WO2025039045A1

WO2025039045A1 - Inhalable formulation for volatile actives

Info

Publication number: WO2025039045A1
Application number: PCT/AU2024/050902
Authority: WO
Inventors: David Andrew Lewis; Robert David Johnson; Paul Michael Young
Original assignee: Inhaler Supplies Pty Ltd
Current assignee: Inhaler Supplies Pty Ltd
Priority date: 2023-08-23
Filing date: 2024-08-23
Publication date: 2025-02-27
Anticipated expiration: 2026-02-23

Abstract

The invention provides for an inhalable formulation comprising a volatile active, a propellant, a C1 to C6 alcohol and a glycol. The inhalable formulation may be delivered in a metered dose inhaler (MDI) for efficient deliver to the lungs of a subject.

Description

Inhalable Formulation for Volatile Actives

Technical Field

[0001] This disclosure relates to an inhalable formulation for volatile actives and a metered dose inhaler containing the inhalable formulation for volatile actives.

Background

[0002] 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 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.

[0003] This is particularly challenging when the active agent is a highly volatile compound. Examples of such volatile actives include nicotine, nitroglycerin, methoxyflurane, isoflurane, amyl nitrites, and propofol, amongst others. It would be an advantage if a platform formulation were available which is capable of appropriately formulating a range of volatile actives. The formulation needs to be such that volatile actives can be included in therapeutically effective concentrations such that an appropriate inhaled dose is capable of delivering the desired effect. It 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 volatile active is restrained from quickly evaporating and 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.

Summary

[0004] In a first aspect, the disclosure resides in an inhalable formulation comprising: a volatile active; at least 90% w/w of a propellant; between about 2% to about 8% w/w of a Ci to G> alcohol; and between about 1.5% to about 5% w/w of a glycol, wherein the volatile active is not nicotine, or a pharmaceutically acceptable derivative or salt thereof.

[0005] In a second aspect, the disclosure resides in a metered dose inhaler comprising an inhalable formulation, said inhalable formulation comprising: a volatile active; at least 90% w/w of a propellant; between about 2% to about 8% w/w of a Ci to Ce alcohol; and between about 1.5% to about 5% w/w of a glycol, wherein the volatile active is not nicotine, or a pharmaceutically acceptable derivative or salt thereof.

[0006] In embodiments of the first or second aspect, the volatile active may have a vapour pressure of between about 0.00001 mm Hg to about 900 mm Hg at 20 °C.

[0007] In embodiments, the volatile active may have a vapour pressure of between about 0.00001 mm Hg to about 800 mm Hg, or between about 0.00001 mm Hg to about 700 mm Hg, or between about 0.00001 mm Hg to about 600 mm Hg, or between about 0.00001 mm Hg to about 500 mm Hg, or between about 0.00001 mm Hg to about 400 mm Hg, or between about 0.00001 mm Hg to about 300 mm Hg, at 20 °C.

[0008] In embodiments, the volatile active may have a vapour pressure of between about 0.00002 mm Hg to about 900 mm Hg, or between about 0.00003 mm Hg to about 900 mm Hg, or between about 0.00004 mm Hg to about 900 mm Hg, or between about 0.00005 mm Hg to about 900 mm Hg, or between about 0.00006 mm Hg to about 900 mm Hg, or between about 0.00007 mm Hg to about 900 mm Hg, or between about 0.00008 mm Hg to about 900 mm Hg, or between about 0.00009 mm Hg to about 900 mm Hg, or between about 0.0001 mm Hg to about 900 mm Hg, at 20 °C.

[0009] In embodiments, the volatile active may have a vapour pressure of between about 0.00002 mm Hg to about 700 mm Hg, or between about 0.00003 mm Hg to about 700 mm Hg, or between about 0.00004 mm Hg to about 700 mm Hg, or between about 0.00005 mm Hg to about 700 mm Hg, or between about 0.00006 mm Hg to about 700 mm Hg, or between about 0.00007 mm Hg to about 700 mm Hg, or between about 0.00008 mm Hg to about 700 mm Hg, or between about 0.00009 mm Hg to about 700 mm Hg, at 20 °C.

[0010] In embodiments, the volatile active may have a vapour pressure of between about 0.0001 mm Hg to about 700 mm Hg at 20 °C.

[0011] In embodiments of the first or second aspect, the volatile active has a molecular weight of between about 30 g/mol to about 300 g/mol.

[0012] In embodiments, the volatile active may have a molecular weight of between about 50 g/mol to about 300 g/mol, or between about 70 g/mol to about 300 g/mol, or between about 90 g/mol to about 300 g/mol, or between about 110 g/mol to about 300 g/mol, or between about 50 g/mol to about 280 g/mol, or between about 70 g/mol to about 280 g/mol, or between about 90 g/mol to about 280 g/mol, or between about 110 g/mol to about 280 g/mol, or between about 50 g/mol to about 260 g/mol, or between about 70 g/mol to about 260 g/mol, or between about 90 g/mol to about 260 g/mol, or between about 110 g/mol to about 260 g/mol, or between about 50 g/mol to about 240 g/mol, or between about 70 g/mol to about 240 g/mol, or between about 90 g/mol to about 240 g/mol, or between about 110 g/mol to about 240 g/mol.

[0013] In embodiments, the volatile active may have a boiling point of between about 0 °C to about 300 °C, or between about 20 °C to about 300 °C, or between about 0 °C to about 280 °C, or between about 20 °C to about 280 °C, or between about 0 °C to about 260 °C, or between about 20 °C to about 260 °C, or between about 0 °C to about 240 °C, or between about 20 °C to about 240 °C, or between about 0 °C to about 220 °C, or between about 20 °C to about 220 °C, or between about 0 °C to about 200 °C, or between about 20 °C to about 200 °C, or between about 0 °C to about 180 °C, or between about 20 °C to about 180 °C. [0014] In embodiments of the first aspect, the volatile active may be selected from the group consisting of nitroglycerin, methoxyflurane, isoflurane, desflurane, sevoflurane, halothane, nitrous oxide, an amyl nitrite and propofol. In an embodiment, the volatile active may be selected from the group consisting of nitroglycerin and methoxyflurane.

[0015] In an embodiment, the volatile active may be nitroglycerin.

[0016] In an embodiment, the volatile active may be methoxyflurane.

[0017] In an embodiment, the volatile active may be isoflurane.

[0018] In an embodiment, the volatile active may be desflurane.

[0019] In an embodiment, the volatile active may be sevoflurane.

[0020] In an embodiment, the volatile active may be halothane.

[0021] In an embodiment, the volatile active may be nitrous oxide.

[0022] In an embodiment, the volatile active may be an amyl nitrite.

[0023] In an embodiment, the volatile active may be propofol.

[0024] In embodiments, the propellant may be a hydrofluorocarbon propellant.

[0025] In embodiments, the hydrofluorocarbon propellant may be selected from the group consisting of HF A 134a, HFA 152a, HFA 227 and HFO 1234ze.

[0026] 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.

[0027] In a preferred embodiment, the Ci to Ce alcohol may be ethanol.

[0028] In embodiments, the Ci to Ce alcohol may be present at between about 2% to about 8% w/w of the entire inhalable formulation.

[0029] In another embodiment, the Ci to Ce alcohol may be present at between about 3% to about 7% w/w of the entire inhalable formulation.

[0030] In another embodiment, the Ci to Ce alcohol may be present at about 5% w/w of the entire inhalable formulation.

[0031] In a preferred embodiment, the glycol may be propylene glycol.

[0032] In an embodiment, the glycol content may be between about 1.5% to about 5% w/w of the entire inhalable formulation.

[0033] In another embodiment, the glycol content may be between about 2% to about 4% w/w of the entire inhalable formulation.

[0034] In embodiments, the inhalable formulation may optionally comprise glycerol. [0035] In an embodiment, the glycerol content may be between about 0.01% to about 0.5% w/w of the entire inhalable formulation.

[0036] In another embodiment, the glycerol content may be between about 0.05% to about 0.25% w/w of the entire inhalable formulation.

[0037] In another embodiment, when present, the glycerol content may be around 0.1% w/w of the entire inhalable formulation.

[0038] In a third aspect, the disclosure resides in a method of delivering a volatile active to a subject including the steps of: providing the inhalable formulation of the first aspect to the subject; allowing the subject to inhale the inhalable formulation, to thereby deliver the volatile active to the subject.

[0039] In embodiments of the third aspect, the method of delivering a volatile active may be a method of delivering a volatile active to the lungs of the subject.

[0040] In a fourth aspect, the disclosure resides in a method of treating or preventing a disease, disorder or condition in a subject including the steps of: providing the inhalable formulation of the first aspect to the subject; allowing the subject to inhale the formulation, to thereby treat or prevent the disease, disorder or condition in the subject. [0041] Each aspect or embodiment as defined herein may be combined with any other aspect(s) or embodiment(s) unless clearly indicated otherwise.

Brief Description of Drawings

[0042] FIG 1. shows a Dosage Unit Sampling Apparatus (DUS A) for the evaluation of particle-vapour phase mass. The setup consists of a vapour trap, a DUSA/filter and an actuator. The flow rate is around 30L per minute.

[0043] FIG 2. shows the apparatus for evaluation of particle size distribution.

[0044] FIG 3. shows the nicotine deposition within the DUSA and vapour trap apparatus.

[0045] FIG 4. shows the particle size distribution (%) for an inhalable formulation comprising 3% w/w ethanol, 2% w/w PG in HFA 134a (50 pg/50 pL nicotine). [0046] FIG 5. shows the particle size distribution (pg) for an inhalable formulation comprising 3% w/w ethanol, 2% w/w PG in HFA 134a (50 pg/50 pL nicotine).

[0047] FIG 6. shows that the formulations prepared with HFA 152a (left) and HFO1234ze (right) are clear solutions at 5 °C.

Description of Embodiments

[0048] Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. Unless otherwise specified, the term “consisting essentially of’ refers to a formulation whose only components are those recited and allowing only for further components that do not materially affect the basic and novel characteristics of the formulation. The term “consisting of’, as used herein, means the formulation includes only the components specifically recited.

[0049] 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.

[0050] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each of the appended claims.

