Treatment of breakthrough cancer pain

Abstract

The present invention relates to improved method of treating breakthrough cancer pain. In particular the present invention relates to methods and devices for the treatment of breakthrough cancer pain through inhalation of tetrahydrocannabinol.

Description

Related application This application claims priority of Australian provisional application no. 2023904186 (filed on 21 December 2023), the entire contents of which is incorporated herein by reference. Field of the invention The present invention relates to improved method of treating breakthrough cancer pain (BTcP). In particular the present invention relates to methods and devices for the treatment of BTcP through inhalation of tetrahydrocannabinol (THC). Background of the invention BTcP is a heterogenous condition that can generally be described as an episode of severe pain of variable duration that occurs in patients with well-controlled background chronic pain. The overall pooled prevalence of BTcP has been estimated at approximately 59.2% of cancer patients, depending on the adequacy and type of assessment used. BTcP is most common during end-stage disease, and has been estimated to be present in as high as 80.5% of patients in hospice care. National and international guidelines for treatment of BTcP differ. BTcP has significant negative effects on quality of life. Current standard of care treatment for BTcP includes both pharmacological and non-pharmacological interventions. However, both non-pharmacological interventions and breakthrough (“rescue”) medication have been reported not to be effective for all patients. Generally, the use of opioids (typically oral morphine) as needed is recommended for the management of BTcP. There is therefore a continuing need for alternative treatments of BTcP. Reference to any prior art in the specification is not an acknowledgment or suggestion that this prior art forms part of the common general knowledge in any jurisdiction or that this prior art could reasonably be expected to be understood, regarded as relevant, and / or combined with other pieces of prior art by a skilled person in the art. Summary of the invention The present invention is based on the surprising finding that THC is effective in the treatment of BTcP when administered by a pressurized metered dose inhaler (PMDI). The lipophilic nature of phytocannabinoids leads to absorption issues with orally ingested THC. However, the present inhalation dosing circumvents this and leads to increased bioavailability with a rapid time to reach maximum concentration (tmax) and maximum concentration (Cmax), making it well suited to acute application. The invention also relates to a surprisingly effective dose administrable by single actuation of the developed PMDI. In a first aspect, the present invention relates to a method of treating BTcP in a subject, the method comprising administering a therapeutically effective amount of a THC to the subject by inhalation. In a second aspect, the present invention relates to the use of a THC for the manufacture of a medicament for treating BTcP in a subject. In a third aspect, the present invention relates to a composition comprising a THC for use in the treatment of BTcP in a subject. In one embodiment, the method comprises administering to a subject in need thereof by inhalation a therapeutically effective amount of a composition comprising tetrahydrocannabinol (THC), a co-solvent, and a propellant, wherein the composition comprises less than about 3.5% (w / w) THC. In some embodiments, the composition comprises about 0.6% to about 0.7% (w / w) THC. In one embodiment, the THC is administered to the subject at the onset of pain. In one embodiment, the THC is administered to the subject after the onset of pain. In one embodiment, the THC reduces the symptoms of BTcP. In one embodiment, the THC reduces the number of occurrences of pain. In one embodiment, the THC prevents recurrence of pain. In one embodiment, the THC relieves and / or reduces the severity of pain. In one embodiment, the THC reduces the number of BTcP episodes per 24 hours. In one embodiment, the THC reduces pain intensity for at least one BTcP episode per day. In one embodiment, the THC provides pain relief for at least one BTcP episode per day. In one embodiment, the THC provides pain relief such that the dose of a previously prescribed medication, such as an opioid, to treat BTcP is reduced. In one embodiment, the THC is a synthetic THC (which may be referred to herein as dronabinol). In one embodiment, the dronabinol is administered to the subject in the form of a unit dose. In one embodiment, the unit dose comprises about 0.5 mg of dronabinol. In one embodiment, the unit dose comprises about 2.5 mg of dronabinol. In one embodiment, the unit dose further comprises a co-solvent and a propellant. In one embodiment, the unit dose comprises about 0.5 mg dronabinol, about 1.5 mg ethanol and about 74.3 mg 1,1,1,2-tetrafluoroethane. In one embodiment, the unit dose comprises about 2.5 mg dronabinol, about 7.3 mg ethanol and about 63.3 mg 1,1,1,2-tetrafluoroethane. In one embodiment, 1 unit dose is administered to the subject. In one embodiment, more than 1 unit dose is administered to the subject. In embodiments, 2 to 7 unit doses are administered to the subject in succession. In one embodiment, 2 to 4 unit doses are administered to the subject in succession. In some embodiments, not more than 7 unit doses are administered to the subject in a 24 hour period. Accordingly, multiple unit doses combine to provide the dose of THC administered to the subject. Each unit dose may be delivered by a single actuation of an inhaler. In some embodiments, each successive unit dose is administered a few seconds to minutes, or as practical and / or tolerated, after administration of the previous dose. In a fourth aspect, the present invention relates to a pharmaceutical composition for inhalation comprising dronabinol, a co-solvent and a propellant. In one embodiment, the composition comprises about 0.655% w / w of dronabinol, about 2% w / w of ethanol and about 97.3% w / w of 1,1,1,2 tetrafluoroethane. In one embodiment, the composition comprises about 3.4% w / w of dronabinol, about 10% w / w of ethanol and about 86.6% w / w of 1,1,1,2 tetrafluoroethane. In a fifth aspect, the present invention relates to an inhaler system comprising an actuator and an interchangeable canister, wherein the canister contains the pharmaceutical composition of the fourth aspect. In one embodiment, the inhaler system is adapted to dispense about 0.5 mg of dronabinol with each actuation. In one embodiment, the inhaler system is adapted to dispense about 2.5 mg of dronabinol with each actuation. In one embodiment, the canister contains about 14 ml of the pharmaceutical composition. In a sixth aspect, the present invention relates to a kit, wherein the kit comprises an inhaler system of the fifth aspect and instructions for its use, for example in any method described herein. As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude further additives, components, integers or steps. As used herein, the term “therapeutically effective amount” means an amount of compound or agent sufficient to elicit the required or desired therapeutic response, as the particular treatment context may require. It will be understood that a therapeutically effective amount of a drug for a subject may be dependent on variables such as the body weight of the subject as well as other factors known to a person of ordinary skill in the art. As used herein the terms “tetrahydrocannabinol” and “THC” refer to the delta-9-THC isomer with the with chemical name (-)-trans-A9-tetrahydrocannabinol. The term “dronabinol” refers to the synthetic form of the delta-9-THC isomer. As used herein, the term “breakthrough pain” means a sudden and transient increase in pain in subjects already on pain medicine for chronic pain. During breakthrough pain, the level of pain may be severe but the type of pain and where it is in the body are usually the same as the subject’s chronic pain. Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings. Brief description of the drawings Figure 1: Representative drawings and photographs of the PMDI of the invention. (A) Front view, (B) cross section along line A-A, (C) enlarged view of “DETAIL A”, (D) rear view showing the dose counter, (E) exploded perspective view, (F) top view, (G) cross section along line B-B, (H-J) alternative PMDI configurations, (K-L) photographs of PMDI. Figure 2: Representative drawing of 14 mL aerosol can that may be used with the PMDI. Figure 3: Representative HPLC profile for measurement of THC stability. Figure 4: Representative force displacement graph for actuator fitted with a dose counter. Figure 5: Solubility of dronabinol in ethanol for 0.5 mg dronabinol formulation Figure 6: Solubility of dronabinol in ethanol for 2.5 mg dronabinol formulation shown in (A) %(w / w) dronabinol and (B) mg / 63pl dronabinol against ethanol concentration (% (w / w)). Figure 7: Dose content uniformity through can life for 0.5 mg dronabinol formulation Figure 8: Dose content uniformity through can life for 2.5 mg dronabinol formulation. (A) metered dose (pg), and (B) delivered dose (pg) against dose number. Figure 9: Particle size distribution through can life for 0.5 mg dronabinol formulation. (A) Cumulative mass undersize (pg), and (B) percentage (%) against upper aerodynamic particle diameter (pm). Figure 10: Particle size distribution through can life for 2.5 mg dronabinol formulation. (A) Cumulative mass undersize (pg), and (B) percentage (%) against upper aerodynamic particle diameter (pm) for beginning and end of can-use life. Figure 11: PMDI priming requirements and PMDI tailing for 0.5 mg dronabinol formulation. Shot weight (mg) against shot number for (A) shot number 1 -5, and (B) shot number 140-164. Figure 12: PMDI priming requirements and PMDI tailing for 2.5 mg dronabinol formulation. Shot mass (mg) against dose number for (A) dose number 1 -5, and (B) dose number 120-162. Figure 13: Study design of clinical trial described in Example 3. Figure 14: Visual Summary of Phase 1 clinical trial described in Example 3. Figure 15: Mean plasma THC concentration-time profiles by treatment (A) 0-2.5 hours and (B) 0-24 hours post-dose (linear scale, PK concentrations analysis set), (C) 0-24 hours post-dose (semi-log scale, PK concentrations analysis set). Concentrations below the lower limit of quantification (BLQ) are set to zero for the calculation of summary statistics [LLOQ = 0.1 ng / mL], Figure 16: Mean Plasma COOHTHC Concentration-Time Profiles By Treatment 0-24 