Inhalable formulation

Abstract

This disclosure relates to an inhalable formulation comprising melatonin and, optionally, a cannabinoid. Furthermore, this disclosure relates to a metered dose inhaler containing the inhalable formulation and methods and uses of the inhalable formulation.

Description

Inhalable FormulationTechnical Field

[0001] This disclosure relates to an inhalable formulation comprising melatonin and, optionally, a cannabinoid. Furthermore, this disclosure relates to a metered dose inhaler containing the inhalable formulation and methods and uses of the inhalable formulation.Background

[0002] Melatonin, secreted by the pineal gland, is an important hormone involved in the regulation of the circadian rhythm, including sleep-wake timing, blood pressure regulation, seasonal reproduction and others. Melatonin has been shown to modify immunity, the stress response, and certain aspects of the aging process. Melatonin has further been found to have antioxidant properties which may be of potential use for conditions in which oxidative stress is involved in the pathophysiologic processes. The multiplicity of actions and variety of biological effects of melatonin suggest the potential for a range of clinical and wellness-enhancing uses, especially considering that melatonin production steadily decreases with ageing and certain medical conditions, such as cardiovascular and neurodegenerative diseases.

[0003] The average melatonin profile shows an evening rise between around 8 pm and midnight, reaches peak values between around 2 am and 4 am and then drops to low daytime levels. Circulating nocturnal levels of melatonin are commonly 10 to 20 times higher than concentrations measured during the day. When this natural circadian rhythm is disrupted, for example in people suffering from chronic insomnia, jet lag or shift workers and in elderly subjects with low natural melatonin levels, several studies suggest that night-time melatonin administration can help induce sleep. Melatonin has been successfully used to enhance sleep processes in elderly individuals with insomnia and in individuals with restless leg syndrome, REM sleep disorder behaviour, delayed sleep phase syndrome, manic patients with insomnia and in patients with fibromyalgia.

[0004] Melatonin supplements are mostly available for oral administration, such as tablets, capsules, liquid, lozenges, sublingual tablets, tea and timed release tablets. However, as with most oral preparations, it can take more than 30 minutes afteradministration for the blood plasma concentration of melatonin to reach its peak. This is due, in part, to the need for gastrointestinal absorption to occur before the melatonin is available in the bloodstream. Further, melatonin's oral bioavailability is poor and erratic. Melatonin's absolute oral bioavailability has been shown to be approximately 15% and peak plasma concentrations can vary over a 20 fold range (DeMuro R L, Nafziger A N, Blask D E, Menhinick A M, Bertino J S: Journal of Clinical Pharmacology 2000: 40; 781; Di W L, Kadva A, Johnston A, Silman R: New England Journal of Medicine 1997: 336; vol. 14, 1028). Because of the low bioavailability of melatonin, oral formulations require high amounts of melatonin of up to 5 mg per dose. Thus, oral administration of melatonin in currently available preparations does not provide for rapid onset of action, and its poor and erratic GI absorption make it a suboptimal route of administration. Accordingly, there is a need to provide a delivery method for melatonin that addresses these shortcomings or which at least provides a useful commercial alternative.Summary

[0005] In a first aspect, the disclosure resides in an inhalable formulation comprising: melatonin; a Ci to Ce alcohol; and a propellent which is traw -l,3,3,3-tetrafhioroprop-l-ene (HFO 1234ze).

[0006] In a second aspect, the disclosure resides in a metered dose inhaler comprising an inhalable formulation, the inhalable formulation comprising: melatonin; a Ci to Ce alcohol; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).

[0007] In embodiments of the first and second aspect, the melatonin may be present at between about 0.01% w / w and about 0.5% w / w, or about 0.01% w / w and about 0.4% w / w, or about 0.01% w / w and about 0.3% w / w, or about 0.01% w / w and about 0.2% w / w, or 0.01% w / w and about 0.15% w / w, or between about 0.01% w / w and about 0.1% w / w, or at between about 0.025% w / w and about 0.1% w / w of the formulation.

[0008] In embodiments of the first and second aspect, the melatonin may be present at between about 5 pg / 50 pL w / v and about 250 pg / 50 pL w / v, or between about 5 pg / 50pL w / v and about 200 pg / 50 pL w / v, or between about 5 pg / 50 pL w / v and about 150 pg / 50 pL w / v, or between about 5 pg / 50 pL w / v and about 100 pg / 50 pL w / v, or between about 10 pg / 50 pL w / v and about 250 pg / 50 pL w / v, or between about 10 pg / 50 pL w / v and about 200 pg / 50 pL w / v, or between about 10 pg / 50 pL w / v and about 150 pg / 50 pL w / v, or between about 10 pg / 50 pL w / v and about 100 pg / 50 pL w / v of the formulation.

[0009] In embodiments of the first and second aspects, the propellant may be present at an amount of at least 50% w / w, 55% w / w, 60% w / w, 65% w / w, 70% w / w, 75% w / w, 80% w / w, 85% w / w, or 90% w / w, or 95% w / w of the entire formulation.

[0010] In embodiments, the Ci to Ce alcohol may be present at between l%-20% w / w, or between 1%-19% w / w, or between 1%-18% w / w, or between 1%-17% w / w, or between 1%- 16% w / w, or between 1%- 15% w / w, or between 1%- 14% w / w, or between 1%-13% w / w, or between 1%-12% w / w, or between 1%-11% w / w, or between l%-10% w / w, or between 2%-20% w / w, or between 2%-19% w / w, or between 2%-l 8% w / w, or between 2%-17% w / w, or between 2%-16% w / w, or between 2%-15% w / w of the formulation.

[0011] In embodiments, the Ci to Ce alcohol may be present at between 1%- 10% w / w, or between l%-8% w / w, or between l%-7% w / w, or between l%-6% w / w, or between l%-5% w / w.

[0012] In an embodiment, the Ci to Ce alcohol may be present at around 5% w / w.

[0013] In embodiments, the Ci to Ce alcohol may be selected from a Ci to C4 alcohol, a C2 to C4 alcohol, and a C2 or C3 alcohol.

[0014] In an embodiment, the Ci to Ce alcohol may be ethanol.

[0015] In embodiments of the first and second aspect, the inhalable formulation may be an inhalable solution.

[0016] In certain embodiments of the first and second aspect, the melatonin may be the only non-volatile component of the inhalable formulation or may be the only biologically active agent (in terms of treatment of sleep-related disorders) in the inhalable formulation or is the only component of the formulation which is a solid (when not dissolved or otherwise in any formulation or mixture) at room temperature.

[0017] In alternative embodiments of the first and second aspect, the inhalable formulation may further comprise one or more cannabinoids.

[0018] In embodiments, the one or more cannabinoids may be selected from the group consisting of anandamide, 2-arachidonoylglycerol, cannabichromene (CBC), cannabichromenic acid (CBCA), cannabichormevarin (CBCV), cannabichromevarinic acid (CBCVA), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabielsoin (CBE), cannabicyclol (CBL), cannabinodiol (CBND), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerovarin (CBGV), cannabigerovarinic acid (CBGVA), cannabinol (CBN), cannabinolic acid (CBNA), cannabitriol (CBT), delta-8-tetrahydrocanninol, deleta-8- tetrahydrocannabinolic acid, delta-9-tetrahydrocannabinol (THC; dronabinol), delta-9- tetrahydrocannabinolic acid (THCA), delta-9-tetrahydrocannabivarin (THCV), delta-9- tetrahydrocannabivarinic acid (THCVA), 1 l-nor-9-carboxy-delta-9- tetrahydrocannabinol (THCCOOCH), 1 l-nor-9-carboxy-delta-8-tetrahydrocannabinol, 1 l-hydroxy-delta-8-tetrahydrocannabinol, and 1 l-hydroxy-delta-9- tetrahydrocannabinol, dimethyl heptylpentyl cannabidiol (DMHP-CBD), 6,12-dihydro- 6-hydroxy-cannabidiol, (3 S,4R)-7-hydroxy-.DELTA.6-tetrahydrocannabinol homologs and derivatives, (+)-4-[4-DMH-2,6-diacetoxy-phenyl]-2-carboxy-6,6- dimethylbicyclo[3.1.1]he- pt-2-en, and other 4-phenylpinene derivatives, and cannabidiol (-)(CBD) analogs such as (-)CBD-monomethylether, (-)CBD dimethyl ether; (-)CBD diacetate; (-)3'-acetyl-CBD monoacetate, cannabinol propyl variant (CBNV), and nabilone.

[0019] In an embodiment, the one or more cannabinoids may be cannabidiol (CBD) or dronabinol.

[0020] In an embodiment, the one or more cannabinoids may be cannabidiol (CBD) and dronabinol.

[0021] In embodiments, the one or more cannabinoids may be present in a total amount at between about 0.1% w / w and about 4.0% w / w, or between about 0.1% w / w and about 3.5% w / w, or between about 0.1% w / w and about 3.0% w / w, or between about 0.1% w / w and about 2.5% w / w, or between about 0.1% w / w and about 2.0% w / w, or between about 0.1% w / w and about 1.5% w / w, or between about 0.1% w / w and about 1.0% w / w, or at between about 0.1% w / w and about 0.9% w / w, or at between about 0.1% w / w and about 0.8% w / w of the formulation.

[0022] In embodiments, the one or more cannabinoids are present in a total amount at between about 0.2% w / w and about 4.0% w / w, or between about 0.2% w / w and about 3.5% w / w, or between about 0.2% w / w and about 3.0% w / w, or between about 0.2% w / w and about 2.5% w / w, or between about 0.2% w / w and about 2.0% w / w, or between about 0.2% w / w and about 1.5% w / w, or between about 0.2% w / w and about 1.0% w / w, or at between about 0.2% w / w and about 0.9% w / w, or at between about 0.2% w / w and about 0.8% w / w of the formulation.

[0023] In embodiments, the one or more cannabinoids are present in a total amount at between about 50 pg / 50 pL w / v and about 2000 pg / 50 pL w / v, or at between about 100 pg / 50 pL w / v and about 2000 pg / 50 pL w / v, or at between about 150 pg / 50 pL w / v and about 2000 pg / 50 pL w / w, or at between about 200 pg / 50 pL w / v and about 2000 pg / 50 pL w / v, or at between about 50 pg / 50 pL w / v and about 1500 pg / 50 pL w / v, or at between about 100 pg / 50 pL w / v and about 1500 pg / 50 pL w / v, or at between about 150 pg / 50 pL w / v and about 1500 pg / 50 pL w / v, or at between about 200 pg / 50 pL w / v and about 1500 pg / 50 pL w / v, or at between about 50 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or at between about 100 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or at between about 150 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or at between about 200 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or at between about 50 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or atbetween about 100 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or at between about 150 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or at between about 200 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or between about 50 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or atbetween about 100 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or atbetween about 150 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or at between about 200 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or between about 50 pg / 50 pL w / v and about 700 pg / 50 pL w / v, or atbetween about 100 pg / 50 pL w / v and about 700 pg / 50 pL w / v, or atbetween about 150 pg / 50 pL w / v and about 700 pg / 50 pL w / v, or at between about 200 pg / 50 pL w / v and about 700 pg / 50 pL w / v, or between about 50 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or atbetween about 100 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or atbetween about 150 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or at between about 200 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or between about 50 pg / 50 pL w / v and about 500 pg / 50 pL w / v, or atbetween about 100 pg / 50 pL w / v and about 500 pg / 50 pL w / v, or atbetweenabout 150 pg / 50 pL w / v and about 500 pg / 50 pL w / v, or at between about 200 pg / 50 pL w / v and about 500 pg / 50 pL w / v, or at between about 50 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 100 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 150 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 200 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 50 pg / 50 pL w / v and about 350 pg / 50 pL w / v, or at between about 100 pg / 50 pL w / v and about 350 pg / 50 pL w / v, or at between about 150 pg / 50 pL w / v and about 350 pg / 50 pL w / v, or at between about 200 pg / 50 pL w / v and about 350 pg / 50 pL w / v of the formulation.

[0024] In embodiments of the first and second aspects, the inhalable formulation provides for a fine particle fraction of greater than 40%, or greater than 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%. The fine particle fraction may be measured under standard industry conditions and / or as described in the Examples section.

[0025] In embodiments of the first and second aspects, the inhalable formulation may comprise, consist of or consist essentially of : melatonin; a Ci to Ce alcohol; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (UFO 1234ze); and, optionally, one or more cannabinoids, optionally one of delta-9-tetrahydrocannabinol (THC; dronabinol) and / or cannabidiol (CBD).

[0026] In embodiments of the first and second aspects, the total mass of melatonin and any one or more cannabinoids per 50 pL metered dose of the formulation may be less than 1 mg, optionally less than 900 pg, or less than 800 pg, or less than 700 pg, or less than 600 pg, or less than 500 pg, or less than 450 pg.

[0027] In embodiments of the first and second aspects, the inhalable formulation, optionally an inhalable solution, may consist of or consist essentially of : melatonin, optionally present at between about 0.025% w / w and about 0.1% w / w of the formulation; a Ci to Ce alcohol, optionally ethanol, optionally present at between about 2% and about 20% w / w of the formulation; anda propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).

[0028] In embodiments of the first and second aspects, the inhalable formulation, optionally an inhalable solution, may consist of or consist essentially of: melatonin, optionally present at between about 0.025% w / w and about 0.1% w / w of the formulation; a Ci to Ce alcohol, optionally ethanol, optionally present at between about 2% and about 20% w / w of the formulation; one or more cannabinoids, optionally present at between about 0.2% w / w and about 0.8% w / w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).

[0029] In embodiments of the first and second aspects, the inhalable formulation, optionally an inhalable solution, may consist of or consist essentially of : melatonin, optionally present at between about 0.025% w / w and about 0.1% w / w of the formulation; a Ci to Ce alcohol, optionally ethanol, optionally present at between about 2% and about 20% w / w of the formulation; cannabidiol (CBD), optionally present at between about 0.2% w / w and about 0.8% w / w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).

[0030] In embodiments of the first and second aspects, the inhalable formulation, optionally an inhalable solution, may consist of or consist essentially of : melatonin, optionally present at between about 0.025% w / w and about 0.1% w / w of the formulation; a Ci to Ce alcohol, optionally ethanol, optionally present at between about 2% and about 20% w / w of the formulation; dronabinol, optionally present at between about 0.2% w / w and about 0.8% w / w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).