[0051] The high volatility of certain actives creates great challenges when being used in an MDI formulation since these volatile compounds have a natural tendency to evaporate quickly and to separate from the other components in the formulation. In addition to storage challenges this can also lead to them being considerably more likely to settle in the oral cavity rather than travelling to the deep lungs for appropriate absorption into the bloodstream. The unique and challenging physical and chemical properties of these actives cannot easily be compared to other less volatile actives, such as cannabinoids, which can be found used in inhalable formulations, and requires a bespoke formulation approach.

[0052] Cannabinoids, such as CBD and THC, are solid powders at room temperature. If left open to the atmosphere, CBD and THC will remain a solid powder while the volatile actives of the present invention will quickly be lost to evaporation. An evaporating aerosol from an MDI containing either CBD or THC will result in residual non-volatile CBD or THC droplets, respectively.

[0053] CBD and THC behave very much like typical inhalable pharmaceutical drugs. For example, drug delivery measurements can be performed at room temperature and the residual (non-volatile) drugs can be collected upon filters and cascade impactors. Both CBD and THC can be delivered to the deep lungs by an MDI using formulations simply containing ethanol and propellant alone due to their physical properties.

[0054] The volatile actives for delivery with the present application, on the other hand, are very different and considerably more challenging to formulate and deliver via an MDI approach. When the MDI is pressed, a puff of formulation containing the volatile active is emitted from the MDI. However, the active is highly volatile (particularly in aerosol format), making it extremely difficult to quantify using USP techniques. A residual active droplet will not be formed; instead, a vapor will be created. Dilution of the expanding aerosol by the surrounding air stream will occur rapidly, and this will drive the active from the aerosol droplets into the surrounding air. The result is that inhaled active vapor will be lost to the atmosphere and also to surfaces of the oropharynx resulting in a harsh sensation being felt by the patient and, importantly, failure to deliver a full dose of the active to the lungs. To control this process therefore presents a very significant challenge t to achieve efficient delivery into the deep lungs.

[0055] It will be understood by a person of skill in the art that a ‘volatile active’ or ‘volatile compound’ as used herein can broadly refer to a chemical compound which readily evaporates at standard temperature and pressures, for example at 20 °C at atmospheric pressure (101,325 Pa); or which have a measurable vapor pressure. In embodiments, the volatile active or volatile compound is one having a high vapor pressure relative to a known non-volatile comparator compound. In embodiments, the volatile active or volatile compound is one having a vapour pressure of over 0.0001 mm Hg at 20 °C. In embodiments, the volatile active or volatile compound is one having a boiling point less than 250 °C. It will be appreciated by a person of skill in the art that there are a number of known methods to measure the vapour pressure of any given compound. For example, a manometer (isoteniscope) may be used. In other embodiments, the volatile active may be defined by its molecular weight. In embodiments, the volatile active may have a molecular weight of less than 300 g/mol, preferably less than 250 g/mol.

[0056] The volatile actives of the present invention demonstrate similar chemical and physical properties to nicotine, which is a highly volatile compound with a high vapour pressure. As demonstrated in the Examples, it has been shown that the volatility of nicotine can be controlled by carefully selecting the formulation excipients and composition. Similarly to nicotine, it is hypothesised that the volatility of the compounds of the present invention, for example nitroglycerin and methoxyflurane, when delivered from a metered dose inhaler can be controlled by careful selection of formulation excipients and composition. The present disclosure describes how an inhalable formulation comprising a volatile active may be uniquely tailored for delivery via an MDI to a subject’s lungs.

[0057] The approach may have a range of benefits versus the current standard delivery approach for a particular active including stability of formulation; reduction of risk of loss of active through evaporation prior to delivery; ability to deliver a lower dose to the patient; more rapid onset of therapeutic effect; reduced side effects; and ability to access administration by inhalation when the current standard delivery form does not allow for that.

[0058] By carefully maintaining control of the volatility of the actives, by selection of formulation components and relative amounts, it is proposed that aerosol particles or droplets emitted by an MDI can retard the volatile actives from separating from the particle both during storage and also, following activation of the MDI, too early in the inhalation process and thereby allow them to be deposited within the deep lung rather than the oral cavity or pharynx and so greatly improve user sensation/experience as well as maximise delivery of the available volatile active. [0059] Particularly, the present disclosure describes the use of a Ci to Ce alcohol, particularly ethanol, and a glycol, particularly propylene glycol, as a platform formulation to form a particle encapsulating the volatile active, for example nitroglycerin or methoxyflurane. These components, in certain % w/w amounts in an inhalable formulation, can appropriately control the diffusion of actives to the particle surface and its subsequent evaporation. This control may occur in spite of the complex thermodynamic changes occurring in the particle relating to expansion of the formulation, the rapid flash evaporation of the hydrofluorocarbon propellant and the consequent cooling and the ongoing partitioning of the alcohol, glycol and the volatile active while they too seek to escape and evaporate from the particle.

[0060] Without wishing to be bound by theory, particles within liquids generally follow a diffusion gradient from high to low concentrations and, therefore, move to the particle surface to exit the liquid droplet. Likewise, the diffusion of the volatile active from the surface of the aerosol particles is proportional to the concentration gradient of the active at the surface of the particle and just above the surface of the particle. Thus, by careful design of the inhalable formulation, the processes that occur during droplet formation and aerosol maturation phases may be engineered such that propellant flashing and partial ethanol evaporation occurs and controlled partitioning also takes place within remaining formulation components. The active may be encapsulated within the particle and its diffusion to the particle surface may be hindered and evaporation into the surrounding airstream may be prevented which may allow for optimal delivery of the active to the lungs of the subject.

[0061] In a first aspect, the disclosure resides in an inhalable formulation comprising: a volatile active; at least 90% w/w of a propellant; between about 2% to about 8% w/w of a Ci to Ce alcohol; and between about 1.5% to about 5% w/w of a glycol, wherein the volatile active is not nicotine, or a pharmaceutically acceptable derivative or salt thereof, optionally wherein the volatile active is nitroglycerin or methoxyflurane. [0062] The volatile active in the inhalable formulation of the description is therefore not nicotine or, for example, a nicotine salt formed using an acid selected from the group consisting of formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, caprylic acid, capric acid, citric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, phenylacetic acid, benzoic acid, tartaric acid, bitartaric acid, lactic acid, malonic acid, succinic acid, fumaric acid, finnaric acid, gluconic acid, saccharic acid, malonic acid, malic acid, glycolic, pyruvic, levulinic, and salicylic.

[0063] In embodiments, the volatile active is not a lactic salt of nicotine, a benzoic salt of nicotine or a levulinic acid salt of nicotine.

[0064] In embodiments, the volatile active is not an N-oxide derivative of nicotine, a glucuronide derivative of nicotine, an N-alkyl derivative of nicotine or an isomer of nicotine or any such derivatives.

[0065] In embodiments of the first aspect, the volatile active may have a vapour pressure of between about 0.00001 mm Hg to about 900 mm Hg at 20 °C.

[0066] In embodiments, the volatile active may have a vapour pressure of between about 0.00001 mm Hg to about 800 mm Hg, or between about 0.00001 mm Hg to about 700 mm Hg, or between about 0.00001 mm Hg to about 600 mm Hg, or between about 0.00001 mm Hg to about 500 mm Hg, or between about 0.00001 mm Hg to about 400 mm Hg, or between about 0.00001 mm Hg to about 300 mm Hg, or between about 0.00001 mm Hg to about 290 mm Hg, or between about 0.00001 mm Hg to about 280 mm Hg, or between about 0.00001 mm Hg to about 270 mm Hg, or between about 0.00001 mm Hg to about 260 mm Hg, or between about 0.00001 mm Hg to about 250 mm Hg, at 20 °C.

[0067] In embodiments, the volatile active may have a vapour pressure of between about 0.00002 mm Hg to about 900 mm Hg, or between about 0.00003 mm Hg to about 900 mm Hg, or between about 0.00004 mm Hg to about 900 mm Hg, or between about 0.00005 mm Hg to about 900 mm Hg, or between about 0.00006 mm Hg to about 900 mm Hg, or between about 0.00007 mm Hg to about 900 mm Hg, or between about 0.00008 mm Hg to about 900 mm Hg, or between about 0.00009 mm Hg to about 900 mm Hg, or between about 0.0001 mm Hg to about 900 mm Hg, at 20 °C. [0068] In embodiments, the volatile active may have a vapour pressure of between about 0.00002 mm Hg to about 800 mm Hg, or between about 0.00003 mm Hg to about 800 mm Hg, or between about 0.00004 mm Hg to about 800 mm Hg, or between about 0.00005 mm Hg to about 800 mm Hg, or between about 0.00006 mm Hg to about 800 mm Hg, or between about 0.00007 mm Hg to about 800 mm Hg, or between about 0.00008 mm Hg to about 800 mm Hg, or between about 0.00009 mm Hg to about 800 mm Hg, or between about 0.0001 mm Hg to about 800 mm Hg, at 20 °C.

[0069] In embodiments, the volatile active may have a vapour pressure of between about 0.00002 mm Hg to about 700 mm Hg, or between about 0.00003 mm Hg to about 700 mm Hg, or between about 0.00004 mm Hg to about 700 mm Hg, or between about 0.00005 mm Hg to about 700 mm Hg, or between about 0.00006 mm Hg to about 700 mm Hg, or between about 0.00007 mm Hg to about 700 mm Hg, or between about 0.00008 mm Hg to about 700 mm Hg, or between about 0.00009 mm Hg to about 700 mm Hg, or between about 0.0001 mm Hg to about 700 mm Hg, at 20 °C.