Hours Post-Dose (linear scale, PK Concentrations Analysis Set). Concentrations below the lower limit of quantification (BLQ) are set to zero for the calculation of summary statistics [LLOQ = 1.0 ng / mL], Figure 17: Mean Plasma OHTHC Concentration-Time Profiles By Treatment 0-24 Hours Post-Dose (linear scale, PK Concentrations Analysis Set). Concentrations below the lower limit of quantification (BLQ) are set to zero for the calculation of summary statistics [LLOQ = 0.1 ng / mL], Figure 18: Study design of clinical trial described in Example 5. Figure 19: Instructions for use of dronabinol inhaler. Detailed description of the embodiments Breakthrough cancer pain (BTcP) is characterised by high intensity, the short time interval between onset and peak intensity, short duration, potential recurrence over 24 hours, and non-responsiveness to standard analgesic regimes. BTcP is typically considered a transient exacerbation of pain that occurs spontaneously or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain. Breakthrough cancer pain (BTcP) is a complex and varying phenomenon that may change its presentation during the course of disease in a single individual, and significantly negatively impacts general activities, quality of life, and pain management of patients. THC is a naturally occurring component in Cannabis sativa and dronabinol is the synthetic form of the delta-9-THC isomer. THC exerts its effect via modulation of 2 inhibitory G-protein coupled receptors, the cannabinoid receptors CB1 and CB2 (Legare et al. 2022, Pharmacology 28:1-19). CB1 is a G protein-coupled receptor that is expressed mainly in the central nervous system (CNS), however is also expressed in sensory neurons of the dorsal root ganglia. CB2 is expressed mainly in the immune system, hematopoietic cells, and in peripheral nerves, where it is upregulated after injury. CB1 and CB2 only share 40% homology, but THC shows similar binding affinity for both receptors (Pertwee et al. 2006, Br J Pharmacol. 147 (Suppl 1): S163-71). Due to their effect on neuronal cells, analgesia is one of the pharmacological actions of cannabinoids (Anand et al. 2021, Pain Manag. 11 (4):395-403). The therapeutic potential of many phytocannabinoids, especially THC, is limited by the strongly lipophilic chemistry. When ingested orally this leads to inconsistent bioavailability (estimated to be as low as 6%) due to irregular absorption and the extensive first-pass metabolism (first pass metabolism is caused by the actions of enzymes of the gastrointestinal lumen, gut wall enzymes, bacterial enzymes, and hepatic enzymes before THC reaches the circulatory system). After absorption, THC is rapidly metabolized in the liver and other extra-hepatic tissues by cytochrome P450 (CYP450) isozymes CYP2C9, CYP2C19, and CYP3A4. THC is mainly metabolised to 11 -hydroxy-THC (11 -OH-THC) and 11 -carboxy-THC (11 -COOH-THC), which undergoes glucuronidation and is subsequently excreted in the faeces and urine. The present invention relates to a pharmaceutical composition containing THC as its active pharmaceutical ingredient (API) for delivery via a pressurized metered-dose inhaler (PMDI). In accordance with various embodiments of the present disclosure, a pharmaceutical composition can comprise THC, a co-solvent and a propellant. A pharmaceutical composition can be configured for pulmonary administration, such as via a PMDI. A pharmaceutical composition in accordance with various embodiments can be configured to provide for stability of the pharmaceutical composition, including, for example, physical and chemical stability of the pharmaceutical composition during manufacturing, storage, handling, and use of a PMDI system comprising the pharmaceutical composition. In various embodiments, a pharmaceutical composition can be formulated to provide for solubility of the THC in a liquid solution comprising THC, the co-solvent and the propellant in a PMDI canister assembly. In accordance with various embodiments, THC, a co-solvent and a propellant may be combined in relative quantities that provide for a stable solution. For example, in various embodiments, a pharmaceutical composition can be configured such that the THC comprises about 0.5% to about 20% by weight (w / w) of the composition, the co-solvent comprises about 5% to about 20% by weight (w / w) of the composition, and the propellant comprises about 60% to about 94% (w / w) of the composition. Various pharmaceutical compositions in accordance with various embodiments of the present disclosure are described in greater detail below. The THC may be derived from a cannabis or hemp extract and can be a cannabis or hemp extract molecular distillate that may comprise further cannabinoid compounds, or the THC can be derived from a THC isolate, whether synthesized or obtained by purification from a cannabis or hemp source. The THC may be dronabinol, which is the synthetic form of the delta-9-THC isomer. In various embodiments, a pharmaceutical composition can comprise THC formulated to provide a particular therapeutic benefit. Such a composition can be configured to provide a pharmacologically effective amount and / or a therapeutically effective amount of THC. In various embodiments the composition may comprise from about 0.5% to about 20%, or about 1 % to about 19%, or from about 2% to about 18%, or from about 3% to about 17%, or from about 4% to about 16%, or from about 5% to about 15%, or from about 6% to about 14%, or from about 7% to about 13%, or from about 8% to about 12%, or from about 9% to about 11%, from about 0.5% to about 20.0%, from about 1.0% to about 10.0%, or from about 1.1% to about 9.9%, or from about 1.2% to about 9.8%, or from about 1.3% to about 9.7%, or from about 1.4% to about 9.6%, or from about 1.5% to about 9.5%, or from about 1.6% to about 9.4%, or from about 1.7% to about 9.3%, or from about 1.8% to about 9.2%, or from about 1.9% to about 9.1%, or from about 2.0% to about 9.0%, or from about 2.1% to about 8.9%, or from about 2.2% to about 8.8%, or from about 2.3% to about 8.7%, or from about 2.4% to about 8.6%, or from about 2.5% to about 8.5%, or from about 2.6% to about 8.4%, or from about 2.7% to about 8.3%, or from about 2.8% to about 8.2%, or from about 2.9% to about 8.1%, or from about 3.0% to about 8.0%, or from about 3.1% to about 7.9%, or from about 3.2% to about 7.8%, or from about 3.3% to about 7.7%, or from about 3.4% to about 7.6%, or from about 3.5% to about 7.5%, or from about 3.6% to about 7.4%, or from about 3.7% to about 7.3%, or from about 3.8% to about 7.2%, or from about 3.9% to about 7.1%, or from about 4.0% to about 7.0%, or from about 4.1% to about 6.9%, or from about 4.2% to about 6.8%, or from about 4.3% to about 6.7%, or from about 4.4% to about 6.6%, or from about 4.5% to about 6.5%, or from about 4.6% to about 6.4%, or from about 4.7% to about 6.3%, or from about 4.8% to about 6.2%, or from about 4.9% to about 6.1%, or from about 5.0% to about 6.0%, or from about 5.1% to about 5.9%, or from about 5.2% to about 5.8%, or from about 5.3% to about 5.7%, or from about 5.4% to about 5.6%, or from about 5.5% to about 5.5% THC by weight (w / w) of a pharmaceutical composition. In various embodiments, the composition can comprise about 0.5%, or about 0.6%, or about 0.7%, or about 0.8%, or about 0.9%, or aboutl .0%, or about 1.1%, or about 1.2%, or about 1.3%, or about 1.4%, or about 1.5%, or about 1.6%, or about 1.7%, or about 1.8%, or about 1.9%, or about 2.0%, or about 2.1%, or about 2.2%, or about 2.3%, or about 2.4%, or about 2.5%, or about 2.6%, or about 2.7%, or about 2.8%, or about 2.9%, or about 3.0%, or about 3.1%, or about 3.2%, or about 3.3%, or about 3.4%, or about 3.5%, or about 3.6%, or about 3.7%, or about 3.8%, or about 3.9%, or about 4.0%, or about 4.1%, or about 4.2%, or about 4.3%, or about 4.4%, or about 4.5%, or about 4.6%, or about 4.7%, or about 4.8%, or about 4.9%, or about 5.0%, or about 5.1%, or about 5.2%, or about 5.3%, or about 5.4%, or about 5.5%, or about 5.6%, or about 5.7%, or about 5.8%, or about 5.9%, or about 6.0%, or about 6.1 %, or about 6.2%, or about 6.3%, or about 6.4%, or about 6.5%, or about 6.6%, or about 6.7%, or about 6.8%, or about 6.9%, or about 7.0%, or about 7.1%, or about 7.2%, or about 7.3%, or about 7.4%, or about 7.5%, or about 7.6%, or about 7.7%, or about 7.8%, or about 7.9%, or about 8.0%, or about 8.1%, or about 8.2%, or about 8.3%, or about 8.4%, or about 8.5%, or about 8.6%, or about 8.7%, or about 8.8%, or about 8.9%, or about 9.0%, or about 9.1%, or about 9.2%, or about 9.3%, or about 9.4%, or about 9.5%, or about 9.6%, or about 9.7%, or about 9.8%, or about 9.9%, or about 10.0%, or about 10.1%, or about 10.2%, or about 10.3%, or about 10.4%, or about 10.5%, or about 10.6%, or about 10.7%, or about 10.8%, or about 10.9%, or about 11.0%, or about 11.1%, or about 11.2%, or about 11.3%, or about 11.4%, or about 11.5%, or about 11.6%, or about 11.7%, or about 11.8%, or about 11.9%, or about 12.0%, or about 12.1%, or about 12.2%, or about 12.3%, or about 12.4%, or about 12.5%, or about 12.6%, or about 12.7%, or about 12.8%, or about 12.9%, or about 13.0%, or about 13.1%, or about 13.2%, or about 13.3%, or about 13.4%, or about 13.5%, or about 13.6%, or about 13.7%, or about 13.8%, or about 13.9%, or about 14.0%, or about 14.1%, or about 14.2%, or about 14.3%, or about 14.4%, or about 14.5%, or about 14.6%, or about 14.7%, or about 14.8%, or about 14.9%, or about 15.0%, or about 15.1%, or about 15.2%, or about 15.3%, or about 15.4%, or about 15.5%, or about 15.6%, or about 15.7%, or about 15.8%, or about 15.9%, or about 16.0%, or about 16.1%, or about 16.2%, or about 16.3%, or about 16.4%, or about 16.5%, or about 16.6%, or about 16.7%, or about 16.8%, or about 16.9%, or about 17.0%, or about 17.1%, or about 17.2%, or about 17.3%, or about 17.4%, or about 17.5%, or about 17.6%, or about 17.7%, or about 17.8%, or about 17.9%, or about 18.0%, or about 18.1%, or about 18.2%, or about 18.3%, or about 18.4%, or about 18.5%, or about 18.6%, or about 18.7%, or about 18.8%, or about 18.9%, or about 19.0%, or about 19.1%, or about 19.2%, or about 19.3%, or about 19.4%, or about 19.5%, or about 19.6%, or about 19.7%, or about 19.8%, or about 19.9%, or about 20.0%, THC by weight (w / w) of a pharmaceutical composition. Surprisingly, the inventors found that the concentration of THC may be associated with a desirable distribution of particles ameniable for administration by inhalation on actuation of the inhalation device. In these embodiments, the composition may comprise THC in a maximum concentration of not more than about 3.4% (w / w), about 3.3% (w / w), about 3.2% (w / w), about 3.1% (w / w), about 3% (w / w), about 2.9% (w / w), about 2.8% (w / w), about 2.75% (w / w), about 2.7% (w / w), about 2.6% (w / w), about 2.5% (w / w), about 2.4% (w / w), about 2.3% (w / w), about 2.25% (w / w), about 2.2% (w / w), about 2.1% (w / w), about 2% (w / w), about 1.9% (w / w), about 1.8% (w / w), about 1.75% (w / w), about 1.7% (w / w), about 1.6% (w / w), about 1.5% (w / w), about 1.4% (w / w), about 1.3% (w / w), about 1.25% (w / w), about 1.2% (w / w), about 1.1% (w / w), about 1% (w / w), about 0.9% (w / w), about 0.8% (w / w), about 0.75% (w / w), about 0.7% (w / w), about 0.69% (w / w), about 0.68% (w / w), or about 0.6% (w / w). The minimum concentration of THC in the composition may be at least about 0.001% (w / w), about 0.005% (w / w), about 0.01% (w / w), about 0.05% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.25% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.55% (w / w), about 0.6% (w / w) or about 0.65% (w / w). The composition may comprise THC in a concentration from any of these minimum values to any of these maximum values, provided the minimum value is lower than the maximum value. For example, the composition may comprise THC in a concentration from about 0.0001% (w / w) to about 3.4% (w / w), from about 0.1% (w / w) to about 1.5% (w / w) or from about 0.6% (w / w) to about 0.7% (w / w). In various embodiments, a pharmaceutical composition comprising THC can be configured to deliver a particular amount of the THC with each actuation of a PMDI system containing the pharmaceutical composition. For example, in various embodiments, a pharmaceutical composition can be formulated to deliver about 0.1 mg, or about 0.2 mg, or about 0.3 mg, or about 0.4 mg, or about 0.5 mg, or about 0.6 mg, or about 0.7 mg, or about 0.8 mg, or about 0.9 mg, or about 1 mg, or about 1.1 mg, or about 1.2 mg, or about 1.3 mg, or about 1.4 mg, or about 1.5 mg, or about 1.6 mg, or about 1.7 mg, or about 1.8 mg, or about 1.9 mg, or about 2 mg, or about 2.1 mg, or about 2.2 mg, or about 2.3 mg, or about 2.4 mg, or about 2.5 mg, or about 2.6 mg, or about 2.7 mg, or about 2.8 mg, or about 2.9 mg, or about 3 mg, or about 4 mg, or about 5 mg, or about 10 mg, or about 15 mg, or about 20 mg, or about 25 mg, or about 30 mg of THC per actuation. In various embodiments, a pharmaceutical composition can be formulated to deliver a pharmacologically effective amount and / or a therapeutically effective amount of THC. In various embodiments, a co-solvent used in a pharmaceutical composition can comprise an organic solvent such as an alcohol. In various embodiments, a co-solvent can be a monohydric or polyhydric alcohol. Various alcohols may be suitable, such as ethanol, propanol, polypropylene glycol, glycerol, polyethylene glycol, and the like, along with various mixtures thereof. The concentration of co-solvent in the composition also contributes to the solubility of THC in the composition. For example, Figures 5 and 6 show increasing solubility of THC across various embodiments wherein the co-solvent is ethanol. Accordingly, in some embodiments, the composition comprises a concentration of co-solvent sufficient to ensure sufficient THC is dissolved, while ensuring a desirable particle size distribution on actuation of the inhalation device. Thus, in some embodiments, the minimum concentration of co-solvent may be at least about 0.1% (w / w), about 0.15% (w / w), about 0.2% (w / w), about 0.25% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.55% (w / w), about 0.6% (w / w), about 0.65% (w / w), about 0.7% (w / w), about 0.75% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.1% (w / w), about 1.2% (w / w), about 1.25% (w / w), about 1.3% (w / w), about 1.4% (w / w), about 1.5% (w / w), about 1.6% (w / w), about 1.7% (w / w), about 1.75% (w / w), about 1.8% (w / w), about 1.85% (w / w), about 1.9% (w / w) or about 2% (w / w). The maximum concentration of ethanol may be not more than about 20% (w / w), about 18% (w / w), about 17.5% (w / w), about 16% (w / w), about 15% (w / w), about 12.5% (w / w), about 10% (w / w), about 9% (w / w), about 8% (w / w), about 7% (w / w), about 6% (w / w), about 5% (w / w), about 4.5% (w / w), about 4% (w / w), about 3.5% (w / w), about 3% (w / w), about 2.9% (w / w), about 2.8% (w / w), about 2.75% (w / w), about 2.7% (w / w), about 2.6% (w / w), about 2.55% (w / w), about 2.5% (w / w), about 2.45% (w / w), about 2.4% (w / w), about 2.35% (w / w), about 2.3% (w / w), about 2.2% (w / w), about 2.1% (w / w), or about 2% (w / w). The concentration of co-solvent may be from any of these minimum concentrations to any of these maximum concentrations provided the minimum is less than the maximum. For example, the composition may comprise the co-solvent in a concentration from about 0.1% (w / w) to about 20% (w / w), about 0.1% (w / w) to about 10% (w / w), about 0.1% (w / w) to about 5% (w / w), about 0.5% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w) or about 1.5% (w / w) to about 2.5% (w / w). In accordance with various embodiments of the present disclosure, ethanol may be used as a co-solvent. Ethanol may be included in any of the concentrations described herein for the co-solvent. In various embodiments, the THC is solubilised in ethanol, and use of ethanol as a co-solvent may be suitable to provide a pharmaceutical composition with desired solution stability and aerosol performance in a PMDI system. However, a high ethanol content may be undesirable, as it can increase aerosol particle size and velocity and therefore reduce effective pulmonary delivery. In various embodiments, a pharmaceutical composition may be configured to minimize the required ethanol concentrations, for example, to reduce the potential for unpleasant taste sensations or to ensure appropriate aerosol particle size and maintain aerosol particle size below a certain size, while providing for a stable, solution-phase pharmaceutical composition. Accordingly, in various embodiments, a pharmaceutical composition can comprise less than about 20% ethanol, or less than about 19%, or less than about 18%, or less than about 17%, or less than about 16%, or less than about 15%, or less than about 14%, or less than about 13%, or less than about 12%, or less than about 11%, or less than about 10%, or less than about 9%, or less than about 8%, or less than about 7%, or less than about 6%, or less than about 7%, or less than about 6%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1% ethanol by weight (w / w) of the composition. In various embodiments, a pharmaceutical composition can comprise from about 1% to about 20% ethanol, or from about 2% to about 19% ethanol, or from about 3% to about 18% ethanol, or from about 4% to 17% ethanol, or from about 5% to about 16% ethanol, or from about 6% to about 15% ethanol, or from about 7% to about 14% ethanol, or from about 8% to about 13% ethanol, or from about 9% to about 12% ethanol, or from about 10% to about 11 % ethanol by weight (w / w) of the composition. In one embodiment the composition comprises about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1 %, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, about 5.9%, about 6%, about 6.1%, about 6.2%, about 6.3%, about 6.4%, about 6.5%, about 6.6%, about 6.7%, about 6.8%, about 6.9%, about 7%, about 7.1%, about 7.2%, about 7.3%, about 7.4%, about 7.5%, about 7.6%, about 7.7%, about 7.8%, about 7.9%, about 8%, about 8.1%, about 8.2%, about 8.3%, about 8.4%, about 8.5%, about 8.6%, about 8.7%, about 8.8%, about 8.9%, about 9%, about 9.1%, about 9.2%, about 9.3%, about 9.4%, about 9.5%, about 9.6%, about 9.7%, about 9.8%, about 9.9%, about 10%, about 10.1%, about 10.2%, about 10.3%, about 10.4%, about 10.5%, about 10.6%, about 10.7%, about 10.8%, about 10.9%, about 11 %, about 11.1 %, about 11.2%, about 11.3%, about 11.4%, about 11.5%, about 11.6%, about 11.7%, about 11.8%, about 11.9%, about 12%, about 12.1 %, about 12.2%, about 12.3%, about 12.4%, about 12.5%, about 12.6%, about 12.7%, about 12.8%, about 12.9%, about 13%, about 13.1%, about 13.2%, about 13.3%, about 13.4%, about 13.5%, about 13.6%, about 13.7%, about 13.8%, about 13.9%, about 14%, about 14.1, .1%, about 14.2%, about 14.3%, about 14.4%, about 14.5%, about 14.6%, about 14.7%, about 14.8%, about 14.9%, about 15%, about 15.1%, about 15.2%, about 15.3%, about 15.4%, about 15.5%, about 15.6%, about 15.7%, about 15.8%, about 15.9%, about 16%, about 16.1%, about 16.2%, about 16.3%, about 16.4%, about 16.5%, about 16.6%, about 16.7%, about 16.8%, about 16.9%, about 17%, about 17.1%, about 17.2%, about 17.3%, about 17.4%, about 17.5%, about 17.6%, about 17.7%, about 17.8%, about 17.9%, about 18%, about 18.1%, about 18.2%, about 18.3%, about 18.4%, about 18.5%, about 18.6%, about 18.7%, about 18.8%, about 18.9%, about 19%, about 19.1%, about 19.2%, about 19.3%, about 19.4%, about 19.5%, about 19.6%, about 19.7%, about 19.8%, about 19.9%, or about 20.0% ethanol by weight (w / w). In one embodiment, the composition further comprises propylene glycol. The composition may contain about 0.1 to 5% propylene glycol by weight (w / w). The composition may contain about 0.1%, or about 0.2%, or about 0.3%, or about 0.4%, or about 0.5%, or about 0.6%, or about 0.7%, or about 0.8%, or about 0.9%, or about 1.0%, or about 1.1%, or about 1.2%, or about 1.3%, or about 1.4%, or about 1.5%, or about 1.6%, or about 1.7%, or about 1.8%, or about 1.9%, or about 2.0%, or about 2.1%, or about 2.2%, or about 2.3%, or about 2.4%, or about 2.5%, or about 2.6%, or about 2.7%, or about 2.8%, or about 2.9%, or about 3.0%, or about 3.1%, or about 3.2%, or about 3.3%, or about 3.4%, or about 3.5%, or about 3.6%, or about 3.7%, or about 3.8%, or about 3.9%, or about 4.0%, or about 4.1%, or about 4.2%, or about 4.3%, or about 4.4%, or about 4.5%, or about 4.6%, or about 4.7%, or about 4.8%, or about 4.9%, or about 5.0% propylene glycol by weight (w / w). In various embodiments, a propellant comprises a pharmacologically inert liquid with a boiling point of from about room temperature (25° C) to about -25° C. which exerts a high vapor pressure at room temperature. Without wishing to be bound by theory, inclusion of a propellant in a pharmaceutical composition of the present disclosure provides for pressurization of the composition in a canister assembly of the PMDI system and upon activation of the PMDI system, the high vapor pressure of the propellant in the PMDI system forces a metered amount of pharmaceutical composition out through the metering valve and the propellant very rapidly vaporizes, dispersing the pharmaceutical composition as an aerosol. In various embodiments, a propellant may be a