[0031] In embodiments of the first and second aspects, the inhalable formulation, optionally an inhalable solution, may consist of or consist essentially of :melatonin, optionally present at between about 0.025% w / w and about 0.1% w / w of the formulation; a Ci to Ce alcohol, optionally ethanol, optionally present at between about 2% and about 20% w / w of the formulation; dronabinol and cannabidiol (CBD), optionally present at a combined amount of between about 0.2% w / w and about 0.8% w / w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).

[0032] In a third aspect, the disclosure resides in a method of delivering melatonin to a subject including the steps of: providing the inhalable formulation of the first aspect; and allowing the subject to inhale the inhalable formulation, to thereby deliver the melatonin to the subject.

[0033] In embodiments of the third aspect, the inhalable formulation of the first aspect may be delivered to the subject by activation of a metered dose inhaler, preferably the metered dose inhaler of the second aspect.

[0034] In embodiments of the third aspect, the inhalable formulation may be delivered having a fine particle fraction of greater than 40%, or greater than 45%, or greater than 50%, or greater than 55%.

[0035] In embodiments of the third aspect, the inhalable formulation may be delivered having a fine particle dose of melatonin of between about 10 pg and about 35 pg from a 50 pL metered dose.

[0036] In a fourth aspect, the disclosure resides in a method of preventing or treating a disease, disorder or condition in a subject, comprising administering an effective amount of the inhalable formulation of the first aspect to the subject.

[0037] In a fifth aspect, the disclosure resides in a use of the inhalable formulation of the first aspect in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition.

[0038] In a sixth aspect, the disclosure resides in a use of the inhalable formulation of the first aspect for the treatment or prevention of a disease, disorder or condition.

[0039] In an seventh aspect, the disclosure resides in the inhalable formulation of the first aspect for use in the treatment or prevention of a disease, disorder or condition.

[0040] In embodiments of the fourth to seventh aspects, the disease, disorder or condition may be a sleep disorder.

[0041] In embodiments, the sleep disorder may involve difficulty falling asleep, remaining asleep, or excessive sleepiness.

[0042] In embodiments, the sleep disorder may be selected from the group consisting of insomnia; a circadian rhythm sleep disorder (CRSD), including jetlag and shift work sleep disorders; anxiety related sleep disorders; narcolepsy; bruxism; catathrenia; delayed sleep phase disorder (DSPD); fatal familial insomnia; hypopnea syndrome; idiopathic hypersomnia; Kleine-Levin syndrome; night terror; nocturia; parasomnias; periodic limb movements in sleep (PLMS); rapid eye movement sleep behavior disorder (RBD); restless legs syndrome (RLS); sleep apnoea; sleep paralysis; sleepwalking; somniphobia; hypersomnia; failure to wake-up feeling refreshed and rested or fatigue on waking; and related disorders.Brief Description of Drawings

[0043] FIG. 1 is a graphical representation of the drug delivery metrics determined by Next Generation Cascade Impactor (NGI) at 301 / min sampling flow rate for melatonin formulations with 25 pg melatonin. The formulations shown in FIG. 1 contained 25pg / 50pl melatonin, 5% EtOH, HFA134a (NGI-1153 &I 154) and 25pg / 50pl melatonin, 5% EtOH, HFO1234ze (NGI-1155&1156).

[0044] FIG. 2 is a graphical representation of the drug delivery metrics determined by Next Generation Cascade Impactor (NGI) at 301 / min sampling flow rate for melatonin formulations with 50 pg melatonin. The formulations shown in FIG. 2 contained 50pg / 50pl melatonin, 10% EtOH, HFA134a (NGI-1157&1158) and 50pg / 50pl melatonin, 10% EtOH, HFO1234ze (NGI-1159 and NGI-1160).

[0045] FIG. 3 shows the visual appearance of formulation 13; Packaged with Glass Bottles, Melatonin 50pg / 63pl, 5%w / w Ethanol, HFO 1234ze.

[0046] FIG. 4 shows Melatonin Delivered Dose and Metered Dose Through Can-Use Life; HFO1234ze: t = 0 months.

[0047] FIG. 5 shows Melatonin Delivered Dose and Metered Dose Through Can-Use Life; HFO1234ze: t = 3 months @40°C / 75RH.

[0048] FIG. 6 shows Melatonin Delivered Dose and Metered Dose Through Can-Use Life; HFO1234ze: t = 6 months @40°C / 75RH.

[0049] FIG. 7 shows Melatonin Delivered Dose and Metered Dose Through Can-Use Life; HFO1234ze: t = 6 months @25°C / 60RH.

[0050] FIG. 8 shows melatonin cumulative mass undersize (%), t=0, 3, and 6 months.

[0051] FIG. 9 shows tailing, t=0 months.

[0052] FIG. 10 shows tailing, t=6 months.

[0053] FIG. 11 shows Priming: Shot Weights for Doses 1 -5 (HFO1234ze); t = 0.Description of Embodiments

[0054] Definitions

[0055] It is to be understood that the formulation of the present invention comprising the components as described herein may, in another embodiment, consist of those components, or in another embodiment, consist essentially of those components. In some embodiments, the term “comprise” refers to the inclusion of the indicated components as well as the inclusion of other components, active agents, and pharmaceutically or physiologically acceptable carriers, excipients, emollients, stabilisers, etc., as are known in the industry. The term “consisting essentially of’ refers to a formulation whose only main components are the recited components and the formulation excludes all further components that will materially affect the essential characteristics of the formulation. However, other compounds may be included which are not involved directly in giving the formulation the desired characteristics of the formulation. The term “consisting of’, as used herein, means the formulation includes only the components specifically recited.

[0056] As used herein, the term “about” refers to a range of ± 10% of the specified value or a range associated with the experimental error known to the skilled addressee in measuring the specified value, whichever is the greater.

[0057] By “treat” or other forms of the word, such as “treated”, “treating”, or “treatment,” is meant to administer a composition or to perform a method in order to reduce or prevent a particular characteristic or event (e.g., sleep disorder). The term “control” is used synonymously with the term “treat.” To treat a sleep disorder, according to the methods described herein, the treatment does not necessarily provide therapy forthe underlying pathology that is causing the sleep disorder sensation. Treatment of a sleep disorder can be purely symptomatic. For example, treatment of a sleep disorder can include modifying or improving the sleep-wake cycle of a subject.

[0058] The terms “active agent” or “active pharmaceutical ingredient” or “API” are used interchangeably, and refer to a pharmacological agent that can act locally or systemically in the body. The term “active agent” includes agents that can be administered to a subject for the treatment or prevention of a disease, disorder or condition.

[0059] Most known melatonin supplements are delivered orally via tablets, lozenges, or as a liquid. Because of the poor bioavailability of melatonin, this delivery method provides for a number of disadvantages, such as slow drug onset - it can take more than 30 minutes after administration for the blood plasma concentration of melatonin to reach its peak - and high required amounts of melatonin per dose (of up to 5 mg). In contrast, when delivered to the lungs via inhalation, the inventors propose that melatonin will have a much faster onset and will demonstrate much better bioavailability. Because of that, the dose can be up to 20-fold reduced (in comparison to known products) while achieving the desired benefits.

[0060] Hence, the present disclosure describes how an inhalable formulation comprising melatonin can be uniquely tailored for delivery via a metered dose inhaler (MDI) to a subject’s lungs to treat a disease, disorder or condition responsive to melatonin. It has been surprisingly found that a simple formulation of melatonin, an alcohol and a propellant provides for a chemically stable composition (such as one in which the active(s) resist degradation for an extended commercially relevant period for storage and use), with useful particle size distribution characteristics and without the need for further excipients.

[0061] Surprisingly, the inhalable formulations described herein have demonstrated highly favourable fine particle fraction (FPF) and fine particle dose (FPD) thereby indicating that a relatively high proportion of the inhalable formulation, and entrained melatonin, is not just delivered but is delivered with an FPF indicating significant delivery to the subject’s lungs rather than deposition in the oropharynx. While the MDI itself may be manipulated to alter the FPF to some degree, it is typically at the expenseof FPD and so the combined FPF and FPD observed for the inhalable formulations herein is surprisingly advantageous. This outcome was unexpected from such a simple formulation and the efficiency of the dosing delivery allows for significantly lower amounts of melatonin to be formulated and delivered in a single dose.

[0062] Typically, FPFs for commercially available liquid inhalable formulations, such as Clenil, may be around 25-30% but the inhalable formulations described herein are significantly higher even at greater dosing levels. Particularly, even as the melatonin or combined melatonin and one or more cannabinoids approaches significant concentrations such as 1-2% w / w (this value being the combined level of non-volatile in the solution) a useful FPF and FPD profile may be maintained. The use of an alcohol, such as ethanol, surprisingly may be sufficient, even at the low relative amounts used, to maintain the levels of non-volatile in solution and avoid blockage of the MDI which would otherwise present significant challenges.

[0063] The approach described herein, in embodiments, requires only an alcohol such as ethanol and a propellant with no further stability or formulation agents required. This is a very surprising and favourable outcome as it has been found that a simple formulation of melatonin, an alcohol, such as ethanol, and a propellant exhibits excellent chemical stability over an extended storage time as demonstrated in the Examples. For instance, it has been found that the mean residual melatonin after 6 months of storage at 25 °C / 60% RH is greater than 95%.

[0064] The ability to deliver melatonin, and optionally one or more cannabinoids, via an MDI approach with the observed efficiency allows the dosing of active to be kept advantageously low compared with prior art approaches and so the likelihood of the subject detecting an unpleasant taste from the melatonin, and optionally one or more cannabinoids, is advantageously reduced. Further, melatonin, and optionally one or more cannabinoids, at higher levels can induce a cough reflex because of the irritation caused to the subject’s throat. The formulations described herein allow for this to be avoided or minimised based on the low levels of melatonin, and optionally one or more cannabinoids, required to be formulated due to the efficiency of delivery. Finally, as mentioned, delivery to the lungs is known to provide for a fast onset of action of various drugs. The delivery profile of FPF and FPD outlined herein will allow for rapid onset ofaction of the melatonin, and optionally one or more cannabinoids, and so almost immediate benefit to the subject.

[0065] In a first aspect, the disclosure resides in an inhalable formulation comprising: melatonin; a Ci to Ce alcohol; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).

[0066] In embodiments of the first aspect, the melatonin is present at between about 0.01% w / w and about 0.5% w / w, or between about 0.015% w / w and about 0.5% w / w, or at between about 0.02% w / w and about 0.5% w / w, or at between about 0.025% w / w and about 0.5% w / w, or at between about 0.03% w / w and about 0.5% w / w, or at between about 0.035% w / w and about 0.5% w / w, or at between about 0.04% w / w and about 0.5% w / w, or at between about 0.045% w / w and about 0.5% w / w, or at between about 0.05% w / w and about 0.5% w / w, or at between about 0.055% w / w and about 0.5% w / w, or at between about 0.06% w / w and about 0.5% w / w, or at between about 0.065% w / w and about 0.5% w / w, or at between about 0.07% w / w and about 0.5% w / w, or at between about 0.075% w / w and about 0.5% w / w, or at between about 0.08% w / w and about 0.5% w / w of the formulation.

[0067] In embodiments of the first aspect, the melatonin may be present at between about 0.01% w / w and about 0.4% w / w, or between about 0.015% w / w and about 0.4% w / w, or at between about 0.02% w / w and about 0.4% w / w, or at between about 0.025% w / w and about 0.4% w / w, or at between about 0.03% w / w and about 0.4% w / w, or at between about 0.035% w / w and about 0.4% w / w, or at between about 0.04% w / w and about 0.4% w / w, or at between about 0.045% w / w and about 0.4% w / w, or at between about 0.05% w / w and about 0.4% w / w, or at between about 0.055% w / w and about 0.4% w / w, or at between about 0.06% w / w and about 0.4% w / w, or at between about 0.065% w / w and about 0.4% w / w, or at between about 0.07% w / w and about 0.4% w / w, or at between about 0.075% w / w and about 0.4% w / w, or at between about 0.08% w / w and about 0.4% w / w of the formulation.

[0068] In embodiments of the first aspect, the melatonin may be present at between about 0.01% w / w and about 0.3% w / w, or between about 0.015% w / w and about 0.3% w / w, or at between about 0.02% w / w and about 0.3% w / w, or at between about 0.025%w / w and about 0.3% w / w, or at between about 0.03% w / w and about 0.3% w / w, or at between about 0.035% w / w and about 0.3% w / w, or at between about 0.04% w / w and about 0.3% w / w, or at between about 0.045% w / w and about 0.3% w / w, or at between about 0.05% w / w and about 0.3% w / w, or at between about 0.055% w / w and about 0.3% w / w, or at between about 0.06% w / w and about 0.3% w / w, or at between about 0.065% w / w and about 0.3% w / w, or at between about 0.07% w / w and about 0.3% w / w, or at between about 0.075% w / w and about 0.3% w / w, or at between about 0.08% w / w and about 0.3% w / w of the formulation.

[0069] In embodiments of the first aspect, the melatonin may be present at between about 0.01% w / w and about 0.2% w / w, or between about 0.015% w / w and about 0.2% w / w, or at between about 0.02% w / w and about 0.2% w / w, or at between about 0.025% w / w and about 0.2% w / w, or at between about 0.03% w / w and about 0.2% w / w, or at between about 0.035% w / w and about 0.2% w / w, or at between about 0.04% w / w and about 0.2% w / w, or at between about 0.045% w / w and about 0.2% w / w, or at between about 0.05% w / w and about 0.2% w / w, or at between about 0.055% w / w and about 0.2% w / w, or at between about 0.06% w / w and about 0.2% w / w, or at between about 0.065% w / w and about 0.2% w / w, or at between about 0.07% w / w and about 0.2% w / w, or at between about 0.075% w / w and about 0.2% w / w, or at between about 0.08% w / w and about 0.2% w / w of the formulation.