[0070] In embodiments, the volatile active may have a vapour pressure of between about 0.0001 mm Hg to about 100 mm Hg, or between about 0.0001 mm Hg to about 95 mm Hg, or between about 0.0001 mm Hg to about 90 mm Hg, or between about 0.0001 mm Hg to about 85 mm Hg, or between about 0.0001 mm Hg to about 80 mm Hg, or between about 0.0001 mm Hg to about 75 mm Hg, or between about 0.0001 mm Hg to about 70 mm Hg, or between about 0.0001 mm Hg to about 65 mm Hg, or between about 0.0001 mm Hg to about 60 mm Hg, or between about 0.0001 mm Hg to about 55 mm Hg, or between about 0.0001 mm Hg to about 50 mm Hg, or between about 0.0001 mm Hg to about 45 mm Hg, or between about 0.0001 mm Hg to about 40 mm Hg, or between about 0.0001 mm Hg to about 35 mm Hg, or between about 0.0001 mm Hg to about 30 mm Hg, or between about 0.0001 mm Hg to about 25 mm Hg, or between about 0.0001 mm Hg to about 20 mm Hg, or between about 0.0001 mm Hg to about 15 mm Hg, or between about 0.0001 mm Hg to about 10 mm Hg, or between about 0.0001 mm Hg to about 5 mm Hg, or between about 0.0001 mm Hg to about 1 mm Hg, at 20 °C.

[0071] In embodiments, the volatile active may have a vapour pressure of between about 1 mm Hg to about 900 mm Hg, or between about 1 mm Hg to about 800 mm Hg, between about 1 mm Hg to about 700 mm Hg, between about 1 mm Hg to about 600 mm Hg, between about 1 mm Hg to about 500 mm Hg, between about 1 mm Hg to about 400 mm Hg, at 20 °C.

[0072] In embodiments, the volatile active may have a vapour pressure of between about 1 mm Hg to about 700 mm Hg, or between about 5 mm Hg to about 700 mm Hg, or between about 10 mm Hg to about 700 mm Hg, or between about 15 mm Hg to about 700 mm Hg, or between about 20 mm Hg to about 700 mm Hg, or between about 25 mm Hg to about 700 mm Hg, or between about 30 mm Hg to about 700 mm Hg, or between about 35 mm Hg to about 700 mm Hg, or between about 40 mm Hg to about 700 mm Hg, or between about 45 mm Hg to about 700 mm Hg, or between about 50 mm Hg to about 700 mm Hg, or between about 55 mm Hg to about 700 mm Hg, or between about 60 mm Hg to about 700 mm Hg, or between about 65 mm Hg to about 700 mm Hg, or between about 70 mm Hg to about 700 mm Hg, or between about 75 mm Hg to about 700 mm Hg, or between about 80 mm Hg to about 700 mm Hg, or between about 85 mm Hg to about 700 mm Hg, or between about 90 mm Hg to about 700 mm Hg, or between about 95 mm Hg to about 700 mm Hg, or between about 100 mm Hg to about 700 mm Hg, or between about 105 mm Hg to about 700 mm Hg, or between about 110 mm Hg to about 700 mm Hg, or between about 115 mm Hg to about 700 mm Hg, or between about 120 mm Hg to about 700 mm Hg, or between about 125 mm Hg to about 700 mm Hg, or between about 130 mm Hg to about 700 mm Hg, or between about 135 mm Hg to about 700 mm Hg, or between about 140 mm Hg to about 700 mm Hg, or between about 145 mm Hg to about 700 mm Hg, or between about 150 mm Hg to about 700 mm Hg, or between about 155 mm Hg to about 700 mm Hg, or between about 160 mm Hg to about 700 mm Hg, or between about 165 mm Hg to about 700 mm Hg, or between about 170 mm Hg to about 700 mm Hg, or between about 175 mm Hg to about 700 mm Hg, or between about 180 mm Hg to about 700 mm Hg, or between about 185 mm Hg to about 700 mm Hg, or between about 190 mm Hg to about 700 mm Hg, or between about 195 mm Hg to about 700 mm Hg, or between about 200 mm Hg to about 700 mm Hg, at 20 °C.

[0073] In embodiments, the volatile active may have a vapour pressure of between about 1 mm Hg to about 300 mm Hg, or between about 5 mm Hg to about 300 mm Hg, or between about 10 mm Hg to about 300 mm Hg, or between about 15 mm Hg to about 300 mm Hg, or between about 20 mm Hg to about 300 mm Hg, or between about 25 mm Hg to about 300 mm Hg, or between about 30 mm Hg to about 300 mm Hg, or between about 35 mm Hg to about 300 mm Hg, or between about 40 mm Hg to about 300 mm Hg, or between about 45 mm Hg to about 300 mm Hg, or between about 50 mm Hg to about 300 mm Hg, or between about 55 mm Hg to about 300 mm Hg, or between about 60 mm Hg to about 300 mm Hg, or between about 65 mm Hg to about 300 mm Hg, or between about 70 mm Hg to about 300 mm Hg, or between about 75 mm Hg to about 300 mm Hg, or between about 80 mm Hg to about 300 mm Hg, or between about 85 mm Hg to about 300 mm Hg, or between about 90 mm Hg to about 300 mm Hg, or between about 95 mm Hg to about 300 mm Hg, or between about 100 mm Hg to about 300 mm Hg, or between about 105 mm Hg to about 300 mm Hg, or between about 110 mm Hg to about 300 mm Hg, or between about 115 mm Hg to about 300 mm Hg, or between about 120 mm Hg to about 300 mm Hg, or between about 125 mm Hg to about 300 mm Hg, or between about 130 mm Hg to about 300 mm Hg, or between about 135 mm Hg to about 300 mm Hg, or between about 140 mm Hg to about 300 mm Hg, or between about 145 mm Hg to about 300 mm Hg, or between about 150 mm Hg to about 300 mm Hg, or between about 155 mm Hg to about 300 mm Hg, or between about 160 mm Hg to about 300 mm Hg, or between about 165 mm Hg to about 300 mm Hg, or between about 170 mm Hg to about 300 mm Hg, or between about 175 mm Hg to about 300 mm Hg, or between about 180 mm Hg to about 300 mm Hg, or between about 185 mm Hg to about 300 mm Hg, or between about 190 mm Hg to about 300 mm Hg, or between about 195 mm Hg to about 300 mm Hg, or between about 200 mm Hg to about 300 mm Hg, at 20 °C.

[0074] In embodiments, the volatile active may have a vapour pressure of at least 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 5000, 10000 mm Hg, for example up to 50000 mm Hg in the case of gaseous volatile actives, at 20 °C.

[0075] In embodiments, the volatile active may have a vapour pressure of less than 10000, 5000, 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100 mm Hg, at 20 °C. [0076] In examples, the volatile active is nitroglycerin or methoxyflurane and the vapour pressure if between about 0.00015 mm Hg to about 30 mm Hg, at 20 °C. [0077] In embodiments, the volatile active may have a molecular weight of between about 30 g/mol to about 300 g/mol, or between about 40 g/mol to about 300 g/mol, or between about 50 g/mol to about 300 g/mol, or between about 60 g/mol to about 300 g/mol, or between about 70 g/mol to about 300 g/mol, or between about 75 g/mol to about 300 g/mol, or between about 80 g/mol to about 300 g/mol, or between about 85 g/mol to about 300 g/mol, or between about 90 g/mol to about 300 g/mol, or between about 95 g/mol to about 300 g/mol, or between about 100 g/mol to about 300 g/mol, or between about 105 g/mol to about 300 g/mol, or between about 110 g/mol to about 300 g/mol, or between about 115 g/mol to about 300 g/mol, or between about 70 g/mol to about 295 g/mol, or between about 75 g/mol to about 295 g/mol, or between about 80 g/mol to about 295 g/mol, or between about 85 g/mol to about 295 g/mol, or between about 90 g/mol to about 295 g/mol, or between about 95 g/mol to about 295 g/mol, or between about 100 g/mol to about 295 g/mol, or between about 105 g/mol to about 295 g/mol, or between about 110 g/mol to about 295 g/mol, or between about 115 g/mol to about 295 g/mol, or between about 70 g/mol to about 290 g/mol, or between about 75 g/mol to about 290 g/mol, or between about 80 g/mol to about 290 g/mol, or between about 85 g/mol to about 290 g/mol, or between about 90 g/mol to about 290 g/mol, or between about 95 g/mol to about 290 g/mol, or between about 100 g/mol to about 290 g/mol, or between about 105 g/mol to about 290 g/mol, or between about 110 g/mol to about 290 g/mol, or between about 115 g/mol to about 290 g/mol, or between about 70 g/mol to about 285 g/mol, or between about 75 g/mol to about 285 g/mol, or between about 80 g/mol to about 285 g/mol, or between about 85 g/mol to about 285 g/mol, or between about 90 g/mol to about 285 g/mol, or between about 95 g/mol to about 285 g/mol, or between about 100 g/mol to about 285 g/mol, or between about 105 g/mol to about 285 g/mol, or between about 110 g/mol to about 285 g/mol, or between about 115 g/mol to about 285 g/mol, or between about 70 g/mol to about 280 g/mol, or between about 75 g/mol to about 280 g/mol, or between about 80 g/mol to about 280 g/mol, or between about 85 g/mol to about 280 g/mol, or between about 90 g/mol to about 280 g/mol, or between about 95 g/mol to about 280 g/mol, or between about 100 g/mol to about 280 g/mol, or between about 105 g/mol to about 280 g/mol, or between about 110 g/mol to about 280 g/mol, or between about 115 g/mol to about 280 g/mol, or between about 70 g/mol to about 275 g/mol, or between about 75 g/mol to about 275 g/mol, or between about 80 g/mol to about 275 g/mol, or between about 85 g/mol to about 275 g/mol, or between about 90 g/mol to about 275 g/mol, or between about 95 g/mol to about 275 g/mol, or between about 100 g/mol to about 275 g/mol, or between about 105 g/mol to about 275 g/mol, or between about 110 g/mol to about 275 g/mol, or between about 115 g/mol to about 275 g/mol, or between about 70 g/mol to about 270 g/mol, or between about 75 g/mol to about 270 g/mol, or between about 80 g/mol to about 270 g/mol, or between about 85 g/mol to about 270 g/mol, or between about 90 g/mol to about 270 g/mol, or between about 95 g/mol to about 270 g/mol, or between about 100 g/mol to about 270 g/mol, or between about 105 g/mol to about 270 g/mol, or between about 110 g/mol to about 270 g/mol, or between about 115 g/mol to about 270 g/mol, or between about 70 g/mol to about 265 g/mol, or between about 75 g/mol to about 265 g/mol, or between about 80 g/mol to about 265 g/mol, or between about 85 g/mol to about 265 g/mol, or between about 90 g/mol to about 265 g/mol, or between about 95 g/mol to about 265 g/mol, or between about 100 g/mol to about 265 g/mol, or between about 105 g/mol to about 265 g/mol, or between about 110 g/mol to about 265 g/mol, or between about 115 g/mol to about 265 g/mol, or between about 70 g/mol to about 260 g/mol, or between about 75 g/mol to about 260 g/mol, or between about 80 g/mol to about 260 g/mol, or between about 85 g/mol to about 260 g/mol, or between about 90 g/mol to about 260 g/mol, or between about 95 g/mol to about 260 g/mol, or between about 100 g/mol to about 260 g/mol, or between about 105 g/mol to about 260 g/mol, or between about 110 g/mol to about 260 g/mol, or between about 115 g/mol to about 260 g/mol, or between about 70 g/mol to about 255 g/mol, or between about 75 g/mol to about 255 g/mol, or between about 80 g/mol to about 255 g/mol, or between about 85 g/mol to about 255 g/mol, or between about 90 g/mol to about 255 g/mol, or between about 95 g/mol to about 255 g/mol, or between about 100 g/mol to about 255 g/mol, or between about 105 g/mol to about 255 g/mol, or between about 110 g/mol to about 255 g/mol, or between about 115 g/mol to about 255 g/mol, or between about 70 g/mol to about 250 g/mol, or between about 75 g/mol to about 250 g/mol, or between about 80 g/mol to about 250 g/mol, or between about 85 g/mol to about 250 g/mol, or between about 90 g/mol to about 250 g/mol, or between about 95 g/mol to about 250 g/mol, or between about 100 g/mol to about 250 g/mol, or between about 105 g/mol to about 250 g/mol, or between about 110 g/mol to about 250 g/mol, or between about 115 g/mol to about 250 g/mol, or between about 70 g/mol to about 245 g/mol, or between about 75 g/mol to about 245 g/mol, or between about 80 g/mol to about 245 g/mol, or between about 85 g/mol to about 245 g/mol, or between about 90 g/mol to about 245 g/mol, or between about 95 g/mol to about 245 g/mol, or between about 100 g/mol to about 245 g/mol, or between about 105 g/mol to about 245 g/mol, or between about 110 g/mol to about 245 g/mol, or between about 115 g/mol to about 245 g/mol, or between about 70 g/mol to about 240 g/mol, or between about 75 g/mol to about 240 g/mol, or between about 80 g/mol to about 240 g/mol, or between about 85 g/mol to about 240 g/mol, or between about 90 g/mol to about 240 g/mol, or between about 95 g/mol to about 240 g/mol, or between about 100 g/mol to about 240 g/mol, or between about 105 g/mol to about 240 g/mol, or between about 110 g/mol to about 240 g/mol, or between about 115 g/mol to about 240 g/mol, or between about 70 g/mol to about 235 g/mol, or between about 75 g/mol to about 235 g/mol, or between about 80 g/mol to about 235 g/mol, or between about 85 g/mol to about 235 g/mol, or between about 85 g/mol to about 235 g/mol, or between about 90 g/mol to about 235 g/mol, or between about 95 g/mol to about 235 g/mol, or between about 100 g/mol to about 235 g/mol, or between about 105 g/mol to about 235 g/mol, or between about 110 g/mol to about 235 g/mol, or between about 115 g/mol to about 235 g/mol.