hydrofluorocarbon, for example, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134a), 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), or a mixture thereof. The composition may consist essentially of THC, the solvent(s) and the propellent(s). The THC and the solvent may be included in any of the concentrations described herein suitable to achieve the desired strength on actuation of the inhalation system. In these embodiments, the concentration of propellent may be the balance of the composition (other than minor components included as impurities with the THC, solvent and propellent, eg residual water). A pharmaceutical composition in accordance with various embodiments can comprise from about 50% to about 98% propellant, or from about 55% to about 90% propellant, or from about 60% to about 85% propellant, or from about 55% to about 80% propellant, or from about 60% to about 75% propellant, or from about 65% to about 70% propellant by weight (w / w) of the composition. In various embodiments, a pharmaceutical composition comprises about 60%, or about 61%, or about 62%, or about 63%, or about 64%, or about 65%, or about 66%, or about 67%, or about 68%, or about 69%, or about 70%, or about 71%, or about 72%, or about 73%, or about 74%, or about 75%, or about 76%, or about 77%, or about 78%, or about 79%, or about 80%, or about 81%, or about 82%, or about 83%, or about 84%, or about 85%, or about 86%, or about 87%, or about 88%, or about 89%, or about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98% propellant by weight (w / w). A pharmaceutical composition in accordance with various embodiments can comprise from about 50% to about 98% HFA 134a, or from about 55% to about 90% HFA 134a, or from about 60% to about 85% HFA 134a, or from about 55% to about 80% HFA 134a, or from about 60% to about 75% HFA 134a, or from about 65% to about 70% HFA 134a by weight (w / w) of the composition. In various embodiments, a pharmaceutical composition comprises about 60%, or about 61%, or about 62%, or about 63%, or about 64%, or about 65%, or about 66%, or about 67%, or about 68%, or about 69%, or about 70%, or about 71%, or about 72%, or about 73%, or about 74%, or about 75%, or about 76%, or about 77%, or about 78%, or about 79%, or about 80%, or about 81%, or about 82%, or about 83%, or about 84%, or about 85%, or about 86%, or about 87%, or about 88%, or about 89%, or about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98% HFA 134a by weight (w / w). In some embodiments, a composition may comprise: • THC from about 0.001 % (w / w) to about 3.4% (w / w) • solvent(s) from about 0.1 % (w / w) to about 20% (w / w) • propellent(s) from about 76.6% (w / w) to about 99.899% (w / w). In various embodiments, a pharmaceutical composition is configured for delivery of an aerosolized dose of the pharmaceutical composition by a pressurized metered dose inhaler (PMDI) device. A PMDI device can comprise a delivery device consisting of a canister, a metering valve configured to sealably attach to a canister and to deliver a particular quantity of a composition contained within the canister (i.e., a metered dose) per actuation of the valve, and an actuator. A metering valve can be sealably attached to a canister to produce a canister assembly suitable to sealably contain a pressurized pharmaceutical composition. A PMDI device can also comprise a pharmaceutical composition contained within a sealed PMDI canister assembly. In various embodiments, a PMDI system can comprise a PMDI canister assembly or an assembled PMDI device (i.e., an assembled PMDI device including a filled canister assembly and an actuator). In various embodiments, an assembled PMDI device is configured to deliver the pharmaceutical composition in the form of droplets of a respirable size suitable for pulmonary administration. In various embodiments, a PMDI device, including the pharmaceutical composition, is configured to provide an aerosol particle size having a relatively uniform particle size distribution, for example, with substantially all, or at least about 90%, or at least about 80%, or at least about 70%, or at least about 60%, or at least about 50%, of the particles ranging between about 0.1 and about 25 microns, or between about 0.5 and about 10 microns, or between about 1.0 and about 5.0 microns. Particles larger than 25 microns may be deposited in the oropharyngeal cavity, while particles smaller than about 0.5 micron may fail to be deposited in the lungs and be lost due to exhalation. In various embodiments, the aerosol particle size produced by a PMDI device can be measured by cascade impaction and characterized by the mass median aerodynamic diameter (MMAD, i.e., the value for which 50% of the particles are larger or smaller) and the geometric standard deviation (GSD). The pharmaceutical compositions desirably deliver an effective amount of THC in particles with an MMAD from about 0.5 micron to about 25 micron. In embodiments, the minimum MMAD may be at least about 0.5 micron, about 0.75 micron, about 1 micron, about 1.25 micron, about 1.5 micron, about 1.6 micron, about 1.7 micron, about 1.75 micron or about 1.8 micron. The maximum MMAD may be not more than about 25 micron, about 20 micron, about 17.5 micron, about 15 micron, about 12.5 micron, about 10 micron, about 7.5 micron, about 5 micron, about 4 micron, about 3 micron, about 2.5 micron, about 2 micron, about 1.9 micron or about 1.8 micron. The MMAD may be from any of these minimum values to any of these maximum values provided the minimum value is less than the maximum value. For example, the MMAD may be from about 0.5 to about 25 microns, about 0.5 to about 5 microns or about 1 to about 3 microns. In various embodiments, the MMAD is between about 0.5 and about 10 microns, or between about 1.0 and about 5.0 microns. The pharmaceutical compositions desirably deliver the THC in particles with any of the MMADs described herein with a GSD as low as possible. In embodiments, the maximum GSD may be not more than about 10, about 9, about 8, about 7.5, about 7, about 6, about 5, about 4, about 3, about 2.5, about 2, about 1.9 or about 1.8. The minimum GSD may be at least about 0.01, about 0.1, about 0.25, about 0.5, about 0.75, about 1, about 1.25, about 1.5, about 1.6, about 1.7, about 1.75 or about 1.8. The GSD may be from any of these minimum values to any of these maximum values provided the minimum value is less than the maximum value. For example, the GSD may be from about 0.01 to about 10, about 0.1 to about 5 or about 1 to about 3. The aerosol preferably comprises as high a fraction as possible of particles of a respirable size comprising THC. Accordingly, in various embodiments, the aerosol comprises at least about 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.8%, 99.9% or 100% particles of a respirable size compared to all particles in the aerosol. The aerosol may comprise particles of a respirable size from any of these percentages to any other of these percentages. For example, the aerosol may comprse from about 30% to about 100% of particles of a respirable size compared to all particles in the aerosol, about 60% to about 100% of particles of a respirable size compared to all particles in the aerosol or about 60% to about 95% of particles of a respirable size compared to all particles in the aerosol. The fraction of particles of a respirable size compared to all particles in the aerosol may be determined by any technique known in the art, including measuring MMAD and GSD, and / or comparing the weight of THC delivered per actuation compared to theoretical. In various embodiments, a PMDI device will comprise an actuator having an orifice with an orifice diameter. Preferably, the actuator orifice has a diameter in the range of from about 0.10 mm to about 0.70 mm, and more preferably in the range of from about 0.40 mm to about 0.70 mm. In various embodiments, the orifice diameter is in the range of from about 0.50 to about 0.60 mm. In various embodiments, a metering valve used in a PMDI device can be configured to deliver a volume of a pharmaceutical composition in a range of from about 25 to about 100 microliters per actuation. In various embodiments, a PMDI device can be configured with a metering valve configured to deliver about a 50 microliter volume of a pharmaceutical composition. In various embodiments, a PMDI device will comprise an actuator with an actuation or dose counter for counting the number of actuations of the system. The actuation or dose counter may be mechanical or electronic. Compositions for aerosol administration via PMDIs can be formulated as solutions or suspensions. Solution compositions can offer several advantages, including that they can be more convenient to manufacture being completely dissolved in the propellant vehicle and they avoid the physical stability problems associated with suspension compositions. However, solution compositions comprising THC at a suitable concentration while providing appropriate aerosol particle characteristics can be challenging to achieve, particularly for cannabis-extract derived formulations, and compositions can quickly separate, forming sediments or emulsions and leading to clogging or other performance problems that can frustrate a user, such as by interfering with consistent or expected dosing or by preventing access to the product altogether. Moreover, chemical instability leading to the degradation of therapeutic substance components and producing a change in product efficacy can also be problematic for some compositions. As described above, a co-solvent such as ethanol can be used to provide enhanced THC solubility in a pharmaceutical composition for administration by PMDI; however, increasing ethanol concentration can produce increased aerosol particle sizes, which may be undesirable. In various embodiments, a surfactant optionally may be added to lower the surface and interfacial tension between the THC, the propellant and the co-solvent. A surfactant may be any suitable, non-toxic compound which is non-reactive with the pharmaceutical composition components and which substantially reduces the surface tension and / or interfacial tension between the THC, the propellant and / or the co-solvent. However, various formulations disclosed herein do not require a surfactant to produce and / or maintain a stable pharmaceutical composition solution under normal operating conditions, and in various embodiments a pharmaceutical composition may be surfactant-free. Breakthrough cancer pain may occur in individuals with different clinical features, disease stages, and undergoing different treatments for cancer. Although BTcP occurs with