[0070] In embodiments of the first aspect, the melatonin may be present at between about 0.01% w / w and about 0.15% w / w, or between about 0.015% w / w and about 0.15% w / w, or at between about 0.02% w / w and about 0.15% w / w, or at between about 0.025% w / w and about 0.15% w / w, or at between about 0.03% w / w and about 0.15% w / w, or at between about 0.035% w / w and about 0.15% w / w, or at between about 0.04% w / w and about 0.15% w / w, or at between about 0.045% w / w and about 0.15% w / w, or at between about 0.05% w / w and about 0.15% w / w, or at between about 0.055% w / w and about 0.15% w / w, or at between about 0.06% w / w and about 0.15% w / w, or at between about 0.065% w / w and about 0.15% w / w, or at between about 0.07% w / w and about 0.15% w / w, or at between about 0.075% w / w and about 0.15% w / w, or at between about 0.08% w / w and about 0.15% w / w of the formulation.

[0071] In embodiments of the first aspect, the melatonin may be present at between about 0.01% w / w and about 0.1% w / w, or at between about 0.015% w / w and about 0.1% w / w, or at between about 0.02% w / w and about 0.1% w / w, or at between about 0.025% w / w and about 0.1% w / w, or at between about 0.03% w / w and about 0.1% w / w, or at between about 0.035% w / w and about 0.1% w / w, or at between about 0.04% w / w and about 0.1% w / w, or at between about 0.045% w / w and about 0.1% w / w, or at between about 0.05% w / w and about 0.1% w / w, or at between about 0.055% w / w and about 0.1% w / w, or at between about 0.06% w / w and about 0.1% w / w, or at between about 0.065% w / w and about 0.1% w / w, or at between about 0.07% w / w and about 0.1% w / w, or at between about 0.075% w / w and about 0.1% w / w, or at between about 0.08% w / w and about 0.1% w / w of the formulation.

[0072] As discussed above, an advantage of the present inhalable formulation is that much smaller amount of melatonin is needed to achieve the desired effects. While known products contain up to 5 mg of melatonin per dose, the present formulation may comprise as little as 25 pg or 50 pg of melatonin per 50 pL dose or 50 pg of melatonin per 63 pL dose, as demonstrated in the Examples.

[0073] In embodiments of the first aspect, the melatonin may be present at between about 5 pg / 50 pL w / v and about 250 pg / 50 pL w / v, or at between about 7 pg / 50 pL w / v and about 250 pg / 50 pL w / v, or at between about 10 pg / 50 pL w / v and about 250 pg / 50 pL w / v, or at between about 12 pg / 50 pL w / v and about 250 pg / 50 pL w / v, or at between about 15 pg / 50 pL w / v and about 250 pg / 50 pL w / v, or at between about 17 pg / 50 pL w / v and about 250 pg / 50 pL w / v, or at between about 20 pg / 50 pL w / v and about 250 pg / 50 pL w / v, or at between about 22 pg / 50 pL w / v and about 250 pg / 50 pL w / v, or at between about 25 pg / 50 pL w / v and about 250 pg / 50 pL w / v, or at between about 27 pg / 50 pL w / v and about 250 pg / 50 pL w / v, or at between about 30 pg / 50 pL w / v and about 250 pg / 50 pL w / v, or at between about 32 pg / 50 pL w / v and about 250 pg / 50 pL w / v, or at between about 35 pg / 50 pL w / v and about 250 pg / 50 pL w / v of the formulation.

[0074] In embodiments of the first aspect, the melatonin may be present at between about 5 pg / 50 pL w / v and about 200 pg / 50 pL w / v, or at between about 7 pg / 50 pL w / v and about 200 pg / 50 pL w / v, or at between about 10 pg / 50 pL w / v and about 200 pg / 50 pL w / v, or at between about 12 pg / 50 pL w / v and about 200 pg / 50 pL w / v, or at betweenabout 15 pg / 50 pL w / v and about 200 pg / 50 pL w / v, or at between about 17 pg / 50 pL w / v and about 200 pg / 50 pL w / v, or at between about 20 pg / 50 pL w / v and about 200 pg / 50 pL w / v, or at between about 22 pg / 50 pL w / v and about 200 pg / 50 pL w / v, or at between about 25 pg / 50 pL w / v and about 200 pg / 50 pL w / v, or at between about 27 pg / 50 pL w / v and about 200 pg / 50 pL w / v, or at between about 30 pg / 50 pL w / v and about 200 pg / 50 pL w / v, or at between about 32 pg / 50 pL w / v and about 200 pg / 50 pL w / v, or at between about 35 pg / 50 pL w / v and about 200 pg / 50 pL w / v of the formulation.

[0075] In embodiments of the first aspect, the melatonin may be present at between about 5 pg / 50 pL w / v and about 150 pg / 50 pL w / v, or at between about 7 pg / 50 pL w / v and about 150 pg / 50 pL w / v, or at between about 10 pg / 50 pL w / v and about 150 pg / 50 pL w / v, or at between about 12 pg / 50 pL w / v and about 150 pg / 50 pL w / v, or at between about 15 pg / 50 pL w / v and about 150 pg / 50 pL w / v, or at between about 17 pg / 50 pL w / v and about 150 pg / 50 pL w / v, or at between about 20 pg / 50 pL w / v and about 150 pg / 50 pL w / v, or at between about 22 pg / 50 pL w / v and about 150 pg / 50 pL w / v, or at between about 25 pg / 50 pL w / v and about 150 pg / 50 pL w / v, or at between about 27 pg / 50 pL w / v and about 150 pg / 50 pL w / v, or at between about 30 pg / 50 pL w / v and about 150 pg / 50 pL w / v, or at between about 32 pg / 50 pL w / v and about 150 pg / 50 pL w / v, or at between about 35 pg / 50 pL w / v and about 150 pg / 50 pL w / v of the formulation.

[0076] In embodiments of the first aspect, the melatonin may be present at between about 5 pg / 50 pL w / v and about 100 pg / 50 pL w / v, or at between about 7 pg / 50 pL w / v and about 100 pg / 50 pL w / v, or at between about 10 pg / 50 pL w / v and about 100 pg / 50 pL w / v, or at between about 12 pg / 50 pL w / v and about 100 pg / 50 pL w / v, or at between about 15 pg / 50 pL w / v and about 100 pg / 50 pL w / v, or at between about 17 pg / 50 pL w / v and about 100 pg / 50 pL w / v, or at between about 20 pg / 50 pL w / v and about 100 pg / 50 pL w / v, or at between about 22 pg / 50 pL w / v and about 100 pg / 50 pL w / v, or at between about 25 pg / 50 pL w / v and about 100 pg / 50 pL w / v, or at between about 27 pg / 50 pL w / v and about 100 pg / 50 pL w / v, or at between about 30 pg / 50 pL w / v and about 100 pg / 50 pL w / v, or at between about 32 pg / 50 pL w / v and about 100 pg / 50 pL w / v, or at between about 35 pg / 50 pL w / v and about 100 pg / 50 pL w / v of the formulation.

[0077] In embodiments of the first aspect, the melatonin may be present at between about 5 pg / 50 pL w / v and about 90 pg / 50 pL w / v, or at between about 7 pg / 50 pL w / vand about 90 pg / 50 pL w / v, or at between about 10 pg / 50 pL w / v and about 90 pg / 50 pL w / v, or at between about 12 pg / 50 pL w / v and about 90 pg / 50 pL w / v, or at between about 15 pg / 50 pL w / v and about 90 pg / 50 pL w / v, or at between about 17 pg / 50 pL w / v and about 90 pg / 50 pL w / v, or at between about 20 pg / 50 pL w / v and about 90 pg / 50 pL w / v, or at between about 22 pg / 50 pL w / v and about 90 pg / 50 pL w / v, or at between about 25 pg / 50 pL w / v and about 90 pg / 50 pL w / v, or at between about 27 pg / 50 pL w / v and about 90 pg / 50 pL w / v, or at between about 30 pg / 50 pL w / v and about 90 pg / 50 pL w / v, or at between about 32 pg / 50 pL w / v and about 90 pg / 50 pL w / v, or at between about 35 pg / 50 pL w / v and about 90 pg / 50 pL w / v of the formulation.

[0078] In embodiments of the first aspect, the melatonin may be present at between about 5 pg / 50 pL w / v and about 80 pg / 50 pL w / v, or at between about 7 pg / 50 pL w / v and about 80 pg / 50 pL w / v, or at between about 10 pg / 50 pL w / v and about 80 pg / 50 pL w / v, or at between about 12 pg / 50 pL w / v and about 80 pg / 50 pL w / v, or at between about 15 pg / 50 pL w / v and about 80 pg / 50 pL w / v, or at between about 17 pg / 50 pL w / v and about 80 pg / 50 pL w / v, or at between about 20 pg / 50 pL w / v and about 80 pg / 50 pL w / v, or at between about 22 pg / 50 pL w / v and about 80 pg / 50 pL w / v, or at between about 25 pg / 50 pL w / v and about 80 pg / 50 pL w / v, or at between about 27 pg / 50 pL w / v and about 80 pg / 50 pL w / v, or at between about 30 pg / 50 pL w / v and about 80 pg / 50 pL w / v, or at between about 32 pg / 50 pL w / v and about 80 pg / 50 pL w / v, or at between about 35 pg / 50 pL w / v and about 80 pg / 50 pL w / v of the formulation.

[0079] In embodiments of the first aspect, the melatonin may be present at between about 5 pg / 50 pL w / v and about 75 pg / 50 pL w / v, or at between about 7 pg / 50 pL w / v and about 75 pg / 50 pL w / v, or at between about 10 pg / 50 pL w / v and about 75 pg / 50 pL w / v, or at between about 12 pg / 50 pL w / v and about 75 pg / 50 pL w / v, or at between about 15 pg / 50 pL w / v and about 75 pg / 50 pL w / v, or at between about 17 pg / 50 pL w / v and about 75 pg / 50 pL w / v, or at between about 20 pg / 50 pL w / v and about 75 pg / 50 pL w / v, or at between about 22 pg / 50 pL w / v and about 75 pg / 50 pL w / v, or at between about 25 pg / 50 pL w / v and about 75 pg / 50 pL w / v, or at between about 27 pg / 50 pL w / v and about 75 pg / 50 pL w / v, or at between about 30 pg / 50 pL w / v and about 75 pg / 50 pL w / v, or at between about 32 pg / 50 pL w / v and about 75 pg / 50 pL w / v, or at between about 35 pg / 50 pL w / v and about 75 pg / 50 pL w / v of the formulation.

[0080] In embodiments of the first aspect, the melatonin may be present at between about 5 pg / 50 pL w / v and about 70 pg / 50 pL w / v, or at between about 7 pg / 50 pL w / v and about 70 pg / 50 pL w / v, or at between about 10 pg / 50 pL w / v and about 70 pg / 50 pL w / v, or at between about 12 pg / 50 pL w / v and about 70 pg / 50 pL w / v, or at between about 15 pg / 50 pL w / v and about 70 pg / 50 pL w / v, or at between about 17 pg / 50 pL w / v and about 70 pg / 50 pL w / v, or at between about 20 pg / 50 pL w / v and about 70 pg / 50 pL w / v, or at between about 22 pg / 50 pL w / v and about 70 pg / 50 pL w / v, or at between about 25 pg / 50 pL w / v and about 70 pg / 50 pL w / v, or at between about 27 pg / 50 pL w / v and about 70 pg / 50 pL w / v, or at between about 30 pg / 50 pL w / v and about 70 pg / 50 pL w / v, or at between about 32 pg / 50 pL w / v and about 70 pg / 50 pL w / v, or at between about 35 pg / 50 pL w / v and about 70 pg / 50 pL w / v of the formulation.

[0081] In embodiments of the first aspect, the melatonin may be present at between about 5 pg / 50 pL w / v and about 65 pg / 50 pL w / v, or at between about 7 pg / 50 pL w / v and about 65 pg / 50 pL w / v, or at between about 10 pg / 50 pL w / v and about 65 pg / 50 pL w / v, or at between about 12 pg / 50 pL w / v and about 65 pg / 50 pL w / v, or at between about 15 pg / 50 pL w / v and about 65 pg / 50 pL w / v, or at between about 17 pg / 50 pL w / v and about 65 pg / 50 pL w / v, or at between about 20 pg / 50 pL w / v and about 65 pg / 50 pL w / v, or at between about 22 pg / 50 pL w / v and about 65 pg / 50 pL w / v, or at between about 25 pg / 50 pL w / v and about 65 pg / 50 pL w / v, or at between about 27 pg / 50 pL w / v and about 65 pg / 50 pL w / v, or at between about 30 pg / 50 pL w / v and about 65 pg / 50 pL w / v, or at between about 32 pg / 50 pL w / v and about 65 pg / 50 pL w / v, or at between about 35 pg / 50 pL w / v and about 65 pg / 50 pL w / v of the formulation.

[0082] It will be appreciated by a person of skill in the art that while the exemplified embodiments describe a 50 pL dosing volume, other dosing volumes could be used. For example, the dosing volume may be any volume between about 25 to about 100 pL, optionally the dosing volume may be 25 pL, 61 pL, 63 pL and 100 pL. The person of skill in the art would know how to choose a suitable dosing volume for a particular application and based on body mass of the intended subject and the like.

[0083] It will be appreciated by a person of skill in the art that the unit dose of melatonin will be determined by the end application. For example, in the treatment of a shiftwork related sleep disorder or jetlag, using the inhalable formulation of the first aspect at adose of approximately 10 pg to 40 pg may be sufficient when appropriately delivered. For use in treating, for example, insomnia in an adult the required dose may be between about 30 pg to 70 pg. These factors along with typical therapeutic dosing considerations such as the subject’s age, weight and general health would be considered by a skilled formulator or physician and the dose selected accordingly.

[0084] The choice of the right propellant is essential to achieve an inhalable formulation with the desired properties. The propellant / ra / / .s- l ,3,3,3-tetratluoroprop- l - ene (HFO-1234ze) is a hydrofluoroolefm (HFO). It is used as an environmentally friendly alternative to traditional hydrofluoroalkane (HF A) propellants, such as HFA- 134a (1,1,1,2-tetrafhioroethane) and HFA-227ea (1,1,1,2,3,3,3-heptafhioropropane). The traditional propellants HFA-134a and HFA-227ea have been commonly used as propellants in various applications such as air conditioning, refrigeration, and aerosols. However, despite their widespread use, they have several disadvantages, primarily related to their environmental impact and safety concerns. Both HFA-134a and HFA- 227ea have significant Global Warming Potentials (GWP), -1300 and -3350, respectively, thereby contributing to climate change by trapping heat in the atmosphere. Although they do not deplete the ozone layer, their high GWP means they are still potent greenhouse gases. Because of that, they are slowly being phased out and replaced by other, more sustainable propellants.