[0078] In embodiments, the volatile active may be a liquid having a boiling point of between about 0 °C to about 300 °C, or between about 10 °C to about 300 °C, or between about 20 °C to about 300 °C, or between about 30 °C to about 300 °C, or between about 40 °C to about 300 °C, or between about 50 °C to about 300 °C, or between about 0 °C to about 290 °C, or between about 10 °C to about 290 °C, or between about 20 °C to about 290 °C, or between about 30 °C to about 290 °C, or between about 40 °C to about 290 °C, or between about 50 °C to about 290 °C, or between about 0 °C to about 280 °C, or between about 10 °C to about 280 °C, or between about 20 °C to about 280 °C, or between about 30 °C to about 280 °C, or between about 40 °C to about 280 °C, or between about 50 °C to about 280 °C, or between about 0 °C to about 270 °C, or between about 10 °C to about 270 °C, or between about 20 °C to about 270 °C, or between about 30 °C to about 270 °C, or between about 40 °C to about 270 °C, or between about 50 °C to about 270 °C, or between about 0 °C to about 260 °C, or between about 10 °C to about 260 °C, or between about 20 °C to about 260 °C, or between about 30 °C to about 260 °C, or between about 40 °C to about 260 °C, or between about 50 °C to about 260 °C, or between about 0 °C to about 250 °C, or between about 10 °C to about 250 °C, or between about 20 °C to about 250 °C, or between about 30 °C to about 250 °C, or between about 40 °C to about 250 °C, or between about 50 °C to about 250 °C, or between about 0 °C to about 240 °C, or between about 10 °C to about 240 °C, or between about 20 °C to about 240 °C, or between about 30 °C to about 240 °C, or between about 40 °C to about 240 °C, or between about 50 °C to about 240 °C, or between about 0 °C to about 230 °C, or between about 10 °C to about 230 °C, or between about 20 °C to about 230 °C, or between about 30 °C to about 230 °C, or between about 40 °C to about 230 °C, or between about 50 °C to about 230 °C, or between about 0 °C to about 220 °C, or between about 10 °C to about 220 °C, or between about 20 °C to about 220 °C, or between about 30 °C to about 220 °C, or between about 40 °C to about 220 °C, or between about 50 °C to about 220 °C, or between about 0 °C to about 210 °C, or between about 10 °C to about 210 °C, or between about 20 °C to about 210 °C, or between about 30 °C to about 210 °C, or between about 40 °C to about 210 °C, or between about 50 °C to about 210 °C, or between about 0 °C to about 200 °C, or between about 10 °C to about 200 °C, or between about 20 °C to about 200 °C, or between about 30 °C to about 200 °C, or between about 40 °C to about 200 °C, or between about 50 °C to about 200 °C, or between about 0 °C to about 190 °C, or between about 10 °C to about 190 °C, or between about 20 °C to about 190 °C, or between about 30 °C to about 190 °C, or between about 40 °C to about 190 °C, or between about 50 °C to about 190 °C, or between about 0 °C to about 180 °C, or between about 10 °C to about 180 °C, or between about 20 °C to about 180 °C, or between about 30 °C to about 180 °C, or between about 40 °C to about 180 °C, or between about 50 °C to about 180 °C, or between about 0 °C to about 170 °C, or between about 10 °C to about 170 °C, or between about 20 °C to about 170 °C, or between about 30 °C to about 170 °C, or between about 40 °C to about 170 °C, or between about 50 °C to about 170 °C, or between about 0 °C to about 160 °C, or between about 10 °C to about 160 °C, or between about 20 °C to about 160 °C, or between about 30 °C to about 160 °C, or between about 40 °C to about 160 °C, or between about 50 °C to about 160 °C, or between about 0 °C to about 150 °C, or between about 10 °C to about 150 °C, or between about 20 °C to about 150 °C, or between about 30 °C to about 150 °C, or between about 40 °C to about 150 °C, or between about 50 °C to about 150 °C, or between about 0 °C to about 140 °C, or between about 10 °C to about 140 °C, or between about 20 °C to about 140 °C, or between about 30 °C to about 140 °C, or between about 40 °C to about 140 °C, or between about 50 °C to about 140 °C, or between about 0 °C to about 130 °C, or between about 10 °C to about 130 °C, or between about 20 °C to about 130 °C, or between about 30 °C to about 130 °C, or between about 40 °C to about 130 °C, or between about 50 °C to about 130 °C, or between about 0 °C to about 120 °C, or between about 10 °C to about 120 °C, or between about 20 °C to about 120 °C, or between about 30 °C to about 120 °C, or between about 40 °C to about 120 °C, or between about 50 °C to about 120 °C, or between about 0 °C to about 110 °C, or between about 10 °C to about 110 °C, or between about 20 °C to about 110 °C, or between about 30 °C to about 110 °C, or between about 40 °C to about 110 °C, or between about 50 °C to about 110 °C, or between about 0 °C to about 100 °C, or between about 10 °C to about 100 °C, or between about 20 °C to about 100 °C, or between about 30 °C to about 100 °C, or between about 40 °C to about 100 °C, or between about 50 °C to about 100 °C, or between about 0 °C to about 90 °C, or between about 10 °C to about 90 °C, or between about 20 °C to about 90 °C, or between about 30 °C to about 90 °C, or between about 40 °C to about 90 °C, or between about 50 °C to about 90 °C, or between about 0 °C to about 80 °C, or between about 10 °C to about 80 °C, or between about 20 °C to about 80 °C, or between about 30 °C to about 80 °C, or between about 40 °C to about 80 °C, or between about 50 °C to about 80 °C, or between about 0 °C to about 70 °C, or between about 10 °C to about 70 °C, or between about 20 °C to about 70 °C, or between about 30 °C to about 70 °C, or between about 40 °C to about 70 °C, or between about 50 °C to about 70 °C. A person of skill in the art would know how to measure a boiling point of any given substance. Unless otherwise specified, the boiling points refer to boiling points taken at atmospheric pressure.

[0079] In embodiments, wherein the volatile active may be a gaseous volatile active at 20 °C the boiling point may be from between about -200 °C to about 0 °C, or from about -150 °C to about 0 °C, or -100 °C to about 0 °C, or about -100 °C to about -50 °C.

[0080] All of the vapor pressure ranges defined in the preceding paragraphs and all of the boiling points defined in the preceding paragraphs are considered explicitly disclosed with all of the molecular weight ranges in the preceding paragraphs.

[0081] The formulation described herein is postulated to act as a platform formulation, specifically suitable for delivery via an MDI, for a wide range of volatile actives as defined by the above vapor pressure and/or molecular weight range values. The platform formulation may be modified by simple trial and error within the values defined herein to be optimal for each active. The number of components in the formulation are small and the relative amounts are within well-defined ranges thereby not presenting a burden, in light of the present disclosure, to a skilled person to formulate a variety of volatile actives therein.