high frequency in hospice patients (80.5%), breakthrough cancer pain is also relatively common in cancer patients who are undergoing outpatient treatment (39.9%). The skilled person will understand based on common general knowledge that BTcP may occur in patients with different kinds of cancer, and at different stages of cancer. Progresssion of cancers can be described by using several cancer staging systems. For example, the TNM staging system is the most widely used cancer staging system. However, there are specific cancers with different staging systems, for example, brain, spinal cord, and blood cancers. The TNM combinations may be grouped into five less-detailed stages, for example stage 0,1,2, 3, or 4, with stage 4 being the most advanced form of cancer. Stages of cancer may also be sub-divided, for example stage 2 prostate cancer may be further classified as stage 2A, 2B, or 2C (National Cancer Institute, Cancer Staging, accessible at https: / / www.cancer.gov / about-cancer / diagnosis-staging / staging). The methods described herein may be useful to treat BTcP in subjects with different stages of cancer. BTcP is more common and typically more severe in advanced stages of cancer, and is also known to be common in specific types of cancer (for example, bone cancer). In various embodiments, the subject is suspected of having or has been diagnosed with having a cancer, for example, a stage 1, stage 2, stage 3, or stage 4 cancer. In some embodiments, the cancer is a late-stage cancer. In some preferred embodiments, the late-stage cancer is stage 3 or stage 4 cancer. In various embodiments, the subject is suspected of having or has been diagnosed with having at least one cancer. Examples of various cancers include but are not limited to, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, renal cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer and bone cancer. In a preferred embodiment, the at least one cancer is a bone cancer, for example a primary bone cancer and / or metastatic cancer tumour(s) in bone. In various embodiments, the subject may be described by one or more of the following: • able to perform inhalations that are sufficiently deep to allow administration of a therapeutically effective amount of THC; and / or • has a forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) at > 80% of predicted value and FEV1 / FVC ratio of > 0.7; and / or • a negative history of recreational drug use; and / or • not pregnant, breastfeeding (non-lactating), or planning pregnancy; and / or • current diagnosis of cancer; and / or • is currently receiving chemotherapy and / or radiotherapy treatment on a stable regimen for at least one month; and / or • experience 1 or more BTcP episodes(s); and / or • background stable cancer pain and adequately controlled; and / or • opioid-tolerant; and / or • no known history or family history of schizophrenia or other psychotic illness; and / or • no history of any clinically significant cardiopulmonary disease (for example COPD); and / or • no history or presence of active unstable lung disease; and / or • no uncontrolled or rapidly escalating pain; and / or • no history of substance use disorder. Because pain is subjective, treatment of pain can be assessed using several measures that typically involve measuring a change in perceived pain by a subject. For example, effective treatment of BTcP, and a decrease in perceived pain by the subject may be described by at least one of: • a decrease in the number of occurences of pain; and / or • prevention of the recurrence of pain; and / or • reduction in the number of BTcP episodes per 24 hours; and / or • reduction in the dose of a previously prescribed pain medication, such as an opioid, to treat BTcP; and / or • reduction in the symptoms of BTcP; and / or • relieving or reducing of the severity of pain; and / or • reduction in pain intensity; and / or • provision of pain relief. For example, in some embodiments, the methods comprise a decrease in the number of occurrences of BTcP. For example, such methods may include instances when a subject may have experienced 5 episodes of BTcP per 24 hours prior to treatment, which decrease to 3 episodes in the 24 hour period following treatment. In another example, the subject may be able to reduce the dosage of a previously prescribed pain medication, such as an opioid, to treat BTcP, by 40% following treatment. Numerous pain scale metrics may also be used to quantify a change in perceived pain, including numerical scales, visual analog scales, and categorical scales. Examples of such scales include the Numerical Rating Scale (NRS), Wong-Baker Faces Pain Scale, FLACC Pain Scale, CRIES pain scale, COMFORT Pain Scale, McGill Pain Questionaire, Colour Analog Pain Scale, Mankoski Pain Scale, Brief Pain Inventory, Descriptor Differential Scale of Pain Intensity, the Defense and Veterans Pain Rating Scale, and that any suitable pain scale may be used in the method of the invention. In some embodiments, reduction in symptoms of BTcP and / or the relieving or reducing of the severity of pain and / or the reduction in pain intensity and / or the provision of pain relief may be measured by a change in a pain scale metric. For example, reduction in symptoms of BTcP may include a decrease in an NRS score from 10 to 5, or from 7 to 0, compared to before treatment. In some preferred embodiments, the change in a pain scale metric is a reduction in an NRS score (an 11-point scale). In some embodiments, reduction in symptoms of BTcP and / or the relieving or reducing of the severity of pain and / or the reduction in pain intensity and / or the provision of pain relief may be measured by a single pain scale metric, for example a pain relief scale. In one example, the pain relief scale is a 5-point scale with scores of 0, 1,2, 3, and 4, where 0 indicates no pain relief, 2 and 3 moderate pain relief, and 4 maximum pain relief. In some preferred embodiments, the change in a pain scale metric is a non-zero score on a 5-point pain relief scale, for example when the difference in a pain scale metric is a 1-point score on a 5-point pain relief scale, a 2-point score on a 5-point pain relief scale, a 3-point score on a 5-point pain relief scale, or a 4-point score. Further, the skilled person understands that in the current invention, patients may be administered successive unit doses for treatment of BTcP. More than one successive unit doses may be used to administer a therapeutically effective dose, and successive unit doses may be administered to achieve a targeted decrease in perceived pain. In some embodiments, 2 to 7 unit doses (or actuations) are administered to the subject in succession. Accordingly, the methods may comprise administering 2, 3, 4, 5, 6, or 7successive unit doses. The methods may comprise administering from any of these numbers of successive unit doses to any other number of these successive unit doses. For example, the methods may comprise administering from 2 to 7 unit doses, 2 to 6 unit doses, 2 to 5 unit doses, 2 to 4 unit doses or 3 to 4 unit doses. In some embodiments, not more than 7, 6, 5, 4, 3, 2, or 1 unit dose(s) are administered to a subject in a 24 hour period. In some embodiments when more than 1 unit dose is administered to a subject, each successive unit dose may be administered a few seconds to minutes, or as practical or tolerated after administration of the previous dose. In some embodiments, treatment of BTcP may also include a decrease in an NRS score from 10 to 8 after administering a first unit dose, and a further decrease in an NRS score from 8 to 4 after a second unit dose. Each unit dose may be delivered by a single actuation of the device described herein. The present disclosure also provides a method of formulating a pharmaceutical composition having a stable aerosol solution formulation. In various embodiments, a method of formulating a pharmaceutical composition comprises mixing THC with a cosolvent to produce a solution. The solution can be placed in an MDI canister and then mixed with propellant in a two-stage pressure fill pMDI manufacturing method, or the solution can be mixed with propellant and injected into a precrimped pMDI canister using a single-stage pressure fill approach. In various embodiments, the proportions of THC, co-solvent and propellant used in a pharmaceutical composition may be adjusted to produce a pharmaceutical composition that is a stable solution under various storage and handling conditions. A finished pharmaceutical composition can be evaluated optically in accordance with various embodiments following formulation to ensure that the finished pharmaceutical composition is not subject to separation or precipitation. For example, in various embodiments, a THC and co-solvent mixture may be placed in a transparent glass jar suitable for sealing with a metering valve or similar component through which propellant may be added to the mixture and capable of withstanding typical PMDI pressures. Propellant may be gradually added to the mixture in the sealed jar and monitored visually to assess solubility of the mixture in the propellant. In various embodiments, a soluble formulation will have a homogenous optically clear appearance, while an insoluble formulation will appear cloudy due to the presence of an emulsion and / or liquid separation will occur due to immiscibility. In various embodiments, the homogeneity of a pharmaceutical composition formulation can be monitored visually during formulation and for a period of time following formulation to ensure solubility. In various embodiments, if a pharmaceutical composition with a particular formulation undergoes separation following formulation, as determined visually by assessment of the stability of the formulation in a pressurized glass jar, the composition may be reformulated, such as by increasing the proportion of the co-solvent relative to THC and repeating the process outlined above. In various embodiments, the ratio of propellant to the THC and co-solvent components can be titrated to produce a soluble pharmaceutical composition. In various embodiments, the proportion of each of THC, co-solvent, and propellant in a pharmaceutical composition may be separately titrated to produce a soluble pharmaceutical composition. For example, for a pharmaceutical composition formulated in accordance with various embodiments of the present disclosure can comprise THC at a concentration of from about 1% to about 10% by weight (w / w) of the composition, a co-solvent can comprise ethanol at a concentration of from about 5% to about 20% by weight (w / w) of the composition, and a propellant can comprise HFA 134a at a