[0085] HFO-1234ze, on the other hand, has desirable properties, such as a very low Global Warming Potential (GWP) of around 1, making it an attractive alternative to higher-GWP substances. Due to its low toxicity, it is safe to be used in personal care products and pharmaceuticals.

[0086] Another known hydrofluoroalkane propellant is HFA-152a (1,1- difluoroethane). While HFA-152a has a lower GWP than HFA-134a and HFA-227ea (approximately 138 compared to around 1300 and 3350, respectively), it still has a significantly higher GWP than HFO-1234ze, with a difference of two orders of magnitude. Consequently, HFO-1234ze may be a much more environmentally friendly option. Additionally, HFO-1234ze exhibits significantly reduced flammability under standard test conditions compared to HF Al 52a, making it safer to handle and store. In contrast, HFA-152a is flammable, necessitating additional safety measures duringmanufacturing. Therefore, HFO-1234ze may be a much better choice in terms of environmental impact, manufacturing and storage cost, and safety.

[0087] While HFO-1234ze demonstrates these desirable properties in regard to environmental concerns and toxicity and may be an attractive alternative, a person of skill in the art would understand that HFO-1234ze is structurally very different to the traditionally known hydrofluorocarbons HFA-134a and HFA-227ea and, because of that, a person of skill in the art would expect it to behave quite differently in formulations. Structurally, HFO-1234ze is an olefin (an unsaturated fluorocarbon) and has therefore different chemical properties than the commonly used saturated alkane propellants. For example, HFOs may have a different solubility profile than HF As due to them being less polar than HF As. This can influence their interaction with both hydrophobic and hydrophilic drugs, thereby affecting their ability to dissolve these drugs. Additionally, the carbon-carbon double bond usually makes formulations comprising HFOs more reactive and generally less chemically stable than formulations comprising HF As, thereby affecting their ability to maintain a stable solution for pharmaceutical formulations. It is therefore very surprising and unexpected that it was found that the simple formulations of the present invention comprising only an alcohol, such as ethanol, and a propellant, would allow not only dissolution of the melatonin in the desired quantities (HFO-1234ze commonly forms suspensions over solutions) but also would demonstrate the observed excellent stability profile over an extended period of time without the need to add further stabilisers to the formulation.

[0088] In embodiments of the first aspect, the propellant may be present at an amount of at least 50% w / w, 55% w / w, 60% w / w, 65% w / w, 70% w / w, 75% w / w, 80% w / w, or 85% w / w, or 90% w / w, or 95% w / w of the entire formulation.

[0089] In embodiments, the Ci to Ce alcohol may be present at between l%-20% w / w, or between 1%-19% w / w, or between 1%-18% w / w, or between 1%-17% w / w, or between 1%- 16% w / w, or between 1%- 15% w / w, or between 1%- 14% w / w, or between 1%-13% w / w, or between 1%-12% w / w, or between 1%-11% w / w, or between l%-10% w / w, or between 2%-20% w / w, or between 2%-19% w / w, or between 2%-l 8% w / w, or between 2%-17% w / w, or between 2%-16% w / w, or between 2%- 15% w / w, or between 2%-14% w / w, or between 2%- 13% w / w, or between 2%-12% w / w, or between 2%-l 1%w / w, or between 2%-10% w / w, or between 3%-20% w / w, or between 3%- 19% w / w, or between 3%- 18% w / w, or between 3%- 17% w / w, or between 3%- 16% w / w, or between 3%- 15% w / w, or between 3%-14% w / w, or between 3%-l 3% w / w, or between 3%-12% w / w, or between 3%-l 1% w / w, or between 3%- 10% w / w, or between 4%-20% w / w, or between 4%-19% w / w, or between 4%- 18% w / w, or between 4%-17% w / w, or between 4%-16% w / w, or between 4%-l 5% w / w, or between 4%-14% w / w, or between 4%-l 3% w / w, or between 4%-12% w / w, or between 4%-l 1% w / w, or between 4%-10% w / w, or between 5%-20% w / w, or between 5%- 19% w / w, or between 5%- 18% w / w, or between 5%-17% w / w, or between 5%-16% w / w, or between 5%-15% w / w, or between 5%-14% w / w, or between 5%- 13% w / w, or between 5%- 12% w / w, or between 5%-l 1% w / w, or between 5%-10% w / w of the formulation. In an embodiment, the Ci to Ce alcohol may be present at less than 10% w / w, or 9% w / w, or 8% w / w, or 7% w / w, or 6% w / w, or 5% w / w of the formulation. In a preferred embodiment, the Ci to Ce alcohol may be present at about 5% w / w of the formulation.

[0090] In embodiments, the Ci to Ce alcohol may be selected from a Ci to C4 alcohol, a C2 to C4 alcohol, and a C2 or C3 alcohol.

[0091] In a preferred embodiment, the Ci to Ce alcohol may be ethanol. In an even more preferred embodiment, the Ci to Ce alcohol may be ethanol and may be present at about 5% w / w of the formulation.

[0092] In embodiments of the first and second aspect, the inhalable formulation may be an inhalable solution.

[0093] In certain embodiments of the first and second aspect, the melatonin may be the only non-volatile component of the inhalable formulation or may be the only biologically active agent (in terms of treatment of sleep-related disorders) in the inhalable formulation or may be the only component of the formulation which is a solid (when not dissolved or otherwise in any formulation or mixture) at room temperature.

[0094] In instances, it may be beneficial to co-administer melatonin with a cannabinoid. This may be especially useful when the sleep disorder is related to a mental health disorder, such as anxiety, depression, a mood disorder, psychosis and other related conditions. It is an advantage of the present solution formulation approach that one or more cannabinoids can be formulated with melatonin and still provide for a desired FPFand FPD profile. Due to the solution-based formulation this means that when the formulation is delivered to a subject’s lungs each particle comprises similar levels of melatonin and cannabinoid allowing for a synergistic effect on delivery. Different approaches, such as a suspension / emulsion for example, would likely result in an uneven distribution of each of the melatonin and cannabinoid(s) within individual particles. Such approaches would also likely be unable to achieve the FPF delivery profile seen with the present inhalable formulation. The simple active(s) with ethanol and propellant formulation approach described herein therefore provides for significant advantages in operation.

[0095] Hence, in embodiments of the first and second aspect, the inhalable formulation may comprise one or more cannabinoids.

[0096] In embodiments, the one or more cannabinoids may be selected from the group consisting of anandamide, 2-arachidonoylglycerol, cannabichromene (CBC), cannabichromenic acid (CBCA), cannabichormevarin (CBCV), cannabichromevarinic acid (CBCVA), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabielsoin (CBE), cannabicyclol (CBL), cannabinodiol (CBND), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerovarin (CBGV), cannabigerovarinic acid (CBGVA), cannabinol (CBN), cannabinolic acid (CBNA), cannabitriol (CBT), delta-8-tetrahydrocanninol, deleta-8- tetrahydrocannabinolic acid, delta-9-tetrahydrocannabinol (THC; dronabinol), delta-9- tetrahydrocannabinolic acid (THCA), delta-9-tetrahydrocannabivarin (THCV), delta-9- tetrahydrocannabivarinic acid (THCVA), 1 l-nor-9-carboxy-delta-9- tetrahydrocannabinol (THCCOOCH), 1 l-nor-9-carboxy-delta-8-tetrahydrocannabinol, 1 l-hydroxy-delta-8-tetrahydrocannabinol, and 1 l-hydroxy-delta-9- tetrahydrocannabinol, dimethyl heptylpentyl cannabidiol (DMHP-CBD), 6,12-dihydro- 6-hydroxy-cannabidiol, (3 S,4R)-7-hydroxy-.DELTA.6-tetrahydrocannabinol homologs and derivatives, (+)-4-[4-DMH-2,6-diacetoxy-phenyl]-2-carboxy-6,6- dimethylbicyclo[3.1.1]he- pt-2-en, and other 4-phenylpinene derivatives, and cannabidiol (-)(CBD) analogs such as (-)CBD-monomethylether, (-)CBD dimethyl ether; (-)CBD diacetate; (-)3'-acetyl-CBD monoacetate, cannabinol propyl variant (CBNV), and nabilone.

[0097] Unless otherwise specified, the cannabinoids that contain stereochemistry may refer to a single pure enantiomer or racemic mixtures (containing 1 : 1 proportions of the R- and 5-enanti omers), or mixtures of any ratio of the enantiomers.

[0098] It will be appreciated by the person of skill in the art that dronabinol is the generic name for a synthetic delta-9-tetrahydrocannabinol. In other words, dronabinol and delta-9-tetrahydrocannabinol are two accepted terms for the same active pharmaceutical ingredient. That is, the terms may be used interchangeably herein.

[0099] In an embodiment, the one or more cannabinoids may be cannabidiol (CBD) or dronabinol.

[0100] In an embodiment, the one or more cannabinoids may be cannabidiol (CBD) and dronabinol.

[0101] In embodiments, the one or more cannabinoids may be present in a total amount at between about 0.1% w / w and about 4.0% w / w, or at between about 0.15% w / w and about 4.0% w / w, or at between about 0.2% w / w and about 4.0% w / w, or at between about 0.25% w / w and about 4.0% w / w, or at between about 0.3% w / w and about 4.0% w / w, or at between about 0.35% w / w and about 3.5% w / w, or at between about 0.4% w / w and about 3.5% w / w, or between about 0.1% w / w and about 3.5% w / w, or at between about 0.15% w / w and about 3.5% w / w, or at between about 0.2% w / w and about 3.5% w / w, or at between about 0.25% w / w and about 3.5% w / w, or at between about 0.3% w / w and about 3.5% w / w, or at between about 0.35% w / w and about 3.5% w / w, or at between about 0.4% w / w and about 3.5% w / w, or between about 0.1% w / w and about 3.0% w / w, or at between about 0.15% w / w and about 3.0% w / w, or at between about 0.2% w / w and about 3.0% w / w, or at between about 0.25% w / w and about 3.0% w / w, or at between about 0.3% w / w and about 3.0% w / w, or at between about 0.35% w / w and about 3.0% w / w, or at between about 0.4% w / w and about 3.0% w / w, or between about 0.1% w / w and about 2.5% w / w, or at between about 0.15% w / w and about 2.5% w / w, or at between about 0.2% w / w and about 2.5% w / w, or at between about 0.25% w / w and about 2.5% w / w, or at between about 0.3% w / w and about 2.5% w / w, or at between about 0.35% w / w and about 2.5% w / w, or at between about 0.4% w / w and about 2.5% w / w, or between about 0.1% w / w and about 2.0% w / w, or at between about 0.15% w / w and about 2.0% w / w, or at between about 0.2% w / w and about 2.0% w / w, or at between about0.25% w / w and about 2.0% w / w, or at between about 0.3% w / w and about 2.0% w / w, or at between about 0.35% w / w and about 2.0% w / w, or at between about 0.4% w / w and about 2.0% w / w, or between about 0.1% w / w and about 1.5% w / w, or at between about 0.15% w / w and about 1.5% w / w, or at between about 0.2% w / w and about 1.5% w / w, or at between about 0.25% w / w and about 1.5% w / w, or at between about 0.3% w / w and about 1.5% w / w, or at between about 0.35% w / w and about 1.5% w / w, or at between about 0.4% w / w and about 1.5% w / w, or between about 0.1% w / w and about 1.0% w / w, or at between about 0.15% w / w and about 1.0% w / w, or at between about 0.2% w / w and about 1.0% w / w, or at between about 0.25% w / w and about 1.0% w / w, or at between about 0.3% w / w and about 1.0% w / w, or at between about 0.35% w / w and about 1.0% w / w, or at between about 0.4% w / w and about 1.0% w / w, or at between about 0.1% w / w and about 0.95% w / w, or at between about 0.15% w / w and about 0.95% w / w, or at between about 0.2% w / w and about 0.95% w / w, or at between about 0.25% w / w and about 0.95% w / w, or at between about 0.3% w / w and about 0.95% w / w, or at between about 0.35% w / w and about 0.95% w / w, or at between about 0.4% w / w and about 0.95% w / w, or at between about 0.1% w / w and about 0.9% w / w, or at between about 0.15% w / w and about 0.9% w / w, or at between about 0.2% w / w and about 0.9% w / w, or at between about 0.25% w / w and about 0.9% w / w, or at between about 0.3% w / w and about 0.9% w / w, or at between about 0.35% w / w and about 0.9% w / w, or at between about 0.4% w / w and about 0.9% w / w, or at between about 0.1% w / w and about 0.85% w / w, or at between about 0.15% w / w and about 0.85% w / w, or at between about 0.2% w / w and about 0.85% w / w, or at between about 0.25% w / w and about 0.85% w / w, or at between about 0.3% w / w and about 0.85% w / w, or at between about 0.35% w / w and about 0.85% w / w, or at between about 0.4% w / w and about 0.85% w / w, or at between about 0.1% w / w and about 0.8% w / w, or at between about 0.15% w / w and about 0.8% w / w, or at between about 0.2% w / w and about 0.8% w / w, or at between about 0.25% w / w and about 0.8% w / w, or at between about 0.3% w / w and about 0.8% w / w, or at between about 0.35% w / w and about 0.8% w / w, or at between about 0.4% w / w and about 0.8% w / w of the formulation.

