatment Mean Dev Mean Dev Mean Dev 0.028% w/w 2.113 0.671 10.2 3.9 145.7 132.5 nicotine (low) 0.056% w/w 3.733 1.131 7.3 1.6 274.4 146.5 nicotine (medium) 0.084% w/w 4.380 1.186 6.5 1.9 334.4 124.2 nicotine (high)
Pharmacodynamic Data:

(49) The Pharmacodynamic measurements included in all four parts of the study are repeated assessments of craving using a visual analogue scale (VAS) and the Brief Questionnaire of Smoking Urges (QSU-B). The pharmacodynamic data based on VAS are shown in FIG. 2.

(50) The inhalation of a nicotine aerosol from the pinch valve simulated cigarette has a clear effect of reducing craving, which is apparent in all four parts of the study. In Part A, craving fell rapidly on inhalation and then gradually returned towards baseline over the next 5 hours. No statistical testing was performed on part A but the pattern of response is consistent across all 3 nicotine dose strengths.

(51) It is notable that there was not a clear dose response relationship for craving in Part A and this perhaps reflects the importance of the hand to mouth ritual of smoking and the throat catch as well as the pharmacological effect of the rise in circulating nicotine concentrations. The QSU-B showed a consistent pattern to the craving VAS with component and total scores at their lowest 40 minutes post-dose for the low dose (0.028% w/w), and 20 minutes post-dose for the medium (0.056% w/w) and high (0.084% w/w) doses. This suggests that although the low dose has a positive effect on smoking urges, it takes longer to do so than the medium and high doses.

(52) Arterial vs Venous Plots:

(53) FIGS. 3 and 4 show plots of arterial and venous nicotine concentrations experienced by users of the high strength and medium strength compositions. These plots indicate the speed at which nicotine reaches the arterial circulation. Since the composition is inhaled orally, the speed of nicotine delivery is consistent with a degree of pulmonary delivery. Oromucosal delivery, such as that provided by commercially-available inhalers, is very much slower.

(54) Tolerability

(55) All adverse events were categorized as mild or moderate, there were no adverse events reported as severe. There were no significant adverse events (AE) or deaths throughout the study, and no participants discontinued treatment due to an AE.

(56) Paraesthesia oral was by far the most frequently reported treatment-emergent adverse event (TEAE) that was reported in all parts of the study, with an overall of 40 participants (68%) reporting paraesthesia oral at least once. Seventeen (17) of the 59 participants (29%) reported throat irritation, 9 participants (15%) reported headache, 8 participants (14%) reported hypoaesthesia oral, and 6 participants (10%) reported dizziness as a related TEAE. The remaining TEAEs occurred in less than 10% of the overall patient population.

(57) A summary of the results is set out in Table 7 below.

(58) TABLE-US-00007 TABLE 7 Adverse events logged Part A Part B Part C Study Total Total Total Total Adverse Event (N = 18) (N = 23) (N = 18) (N = 59) Paraesthesia oral 12 14 14 40 Throat irritation 3 8 6 17 Headache 3 1 5 9 Hypoaesthesia oral 2 4 2 8 Dizziness 3 2 1 6 Oral discomfort 2 1 2 5 Dry throat 3 3 Glossodynia 1 1 1 3 Lip pain 1 2 3 Nausea 1 2 3 Chest discomfort 1 2 3 Cough 3 3

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