concentration of from about 70% to about 94% by weight (w / w) of the composition. In accordance with various embodiments, the formulation of a pharmaceutical composition can be configured to provide desired aerosol performance characteristics during delivery by a metered dose inhaler system. Factors such as the viscosity of the pharmaceutical composition and the various components thereof, and the interaction of the pharmaceutical composition with the PMDI device during actuation based on various factors such as the nozzle size and shape and the mouthpiece configuration can influence aerosol characteristics during administration of the pharmaceutical composition. In various embodiments, a pharmaceutical composition can be configured to provide the desired aerosol performance characteristics when used with a PMDI device. In various embodiments, the pharmaceutical compositions of the present disclosure may be physically and / or chemically stable under periods of storage and / or thermal stresses of up to about 55° C. for up to about six hours. The ability of a composition to withstand prolonged storage or thermal stress can be measured, for example, by subjecting a composition to storage at elevated temperatures and subsequently measuring fine particle fraction of the composition upon actuation of the delivery system. An instrument such as an Andersen Cascade Impactor can be used to measure the fine particle fraction (FPF), or the mass of aerosol particles with aerodynamic diameters that are less than approximately 5 microns. In various embodiment, a mass of particles of a pharmaceutical composition subjected to temperatures up to about 45° C. for up to about six hours exhibits a FPF that varies from the FPF of a mass of similar particles for the same pharmaceutical composition held at room temperature by less than about 25%, or less than about 20%, or less than about 15%, or less than about 10%. In various embodiment, a mass of particles of a pharmaceutical composition subjected to temperatures up to about 55° C. for up to about six hours exhibits a FPF that varies from the FPF of a mass of similar particles for the same pharmaceutical composition held at room temperature by less than about 25%, or less than about 20%, or less than about 15%, or less than about 10%. In various embodiments, a pharmaceutical composition of the present disclosure can be characterized by the chemical stability of the pharmaceutical composition, including the THC. Without wishing to be bound by theory, it is believed that several factors can influence the chemical stability of a pharmaceutical composition, such as the composition, stability, and / or interactions of the pharmaceutical composition components. Chemical stability can be assessed using various techniques well known in the art, such as high performance liquid chromatography (HPLC) and / or gas chromatography-mass spectrometry (GC-MS). In various embodiments, the pharmaceutical compositions of the present disclosure do not exhibit substantial degradation of the THC composition after being stored at temperatures of up to about 40° C. for up to about three months. In various embodiments, the THC composition is within about 75%, or within about 80%, or within about 85%, or within about 90%, or within about 95%, or within about 98% of the starting THC composition by weight following a storage period of three months at temperatures of up to about 40° C. In various embodiments, a pharmaceutical composition may be formulated to provide a stable solution following mixing and pressurization of the composition in a PMDI canister. A stable solution may not be subject to physical separation or precipitation of composition components during normal product handling and use, or during extended storage and handing periods and conditions such as a product may be subject to during packaging, warehousing, shipping, handling, and the like. In various embodiments, a pharmaceutical composition may remain a stable solution for storage and handling periods of up to about one month, or up to about three months, or up to about six months, or up to about 9 months, or up to about 12 months, under a variety of temperature conditions including temperatures of up to about 30° C., or about 40° C., or about 45° C., or about 50° C., for up to about 1 hour, or up to about 3 hours, or up to about 12 hours, or up to about 24 hours. In various embodiments, the stability of a pharmaceutical composition can be assessed optically. In various embodiments, the stability of a pharmaceutical composition can be assessed based on performance of the PMDI system over the course of simulated or accelerated life cycle testing. For example, in various embodiments, a PMDI system may be evaluated for delivery of a consistent mass of the pharmaceutical composition contained within the system, such as delivery of 0.5 mg or 2.5 mg of THC at the first actuation, the second actuation, the third actuation, and the nth actuation, wherein n may be, for example, the designed maximum number of actuations. In various embodiments, a pharmaceutical formulation and a PMDI system may provide at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 99% delivery consistency by mass of THC per actuation for the first actuation compared to the nth actuation. Similarly, in various embodiments, other physical attributes of the delivered aerosol, such as the FPF or the MMAD may be evaluated for consistent performance of a PMDI system and pharmaceutical formulation over a simulated or accelerated life cycle test of the system. In various embodiments, a pharmaceutical composition and a PMDI system may be configured to deliver a pharmacologically effective amount of THC to a patient in need thereof. As used herein, a pharmacologically effective amount of a compound is an amount sufficient to produce a detectable concentration of the substance, a metabolite of the substance, or some other substance produced in response to administration of an amount of a compound, in a physiological sample obtained from a treated patient at a certain time interval following administration of the amount (or dose). A physiological sample can comprise, for example, a blood serum sample. In various embodiments, a pharmaceutical composition and a PMDI system may be configured to deliver a therapeutically effective amount of THC to a patient in need thereof. As used herein, a therapeutically effective amount of a substance is an amount delivered to a patient sufficient to elicit a required or desired therapeutic response, as the particular treatment context may require. In various embodiments, a therapeutically effective amount may be the amount of a substance sufficient to provide the patient with an objectively or subjectively perceptible effect or therapeutic benefit relative to a treated condition. In various embodiments, the presence of a therapeutically effective amount of THC are necessary and sufficient to produce a therapeutic benefit. In various embodiments, a pharmacologically effective amount of THC in a pharmaceutical composition following administration to a human patient may be determined clinically based on objectively measurable data. A pharmacologically effective amount of a compound can be determined at a particular time interval following administration of a composition to a patient, for example, by collection of a physiological sample such as a blood sample from the treated patient. A blood sample can be collected from minutes after administration of a pharmaceutical composition to hours or days after administration. In various embodiments, a physiological sample such as a blood sample can be collected at about 1 minute, or about 2 minutes, or about 3 minutes, or about 4 minutes, or about 5 minutes, or about 10 minutes, or about 15 minutes, or about 20 minutes, or about 30 minutes, or about 60 minutes, or about 120 minutes following administration of a pharmaceutical composition. In various embodiments, a pharmacologically effective amount of THC measured for a blood sample collected following administration of a pharmaceutical composition can be a blood serum concentration of at least about 0.5 ng / ml, or about 1.0 ng / ml, or about 2.0 ng / ml, or about 3.0 ng / ml, or about 4.0 ng / ml, or about 5.0 ng / ml, or about 6.0 ng / ml, or about 7.0 ng / ml, or about 8.0 ng / ml, or about 9.0 ng / ml, or about 10.0 ng / ml, or about 20 ng / ml, or about 30 ng / ml, or about 50 ng / ml, or about 70 ng / ml, or about 100 ng / ml for the subject compound or a metabolite thereof. An inhaled route of administration avoids gastrointestinal conditions which can change and degrade molecules, reducing the amount of a pharmaceutical substance that is bioavailable. First pass metabolism in the liver can also similarly reduce bioavailability. THC is subject to significant first pass effect. A significant amount of THC is excreted or metabolised to an inactive form when administered orally. PMDIs are able to deliver therapeutic drugs to the respiratory system where they can be readily absorbed through the alveolar region directly into the blood circulation. The current invention provides for three significant advantages over existing MDIs, including a high dose loading per dose, excellent drug delivery and aerodynamic diameter particle size of delivered dose, and stability of the drug compound during storage. Formulating THC within a metered dose inhaler provides the opportunity to avoid first pass metabolism, providing rapid peak blood plasma concentration levels via systemic delivery through the alveoli. Higher peak blood plasma concentrations are observed compared to after ingestion. Furthermore, onset of action is typically rapid (<30s) when inhaled, compared to ~30mins when ingested. The PMDI of the present invention provides an accurate delivery of active material in a form that can be inhaled and absorbed by the body. The present invention thus provides an opportunity to precisely and consistently control the inhaled particle size distribution, tailored to target the active material to the deep lung. The present invention also protects THC from degradation within carefully selected container and formulation. The formulation of the present invention is a solution. This allows for precise, consistent, and accurate dosing by the PMDI without the requirement for shaking. The PMDI of the present invention may also be primed or re-primed (if necessary following prolonged non-usage) by firing a single dose, and achieves delivery of consistent aerodynamic particle size of all doses to the user throughout canister use. Stability of THC within the metered dose inhaler environment is also important. The