[0102] In embodiments, the one or more cannabinoids may be present in a total amount at between about 50 pg / 50 pL w / v and about 2000 pg / 50 pL w / v, or at between about 60pg / 50 pL w / v and about 2000 pg / 50 pL w / v, or at between about 70 pg / 50 pL w / v and about 2000 pg / 50 pL w / v, or at between about 80 pg / 50 pL w / v and about 2000 pg / 50 pL w / v, or at between about 90 pg / 50 pL w / v and about 2000 pg / 50 pL w / v, or at between about 100 pg / 50 pL w / v and about 2000 pg / 50 pL w / v, or at between about 110 pg / 50 pL w / v and about 2000 pg / 50 pL w / v, or at between about 120 pg / 50 pL w / v and about 2000 pg / 50 pL w / v, or at between about 130 pg / 50 pL w / v and about 2000 pg / 50 pL w / v, or at between about 140 pg / 50 pL w / v and about 2000 pg / 50 pL w / v, or at between about 150 pg / 50 pL w / v and about 2000 pg / 50 pL w / v, or at between about 160 pg / 50 pL w / v and about 2000 pg / 50 pL w / v, or at between about 170 pg / 50 pL w / v and about 2000 pg / 50 pL w / v, or at between about 180 pg / 50 pL w / v and about 2000 pg / 50 L w / v, or at between about 190 pg / 50 pL w / v and about 2000 pg / 50 pL w / v, or at between about 200 pg / 50 pL w / v and about 2000 pg / 50 pL w / v, or at between about 210 pg / 50 pL w / v and about 2000 pg / 50 pL w / v, or at between about 220 pg / 50 pL w / v and about 2000 pg / 50 pL w / v, or at between about 230 pg / 50 pL w / v and about 2000 pg / 50 pL w / v of the formulation.

[0103] In embodiments, the one or more cannabinoids may be present in a total amount at between about 50 pg / 50 pL w / v and about 1500 pg / 50 pL w / v, or at between about 60 pg / 50 pL w / v and about 1500 pg / 50 pL w / v, or at between about 70 pg / 50 pL w / v and about 1500 pg / 50 pL w / v, or at between about 80 pg / 50 pL w / v and about 1500 pg / 50 pL w / v, or at between about 90 pg / 50 pL w / v and about 1500 pg / 50 pL w / v, or at between about 100 pg / 50 pL w / v and about 1500 pg / 50 pL w / v, or at between about 110 pg / 50 pL w / v and about 1500 pg / 50 pL w / v, or at between about 120 pg / 50 pL w / v and about 1500 pg / 50 pL w / v, or at between about 130 pg / 50 pL w / v and about 1500 pg / 50 pL w / v, or at between about 140 pg / 50 pL w / v and about 1500 pg / 50 pL w / v, or at between about 150 pg / 50 pL w / v and about 1500 pg / 50 pL w / v, or at between about 160 pg / 50 pL w / v and about 1500 pg / 50 pL w / v, or at between about 170 pg / 50 pL w / v and about 1500 pg / 50 pL w / v, or at between about 180 pg / 50 pL w / v and about 1500 pg / 50 pL w / v, or at between about 190 pg / 50 pL w / v and about 1500 pg / 50 pL w / v, or at between about 200 pg / 50 pL w / v and about 1500 pg / 50 pL w / v, or at between about 210 pg / 50 pL w / v and about 1500 pg / 50 pL w / v, or at between about 220 pg / 50 pL w / v and about1500 pg / 50 pL w / v, or at between about 230 pg / 50 pL w / v and about 1500 pg / 50 pL w / v of the formulation.

[0104] In embodiments, the one or more cannabinoids may be present in a total amount at between about 50 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or at between about 60 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or at between about 70 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or at between about 80 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or atbetween about 90 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or at between about 100 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or at between about 110 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or at between about 120 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or at between about 130 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or at between about 140 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or at between about 150 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or at between about 160 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or at between about 170 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or at between about 180 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or at between about 190 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or at between about 200 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or at between about 210 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or at between about 220 pg / 50 pL w / v and about 1000 pg / 50 pL w / v, or at between about 230 pg / 50 pL w / v and about 1000 pg / 50 pL w / v of the formulation.

[0105] In embodiments, the one or more cannabinoids may be present in a total amount at between about 50 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or at between about 60 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or at between about 70 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or at between about 80 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or at between about 90 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or at between about 100 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or at between about 110 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or at between about 120 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or at between about 130 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or at between about 140 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or at between about 150 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or at between about 160 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or at between about 170 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or at between about 180 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or at betweenabout 190 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or at between about 200 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or at between about 210 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or at between about 220 pg / 50 pL w / v and about 900 pg / 50 pL w / v, or at between about 230 pg / 50 pL w / v and about 900 pg / 50 pL w / v of the formulation.

[0106] In embodiments, the one or more cannabinoids may be present in a total amount at between about 50 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or at between about 60 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or at between about 70 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or at between about 80 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or at between about 90 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or at between about 100 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or at between about 110 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or at between about 120 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or at between about 130 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or at between about 140 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or at between about 150 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or at between about 160 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or at between about 170 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or at between about 180 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or at between about 190 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or at between about 200 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or at between about 210 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or at between about 220 pg / 50 pL w / v and about 800 pg / 50 pL w / v, or at between about 230 pg / 50 pL w / v and about 800 pg / 50 pL w / v of the formulation.

[0107] In embodiments, the one or more cannabinoids may be present in a total amount at between about 50 pg / 50 pL w / v and about 700 pg / 50 pL w / v, or at between about 60 pg / 50 pL w / v and about 700 pg / 50 pL w / v, or at between about 70 pg / 50 pL w / v and about 700 pg / 50 pL w / v, or at between about 80 pg / 50 pL w / v and about 700 pg / 50 pL w / v, or at between about 90 pg / 50 pL w / v and about 700 pg / 50 pL w / v, or at between about 100 pg / 50 pL w / v and about 700 pg / 50 pL w / v, or at between about 110 pg / 50 pL w / v and about 700 pg / 50 pL w / v, or at between about 120 pg / 50 pL w / v and about 700 pg / 50 pL w / v, or at between about 130 pg / 50 pL w / v and about 700 pg / 50 pL w / v, or at between about 140 pg / 50 pL w / v and about 700 pg / 50 pL w / v, or at between about 150 pg / 50 pL w / v and about 700 pg / 50 pL w / v, or at between about 160 pg / 50 pL w / v and about 700 pg / 50 pL w / v, or at between about 170 pg / 50 pL w / v and about 700 pg / 50 pLw / v, or at between about 180 pg / 50 pL w / v and about 700 pg / 50 pL w / v, or at between about 190 pg / 50 pL w / v and about 700 pg / 50 pL w / v, or at between about 200 pg / 50 pL w / v and about 700 pg / 50 pL w / v, or at between about 210 pg / 50 pL w / v and about 700 pg / 50 pL w / v, or at between about 220 pg / 50 pL w / v and about 700 pg / 50 pL w / v, or at between about 230 pg / 50 pL w / v and about 700 pg / 50 pL w / v of the formulation.

[0108] In embodiments, the one or more cannabinoids may be present in a total amount at between about 50 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or at between about 60 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or at between about 70 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or at between about 80 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or at between about 90 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or at between about 100 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or at between about 110 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or at between about 120 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or at between about 130 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or at between about 140 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or at between about 150 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or at between about 160 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or at between about 170 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or at between about 180 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or at between about 190 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or at between about 200 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or at between about 210 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or at between about 220 pg / 50 pL w / v and about 600 pg / 50 pL w / v, or at between about 230 pg / 50 pL w / v and about 600 pg / 50 pL w / v of the formulation.

[0109] In embodiments, the one or more cannabinoids may be present in a total amount at between about 50 pg / 50 pL w / v and about 500 pg / 50 pL w / v, or at between about 60 pg / 50 pL w / v and about 500 pg / 50 pL w / v, or at between about 70 pg / 50 pL w / v and about 500 pg / 50 pL w / v, or at between about 80 pg / 50 pL w / v and about 500 pg / 50 pL w / v, or at between about 90 pg / 50 pL w / v and about 500 pg / 50 pL w / v, or at between about 100 pg / 50 pL w / v and about 500 pg / 50 pL w / v, or at between about 110 pg / 50 pL w / v and about 500 pg / 50 pL w / v, or at between about 120 pg / 50 pL w / v and about 500 pg / 50 pL w / v, or at between about 130 pg / 50 pL w / v and about 500 pg / 50 pL w / v, or at between about 140 pg / 50 pL w / v and about 500 pg / 50 pL w / v, or at between about 150 pg / 50 pL w / v and about 500 pg / 50 pL w / v, or at between about 160 pg / 50 pL w / v andabout 500 pg / 50 pL w / v, or at between about 170 pg / 50 pL w / v and about 500 pg / 50 pL w / v, or at between about 180 pg / 50 pL w / v and about 500 pg / 50 pL w / v, or at between about 190 pg / 50 pL w / v and about 500 pg / 50 pL w / v, or at between about 200 pg / 50 pL w / v and about 500 pg / 50 pL w / v, or at between about 210 pg / 50 pL w / v and about 500 pg / 50 pL w / v, or at between about 220 pg / 50 pL w / v and about 500 pg / 50 pL w / v, or at between about 230 pg / 50 pL w / v and about 500 pg / 50 pL w / v of the formulation.

[0110] In embodiments, the one or more cannabinoids may be present in a total amount at between about 50 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 60 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 70 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 80 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 90 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 100 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 110 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 120 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 130 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 140 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 150 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 160 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 170 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 180 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 190 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 200 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 210 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 220 pg / 50 pL w / v and about 400 pg / 50 pL w / v, or at between about 230 pg / 50 pL w / v and about 400 pg / 50 pL w / v of the formulation.

[0111] In embodiments, the one or more cannabinoids may be present in a total amount at between about 50 pg / 50 pL w / v and about 350 pg / 50 pL w / v, or at between about 60 pg / 50 pL w / v and about 350 pg / 50 pL w / v, or at between about 70 pg / 50 pL w / v and about 350 pg / 50 pL w / v, or at between about 80 pg / 50 pL w / v and about 350 pg / 50 pL w / v, or at between about 90 pg / 50 pL w / v and about 350 pg / 50 pL w / v, or at between about 100 pg / 50 pL w / v and about 350 pg / 50 pL w / v, or at between about 110 pg / 50 pL w / v and about 350 pg / 50 pL w / v, or at between about 120 pg / 50 pL w / v and about 350 pg / 50 pL w / v, or at between about 130 pg / 50 pL w / v and about 350 pg / 50 pL w / v, or at between about 140 pg / 50 pL w / v and about 350 pg / 50 pL w / v, or at between about 150pg / 50 pL w / v and about 350 pg / 50 pL w / v, or at between about 160 pg / 50 pL w / v and about 350 pg / 50 pL w / v, or at between about 170 pg / 50 pL w / v and about 350 pg / 50 pL w / v, or at between about 180 pg / 50 pL w / v and about 350 pg / 50 pL w / v, or at between about 190 pg / 50 pL w / v and about 350 pg / 50 pL w / v, or at between about 200 pg / 50 pL w / v and about 350 pg / 50 pL w / v, or at between about 210 pg / 50 pL w / v and about 350 pg / 50 pL w / v, or at between about 220 pg / 50 pL w / v and about 350 pg / 50 pL w / v, or at between about 230 pg / 50 pL w / v and about 350 pg / 50 pL w / v of the formulation.

[0112] The particle size distribution in the inhalable formulation plays an important role to achieve the desired delivery to the deep lungs. The components of the formulation and their percentage ranges have been carefully chosen to achieve the necessary particle size distribution when delivered.

[0113] In embodiments of the first aspect, the inhalable formulation may provide for a fine particle fraction of greater than 40%, or greater than 40%, or greater than 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%, or greater than 75%, or greater than 80%.

[0114] In embodiments of the first aspect, the inhalable formulation may comprise, consist of or consist essentially of: melatonin; a Ci to Ce alcohol; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze); and, optionally, one or more cannabinoids, optionally one of dronabinol and / or cannabidiol (CBD).

[0115] In embodiments of the first aspect, the inhalable formulation, optionally an inhalable solution, may comprise, consist of or consist essentially of : melatonin, optionally present at between about 0.025% w / w and about 0.1% w / w of the formulation; a Ci to Ce alcohol, optionally ethanol, optionally present at between about 2% and about 20% w / w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).

[0116] In embodiments of the first aspect, the inhalable formulation, optionally an inhalable solution, may consist of or consist essentially of : melatonin, optionally present at between about 0.025% w / w and about 0.1% w / w of the formulation; a Ci to Ce alcohol, optionally ethanol, optionally present at between about 2% and about 20% w / w of the formulation; one or more cannabinoids, optionally present at between about 0.2% w / w and about 0.8% w / w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).

[0117] In embodiments of the first and second aspects, the inhalable formulation, optionally an inhalable solution, may consist of or consist essentially of : melatonin, optionally present at between about 0.025% w / w and about 0.1% w / w of the formulation; a Ci to Ce alcohol, optionally ethanol, optionally present at between about 2% and about 20% w / w of the formulation; cannabidiol (CBD), optionally present at between about 0.2% w / w and about 0.8% w / w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).

[0118] In embodiments of the first and second aspects, the inhalable formulation, optionally an inhalable solution, may consist of or consist essentially of : melatonin, optionally present at between about 0.025% w / w and about 0.1% w / w of the formulation; a Ci to Ce alcohol, optionally ethanol, optionally present at between about 2% and about 20% w / w of the formulation; dronabinol, optionally present at between about 0.2% w / w and about 0.8% w / w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).

[0119] In embodiments of the first and second aspects, the inhalable formulation, optionally an inhalable solution, may consist of or consist essentially of : melatonin, optionally present at between about 0.025% w / w and about 0.1% w / w of the formulation;a Ci to Ce alcohol, optionally ethanol, optionally present at between about 2% and about 20% w / w of the formulation; dronabinol and cannabidiol (CBD), optionally present at a combined amount of between about 0.2% w / w and about 0.8% w / w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).

[0120] In any embodiment of the first aspect, the total mass of melatonin and any one or more cannabinoids per 50 pL metered dose of the formulation may be less than 1 mg, or less than 950 pg, or less than 900 pg, or less than 850 pg, or less than 700 pg, or less than 650 pg, or less than 600 pg, or less than 550 pg, or less than 500 pg, or less than 450 pg.

[0121] In any embodiment of the first aspect, the total mass of melatonin and any one or more cannabinoids per 63 pL metered dose of the formulation may be less than 1 mg, or less than 950 pg, or less than 900 pg, or less than 850 pg, or less than 700 pg, or less than 650 pg, or less than 600 pg, or less than 550 pg, or less than 500 pg, or less than 450 pg.

[0122] In a second aspect, the disclosure resides in a metered dose inhaler comprising an inhalable formulation comprising: melatonin; a Ci to Ce alcohol; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).