[0082] In embodiments, the volatile active may be selected from the group consisting of a volatile anaesthetic, a volatile vasodilator, a volatile sedative, and a volatile analgesic.

[0083] In embodiments, the volatile active may be selected from the group consisting of a volatile anaesthetic, a volatile vasodilator, a volatile sedative, and a volatile analgesic having a molecular weight of between about 100 g/mol to about 300 g/mol, or between about 140 g/mol to about 250 g/mol.

[0084] In embodiments, when the volatile active may be a volatile anaesthetic or analgesic then it may be a halogenated volatile anaesthetic or analgesic.

[0085] In embodiments, when the volatile active may be a volatile anaesthetic then it may be a halogenated ether volatile anaesthetic or analgesic.

[0086] In embodiments, when the volatile active may be a volatile anaesthetic then it may be a fluorinated volatile anaesthetic or analgesic. [0087] In embodiments, when the volatile active may be a volatile anaesthetic then it may be a fluorinated ether volatile anaesthetic or analgesic.

[0088] In embodiments, when the volatile active may be a volatile anaesthetic then it may be a chlorinated and/or fluorinated volatile anaesthetic or analgesic.

[0089] In embodiments, when the volatile active may be a volatile anaesthetic then it may be a chlorinated and fluorinated ether volatile anaesthetic or analgesic.

[0090] In embodiments, when the volatile active may be a volatile anaesthetic then it may be selected from the group consisting of methoxyflurane, isoflurane, desflurane, sevoflurane, and halothane.

[0091] In embodiments, when the volatile active may be a volatile anaesthetic then it may be a chlorinated and fluorinated ether volatile anaesthetic or analgesic having a molecular weight of between about 100 g/mol to about 300 g/mol, or between about 140 g/mol to about 250 g/mol.

[0092] In embodiments, when the volatile active may be a volatile sedative then it may be a volatile nitrite. Optionally, the volatile nitrite may be selected from one or more isomers of amyl nitrite.

[0093] In embodiments, the volatile active may be selected from the group consisting of nitroglycerin, methoxyflurane, isoflurane, desflurane, sevoflurane, halothane, nitrous oxide, an amyl nitrite and propofol.

[0094] In embodiments, the volatile active is nitroglycerin or methoxyflurane.

[0095] In an embodiment, the volatile active may be nitroglycerin. Nitroglycerin is a vasodilatory drug used to treat cardiac disorders, such as anginal chest pain.

Nitroglycerin is usually given via the oral route in form of tablets or intravenously but can also be delivered via sublingual or tablet sprays which have been shown to have much quicker onsets.

[0096] In an embodiment, the volatile active may be methoxyflurane. Methoxyflurane is a fast-acting anaesthetic and/or analgesic used in acute pain management. While often used for the treatment of pain it may also be classified as an anaesthetic. Due to its high volatility, it is commonly administered through inhalation. [0097] In an embodiment, the volatile active may be isoflurane. Isoflurane is an anaesthetic used to induce and maintain general anaesthesia. Due to its high volatility, it is usually delivered via inhalation.

[0098] In an embodiment, the volatile active may be desflurane. Desflurane is a general anaesthetic commonly used to induce and maintain general anaesthesia. It is usually delivered via inhalation.

[0099] In an embodiment, the volatile active may be sevoflurane. Sevoflurane is a volatile anaesthetic used for induction and maintenance of general anaesthesia. Due to its high volatility, it is usually administered via inhalation.

[0100] In an embodiment, the volatile active may be halothane. Halothane is an inhalational anaesthetic used to induce and maintain general anaesthesia.

[0101] In an embodiment, the volatile active may be nitrous oxide.

[0102] In an embodiment, the volatile active may be an isomer of amyl nitrite. Amyl nitrites may be used to treat cardiac disorders, such as heart diseases and angina. Due to its high volatility, it is usually delivered via inhalation. In embodiments, the amyl nitrite isomer may be selected from isopropyl nitrite, isobutyl nitrite and butyl nitrite. [0103] In an embodiment, the volatile active may be propofol. Propofol, also known as 2,6-Diisopropylphenol, is an anaesthetic used to induce and maintain general anaesthesia. It is usually administered through intravenous injections.

[0104] In embodiments, the propellant may be a hydrofluorocarbon propellant.

[0105] In embodiments, the hydrofluorocarbon propellant may be a hydrofluoroalkane or hydrofluoroalkene.

[0106] In an embodiment, the hydrofluoroalkane or hydrofluoroalkene propellant may be selected from the group consisting of 1,1,2,2-tetrafluoroethane (HF A 134a), 1,1- difluoroethane (HFA 152a), 1,1,1,2,3,3-heptafluoropropane (HFA 227) and trans- 1,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze). These hydrofluoroalkanes and hydrofluoroalkenes are particularly effective as propellants and have no adverse effect on the human body.

[0107] In a preferred embodiment, the propellant may be selected from the group consisting of HFA 134a, HFA 152a and HFO 1234ze. [0108] In embodiments, the propellant may be present in at least 90% w/w of the entire formulation, or at least 92% w/w of the entire formulation, or at least 94% w/w of the entire formulation, or at least 95% w/w of the entire formulation.

[0109] 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.

[0110] In embodiments, the Ci to Ce alcohol may be selected from methanol, ethanol, propanol and isopropanol.

[0111] In a preferred embodiment, the Ci to Ce alcohol may be ethanol. The use and amount of ethanol may provide benefits for the solubility of the volatile active in the formulation. It is believed that particular levels of ethanol and glycol create an ideal balance in the solubility and partitioning, within the particle, of each component and appropriately retain the volatile active on this basis within the particle. Decreasing the ethanol content below certain levels may reduce the solubility profile of the particle such that further undesirable changes have to be made in the levels of other components of the formulation to compensate.

[0112] In embodiments, the Ci to Ce alcohol content may be between about 2% to about 8% w/w, or between about 2% to about 7% w/w, or between about 2% or about 6% w/w, or between about 2% to about 5% w/w, or between about 3% to about 8% w/w, or between about 3% to about 7% w/w, or between about 3% to about 6% w/w, or between about 3% to about 5% w/w, or between about 4% to about 8% w/w, or between about 4% to about 7% w/w, or between about 4% to about 6% w/w, or between about 5% to about 7% w/w, of the entire formulation.

[0113] In embodiments, the Ci to Ce alcohol content may be about 6% w/w, or about 5.5% w/w, or about 5% w/w, or about 4.5% w/w, or about 4% w/w of the entire formulation.

[0114] In embodiments, the glycol may be selected from the group consisting of propylene glycol, polypropylene glycol and polyethylene glycol.

[0115] In a preferred embodiment, the glycol may be propylene glycol.

[0116] Without wishing to be bound by theory it is hypothesised that a certain level of propylene glycol, on a % w/w basis, provides for encapsulation of the volatile active both within and following expulsion from the MDI. This may be essential to avoid the volatile active simply flashing out of the formulation along with the propellant and some of the ethanol immediately after activation of the MDI. It is postulated that these levels of propylene glycol retard the movement of the active towards the outer surface of the formed particle from which it could escape prior to delivery to the subject’s lungs. The relative amounts of ethanol to propylene glycol are important in achieving this appropriate solubility and release profile for the active as well as providing for a desirable particle size.

[0117] In embodiments, the glycol content may be between about 1.5% to about 5.0% w/w, or between about 2.0% to about 5.0% w/w, or between about 2.5% to about 5.0% w/w, or between about 3.0% to about 5.0% w/w, or between about 1.5% to about 4.5% w/w, or between about 2.0% to about 4.5% w/w, or between about 2.5% to about 4.5% w/w, or between about 1.5% to about 4.0% w/w, or between about 2.0% to about 4.0% w/w, or between about 2.5% to about 4.0% w/w, or between about 3.0% to about 5.0% w/w, of the entire formulation.

[0118] In embodiments, the glycol content may be present in the inhalable formulation at about 4.0% w/w, about 3.5% w/w, about 3.0% w/w, about 2.5% w/w, or about 2.0% w/w of the entire formulation.

[0119] In some embodiments, it may be beneficial to further add glycerol to the inhalable formulation to modify the properties thereof. In another embodiment, the formulation does not contain any glycerol.

[0120] In embodiments, the glycerol may be present at between about 0.01% to about 0.5% w/w, between about 0.05% to about 0.25% w/w, or between about 0.075% to about 0.2% w/w, of the entire formulation.

[0121] In another embodiment, the glycerol may be present at about 0.1% w/w of the entire formulation.

[0122] The careful balance of all components in the formulation is important for the invention to provide the observed benefits of delivering the volatile active deep to the lungs. Because of the similar chemical and physical properties of nicotine and the volatile actives as defined in the present invention, such as nitroglycerin and methoxyflurane, it may be reasonably expected that these compounds behave similarly to nicotine in the tests as described in the Examples. As demonstrated in the Examples, if the ethanol content is too low or no propylene glycol was added to the formulation, most of the nicotine was trapped in the device instead of being delivered appropriately to the subject. This is representative of nicotine escaping from the particle within the oral cavity or pharynx of the user and does not provide for delivery to the lungs.

[0123] In embodiments, the inhalable formulation may further comprise a flavourmasking agent. Flavour-masking agents refer to a variety of flavour materials of natural or synthetic origin. They include single compounds and mixtures and are commonly employed in formulating ingestible compositions to improve acceptance of the user. Preferably, the flavour-masking agent has flavour properties that enhance the user’s sensory experience of the inhalable formulation.

[0124] Suitable flavours and aromas include, but are not limited to, any one or more natural or synthetic flavour or aroma, such as chocolate, liquorice, citrus and other fruit flavours, 1-menthol, gamma octalactone, vanillin, ethyl vanillin, breath freshener flavours, spice flavours such as cinnamon, methyl salicylate, linalool, bergamot oil, geranium oil, lemon oil, and ginger oil, and the like.

[0125] Other suitable flavours and aromas may include flavour compounds selected from the group consisting of an acid, an alcohol, an ester, an aldehyde, a ketone, a pyrazine, combinations or blends thereof and the like. Suitable flavour compounds may be selected, for example, from the group consisting of phenylacetic acid, solanone, megastigmatrienone, 2-heptanone, benzylalcohol, cis-3-hexenyl acetate, valeric acid, valeric aldehyde, ester, terpene, sesquiterpene, nootkatone, maltol, damascenone, pyrazine, lactone, anethole, iso-s valeric acid, combinations thereof, and the like.