present invention achieves this through manufacture within an oxygen free environment, and specific selection of canister / valve / elastomers to ensure that this is maintained over the duration of product life. Metered dose inhaler (MDI) performance tends to decrease as the drug loading within each puff increases. The dose loading of a marketed MDI can be as high as 250 pg per dose. Moving from a MDI to a marketed dry powder inhaler (DPI) can double this to 500 pg. However, both MDI and DPIs technologies have found it challenging to achieve delivery of greater than 250 pg and 500 pg of drug per “puff” respectively. The PMDI of 28 the present invention delivers 2,500 pg per puff, up to ten times more than that of currently marketed MDIs. Importantly, the PMDI of the present invention maintains the drug delivery efficiency and particle size distribution required to achieve an inhaled therapeutic effect. It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention. Example 1: Dosage device The dimensions and features of a PMDI of the invention is shown in Figure 1. Figure 1A shows a front view of the PMDI with the cross section along line A-A shown in Figure 1B. Figure 1C shows an enlarged view of “DETAIL A” referred to in Figure 1B. Figure 1D is a rear view of the PMDI showing the dose counter and Figure 1E is an exploded perspective view showing the PMDI casing (1), cap (2) for covering the mouthpiece and the actuator within the casing (3). Figure 1F is a top view of the PMDI with the cross section along line B-B shown in Figure 1G. The stem block diameter is 3.13 to 3.17 mm, the spray hole length is 0.65mm to 0.80 mm and the spray hole diameter is 0.2 to 0.3 mm. Non-volatile components of the formulation are added to the canister and the valve is crimped to the canister. The propellant is added through the crimped valve into the canister. The completed canister / valve assembly is coupled to the actuator by inserting the valve stem into the stem seat of the actuator (inhaler body). Alternative configurations that may be used for the inhaler include with and without dose counter, with and without breath actuated / coordinated device, and with and without spacer device to remove unwanted oropharyngeal drug deposition. Alternative PMDI configurations are shown in Figures 1H to 1 J. Photographs are shown in Figures 1K and 1L. The dimensions and features of a 14 ml aerosol canister that may be used with the PMDI of the present invention are shown in Figure 2. The canister is made from an aluminium-magnesium alloy and can be uncoated (mean weight 3.75 to 3.85 g), treated with plasma (mean weight 3.75 to 3.85 g) or anodised (mean weight 3.65 to 3.75 g). Aerosol canisters of other volumes and dimensions, for example a 19 ml canister, may also be used with the PMDI of the present invention. Stability of Dronabinol during storage in the canister was measured using a HPLC method that is able to identify 16 cannabinoids, according to the parameters set out in Table 1. Table 1: HPLC protocol Parameter / item Description Column Waters CORTECS® Shield RP18 2.7pm (4.6x150mm) Mobile Phase (Isocratic) Acetonitrile : water(0.1% TFA) 59    :      41 Flow Rate 2.0 mimin'1 Injection Volume 5 pl Column Oven Temperature 35SC Sample Temperature 10sC in HPLC chiller unit Air-Conditioned laboratory (20sC ±1.5SC) Detection, Wavelength 228 nm Chromatograph Run Time* 20 Minutes Expected Drug Retention Time 6.6 (CBD) Minutes, 11.1 (DBN) Minutes Syringe Wash Solution 50:50 Acetonitrile:Water Dilution Solvent Methanol Linear Range 2.5 -130 pgml'1 Vials Chromatography Direct (Amber) Injection Overlap Begin draw at 18 mins A representative HPLC separation profile is shown in Figure 3, with the highlighted peak (see arrow) at 11.088 minutes representing dronabinol. In accordance with FDA guidance, the PMDI on the present invention has a bias to count not fire (rather than fire not count). As shown in Figure 4, if a patient applies a 10 force of > 33.59 ± 0.03N and < 37.366 ± 0.040N, the PMDI will count and not fire (stem displacement of between 2.1 and 2.4mm). Table 2 shows data measuring the force necessary for firing and the bias in dose counting for a 0.25 mm actuator with dose counter. The actuator with dose counter was tested for the verification, and 120 doses were fired. A total of 160 doses were included (120 target doses and 40 overage doses). The shot weights of the actuator with dose counter (69.7 ± 1.2 mg, n = 54) were comparable with that of a conventional actuator (70.6 ± 2.1 mg, n = 56). Table 2: Dose counter verification Mean ± Standard Deviation (n = 5) Dose Fired Dose Count Committed Stem Displacement (mm) Force (N) 0.000 ±0.000 0.000 ±0.000 no no 0.200 ±0.000 10.940 ±0.050 no no 0.500 ±0.000 21.874 ±0.048 no no 0.800 ±0.000 24.360 ±0.066 no no 0.900 ±0.000 24.894 ±0.053 no no 1.200 ±0.000 28.152 ±0.050 no no 1.500 ±0.000 30.470 ±0.058 no no 2.000 ±0.000 33.300 ±0.049 no no 2.100 ±0.000 33.594 ±0.034 no yes 2.200 ±0.000 34.434 ± 0.296 no yes 2.300 ±0.000 35.916 ±0.068 no yes 2.400 ±0.000 37.366 ±0.040 yes yes 2.500 ±0.000 38.170 ±0.042 yes yes 2.700 ±0.000 39.342 ±0.050 yes yes 3.000 ±0.000 39.930 ±0.057 yes yes 3.400 ±0.000 42.740 ± 0.050 yes yes 3.500 ±0.000 44.122 ±0.079 yes yes 3.600 ±0.000 49.178 ±0.111 yes yes 3.700 ±0.000 53.200 ±1.058 yes yes 3.500 ±0.000 40.948 ±1.004 yes yes 3.000 ±0.000 32.776 ±0.388 yes yes 2.800 ±0.000 30.770 ± 0.346 yes yes 2.400 ±0.000 26.682 ±0.143 yes yes 2.200 ±0.000 24.330 ±0.505 yes yes 1.700 ±0.000 20.930 ±0.123 yes yes 1.200 ±0.000 19.100 ±0.094 yes yes 1.000 ±0.000 18.144 ± 0.192 yes yes 0.800 ±0.000 16.420 ±0.089 yes yes 0.600 ±0.000 15.472 ±0.135 yes yes 0.200 ±0.000 6.638 ±0.503 yes yes Example 2: Formulations and pharmacokinetic data Two formulations of dronabinol (shown in Tables 3 and 4) were manufactured under nitrogen and the stability tested. Table 3: 0.5 mg dronabinol formulation Component % w / w Per canister (mg) Per 63 pl (mg) Dronabinol 0.655 80.038 0.500 Anhydrous Ethanol 2.000 244.540 1.528 HFA 134a 97.345 11902.422 74.354 Total 100.00 12227.000 76.382 5 Table 4:2.5 mg dronabinol formulation Component mg / Dose mg / MDI % w / w Dronabinol 2.5 400.5 3.42 Ethanol 7.3 1171.7 10.00 HFA 134a 63.3 10144.8 86.58 Total 100.00 11717.0 73.1 Solubility of dronabinol was assessed at 5 °C and 20 °C at different ethanol concentrations for the 0.5 mg dronabinol formation (see Table 5 and Figure 5) and the 2.5 mg dronabinol formation (see Figure 6). 10 Table 5: solubility of the 0.5 mg dronabinol formulation Ethanol in Dronabinol solubility (mean ± standard deviation, n = 4) HFA 134a %( w / w) per 63 pl dose % (w / w) T = 5 °C T = 20 °C T = 5 °C T = 20 °C 1.1 ±0.0 0.37 ± 0.02 0.42 ±0.02 315 ± 12 348 ± 21 2.1 ±0.0 0.62 ±0.02 0.70 ±0.04 520 ±17 580 ± 42 3.1 ±0.0 1.00 ±0.09 1.09 ±0.04 841 ± 85 887 ± 32 The stability of dronabinol was determined for storage under different conditions, including before the test (t = 0), 1 month (at 40 °C 175% relative humidity), 3 months (at 40°C / 75% relative humidity), and 6 months (at 40 °C / 75% relative humidity). No unspecified peaks were identified at t = 0. Data for the stability of different formulations as determined by HPLC are shown in Tables 6 to 12. co Table 6: Stability matrix: t=0, 1, 3, and 6 month time point (2.5 mg / 63 pl Dronabinol dose) Formulation Batch Ap t a r Valve ID w Inv t=0 t= 1 month t= 3 months t=6 months 4G°C / 75%RE 25°C 4(PC / 75%RH 4GCC'75%RH Rg total RS (%) Pg % of t=0 total RS (%) total RS (A%) Pg % of t=0 total RS (%) total RS (A%) Pg % of t=0 total RS (%) total RS (A%) Pg % of t=0 total RS (%) total RS (A%) DEL 2.5mgy'63pl, 10%E, 134a OZ 220^30 DALA 357 (POM -PBT) Lp 416854 1.2 407001 97 1.6 0.4 373457 91 19 0.7 387357 93 3.8 2.6 384021 385730 93 4.9 3.7 413628 398134 384348 384055 Inv - - 400563 96 1.8 0.6 384106 93 17 0.5 373651 91 3.6 2.4 383182 92 5.4 4.3 40O592 387174 378261 oz 220-636 DALE 355 (Full PBT) Up 414524 12 410222 98 1.5 0.3 367479 90 1.5 0.3 386799 92 3.2 2.0 422018 410007 384713 379728 Inv - - 400010 96 1.5 0.3 393010 94 15 0.2 360413 87 3.1 1.9 405008 369927 WO 2025 / 129263                                   PCT / AU2024 / 051391 co cn Table 7: Specified peaks for related substances at 0 month at 40 °C and 75% relative humidity (2.5 mg / 63 pl Dronabinol dose) Formulation Batch Aptar Valve ID Up / Irv Specified Peaks Dronabinol CBL D8-THC CE N Total Specified Total (All) Area pg pg %of DBL PS %of DBL pg % of DBL pg % of DBL pg % of DBL DBL 2.5mg. / 63fjl, 10%E, 134a OZ220630 DALA ID 357 (POM+PBT) Up 553777 416-854 783 0.2 3629 0.9 669 0.2 5080 1.2 5080 1.2 549492 413628 639 0.2 3490 0.8 745 0.2 4875 1.2 4875 1.2 OZ220630 DALB ID 355 (Full PBI) Up 550683 414524 704 0.2 3673 0.9 702 0.2 5079 1.2 5079 1.2 560639 422018 666 0.2 3718 0.9 665 0.2 5049 1.2 5049 1.2 WO 2025 / 129263                                   PCT / AU2024 / 051391 co cd Table 8: Specified peaks for related substances after 1 month at 40 °C and 75% relative humidity (2.5 mg / 63 pl Dronabinol dose) Formulation Satoh Aptar Valve ID Up / Inv Specified Peaks Dronabinol C BL D8-TI -IC CBN CBDV-A TH cv Total Specified Total (All) Area pg pg % of DBL pg %of DBL pg % of DBL pg % of DBL pg %of DBL pg % of DBL pg % of DBL DBL 2.5mg, / 63^1, 134a OZ220630 DALA ID 357 (POM + PBT) Up 630631 407001 560.0 0.14 3668.46 0.90 902 0.2 736.3 0.2 0.0 0.0 5867 1.4 6363 1.6 616891 398134 601.7 0.15 375-8.31 0.94 887 0.2 597.3 0.2 490. 6 0.1 6335 1.6 6815 1.7 Inv 6206-54 400563 587.7 0.15 3843.23 0.96 983 0.2 651.8 0.2 442. 0.1 6508 1.6 7019 1.8 620700 400592 672.8 0.17 39QO.90 0.97 984 0.2 661.4 0.2 424. 