[0123] Metered dose inhalers (MDIs) are used to treat respiratory diseases, among other conditions, by delivering a reliable, consistent dose of a pharmaceutical to the patients’ airways through inhalation. They do not rely on heating and are safe and convenient for users to carry and draw an inhalation breath from when in use. However, MDIs present challenges in terms of suitable formulations which will be chemically stable and will generate appropriate particle sizes containing the active agent. Since they do not rely on heating, and produce almost instantaneous evaporation of multiple formulation components, it is necessary to achieve a thermodynamic balance of the formulation components to ensure the active agent is appropriately maintained within the droplets so that the active agent can be delivered to the lungs. Formulation is also key to ensuring the active agent is not lost or separates out during storage.

[0124] The formulation must also be capable of relatively long-term storage without significant deterioration of the formulation and, in at least some instances, be such that in being dispensed from an MDI the active is restrained from separating from other components of the formulation and depositing in the oral cavity or pharynx which may result in a limited therapeutic response. This requires control of a highly dynamic system of formulation components which are expanding, following release from the MDI, and rapidly cooling and condensing. Careful balance of the relative solubilities of the components is crucial along with achieving particles having an appropriate average particle or droplet diameter to provide desirable delivery to the deep lungs.

[0125] Metered dose inhalers are well-known in the art and a wide range of such MDIs may be selected for use with the formulation of the first aspect. Such MDIs are familiar to the person of skill in the art and may be selected from those which are commercially available.

[0126] The MDIs which are available all have a canister which can be attached to the MDI or which may be built into it and which can contain the active agent being delivered. Such canisters are adapted to contain a pressurised fluid and often are designed for containing hydrofluorocarbon-type propellant formulations.

[0127] The valve of the canister that is used to store the formulation controls the release of the inhalable formulation from the canister. It is designed to release a precise amount of the inhalable formulation, to prevent leakage of the propellant or the API and to help regulate the aerosol mist. The type of valve may therefore influence the accuracy of the dose and reliability of the delivery system. The person of skill in the art would know how to select a suitable valve. In embodiments, the valve may be an Aptar valve. In an embodiment, the valve may be an Aptar DF316 (DF30PLUS) / 63 RCU PRE7R or an Aptar ZEN316 PRE7R valve. In an embodiment, the valve may be an Aptar ZEN316 PRE7R valve.

[0128] A gasket is commonly used as a sealing component that ensures that the valve fits securely within the canister and prevents any unwanted leakage of the contents. The gasket is placed between the valve and the canister. Gaskets have lower leakage rates which are generally much higher with low GWP propellant formulations (such as HFO- 1234 ze) when compared to traditional propellants. A Cyclo-olefin copolymer (COC)gasket reduces Oxygen and water uptake rates when compared to traditional gaskets. In an embodiment, the gasket may be a Cyclo-olefin copolymer (COC) gasket.

[0129] The diameter of the aperture of the MDI may influence the average particle size which is subsequently formed and so can have an influence on delivery.

[0130] In embodiments, the aperture of the MDI may have a diameter of between 0.10 mm and 0.50 mm, or between 0.15 mm and 0.40 mm or between 0.20 mm and 0.30 mm.

[0131] In an embodiment, the aperture has a diameter of about 0.23 mm. In an embodiment, the metered dose inhaler may comprise an inhalable formulation comprising: melatonin; a Ci to Ce alcohol; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze); wherein the metered dose inhaler comprises an Aptar valve, preferably an Aptar ZEN316 PRE7R valve, and, optionally, a COC gasket.

[0132] It will be appreciated by a person of skill in the art that a metered dose inhaler typically is a pre-metered multidose inhaler. In an embodiment, the canister of the metered dose inhaler may comprise up to 200 doses, or up to 190 doses, or up to 180 doses, or up to 170 doses, or up to 160 doses of the inhalable formulation. As discussed above, the dosing volume may be any volume between about 25 pL to about 100 pL, optionally the dosing volume may be 25 pL, 61 pL, 63 pL and 100 pL.

[0133] In embodiments of the second aspect, the inhalable formulation may be as defined in any one or more embodiments of the first aspect.

[0134] In a third aspect, the disclosure resides in a method of delivering melatonin to a subject including the steps of: providing the inhalable formulation of the first aspect; and allowing the subject to inhale the inhalable formulation, to thereby deliver the melatonin to the subject.

[0135] In embodiments of the third aspect, the inhalable formulation of the first aspect may be delivered to the subject by activation of a metered dose inhaler, preferably the metered dose inhaler of the second aspect.

[0136] In embodiments of the third aspect, the inhalable formulation of the first aspect may be delivered to the lungs of the subj ect by the subj ect’ s inhalation of the dose emitted (the emitted dose) from the MDI of the second aspect.

[0137] The careful design and balance of all components of the formulation is crucial to achieve particles, in the emitted dose, having an appropriate average particle or droplet diameter to provide desirable delivery of melatonin to the deep lungs.

[0138] Fine particle fraction (FPF) is defined in general terms as the fraction or percentage of the drug mass contained in an aerosol cloud that may be small enough to enter the lungs and exert a clinical effect. In general, an aerodynamic diameter of 5 pm is considered to be the approximate border between "fine" and "coarse" particles. Unless stated otherwise, fine particle fraction (FPF) herein refers to the percentage of the drug mass contained in an aerosol cloud having an aerodynamic diameter of below 5 pm. For example, if it is stated that the fine particle fraction is greater than 40% then at least 40% of the inhalable formulation forms particles with an aerodynamic diameter of below 5 pm when aerosolised. A person of skill in the art will be aware of standard approaches and analytical tools by which to measure the fine particle fraction of an inhalable solution. The PSA could, for example, use a next generation cascade impactor (NGI). Unless stated otherwise, the FPF described herein have been determined using a next generation cascade impactor (NGI). It has been surprisingly found that the relatively simple inhalable formulation of the first aspect comprising melatonin, an alcohol and the propellant HFO 1234ze provides for an emitted dose demonstrating the fine particle fraction necessary for deep lung delivery. The surprisingly high FPF for all tested formulations, as described in the Examples, allows for efficient delivery of the desired dose to the deep lungs. This is a distinct advantage of the formulation of the present disclosure.

[0139] In embodiments of the third aspect, the inhalable formulation may be delivered as an emitted dose having a fine particle fraction of greater than 40%, or greater than 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%, or greater than 75%, or greater than 80%.

[0140] In certain embodiments, the inhalable formulation is delivered having a fine particle fraction of about 40%, about 45%, about 50%, about 55%, about 60%, or about 65%, or about 70%, or about 75%, or about 80%.

[0141] Fine particle dose (FPD) refers to the mass of particles that have an aerodynamic diameter of below 5 pm within the total emitted dose. To ensure delivery of a high percentage of the melatonin to the deep lungs, it is desirable to have a FPD that is as close as possible to the delivered dose. As can be seen in the Examples, it has been surprisingly found that all prepared formulations have high FPD relative to the delivered dose.

[0142] In embodiments of the third aspect, the inhalable formulation may be delivered as an emitted dose having a fine particle dose of melatonin of between about 10 pg and about 35 pg, or of between about 11 pg and about 35 pg, or of between about 12 pg and about 35 pg, or of between about 13 pg and about 35 pg, or of between about 14 pg and about 35 pg, or of between about 15 pg and about 35 pg, or of between about 10 pg and about 34 pg, or of between about 11 pg and about 34 pg, or of between about 12 pg and about 34 pg, or of between about 13 pg and about 34 pg, or of between about 14 pg and about 34 pg, or of between about 15 pg and about 34 pg, or of between about 10 pg and about 33 pg, or of between about 11 pg and about 33 pg, or of between about 12 pg and about 33 pg, or of between about 13 pg and about 33 pg, or of between about 14 pg and about 33 pg, or of between about 15 pg and about 33 pg, or of between about 10 pg and about 32 pg, or of between about 11 pg and about 32 pg, or of between about 12 pg and about 32 pg, or of between about 13 pg and about 32 pg, or of between about 14 pg and about 32 pg, or of between about 15 pg and about 32 pg, or of between about 10 pg and about 31 pg, or of between about 11 pg and about 31 pg, or of between about 12 pg and about 31 pg, or of between about 13 pg and about 31 pg, or of between about 14 pg and about 31 pg, or of between about 15 pg and about 31 pg, or of between about 10 pg and about 30 pg, or of between about 11 pg and about 30 pg, or of between about 12 pg and about 30 pg, or of between about 13 pg and about 30 pg, or of between about 14 pg and about 30 pg, or of between about 15 pg and about 30 pg, or of between about 10 pg and about 29 pg, or of between about 11 pg and about 29 pg, or of between about 12 pg and about 29 pg, or of between about 13 pg and about 29 pg, or of between about 14 pg andabout 29 pg, or of between about 15 pg and about 29 pig, or of between about 10 pig and about 28 pig, or of between about 11 pig and about 28 pig, or of between about 12 pig and about 28 pig, or of between about 13 pig and about 28 pig, or of between about 14 pig and about 28 pig, or of between about 15 pig and about 28 pig from a 50 pig / 50 piL metered dose.

[0143] In embodiments of the third aspect, the inhalable formulation may be delivered as an emitted dose having a fine particle dose of melatonin of between about 17 pg and about 35 pg, or of between about 18 pg and about 35 pg, or of between about 19 pg and about 35 pg, or of between about 20 pg and about 35 pg, or of between about 21 pg and about 35 pg, or of between about 17 pg and about 34 pg, or of between about 18 pg and about 34 pg, or of between about 19 pg and about 34 pg, or of between about 20 pg and about 34 pg, or of between about 21 pg and about 34 pg, or of between about 17 pg and about 33 pg, or of between about 18 pg and about 33 pg, or of between about 19 pg and about 33 pg, or of between about 20 pg and about 33 pg, or of between about 21 pg and about 33 pg, or of between about 17 pg and about 32 pg, or of between about 18 pg and about 32 pg, or of between about 19 pg and about 32 pg, or of between about 20 pg and about 32 pg, or of between about 21 pg and about 32 pg, or of between about 17 pg and about 31 pg, or of between about 18 pg and about 31 pg, or of between about 19 pg and about 31 pg, or of between about 20 pg and about 31 pg, or of between about 21 pg and about 31 pg, or of between about 17 pg and about 30 pg, or of between about 18 pg and about 30 pg, or of between about 19 pg and about 30 pg, or of between about 20 pg and about 30 pg, or of between about 21 pg and about 30 pg, or of between about 17 pg and about 29 pg, or of between about 18 pg and about 29 pg, or of between about 19 pg and about 29 pg, or of between about 20 pg and about 29 pg, or of between about 21 pg and about 29 pg, from a 50 pg / 50 pL metered dose.

[0144] In embodiments of the third aspect, the inhalable formulation may be delivered as an emitted dose having a fine particle dose of melatonin of between about 15 pg and about 40 pg, or of between about 16 pg and about 40 pg, or of between about 17 pg and about 40 pg, or of between about 18 pg and about 40 pg, or of between about 19 pg and about 40 pg, or of between about 20 pg and about 40 pg, or of between about 15 pg and about 39 pg, or of between about 16 pg and about 39 pg, or of between about 17 pg andabout 39 pg, or of between about 18 pg and about 39 pig, or of between about 19 pig and about 39 pig, or of between about 20 pig and about 39 pig, between about 15 pig and about 38 pig, or of between about 16 pig and about 38 pig, or of between about 17 pig and about 38 pig, or of between about 18 pig and about 38 pig, or of between about 19 pig and about 38 pig, or of between about 20 pig and about 38 pig, between about 15 pig and about 37 pig, or of between about 16 pig and about 37 pig, or of between about 17 pig and about 37 pig, or of between about 18 pig and about 37 pig, or of between about 19 pig and about 37 pig, or of between about 20 pig and about 37 pig, between about 15 pig and about 36 pig, or of between about 16 pig and about 36 pig, or of between about 17 pig and about 36 pig, or of between about 18 pig and about 36 pig, or of between about 19 pig and about 36 pig, or of between about 20 pig and about 36 pig, between about 15 pig and about 35 pig, or of between about 16 pig and about 35 pig, or of between about 17 pig and about 35 pig, or of between about 18 pig and about 35 pig, or of between about 19 pig and about 35 pig, or of between about 20 pig and about 35 pig, from a 50 pig / 63 piL metered dose.

[0145] In embodiments of the third aspect, the inhalable formulation may be delivered as an emitted dose having a fine particle dose of melatonin of between about 21 pg and about 40 pg, or of between about 22 pg and about 40 pg, or of between about 23 pg and about 40 pg, or of between about 24 pg and about 40 pg, or of between about 25 pg and about 40 pg, or of between about 21 pg and about 39 pg, or of between about 22 pg and about 39 pg, or of between about 23 pg and about 39 pg, or of between about 24 pg and about 39 pg, or of between about 25 pg and about 39 pg, between about 21 pg and about 38 pg, or of between about 22 pg and about 38 pg, or of between about 23 pg and about 38 pg, or of between about 24 pg and about 38 pg, or of between about 25 pg and about 38 pg, between about 21 pg and about 37 pg, or of between about 22 pg and about 37 pg, or of between about 23 pg and about 37 pg, or of between about 24 pg and about 37 pg, or of between about 25 pg and about 37 pg, between about 21 pg and about 36 pg, or of between about 22 pg and about 36 pg, or of between about 23 pg and about 36 pg, or of between about 24 pg and about 36 pg, or of between about 25 pg and about 36 pg, between about 21 pg and about 35 pg, or of between about 22 pg and about 35 pg, or of between about 23 pg and about 35 pg, or of between about 24 pg and about 35 pg, or of between about 25 pg and about 35 pg, from a 50 pg / 63 pL metered dose.

[0146] In embodiments of the third aspect, the inhalable formulation may be delivered as an emitted dose having a fine particle dose of melatonin of between about 10 pg and about 21 pg, or of between about 11 pg and about 21 pg, or of between about 12 pg and about 21 pg, or of between about 13 pg and about 21 pg, or of between about 1 pg and about 21 pg, or of between about 15 pg and about 21 pg, or of between about 10 pg and about 20 pg, or of between about 11 pg and about 20 pg, or of between about 12 pg and about 20 pg, or of between about 13 pg and about 20 pg, or of between about 14 pg and about 20 pg, or of between about 15 pg and about 20 pg, or of between about 10 pg and about 19 pg, or of between about 11 pg and about 19 pg, or of between about 12 pg and about 19 pg, or of between about 13 pg and about 19 pg, or of between about 14 pg and about 19 pg, or of between about 15 pg and about 19 pg, or of between about 10 pg and about 18 pg, or of between about 11 pg and about 18 pg, or of between about 12 pg and about 18 pg, or of between about 13 pg and about 18 pg, or of between about 14 pg and about 18 pg, or of between about 15 pg and about 18 pg, from a 25 pg / 50 pL metered dose.