[0126] In embodiments, the inhalable formulation does not comprise an aroma and/or flavour-enhancing oil. In embodiments, the inhalable formulation does not comprise a menthol-containing essential oil or peppermint oil.

[0127] The size of the particles in the inhalable formulation may play an important role to achieve the desired delivery to the deep lungs. In embodiments, the particle size may be less than 10 pm, or less than 5 pm. It may be beneficial to have an even smaller particle size of between 0.5 pm to 3.5 pm or between 0.5 pm to 2 pm to allow the particles to reach the deep lung. In a preferred embodiment, the particle size may be between 0.5 pm to 2 pm or between 0.5 pm to 1 pm. [0128] In embodiments of the first aspect, the disclosure resides in an inhalable formulation consisting essentially of or consisting of: a volatile active; at least 90% w/w of a propellant; between about 2% to about 8% w/w of a Ci to G> alcohol; and between about 1.5% to about 5% w/w of a glycol, wherein the volatile active is not nicotine, or a pharmaceutically acceptable derivative or salt thereof.

[0129] In embodiments of the first aspect, the disclosure resides in an inhalable formulation consisting essentially of or consisting of: a volatile active, wherein the volatile active is selected from the group consisting of a volatile anaesthetic, a volatile vasodilator, a volatile sedative, and a volatile analgesic; at least 90% w/w of a propellant; between about 2% to about 8% w/w of a Ci to Ce alcohol; and between about 1.5% to about 5% w/w of a glycol, wherein the volatile active is not nicotine, or a pharmaceutically acceptable derivative or salt thereof.

[0130] In embodiments of the first aspect, the disclosure resides in an inhalable formulation consisting essentially of or consisting of: a volatile active, wherein the volatile active is selected from the group consisting of a volatile anaesthetic, a volatile vasodilator, a volatile sedative, and a volatile analgesic having a molecular weight of between about 100 g/mol to about 300 g/mol, or between about 140 g/mol to about 250 g/mol; at least 90% w/w of a propellant; between about 2% to about 8% w/w of a Ci to Ce alcohol; and between about 1.5% to about 5% w/w of a glycol, wherein the volatile active is not nicotine, or a pharmaceutically acceptable derivative or salt thereof.

[0131] In embodiments of the first aspect, the disclosure resides in an inhalable formulation consisting essentially of or consisting of: a volatile active selected from the group consisting of nitroglycerin, methoxyflurane, isoflurane, desflurane, sevoflurane, halothane, nitrous oxide, an amyl nitrite and propofol, preferably selected from the group consisting of nitroglycerin and methoxyflurane; at least 90% w/w of a propellant; between about 2% to about 8% w/w of a Ci to G> alcohol; and between about 1.5% to about 5% w/w of a glycol, wherein the volatile active is not nicotine, or a pharmaceutically acceptable derivative or salt thereof.

[0132] In embodiments of the first aspect, the disclosure resides in an inhalable formulation comprising or consisting essentially of or consisting of: nitroglycerin or methoxyflurane; at least 90% w/w of a propellant, optionally of a hydrofluorocarbon propellant, optionally of a propellant selected from the group consisting of 1, 1,2,2- tetrafluoroethane (HF A 134a), 1,1 -difluoroethane (HF A 152a), 1, 1,1, 2,3,3- heptafluoropropane (HFA 227) and traw -l,3,3,3-tetrafhroroprop-l-ene (HFO 1234ze); between about 2% to about 8% w/w of a Ci to Ce alcohol, optionally between about 3.5% to about 6% w/w of a Ci to Ce alcohol, optionally wherein the Ci to Ce alcohol is ethanol; and between about 1.5% to about 5% w/w of a glycol, optionally between about 2.0% to about 4% w/w of a glycol, optionally wherein the glycol is propylene glycol, wherein the formulation optionally further comprises glycerol at between about 0.01% to about 0.5% w/w, or between about 0.05% to about 0.25% w/w, or between about 0.075% to about 0.2% w/w, of the entire formulation.

[0133] In embodiments wherein the inhalable formulation may consist or consist essentially of the recited components then the volatile active may have a molecular weight of between 100 g/mol to 250 g/mol.

[0134] In embodiments, when the volatile active is a volatile anaesthetic then it may be a chlorinated and fluorinated ether volatile anaesthetic or analgesic

[0135] In a second aspect, the disclosure resides in a metered dose inhaler comprising an inhalable formulation, said inhalable formulation comprising: a volatile active; at least 90% w/w of a propellant; between about 2% to about 8% w/w of a Ci to G> alcohol; and between about 1.5% to about 5% w/w of a glycol, wherein the volatile active is not nicotine, or a pharmaceutically acceptable derivative or salt thereof.

[0136] In embodiments, the inhalable formulation of the second aspect is that as described in any embodiment of the first aspect.

[0137] In embodiments, the inhalable formulation of the second aspect comprises or consists essentially of or consists of: nitroglycerin or methoxyflurane; at least 90% w/w of a propellant, optionally of a hydrofluorocarbon propellant, optionally of a propellant selected from the group consisting of 1, 1,2,2- tetrafluoroethane (HF A 134a), 1,1 -difluoroethane (HF A 152a), 1, 1,1, 2,3,3- heptafluoropropane (HFA 227) and traw -l,3,3,3-tetrafhioroprop-l-ene (HFO 1234ze); between about 2% to about 8% w/w of a Ci to Ce alcohol, optionally between about 3.5% to about 6% w/w of a Ci to Ce alcohol, optionally wherein the Ci to Ce alcohol is ethanol; and between about 1.5% to about 5% w/w of a glycol, optionally between about 2.0% to about 4% w/w of a glycol, optionally wherein the glycol is propylene glycol, wherein the formulation optionally further comprises glycerol at between about 0.01% to about 0.5% w/w, or between about 0.05% to about 0.25% w/w, or between about 0.075% to about 0.2% w/w, of the entire formulation.

[0138] 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. Particularly suitable MDIs will be any designed for use in the delivery of volatile compounds.

[0139] The MDIs which are available all have a container which can be attached to the MDI or which may be built into it and which can contain the active agent being delivered. Such containers are adapted to contain a pressurised fluid and often are designed for containing hydrofluorocarbon-type propellant formulations.

[0140] 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.

[0141] 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 0.35 mm. In an embodiment, the aperture may have a diameter of about 0.22 mm or about 0.30 mm.

[0142] In a third aspect, the disclosure resides in a method of delivering a volatile active to a subject including the steps of: providing the inhalable formulation of the first aspect; allowing the subject to inhale the inhalable formulation, to thereby deliver the volatile active to the subject.

[0143] In embodiments of the third aspect, the method of delivering a volatile active may be a method of delivering the volatile active to the lungs of the subject.

[0144] The careful design and balance of all components of the inhalable formulation of the present disclosure aim to encapsulate the active within the fluid particle during the droplet formation and aerosol maturation process. The careful balance of ethanol, propylene glycol and, in certain optional embodiments, glycerol is aimed to hinder diffusion of the active to the particle surface which may result in delayed evaporation into the surrounding airstream and, consequently, this may result in the delivery of the active to the deep lungs of the subject. The formulations may also facilitate delivery of the volatile active in a form not otherwise possible i.e., by inhalation.

[0145] This is a distinct advantage of the formulation of the present disclosure. Most prior art approaches either use significantly more volatile fluid components or employ relevant amounts of excipients which cannot achieve a balance between solubility of the active and retention of the active within the fluid droplets following expulsion from the MDI. Most known approaches simply ignore the complex thermodynamics of this multi-component system and result in rapid loss of the volatile active including deposition of the active within the oral cavity or pharynx of the user thereby resulting in a harsh sensation in the pharynx and a failure to properly deliver the active to the lungs.

[0146] The approach described herein may also facilitate delivery of a reduced dose of the volatile active due to improved systemic available via pulmonary delivery.

[0147] In a fourth aspect, the disclosure resides in a method of treating or preventing a disease, disorder or condition in a subject including the steps of: providing the inhalable formulation of the first aspect to the subject; allowing the subject to inhale the formulation, to thereby treat or prevent the disease, disorder or condition in the subject. [0148] The inhalable formulation may be as described in any embodiment of the first aspect. The delivery may be as described in the second or third aspect.

[0149] In embodiments, the inhalable formulation of the third aspect comprises or consists essentially of or consists of: nitroglycerin or methoxyflurane; at least 90% w/w of a propellant, optionally of a hydrofluorocarbon propellant, optionally of a propellant selected from the group consisting of 1, 1,2,2- tetrafhioroethane (HF A 134a), 1,1 -difluoroethane (HF A 152a), 1, 1,1, 2,3,3- heptafluoropropane (HFA 227) and trans- ,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze); between about 2% to about 8% w/w of a Ci to G> alcohol, optionally between about 3.5% to about 6% w/w of a Ci to Ce alcohol, optionally wherein the Ci to Ce alcohol is ethanol; and between about 1.5% to about 5% w/w of a glycol, optionally between about 2.0% to about 4% w/w of a glycol, optionally wherein the glycol is propylene glycol, wherein the formulation optionally further comprises glycerol at between about 0.01% to about 0.5% w/w, or between about 0.05% to about 0.25% w/w, or between about 0.075% to about 0.2% w/w, of the entire formulation.

[0150] 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. Experimental

[0151] The following examples are shown for nicotine which can be considered to have representative chemical and physical properties to the volatile actives of the inhalable formulation of the present invention.