[0147] In embodiments of the third aspect, the inhalable formulation may comprise melatonin; a Ci to Ce alcohol, optionally ethanol; and a propellent, which is / ra / z.s- l ,3,3,3-tetrafluoroprop- l -ene (HFO 1234ze); wherein, an emitted dose distribution as follows is provided: an FPF of greater than 40%, optionally greater than 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%, or greater than 75%, or greater than 80%; and / or an FPD of between about 10 pg and about 35 pg from a 50 pg / 50 pL metered dose, optionally an FPD of between about 13 pg and about 32 pg, or of between about 15 pg and about 30 pg, or of between about 17 pg and about 30 pg, or of between about 20 pg and about 30 pg, from a 50 pg / 50 pL metered dose.

[0148] In embodiments of the third aspect, the inhalable formulation may comprise melatonin; a Ci to Ce alcohol, optionally ethanol; and a propellent, which is / ra / z.s- l ,3,3,3-tetrafluoroprop- l -ene (HFO 1234ze);wherein, an emitted dose distribution as follows is provided: an FPF of greater than 40%, optionally greater than 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%, or greater than 75%, or greater than 80%; and / or an FPD of between about 10 pg and about 35 pg from a 25 pg / 50 pL metered dose, optionally an FPD of between about 11 pg and about 25 pg, or of between about 12 pg and about 20 pg, or of between about 13 pg and about 20 pg, or of between about 15 pg and about 20 pg, from a 25 pg / 50 pL metered dose.

[0149] In embodiments of the third aspect, the inhalable formulation may comprise melatonin; a Ci to Ce alcohol, optionally ethanol; and a propellent, which is lrans- \ ,3,3,3-tetrafluoroprop-l -ene (HFO 1234ze); wherein, an emitted dose distribution as follows is provided: an FPF of greater than 40%, optionally greater than 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%, or greater than 75%, or greater than 80%; and / or an FPD of between about 15 pg and about 40 pg from a 50 pg / 63 pL metered dose, optionally an FPD of between about 17 pg and about 39 pg, or of between about 20 pg and about 38 pg, or of between about 22 pg and about 37 pg, or of between about 25 pg and about 35 pg, from a 50 pg / 63 pL metered dose.

[0150] In embodiments of the third aspect, the inhalable formulation may comprise melatonin; a Ci to Ce alcohol, optionally ethanol; one or more cannabinoids, optionally present at between about 0.2% w / w and about 0.8% w / w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze); wherein, an emitted dose distribution as follows is provided: an FPF of greater than 40%, optionally greater than 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%, or greater than 75%, or greater than 80%;and / or an FPD of between about 10 pg and about 35 pg from a 50 pg / 50 pL metered dose, optionally an FPD of between about 13 pg and about 32 pg, or of between about 15 pg and about 30 pg, or of between about 17 pg and about 30 pg, or of between about 20 pg and about 30 pg, from a 50 pg / 50 pL metered dose.

[0151] In embodiments of the third aspect, the inhalable formulation may comprise melatonin; a Ci to Ce alcohol, optionally ethanol; one or more cannabinoids, optionally present at between about 0.2% w / w and about 0.8% w / w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze); wherein, an emitted dose distribution as follows is provided: an FPF of greater than 40%, optionally greater than 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%, or greater than 75%, or greater than 80%; and / or an FPD of between about 15 pg and about 40 pg from a 50 pg / 63 pL metered dose, optionally an FPD of between about 17 pg and about 39 pg, or of between about 20 pg and about 38 pg, or of between about 22 pg and about 37 pg, or of between about 25 pg and about 35 pg, from a 50 pg / 63 pL metered dose.

[0152] In embodiments of the third aspect, the inhalable formulation may comprise melatonin; a Ci to Ce alcohol, optionally ethanol; one or more cannabinoids, optionally present at between about 0.2% w / w and about 0.8% w / w of the formulation; and and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze); wherein, an emitted dose distribution as follows is provided: an FPF of greater than 40%, optionally greater than 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%, or greater than 75%, or greater than 80%; and / or an FPD of between about 10 pg and about 35 pg from a 25 pg / 50 pL metered dose, optionally an FPD of between about 11 pg and about 25 pg, or of betweenabout 12 pg and about 20 pg, or of between about 13 pg and about 20 pg, or of between about 15 pg and about 20 pg, from a 25 pg / 50 pL metered dose.

[0153] It is hypothesised that when melatonin is co-delivered with one or more cannabinoids the hydrophobic nature of the cannabinoids facilitates co-particle formation with melatonin during atomisation. This may modulate dissolution rates and therefore systemic absorption of the melatonin.

[0154] In embodiments, the inhalable formulation may be as described in any one of the embodiments of the first aspect.

[0155] In embodiments, the metered dose inhaler may be as described in any one of the embodiments of the second aspect.

[0156] In a fourth aspect, the disclosure resides in a method of treating a disease, disorder or condition in a subject, comprising administering an effective amount of the inhalable formulation of the first aspect.

[0157] In a fifth aspect, the disclosure resides in a use of the inhalable formulation of the first aspect in the manufacture of a medicament for the treatment of a disease, disorder or condition.

[0158] In a sixth aspect, the disclosure resides in a use of the inhalable formulation of the first aspect for the treatment of a disease, disorder or condition.

[0159] In an seventh aspect, the disclosure resides in the inhalable formulation of the first aspect for use in the treatment of a disease, disorder or condition responsive to melatonin.

[0160] In embodiments of the fourth to seventh aspects, the disease, disorder or condition may be a sleep disorder.

[0161] In embodiments, the sleep disorder may involve difficulty falling asleep, remaining asleep, or excessive sleepiness. In embodiments, treating a subject with a sleep disorder means modifying or improving the sleep-wake cycle.

[0162] In some aspects, treating a sleep disorder or modifying or improving the sleepwake cycle in a subject may include improving sleep sensation determined by subjective judgment using psychological evaluation techniques or improving the sleep state determined objectively using techniques of estimating sleep and wakefulness states based on continuous recording of activity amounts. For example, the obstructive sleep apnoeaquestionnaire can be used to examine the sleep sensation of the previous night to the present morning upon arising. The questionnaire is based on the five factors of sleepiness upon arising, sleep initiation and sleep maintenance, dream quality, recovery from fatigue, and elongation of sleep length and has been verified in regard to the reliability and validity of the respective factors.

[0163] Methods of sleep recovery including enhancing mental acuity or cognitive activity in a subject are also disclosed. Specifically, methods of sleep recovery after sleeping without unpleasant feeling or grogginess are disclosed. Sleep recovery can be determined objectively, for example, by measuring changes in the brain activity within the alpha frequency band using an electroencephalogram, or subjectively using the Toronto Hospital Alertness Test (THAT).

[0164] In embodiments, the sleep disorder may be a dyssomnia. Dyssomnia can include psychophysiological insomnia, sleep state misperception, idiopathic insomnia, obstructive sleep apnoea syndrome, central sleep apnoea syndrome, central alveolar hypoventilation syndrome, periodic limb movement disorder, restless leg syndrome, inadequate sleep hygiene, environmental sleep disorder, altitude insomnia, adjustment sleep disorder, insufficient sleep syndrome, limit-setting sleep disorder, sleep-onset association disorder, nocturnal eating or drinking syndrome, hypnotic dependent sleep disorder, stimulant-dependent sleep disorder, alcohol-dependent sleep disorder, toxin- induced sleep disorder, time zone change (jet lag) syndrome, shift work sleep disorder, irregular sleep-wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome and non-24-hour sleep-wake disorder.

[0165] In embodiments, the sleep disorder may be a parasomnia. Parasomnia can include confusional arousals, sleepwalking and sleep terrors, rhythmic movement disorder, sleep starts, sleep talking and nocturnal leg cramps.

[0166] In embodiments, the sleep disorder may be associated with a medical or psychiatric disorder. The medical or psychiatric disorder can include psychoses, mood disorders, anxiety disorders, panic disorders, alcoholism, cerebral degenerative disorders, dementia, parkinsonism, fatal familial insomnia, sleep-related epilepsy, electrical status epilepticus of sleep, sleep-related headaches, sleeping sickness, nocturnal cardiac ischemia, chronic obstructive pulmonary disease, sleep-related asthma,sleep-related gastroesophageal reflux, peptic ulcer disease, fibrositis syndrome, osteoarthritis, rheumatoid arthritis, fibromyalgia and post-surgical sleep disorder.

[0167] In embodiments, the treatment can include administering one dose or two or more doses of the formulations of the first aspect.

[0168] In embodiments, the treatment may be administered before bedtime, preferably within 2 hours, or 1.5 hours, or 1 hour, or 30 minutes, or 20 minutes, or 15 minutes, or 10 minutes before bedtime.

[0169] It will be appreciated by persons skilled in the art that numerous variations and / or modifications may be made to the above-described embodiments, without departing from the broad general scope of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.ExperimentalExample 1: Preparation of melatonin formulations (50 pL dose)

[0170] Four different melatonin formulations with 50 pL doses were prepared with different amounts of melatonin and ethanol and two different propellants (see table 1). Formulations 1 and 3 contain 25 pg / 50 pL of melatonin and formulations 2 and 4 contain 50 pg / 50 pL of melatonin.

[0171] To prepare each formulation, the required amount of melatonin was weighted into a vessel and ethanol was added. The mixture was stirred until complete dissolution of melatonin. The solution was dispensed into an open MDI cannister, and the MDI valve was crimped onto the cannister. The propellant was added through the metering valve.Table 1 : Melatonin formulations with HFA134a and HFO1234ze as propellants.Example 2: Drug Delivery Metrics (50 pL dose)

[0172] Drug Delivery Metrics were determined by Next Generation Cascade Impactor (NGI) at 301 / min sampling flow rate as described in United States Pharmacopoeia <601> Apparatus 6 for Metered-Dose Inhalers (see table 2 and FIGs 1 and 2). The metered doses in pg, the delivered doses in pg, and fine particle doses in pg and fine particle fractions in % based on the delivered doses were determined for the four prepared melatonin formulations.

[0173] It can be clearly seen that the metered doses and delivered doses of all four formulations were close to the respective target doses of 25 pg for formulations 1 and 3 and 50 pg for formulations 2 and 4. Formulations 1 and 3 have fine particle fractions of above 75%, and formulations 2 and 4 have fine particle fractions of above 50%. Mass median aerodynamic diameters (MMAD) of below 1.5 pm were observed for all four formulations.Table 2: Drug Delivery Metrics.Example 3: Stability testing (50 pL dose)

[0174] The chemical stability of the four prepared melatonin formulations 1 to 4 was tested (see table 3).

[0175] To measure chemical stability, the cans were removed from stability cabinets at the given timepoints. The MDIs were chilled, opened and the formulations were collected into volumetric flasks after brief storage below the propellant boiling point. The MDI was washed out and made to volume using diluent. The solution concentration was quantitatively determined via a HPLC-UV method derived fromUSP Melatonin monograph. The column used was a C18 150x4.6mm 5pm and the mobile phase was potassium phosphate buffer and acetonitrile.Table 3: Residual melatonin can content after 6 months storage.0176] As can be seen from the data in table 3, even after 6-months storage at40°C / 75%RH the formulations demonstrated high chemical stability. The residual melatonin content was over 90% for all formulations.Example 4: Preparation of melatonin formulations with CBD

[0177] Eight formulations comprising melatonin and CBD were prepared in the same way as the formulations comprising melatonin (see Example 1 for procedure).

[0178] Formulations 5 and 6 contain 50 pg / 50 pL of melatonin and formulations 7 and 8 contain 25 pg / 50 pL of melatonin (see table 4). The can closure system & actuator canister includes a 19 mL aluminium plasma treated canister (Presspart), a 50 pL metering valve and a Presspart NM200 actuator with 0.23 mm orifice diameter.

[0179] Formulations 9 and 10 contain 50 pg / 63 pL of melatonin and formulations 11 and 12 contain 25 pg / 63 pL of melatonin (see table 5). The can closure system & actuator canister includes a 19 mL aluminium plasma treated canister (Presspart), a 63 pL metering valve and a Presspart NM200 actuator with 0.23 mm orifice diameter.

[0180] Formulations 5 to 8 contain 300 pg / 50 pL of CBD and formulations 9 to 12 contain 300 pg / 63 pL of CBD. All formulations comprise HFO1234ze as propellant.Table 4: Melatonin formulations with CBD (50pl Metered Dose).Table 5: Melatonin formulation with CBD (63 pl Metered Dose).Example 5: Drug Delivery Metrics of formulations comprising melatonin with CBD

[0181] Drug Delivery Metrics were determined by Next Generation Cascade Impactor (NGI) at 301 / min sampling flow rate as described in United States Pharmacopoeia <601> Apparatus 6 for Metered-Dose Inhalers (see table 6 and 7). The metered doses in pg, the delivered doses in pg, and fine particle doses in pg and fine particle fractions in % based on the delivered doses were determined for the four prepared melatonin + CBD formulations.

[0182] It can be clearly seen that the metered doses and delivered doses of melatonin and CBD were close to the respective target doses of melatonin and CBD for all formulations. Formulations 5, 7, 9 and 11 have fine particle fractions of above 60%, and formulations 6, 8 and 12 have fine particle fractions of above 50%. Mass median aerodynamic diameters (MMAD) of 2.6 pm or lower were observed for all eight formulations.Table 6: Drug Delivery Metrics for formulations 5 to 8.Table 7: Drug Delivery Metrics for formulations 9 to 12,Example 6: Melatonin formulations (63 pL dose)Materials:

[0183] API: melatonin, Sigma Aldrich

[0184] Canister: 19ml Plasma Treated C128 Aluminium Canister

[0185] Valve: Aptar DF316 (DF30PLUS) / 63 RCU PRE7R

[0186] Actuator: NM200 DIS 0T3.16A 0SO.23 JL0.65 (0.23mm)

[0187] MDI Excipients: Absolute Ethanol (EP) > 99.5%, VWR and HFO1234ze, HoneywellFormulation:

[0188] Formulation 13 with 50 pg per 63 L melatonin, 5% w / w ethanol, and HFO1234ze as propellant was prepared (Table 8) according to the following procedure.

[0189] Melatonin was added by mass to a conical flask. The mass of ethanol was added to the same conical flask. The conical flask was ultrasonicated for 10 mins to form a clear solution. The bulk formulation mass (less propellant) was added (± 2%) to a C128 plasma treated aluminium canister (Presspart, UK). An Aptar 63pl valve was placed and crimped to the canister using a Pamasol P2002 pneumatic crimper. The propellant was filled by mass (± 2%) through the valve using a Pamasol P2011 / 10 pneumatic propellant filler. The mass of each canister-valve assembly was recorded, before and after bulk addition, and after propellant mass addition. The formulation was also filled in glass bottles to allow visual assessment of the final formulation (see FIG. 3). A clear solution was observed at manufacture and after four weeks at 5°C.Table 8: Melatonin formulationWater Content after 6 Month

[0190] The water content was determined following storage at 40°C / 75%RH at t=0, 3 and 6-months (Table 9).Table 9: Water Content of Melatonin 50pg / 63pL, 5%w / w Ethanol in HFO 1234ze propellant following 40°C / 75%RH Storage at t=0, t=3, and t=6-monthsFormulation Stability 0. 3, 6-Months Data

[0191] The melatonin can content observed in MDIs following storage for 0, 3 and 6- months at 40°C / 75%RH is presented in Table 10. Percentage relative to the target melatonin content (6893pg) is presented (initial time point range was 98-100%, seeTable 10).

[0192] Table 10: Residual melatonin can content after 6 months storage.

[0193] It can be seen that the prepared formulations demonstrate high chemical stability (high residual melatonin even after 6 months of storage at 40 °C and 75% RH). The mean residual melatonin is above 95% (25 °C / 60% RH).Melatonin Delivered Dose and Metered Dose

[0194] The melatonin through can-use life delivered dose and metered dose observed for Formulation 13 are presented in:

[0195] Table 11 and Figure 4; t = 0Table 11: Melatonin Delivered Dose and Metered Dose Through Can-Use Life;HFO1234ze: t = 0Metered Dose (mean ± standard deviation, n = 20) = 50.5 ± 1.8; Delivered Dose (mean ± standard deviation, n = 20) = 44.5 ± 1.6.

[0196] Table 12 and Figure 5; t = 3 months @40°C / 75%Table 12: Melatonin Delivered Dose and Metered Dose Through Can-Use Life;HFO1234ze: t = 3 months @ 40°C / 75%RH

[0197] Table 13 and Figure 6; t = 6 months @40°C / 75%.Table 13: Melatonin Delivered Dose and Metered Dose Through Can-Use Life;HFO1234ze (Batch: Oz240223DLA): t = 6 months @ 40°C / 75%RH

[0198] Figure 7 shows t = 6 months @25°C / 60%.

[0199] It can be seen that at all timepoints an excellent delivered dose (DD) through use-life uniformity was achieved. A small rise (concentrating up) at EOL was anticipated to be reduced when using a higher fill mass and concurrent higher ullage at the target no. of doses.Particle Size Distribution and Drug Delivery Metrics: NGI Data

[0200] Table 14 (HFO1234ze) presents the drug delivery metrics for MDIs stored for up to 6-months at 40°C / 75%RH; as determined by NGI at a sampling flow rate of 301 / min.Table 14: Melatonin Drug Delivery Metrics Through Can-Use Life; HFO1234ze:Storage at 40°C / 75%RH (valve up & valve down)

[0201] Excellent drug delivery performance is observed for HFO1234ze MDIs; fine particle fractions of 72 ± 5% was observed. A cumulative undersize graph at t=0, 3, and 6 months timepoints is presented in FIG. 8; mass median aerodynamic diameters (MMAD) of 1.1 ± 0.1pm were observed. Due to the small particle size and highefficiency, the formulation is ideal for delivery via inhalation to the deep lung, offering excellent therapeutic potential.Priming, Tailing and Number of Doses

[0202] Number of doses were confirmed to be 120 for formulation 13. Tailing occurred from dose 143 onwards over two - three doses for batch Oz240223DLA (HFO1234ze), see FIG. 9 at t=0 months and FIG. 10 at t=6 months. Additional formulation mass may be included within the MDI to guarantee 120 doses are obtained at the end of shelf life. Formulation mass may, for example, be increased by 15% such that the target formulation becomes 160 doses total, i.e. 120 target doses with 40 additional doses (overage).

[0203] Regarding canister priming, all canisters were within expectation after one dose had been fired (see FIG. 11). Thus, a single priming dose (dose number 1) is sufficient to prime all metering valves to within 25% of target shot weight.

[0204] Shot weights (mean ± standard deviation) observed during the study are presented in Table 15.Table 15: Shot weights (mean ± standard deviation) at 0, 3, and 6 months.Conclusion

[0205] Data is presented for Melatonin 50pg / 63pl MDIs containing 5%w / w ethanol and HFO1234ze. Excellent drug delivery performance is observed for HFO1234ze MDIs; a fine particle fraction of 72 ± 5% was observed. Mass median aerodynamic diameters (MMAD) of 1.1 ± 0.1pm was observed for HFO1234ze MDIs. Due to the small particle size and high efficiency, the formulation is ideal for delivery via inhalation to the deep lung, offering excellent therapeutic potential.

Claims

CLAIMS:

1. An inhalable formulation comprising: melatonin; a Ci to Ce alcohol; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).

2. The inhalable formulation of claim 1, wherein the melatonin is present at between about 0.01% w / w and about 0.5% w / w of the formulation.

3. The inhalable formulation of claim 1 or claim 2, wherein the melatonin is present at between about 0.025% w / w and about 0.2% w / w of the formulation.

4. The inhalable formulation of any one of the preceding claims, wherein the melatonin is present at between about 5 pg / 50 pL w / v and about 250 pg / 50 pL w / v of the formulation; or wherein the melatonin is present at between about 5 pg / 63 pL w / v and about 250 pg / 63 pL w / v of the formulation.

5. The inhalable formulation of any one of the preceding claims, wherein the melatonin is present at between about 10 pg / 50 pL w / v and about 100 pg / 50 pL w / v of the formulation; or wherein the melatonin is present at between about 10 pg / 63 pL w / v and about 100 pg / 63 pL w / v of the formulation.

6. The inhalable formulation of any one of the preceding claims, wherein the propellant is present at an amount of at least 80% w / w of the formulation.

7. The inhalable formulation of any one of the preceding claims, wherein the propellant is present at an amount of at least 85% w / w of the formulation.

8. The inhalable formulation of any one of the preceding claims, wherein the Ci to Ce alcohol is present at between l%-20% w / w of the formulation.

9. The inhalable formulation of any one of the preceding claims, wherein the Ci to Ce alcohol is present at between 1%- 10% w / w of the formulation.

10. The inhalable formulation of any one of the preceding claims, wherein the Ci to Ce alcohol is selected from a Ci to C4 alcohol, a C2 to C4 alcohol, and a C2 or C3 alcohol.

11. The inhalable formulation of any one of the preceding claims, wherein the Ci to Ce alcohol is ethanol.

12. The inhalable formulation of any one of the preceding claims, wherein the inhalable formulation further comprises one or more cannabinoids.

13. The inhalable formulation of claim 12, wherein the one or more cannabinoids is selected from the group consisting of anandamide, 2-arachidonoylglycerol, cannabichromene (CBC), cannabichromenic acid (CBCA), cannabichormevarin (CBCV), cannabichromevarinic acid (CBCVA), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabielsoin (CBE), cannabicyclol (CBL), cannabinodiol (CBND), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerovarin (CBGV), cannabigerovarinic acid (CBGVA), cannabinol (CBN), cannabinolic acid (CBNA), cannabitriol (CBT), delta-8- tetrahydrocanninol, deleta-8-tetrahydrocannabinolic acid, delta-9-tetrahydrocannabinol (THC; dronabinol), delta-9-tetrahydrocannabinolic acid (THCA), delta-9- tetrahydrocannabivarin (THCV), delta-9-tetrahydrocannabivarinic acid (THCVA), 11- nor-9-carboxy-delta-9-tetrahydrocannabinol (THCCOOCH), 1 l-nor-9-carboxy-delta-8- tetrahydrocannabinol, 1 l-hydroxy-delta-8-tetrahydrocannabinol, and 11-hydroxy-delta- 9-tetrahydrocannabinol, dimethyl heptylpentyl cannabidiol (DMHP-CBD), 6,12- dihydro-6-hydroxy-cannabidiol, (3S,4R)-7-hydroxy-.DELTA.6-tetrahydrocannabinol homologs and derivatives, (+)-4-[4-DMH-2,6-diacetoxy-phenyl]-2-carboxy-6,6- dimethylbicyclo[3.1.1]he- pt-2-en, and other 4-phenylpinene derivatives, and cannabidiol (-)(CBD) analogs such as (-)CBD-monomethylether, (-)CBD dimethyl ether;(-)CBD diacetate; (-)3'-acetyl-CBD monoacetate, cannabinol propyl variant (CBNV), and nabilone.

14. The inhalable formulation of claim 12 or claim 13, wherein the one or more cannabinoids is cannabidiol (CBD) or dronabinol.

15. The inhalable formulation of claim 12 or claim 13, wherein the one or more cannabinoids are cannabidiol (CBD) and dronabinol.

16. The inhalable formulation of any one of claims 12 to 15, wherein the one or more cannabinoids are present in a total amount at between about 0.1% w / w and about 4.0% w / w of the formulation.

17. The inhalable formulation of any one of claims 12 to 16, wherein the one or more cannabinoids are present in a total amount at between about 0.2% w / w and about 2.0% w / w of the formulation.

18. The inhalable formulation of any one of claims 12 to 16, wherein the one or more cannabinoids are present in a total amount at between about 50 pg / 50 pL w / v and about 2000 pg / 50 pL w / v of the formulation; or wherein the one or more cannabinoids are present in a total amount at between about 50 pg / 63 pL w / v and about 2000 pg / 63 pL w / v of the formulation.

19. The inhalable formulation of any one of claims 12 to 16, wherein the one or more cannabinoids are present in a total amount at between about 100 pg / 50 pL w / v and 900 pg / 50 pL w / v of the formulation; or wherein the one or more cannabinoids are present in a total amount at between about 100 pg / 63 pL w / v and about 900 pg / 63 pL w / v of the formulation.

20. The inhalable formulation of any one of the preceding claims wherein the inhalable formulation provides for a fine particle fraction of greater than 40%, or greaterthan 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%.

21. The inhalable formulation of any one of the preceding claims wherein the inhalable formulation consists of or consists essentially of: melatonin; a Ci to Ce alcohol; and a propellent, which is / ra / ?.s- l ,3,3,3-tetrafluoroprop- l -ene (HFO 1234ze); and, optionally, one or more cannabinoids, optionally one of delta-9-tetrahydrocannabinol (THC; dronabinol) and / or cannabidiol (CBD).

22. The inhalable formulation of any one of claims 12 to 21 wherein the total mass of melatonin and any one or more cannabinoids per 50 pL metered dose of the formulation is less than 1 mg, optionally less than 700 pg, or less than 600 pg, or less than 500 pg, or less than 450 pg.

23. The inhalable formulation of claim 22, wherein the 50 pL metered dose of the formulation has a fine particle fraction of greater than 40%, or greater than 45%, or greater than 50%.

24. A metered dose inhaler comprising the inhalable formulation of any one or more of claim 1 to claim 23.

25. The metered dose inhaler of claim 24 comprising an Aptar valve, preferably an Aptar ZEN316 PRE7R valve, and, optionally, a COC gasket.

26. A method of delivering melatonin to a subject including the steps of: providing the inhalable formulation of any one of claim 1 to claim 23; and allowing the subject to inhale the inhalable formulation, to thereby deliver the melatonin to the subject.

27. The method of claim 26, wherein the inhalable formulation is delivered to the subject by activation of a metered dose inhaler.

28. The method of claim 26 or 27, wherein the inhalable formulation is delivered having a fine particle fraction of greater than 40%, or greater than 45%, or greater than 50%, or greater than 55%.

29. The method of any one of claim 26 to claim 27, wherein the inhalable formulation is delivered having a fine particle dose of melatonin of between about 10 pg and about 35 pg from a 50 pL metered dose, or of between about 15 pg and about 40 pg from a 63 pL metered dose.

30. A metered dose inhaler comprising an inhalable formulation comprising melatonin; a Ci to Ce alcohol; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze); wherein the inhalable formulation is delivered having an emitted dose distribution as follows: an FPF of greater than 40%, optionally greater than 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%, or greater than 75%, or greater than 80%; and / or an FPD of between about 15 pg and about 40 pg from a 50 pg / 63 pL metered dose, optionally an FPD of between about 17 pg and about 39 pg, or of between about 20 pg and about 38 pg, or of between about 22 pg and about 37 pg, or of between about 25 pg and about 35 pg, from a 50 pg / 63 pL metered dose.

31. A metered dose inhaler comprising an inhalable formulation comprising melatonin; a Ci to Ce alcohol; one or more cannabinoids; anda propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze); wherein the inhalable formulation is delivered having an emitted dose distribution as follows: an FPF of greater than 40%, optionally greater than 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%, or greater than 75%, or greater than 80%; and / or an FPD of between about 10 pg and about 35 pg from a 50 pg / 50 pL metered dose, optionally an FPD of between about 13 pg and about 32 pg, or of between about 15 pg and about 30 pg, or of between about 17 pg and about 30 pg, or of between about 20 pg and about 30 pg, from a 50 pg / 50 pL metered dose32. A method of treating a disease, disorder or condition in a subject, comprising administering an effective amount of the inhalable formulation of any one of claim 1 to claim 23 to the subject.

33. Use of the inhalable formulation of any one of claim 1 to claim 23 in the manufacture of a medicament for the treatment of a disease, disorder or condition responsive to melatonin.

34. The method of claim 32 or the use of claim 33, wherein the disease, disorder or condition is a sleep disorder.

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