Materials:

• 15ml glass Aerosol tubes, St Gobain, Batch 711175

• 14ml C0842 plasma coated canisters, Presspart, Batch PPB0021336 and 19ml plasma treated canisters, Presspart, Batch PPB0022230

• 50pl Metering Valves for inverted use (EPDM gaskets EF327), Bespak and Aptar

• Continuous spray valve for glass bottle inverted use, Bespak, Batch BK0642138

• 0.30mm BK634TM Actuators, Bespak, Batch BK0486487

• 0.22mm BK633TM Actuators, Bespak, Batch BK0130974

• 0.23mm Actuators, Presspart, Batch PPT0031512

• Nicotine, Sigma, Batch S7840677047

• Glycerol, Sigma, Batch BCBK0214V

• Propylene Glycol, Batch SHBM3251

• Ethanol, SLS, Batch 315327, and Sigma, Batch SHBL0003

• Lactic Acid 90%, Sigma, Batch BCCF1169

• HF A 134a, Mexichem, Batch RB21634-1, and Zephex MDI, Mexichem

• HF A 152a, Mexichem

• HFO 1234ze, Honeywell

Methodology:

[0152] Metered dose inhalers (50pg/50pl Nicotine dose) were manufactured by weight using a two-stage fill methodology. Predetermined quantities of Nicotine, Ethanol, Propylene Glycol, Glycerol and Lactic acid were weighed into a glass stoppered conical flask and mixed to form clear bulk solutions. Bulks were weighed into either 15ml St Gobain glass bottle aerosol tubes or Presspart 14ml C0842 plasma coated canisters; crimped with Bespak valves; and gassed with HFA 134a propellant using a Pamasol P2016 laboratory filling plant.

[0153] Formulations packaged in glass bottles were used to confirm the final formulations were clear solutions at T = 5°C and T=20°C.

[0154] Formulations packaged in 14ml canisters (Presspart) and 50pl valves (Bespak) were used to characterise nicotine delivery. All MDIs were actuated using BK630 series Actuators (Bespak).

[0155] Table 1 presents the formulations investigated. Batch OZ211018/DS/A (see Table 1) was based upon earlier known formulations provided by the client. However, a 50pl (rather than 75 pl) metering valve was utilised; thus, nicotine and lactic acid concentrations were adjusted accordingly.

Table 1 : Formulations investigated

[0156] Volatility of formulations were evaluated by use of a Dosage Unit Sampling Apparatus (DUSA), USP methodology with the addition of a Drechsel Gas Trap containing 70ml of diluent, see FIG 1.

[0157] In accordance with USP <601>, particle size distributions were evaluated by next generation impactor fitted with USP induction port (NGI, Copley Scientific Limited) (see FIG 2). The NGI was chilled for 2 hours at 5°C before sampling two doses from each test inhaler at flow rate of 30L/min.

[0158] For each test inhaler the drug deposition within each stage of the NGI was determined by quantitative extraction to volume with methanol and determination of nicotine within each test sample by a high-pressure liquid chromatography (HPLC). Drug delivery metrics and particle size distribution was calculated using CITDAS V3.10 software (Copley Scientific Limited).

Example 1: Results for investigated formulations

[0159] Data obtained for the MDI Batches evaluated with the DUSA/Trap Apparatus are presented in Table 2 and FIG 3.

Table 2: Results: DUSA/trap nicotine mass observed (in order of decreasing vapour trap mass)

[0160] Except for the very low ethanol formulation (0.2% w/w ethanol), actuator nicotine deposition was similar for all batches (range: 3-4pg; <10% of the target 50pg metered dose). The low ethanol content formulation (batch OZ211018/DS/A) had an actuator nicotine deposition of 12 ± 2pg (24% of the 50pg target dose).

[0161] Metered dose values approached 46 pg (92% of the 50 pg target dose) as the vapour mass measured in the trap decreased. Metered dose was lowest (33 pg, 66% of the target 50pg metered dose) for the formulation with the most nicotine measured within the vapour trap.

[0162] The formulation composition had a key impact upon whether the nicotine was efficiently collected within the DUSA/Filter (particulate) or was passed through to be collected in the vapour trap.

[0163] High nicotine was observed in the vapour trap for formulations not containing low/non-volatile excipients (propylene glycol (PG) and glycerol (VG) respectively).

[0164] Low nicotine was observed in the vapour trap for formulations that did contain low/non-volatile excipients (propylene glycol (PG) and glycerol (VG) respectively).

[0165] However, formulation batch OZ211018/DS/M indicates that 8% w/w ethanol 0.5%w/w VG is not enough to encapsulate the nicotine. Addition of small quantities of PG were required to reduce vapour trap nicotine mass. Furthermore, reduction of ethanol from 8% w/w to 5% w/w further decreased the mass of nicotine in the vapour trap.

[0166] The experiments presented demonstrate an important interplay between the solvent components and indicate that preferred combinations contain approximately 5% w/w ethanol which appears to be an optimal amount to solubilize PG when present within a 2-4% w/w range with an optional but advantageous small addition of VG at approximately 0.1% w/w.

[0167] The particle size distribution data for an additional 50pg/50pl Nicotine, 3%w/w ethanol, 2%w/w PG formulation in HFA 134a for actuator orifice diameters 0.22mm and 0.30mm is shown in FIG 4 and FIG 5. The trace for the 0.22mm orifice diameter is the upper trace (red) in both FIG 4 and FIG 5 at the 5pm mass median aerodynamic diameter (MMAD) point with the 0.30mm orifice being the lower trace in each of those figures. A fine particle dose <5 pm of 22pg and 15 pg was observed for each respective actuator. A further reduction in PG towards 1% w/w would reduce the mass median aerodynamic diameter (MMAD) from the rather high value of 4.2pm (0.30mm) and 3.7pm (0.22mm) to approximately 3pm. It is interesting to note that no nicotine was observed in the vapour trap for either of these impactor measurements and metered dose values were 44 g and 42 pg respectively. When evaluated with the DUSA/Filter apparatus a metered dose of 43 pg was observed with just 4pg in the vapour trap.

Example 2: Reduction of propylene glycol (PG) content to 1% w/w in 3% w/w ethanol

[0168] In an additional evaluation, PG content was reduced to l%w/w. It was necessary to include 3%w/w ethanol content to maintain miscibility of the formulation. Glycerol was also included at a level of 0.09%w/w. The observed drug delivery data is presented in Table 3. Three canisters of the batch were evaluated in duplicate by Next Generation Impactor (NGI; n = 6). Metered dose and delivered dose were close to target 51±lpg and 47±lpg respectively. Fine particle dose <5pm aerodynamic diameter was 28 ± 2pg (FPF = 60 ± 5%) and MMAD reduced to 3.4 ± 0.2pm.

Table 3: Drug Delivery observed by NGI for 50pg/50pl nicotine, 0.4%w/w lactic acid, 3%w/w ethanol, 0.09%w/w glycerol in HFA 134a (Batch: OZ211122/D AL/ A, Cans 1, 2 & 3).

[0169] However, reducing the PG content also effected the ability for nicotine encapsulation. When evaluated by DUSA with vapour trap, 13.7 ± 7.0pg (out of a total of 47.7 ± 3.1 pg) reached the trap. This would rank as the fourth most volatile formulation described in this patent (according to the data presented in Table 2 and FIG. 1), suggesting that 2 - 4%w/w PG is required within low ethanol content (e.g. 5%w/w) formulations to achieve a low volatile “encapsulated” nicotine formulation.

Reducing PG or increasing ethanol content has been observed to increase nicotine volatility.

Table 4: Drug Delivery observed by DUSA/Vapour Trap for 50pg/50pl nicotine, 0.4%w/w lactic acid, 3%w/w ethanol, 0.09%w/w glycerol in HFA 134a (Batch: OZ211122/D AL/ A, Cans 1, 2 & 3).

[0170] In conclusion, it is possible to control the volatility of nicotine delivered from a metered dose inhaler. Inclusion of propylene glycol (PG), glycerol (VG) and ethanol at low levels has demonstrated that nicotine delivery approaches the performance of a non-volatile molecule. However, when reducing PG to l%w/w and ethanol to 3%w/w the volatility of nicotine was “restored”; demonstrating that careful balancing of formulation content is required if a low volatile nicotine formulation is to be achieved.

Example 3: Formulation with HFA 134a

[0171] The following table shows a formulation comprising nicotine, lactic acid, ethanol, propylene glycol and propellant HFA 134a.

Table 5: Formulation for MDI nicotine.

Example 4: Alternative Propellants in MDI Nicotine Formulation

[0172] In the following experiments, the propellant HFA 134a has been replaced with HFA 152a and HFO 1234ze and particle size distribution was measured.

[0173] Metered dose inhalers (50pg/50pl Nicotine dose) were manufactured by weight using a two-stage fill methodology. Pre-determined quantities of Nicotine, Ethanol, Propylene Glycol, and Lactic acid were weighed into a glass stoppered conical flask and mixed to form clear bulk solutions. Bulks were weighed into either 15ml St Gobain glass bottle aerosol tubes or Presspart 19ml C0128 plasma treated canisters; crimped with Aptar valves; and gassed with propellant using a Pamasol P2016 laboratory filling plant.

[0174] Formulations packaged in glass bottles were used to confirm the final formulations were clear solutions at T = 5°C and T=20°C (see FIG 6).

[0175] Formulations packaged in 19ml Plasma treated canisters (Presspart) and 50pl valves (Aptar) were used to characterise Nicotine delivery. All MDIs were actuated using Presspart 0.23mm actuators (Presspart). Tables 6 and 7 presents the formulations investigated.

Table 6: Nicotine formulation with HFA 152a as propellant.

Table 7: Nicotine formulation with HFO 1234ze as propellant.

[0176] Particle size distributions was evaluated by Anderson Cascade Impactor fitted with a USP induction port (USP Apparatus 1). Dose uniformity was determined by DUSA (USP Apparatus A). Anderson Cascade Impactors, USP induction ports and DUSA apparatus were chilled overnight at 5°C by refrigeration.

[0177] A summary of the observed Drug Delivery Metrics is presented in Table 8.

Table 8: Summary of Drug Delivery Metrics

[0178] The metered dose was consistent for all formulations and close to the 50pg/50pl target.

[0179] Shot weights and drug delivery metrics were consistent between formulations containing HFA 134a and HFO1234ze propellants. The lower shot weight of the HFA 152a formulation is a consequence of the low density of the propellant (0.9g/ml) relative to HFA 134a (1.226g/ml) and HFO 1234ze (1.17g/ml).

[0180] In conclusion, the results demonstrate that each of the three tested propellants (HFA 134a, HFA 152a and HFO1234ze) can be used to prepare MDI nicotine formulations with the desired characteristics.

Example 5: Preparation of inhalable formulations with nitroglycerine, methoxyflurane, isoflurane, an amyl nitrite and propofol [0181] Formulations with nitroglycerine, methoxyflurane, isoflurane, amyl nitrites and propofol will be prepared in a similar manner as described in the Methodology section above and will be tested as described in Examples 1 to 4.

Example 6: Inhaled anaesthetics in clinical use

[0182] Table 9 describes the chemical and physical properties of a number of the anaesthetics of interest (https://www.openanesthesia.org/keywords/inhaled-anesthetics- in-clinical-use/), which information and website is hereby incorporated by reference. Table 9: Properties of inhaled anaesthetics.

Comparison of inhaled anaesthetics. MAC: minimum alveolar concentration. Solubility coefficient of 0.65 means that at steady state, 1ml of blood will have 0.65 as much of sevofhirane compared to 1.0 in the alveolar gas. Adapted from Forman SA, Ishizawa Y. Inhaled Anesthetic Uptake, Distribution, Metabolism, and Toxicity. In: Miller RD, Gropper MA, et al. Miller's Anesthesia. Philadelphia, PA 9th ed. Elsevier. 2019: 509- 39.

Measurement of Vapor Pressure

[0183] The vapor pressure of the volatile active may be measured by a number of approaches which are well-known in the art. For example, the vapour pressure is measured by an isoteniscope. This device consists of a submerged manometer and container holding the substance whose vapour pressure is being measured. The liquid in which the manometer is submerged is heated to the required temperature, here 25°C, and the open end of the manometer is connected to a pressure measuring device. A vacuum pump is used to adjust the pressure of the system and purify the sample.

[0184] Alternatively, the Knudsen Effusion Method may be used with a variety of commercially available instruments. For vapor pressure values described in this specification, the following approach is preferred, as described in Measuring Vapor Pressure with an Isoteniscope: A Hands-On Introduction to Thermodynamic Concepts, Wenqian Chen, Andrew J. Haslam, Andrew Macey, Umang V. Shah, and Clemens Brechtelsbauer; Journal of Chemical Education 2016 93 (5), 920-926 DOI: 10.1021/acs.jchemed.5b00990 which is hereby incorporated by reference, https://pubs.acs.org/doi/full/10.1021/acs.jchemed.5b00990.

[0185] Briefly, equipment used includes an isoteniscope (GPE Scientific Ltd., Leighton Buzzard, U.K.), a ballast tank (GPE Scientific Ltd., Leighton Buzzard, U.K.), a diaphragm vacuum pump (ILMVAC GmbH, Ilmenau, Germany), a piezo pressure transducer with digital pressure display (MKS Instruments, Inc., Andover, MA), two valves (GPE Scientific Ltd., Leighton Buzzard, U.K.), a glass cold trap (GPE Scientific Ltd., Leighton Buzzard, U.K.), and a water bath (Julabo UK Ltd., Peterborough, U.K.) [0186] The bulb of the isoteniscope is filled with the test liquid to approximately three-quarter height, so that no liquid flows into the U-tube when the isoteniscope is placed vertically. The isoteniscope is then connected to the ballast tank which is at atmospheric pressure (valves 1 and 2 are closed), before it is placed in the water bath, which is set to 25 °C. Valve 2 is opened slowly to allow the vacuum pump to evacuate the air from the system. As the pressure inside the system decreases below the vapor pressure of the test liquid at 25 °C, the test liquid in the bulb of the isoteniscope starts boiling. The vacuum is maintained for another 5 min in order to remove as much air from the system as possible. Valve 2 is then closed and the vacuum pump is switched off. The isoteniscope is tilted slightly so that some of the test liquid flows into the U- tube. Once the bubbling liquid fills up the U-tube, the U-tube is placed vertically.

[0187] Valve 1 is opened slowly to allow air to enter the ballast tank in order to increase its internal pressure. Boiling ceases and the liquid level on the ballast tank side of the U-tube decreases slowly until it is level with the bulb-side liquid level. Valve 1 is then closed. The pressure indicated by the pressure sensor is recorded, as is the temperature of the water bath. The water bath temperature is increased by 5 °C and valve 1 is opened gradually to maintain the balanced liquid levels in the U-tube. Once the temperature of the water bath stabilizes and the liquid levels in the U-tube are at equal height, valve 1 is closed. The pressure indicated by the pressure sensor is recorded with the temperature of the water bath. This procedure is iterated until the highest target temperature is reached; then, the entire experiment is repeated to check for data consistency.

[0188] Further details on the approach may be found here and are incorporated by reference: https://pubs.acs.org/doi/suppl/10.1021/acs.jchemed.5b00990/suppl_file/ed5b00990_si 001. pdf

Claims

CLAIMS:

1. An inhalable formulation comprising: a volatile active; at least 90% w/w of a propellant; between 2%-8% w/w of a Ci to Ce alcohol; and between 1.5%-5% w/w of a glycol wherein the volatile active is not nicotine, or a pharmaceutically acceptable derivative or salt thereof.

2. The inhalable formulation of claim 1, wherein the volatile active has a vapour pressure of between about 0.00001 mm Hg to about 900 mm Hg at 20 °C.

3. The inhalable formulation of claim 1 or claim 2, wherein the volatile active has a molecular weight of between about 30 g/mol to about 300 g/mol.

4. The inhalable formulation of any one of the preceding claims, wherein the volatile active is selected from the group consisting of nitroglycerin, methoxyflurane, isoflurane, desflurane, sevoflurane, halothane, nitrous oxide, an amyl nitrite and propofol.

5. The inhalable formulation of any one of the preceding claims, wherein the propellant is a hydrofluorocarbon propellant.

6. The inhalable formulation of claim 5, wherein the hydrofluorocarbon propellant is selected from the group consisting of 1,1,2,2-tetrafluoroethane (HFA 134a), 1,1 -difluoroethane (HFA 152a), 1,1,1,2,3,3-heptafhroropropane (HFA 227) and traw -l,3,3,3-tetrafhroroprop-l-ene (HFO 1234ze).

7. 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.

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

9. The inhalable formulation of any one of the preceding claims, wherein the glycol is selected from the group consisting of propylene glycol, polypropylene glycol and polyethylene glycol.

10. The inhalable formulation of any one of the preceding claims, wherein the glycol is propylene glycol.

11. The inhalable formulation of any one of the preceding claims, wherein the Ci to Ce alcohol is present at between 4%-6% w/w of the entire formulation.

12. The inhalable formulation of any one of the preceding claims, wherein the glycol is present at between 2.0%-4.0% w/w of the entire formulation.

13. The inhalable formulation of any one of the preceding claims, wherein the inhalable formulation further comprises glycerol.

14. The inhalable formulation of any one of the preceding claims, wherein the volatile active is nitroglycerin or methoxyflurane.

15. The inhalable formulation of any one of the preceding claims, wherein the formulation comprises or consists essentially of or consists of: nitroglycerin or methoxyflurane; at least 90% w/w of a propellant, optionally of a hydrofluorocarbon propellant, optionally of a propellant selected from the group consisting of 1, 1,2,2- tetrafluoroethane (HF A 134a), 1,1 -difluoroethane (HF A 152a), 1, 1,1, 2,3,3- heptafluoropropane (HFA 227) and traw -l,3,3,3-tetrafhroroprop-l-ene (HFO 1234ze); between about 2% to about 8% w/w of a Ci to Ce alcohol, optionally between about 3.5% to about 6% w/w of a Ci to Ce alcohol, optionally wherein the Ci to Ce alcohol is ethanol; and between about 1.5% to about 5% w/w of a glycol, optionally between about 2.0% to about 4% w/w of a glycol, optionally wherein the glycol is propylene glycol, wherein the formulation optionally further comprises glycerol at between about 0.01% to about 0.5% w/w, or between about 0.05% to about 0.25% w/w, or between about 0.075% to about 0.2% w/w, of the entire formulation.

16. A metered dose inhaler comprising an inhalable formulation, said inhalable formulation comprising: a volatile active; at least 90% w/w of a propellant; between 2%-8% w/w of a Ci to Ce alcohol; and between 1.5%-5% w/w of a glycol, wherein the volatile active is not nicotine, or a pharmaceutically acceptable derivative or salt thereof.

17. The metered dose inhaler of claim 16, wherein the inhalable formulation is as defined in any one or more of claim 1 to claim 15.

18. A method of delivering a volatile active to a subject including the steps of:

(i) providing the inhalable formulation of any one of claims 1 to 15; and

(ii) allowing the subject to inhale the inhalable formulation, to thereby deliver the volatile active to the subject.

19. The method of claim 18, wherein the delivery is delivery of the volatile active to the airways of the subject, preferably to the lungs of the subject.

20. A method of treating or preventing a disease, disorder or condition in a subject, including the steps of:

(i) providing the inhalable formulation of any one of claims 1 to 15; and

(ii) allowing the subject to inhale the inhalable formulation, to thereby treat or prevent the disease, disorder or condition in the subject.

21. The method of any one of claim 16 to claim 20, performed using the metered dose inhaler of claim 16 or claim 17.

22. An inhalable formulation comprising: a volatile active, optionally nitroglycerin or methoxyflurane; at least 90% w/w of a propellant, optionally a hydrofluorocarbon propellant, optionally wherein the hydrofluorocarbon propellant is selected from the group consisting of HF A 134a, HFA 152a, HFA 227 and HFO 1234ze; between 3%-7% w/w, optionally between 3.5%-6.5% w/w or between 4.0%- 6.0% w/w, of a Ci to Ce alcohol such as ethanol; and between 2%-4% w/w of a glycol, such as propylene glycol wherein the volatile active is not nicotine, or a pharmaceutically acceptable derivative or salt thereof.

23. The inhalable formulation of claim 22, wherein the volatile active is selected from the group consisting of a volatile anaesthetic, a volatile vasodilator, a volatile sedative, and a volatile analgesic; optionally wherein the volatile active is selected from the group consisting of nitroglycerin, methoxyflurane, isoflurane, desflurane, sevoflurane, halothane, nitrous oxide, an amyl nitrite and propofol.