6 0.1 6644 1.7 7122 1.8 OZ22O630 DALB ID 355 (Full PBT) Up 635622 410222 662.4 0.16 3651.94 0.89 876 0.2 459.4 0.1 0.0 0.0 5649 1.4 6164 1.5 635289 410007 636.9 0.16 3739.25 0.91 866 0.2 387 0 0.1 0.0 0.0 5639 1.4 6151 1.5 inv 619798 400010 663.9 0.17 3784.37 0.95 913 0.2 443.2 0.1 0.0 0.0 5894 1.5 6345 1.6 627543 405008 559.8 0.14 3630.38 0.90 796 0.2 393.3 0.1 0.0 0..0 5380 1.3 5952 1.5 WO 2025 / 129263                                   PCT / AU2024 / 051391 Table 9: Unspecified peaks for related substances after 1 month at 40 °C and 75% relative humidity (2.5 mg / 63 pl Dronabinol dose) Formulation Batch Aptar Valve ID Up / Inv Unspecified peaks RT~7.9mms Total Peak Area Approx pg pg % of DBL DBL 2.5mg. / 63pL 10%E, 134a OZ220630 DALA ID 357 (P0M+P8T) Up 769 496.3 496 0.12 744 480.2 480 0..12 Inv 791 510.5 511 0..13 740 477.8 478 0.12 OZ220630 DALB ID 355 (Full PBT) Up 798 515.0 515 0.13 808 521.5 521 0.13 Inv 838 540.8 541 0.14 887 572.5 572 0.14 WO 2025 / 129263                                   PCT / AU2024 / 051391 co 00 Table 10: Specified peaks for related substances after 3 months at 40 °C and 75% relative humidity (2.5 mg / 63 pl Dronabinol dose) Batch Aptai Valve ID Up / Inv Temp (8C) Specified Peaks Total (All) Dronabinol CE DV CBDV-A CE IG CBL CE N D8-1 EMC TF ICV Total Specified PS RS %of DBN pg %of DBN pg %of DBN pg %of DBN pg %of DBN pg %of DBN pg % of DBN RO % of DBL pg %of DBL OZ220630 DALA 357 (POM * RBI) Up 25 373457 0.0 0.0 922 0.2 372 0.1 528 0.1 426 0.1 3395 0.9 1220 0,3 6863 1.8 7997 2.1 384345 0.0 0.0 389 0.1 366 0.1 620 0.2 775 0.2 3635 09 448 0.1 6233 1.6 6233 1.6 In 384106 0.0 0.0 506 01 323 0.1 640 0.2 666 0.2 3509 0.9 415 0.1 6060 1.6 6446 1.7 387174 0.9 0.0 359 0.1 418 0.1 660 0.2 830 0.2 3731 1.0 357 0.1 6354 1.6 6354 1.6 Up 40 387357 1233 0.3 4172 1.1 382 0.1 640 0.2 2224 0.6 4668 1..2 377 0.1 13697 3.5 15872 4.1 384055 940 0.2 3246 0.8 393 0.1 541 0.1 1892 0.5 4396 11 372 0.1 11781 3.1 13654 3.6 In 373851 '912 0.2 3238 0.9 352 0.1 659 0.2 2:060 0.6 4576 1.2 296 0.1 12086 3.2 14033 3.8 378261 844 0.2 2994 0.8 391 0.1 617 0.2 1775 0.5 4252 1..1 411 0.1 11284 3.0 12975 3.4 □Z22G630 DALB 355 (Full PBT) Up 25 367479 0.0 0.0 336 0.1 334 0.1 615 0.2 733 0.2 3452 0.9 0 0.0 5471 1.5 5471 1.5 384713 0.0 0.0 304 0.1 387 0.1 532 0.1 760 0.2 3555 0.9 0 0.0 5538 1.4 5538 1.4 In 393010 0.0 0.0 293 0.1 374 0.1 626 0.2 768 0.2 3662 09 0 0.0 5724 1.5 5724 1.5 Up 40 386799 533 0.1 2077 0.5 345 0.1 572 0.1 1673 0.4 4629 1.2 404 0.1 W233 2.6 12153 3.1 379727 668 0.2 2605 0.7 334 0.1 575 0.2 1725 0.5 4524 1..2 444 0.1 10875 2.9 12645 3.3 In 360413 453 0.1 1836 0.5 370 0.1 565 0.2 1532 0.4 4226 12 414 0.1 93-95 2.6 11287 3.1 369927 746 0.2 2677 0.7 349 0.1 657 0.2 1680 0.5 3703 1.0 253 0.1 W064 2.7 11657 3.2 WO 2025 / 129263                                   PCT / AU2024 / 051391 co CD Table 11: Unspecified peaks for related substances after 3 months at 40 °C and 75% relative humidity (2.5 mg / 63 pl Dronabinol dose) Batch Aptar Valve ID Up / lHV Temp (°CJ Unspecified Peaks @RT(mins) Total (AHJ Dronabinol 11. 07 2.75 3.0 4.45 Total Unspecified pg pg % of DBN yg %of DBN pg %of DBN pg %of DBN pg % of DBL pg % of DBL OZ220630 DALA 357 (POM + PBT) Up 25 373457 0 0.0 0 0.0 688 0.2 446 0.1 1134 0..3 7997 2.1 384348 0 0...0 0 0.0 0 0.0 0 0.0 0 0.0 6233 1..6 In 384106 0 0...0 0 0.0 0 0.0 386 0.1 386 0.1 6446 1..7 387174 0 0.0 0 0.0 0 0.0 0 0.0 0 0..0 6354 1.6 Up 40 387357 1487 0.4 689 0.2 0 0.0 0 0.0 2176 0..6 15872 4.1 384055 1286 0...3 587 0.2 0 0.0 0 0.0 1874 0,5 13654 3..6 In 373651 1456 0.4 491 0 1 0 0.0 0 0.0 1947 0..5 14033 3.8 378261 1146 0,3 545 0.1 0 0.0 0 0.0 1691 0.4 12975 3.4 OZ220530 DALB 355 (Full PBT) Up 25 367479 0 0...0 0 0.0 0 0.0 0 0.0 o 0.0 5471 1..5 384713 0 0.0 0 0.0 0 0.0 0 0.0 o 0.0 5538 1.4 In 393010 0 0.0 0 0.0 0 0.0 0 0.0 Q 0.0 5724 1,5 Up 40 386799 1487 0.4 433 0.1 0 0.0 0 0.0 1920 0.5 12153 3.1 379727 1286 0,3 484 0.1 0 0.0 0 0.0 1770 0.5 12645 3,3 In 360413 1456 0...4 0 0.0 436 0.1 0 0.0 1892 0.5 11287 3..1 369927 1146 0.3 446 0.1 0 0.0 0 0.0 1592 0.4 11657 3.2 WO 2025 / 129263                                   PCT / AU2024 / 051391 Table 12: Specified and unspecified peaks for related substances after 6 months at 40 °C and 75% relative humidity (2.5 mg / 63 pl Dronabinol dose) Batch Aptar Valve ID Up / Inv Temp (°C) Specified Peaks Total (AH) Dronabinol ce DV CB D-A CBG-A CBL CBN DS-THC THCV Total Specified pg %of DBN pg % of DBN pg % of DBN pg % of DBN pg %of DBN pg %of DBN pg %of DBN pg % of DBL pg % of DBL OZ220630 DALA 357 (POM + PBT) Up 40 384021 1592 0.4 396 0.1 2367 0.6 0 0.0 3752 1.0 5732 1.5 0 0.0 13840 3.6 20454 5.3 385730 1439 0.4 432 0.1 1757 0.5 0 0.0 3118 0.8 4887 1.3 0 0.0 11633 3.0 17151 4.4 In 383182 1812 0.5 336 0.1 2327 0.6 0 0.0 3765 1.0 5273 1.4 0 0.0 13513 3.5 20879 5.4 Batch Aptar Valve ID Up / Inv Temp (°C) Unspecified Peaks Total (AH) Dronabinol 2.5 2.75 3.7 Total unspecified P0 MS %of DBN PS % of DBN pg %of DBN pg % of DBL pg % of DBL OZ220630 DALA 357 (POM + PBT) Up 40 384021 0 0.0 723 0.2 5891 1.5 6614 17 20454 5.3 385730 0 0 0 399 0.1 5119 1.3 5518 1.4 17151 4.4 In 383182 471 0.1 573 0.1 6322 1.6 7366 1.9 20879 5.4 WO 2025 / 129263                                   PCT / AU2024 / 051391 The stability of Dronabinol in water was also tested. Data for the stability in water as determined by HPLC are shown in Tables 13 to 19. No unspecified peaks were identified for t = 0 and t = 1 month at 40 °C and 75% relative humidity. Table 13: Stability matrix for water robustness: 0, 1 and 3 months at 40 °C and 75% relative humidity (2.5 mg / 63 gl Dronabinol dose) Formulation (Dronabinol 2.5 mg / 63pl) Batch Water Content t=0 t = 1-month t = 3-month t = 6-month Storage T = 40W5%RH T = 4QX / 75%RH T= 4TC / 75%RH pg %of target Total RS (%) PS % of t=o Total RS (%) PS %of t = 0 Total RS (%) pg %of t = 0 Total RS (%) 10% w / w Ethanol HFA 134a Hus 0.16% w / w Water OZ220712 DALA 0,16 334224 332999 331534 102.0 101.5 101.4 0.9 11 1.0 T 331208 326078 99 18 16 316428 309246 94.0 3.4 3.4 312319 93.8 3.5 4 314621 322275 96 bi co 309338 306361 92.5 2.9 3.1 309009 92.8 4.5 WO 2025 / 129263                                   PCT / AU2024 / 051391 Table 14: Specified peaks for water robustness: 0 month at 40 °C and 75% relative humidity (2.5 mg / 63 pl Dronabinol dose) Formulation Batch Water Content Up / Inv Specified Peaks Dronabinol D 8-THC CBN Total Specified Total (All) Area PS pg % of DBL pg % of DBL pg % of DBL pg % of DBL 10% W / W Ethanct. HFA 134 a Pius 0..16% w / w Water OZ220712 DALA 0.16 Up 491673 334224 2620 0.8 250 0.1 2870 0.9 2870 0.9 489870 332999 3290 1..0 332 0.1 3622 1..1 3622 1.1 487714 331534 2842 0.9 315 0.1 3157 1.0 3157 1.0 WO 2025 / 129263                                   PCT / AU2024 / 051391 Table 15: Specified peaks for water robustness: 1 month at 40 °C and 75% relative humidity (2.5 mg / 63 pl Dronabinol dose) Formulation Batch Water Content Up / Inv Specified Peaks Dronabinol DS-THC CBN CBC SV-A THCV CBG-A Total Specified Tota (All) Area PS pg % of DBL pg %of DBL PS % of DBL PS % of DBL PS %of DBL PS % of DBL pg %of DBL 10% w / w Ethanal, HFA 134a Plus 0.16% w / w Water OZ220712 DALA 0,16 Up 492463 331208 3337 1.0 0 0.0 667 0.2 0 0.0 1967 0.6 5971 1.8 5971 1.8 484836 326078 2503 0.8 0 0.0 726 0.2 8 0.0 1910 0.6 5139 1.6 5139 1.6 Im 467800 314621 3234 1..0 1042 0.3 601 0.2 684 0.2 0 0.0 5560 1..8 5560 1.8 479181 322275 3305 1..0 941 0.3 589 0.2 465 0.1 0 0.0 5300 1..6 5300 1.6 WO 2025 / 129263                                   PCT / AU2024 / 051391 Table 16: Specified peaks for water robustness after 3 months at 40 °C and 75% relative humidity (2.5 mg / 63 pl Dronabinol dose) Formulation Batch Water Content %(w / w) Up / Inv Specified F ’eaks Dronabinol D8-THC CBN CBDV-A Tf tcv CE DV c BG-A Total Specified Total (All J Area P0 TO %of DBL TO %of DBL PS %of DBL PS % of DBL MS % of DBL PS % of DBL PS %of DBL pg %of DBL 10% w / w Ethanol, HFA 134a Pte. 0.16% w / w ‘Water OZ 220712 DALA 0..16 Up 482873 316428 3379 1.1 1657 0.5 2997 0.9 Q 0.0 0 0.0 Q 0.0 8033 2.5 10850 3.4 471913 309246 3338 1.1 1461 0.5 2695 0.9 0 0.0 1184 0.4 0 0.0 8678 2.4 10491 3.4 hv 472053 309338 3880 1.3 1721 0.6 2020 0.7 0 0.0 0 0.0 0' 0.0 7621 2.5 9106 2.9 467509 306361 3747 1.2 1670 0.5 2168 0.7 332 0.1 0 0.0 0 0.0 7917 2.6 9478 3.1 WO 2025 / 129263                                   PCT / AU2024 / 051391 Table 17: Unspecified peaks for water robustness after 3 months at 40 °C and 75% relative humidity (2.5 mg / 63 pl Dronabinol dose) Formulation Batch Aptar Valve ID Up / Inv Unspecified peaks RT 2.75mins RT 2 mins RT 3,7mins RT 11.07mins Tol al Peak Area Approx pg Peak Area Approx pg Peak Area Approx pg Peak Area Approx pg pg %of DBN THC 2.5mg, / 63pl, 10%E, 0.16% H 2O 134a OZ220712 DALA Full PBT Up 1002 657 0 0.00 1276 8-36.1672 2021 1324.37 2817.15 0,89 936 613 0 0.00 0 0 1831 1199.86 1813.23 0.59 Inv 510 334 875 573.39 881 577.3229 0 0.00 1484..92 0.48 514 337 934 612.05 935 612.7093 0 0.00 1561.59 0,51 WO 2025 / 129263                                   PCT / AU2024 / 051391 Table 18: Specified peaks for water robustness after 6 months at 40 °C and 75% relative humidity (2.5 mg / 63 pl Dronabinol dose) Formulation Batch Aptar Valve ID Dpi Inv Can Specified Peaks II 4C D9-THC D8-' FHC CE CBDV-A n HCV CB DV CBG-A Total Specified Total (Ail) Area PS PS % of DBN PS % of DBN pg % of DBN PS % of DBN PS %of DBN pg % of DBN PS % of DBN pg % of DBN pg % of DBN THC 2..5mg, / 63pl W%E, 0.16%H2O 134a OZ 220712 DALA Full P8T Up 12 474702 312319 0 0 3456 1.1 2286 0.7 0 0.0 0 0.0 1133 0.4 1212 0.4 8087 2.6 11022 3.5 Inv 11 469671 309009 0 0 4576 1.5 3302 1.1 0 0.0 0 0.0 980 0.3 2015 0.7 10873 3.5 13766 4.5 WO 2025 / 129263                                   PCT / AU2024 / 051391 Table 19: Unspecified peaks for water robustness after 6 months at 40 °C and 75% relative humidity (2.5 mg / 63 pl Dronabinol dose) Formulation Batch Aptar Valve ID Up / Inv Unspecified peaks RT 2. 5mins RT2.75mins RT 3.7mins Total Peak Area Approx Peak Area Approx pg Peak Area Approx pg pg % of DBN THC 2.5mg,B3pl, 10%E, 0J6%H2O 134a OZ220712 DALA Full FBI Up 0 419 275.89 4042 2659.207 2935.10 0.94 Inv 441 290 358 235.71 3598 2367.21 2892.87 0.94 WO 2025 / 129263                                   PCT / AU2024 / 051391 Data for the delivered dose at beginning of can life, middle of can life and end of can life for the 0.5 mg dronabinol formulation is shown in Table 20 and Figure 7, and for the 2.5 mg dronabinol formulation is shown in Table 21 and Figure 8. Table 20: Dose content uniformity (0.5 mg dronabinol formulation) Beginning / Middle or End of Canuse Life Can 72 Can 93 DD (pg) Actuator (pg) MD (pg) DD (pg) Actuator (pg) MD (pg) BOL 401 55 456 387 56 443 399 454 379 435 413 468 390 446 MOL 423 88 511 426 95 520 405 493 416 511 422 510 416 511 387 475 412 507 EOL 449 95 543 427 93 520 441 535 427 520 436 530 437 531 Table 21: Dose content uniformity (2.5 mg dronabinol formulation) B / M / EOL Dose # Test (DUSA / NGI) Can 9 Can 12 DD (pg) Actuator (pg) MD (pg) DD (pg) Actuator (pg) MD (pg) BOL 3 DUSA 1813.7 446.6 2260.3 2265.8 420.0 2685.8 4 1889.3 2335.9 2197.7 2617.7 5 2122.1 2568.7 2151.8 2571.8 MOL 99 DUSA 2070.2 308.7 2378.9 2047.4 400.4 2447.9 100 2151.6 2460.3 2186.0 2586.4 101 2214.0 2522.7 2148.7 2549.1 102 2105.7 2414.4 2180.7 2581.1 EOL 190 DUSA 2042.9 382.4 2425.3 2127.7 433.8 2561.5 191 2132.1 2514.4 2134.7 2568.5 192 2134.8 2517.2 2222.5 2656.3 Particle size distribution for the 0.5 mg dronabinol formulation is shown in Table 22 and Figure 9, and for the 2.5 mg dronabinol formulation in Table 23 and Figure 10. Table 22: Particle size distribution (0.5 mg dronabinol formulation) Metered Dose [pig] 480 ± 19 Delivered Dose [pg] 394 ± 13 Fine Particle Dose [pg] 323 ± 18 Fine Particle Fraction [%] 82 ±2 MMAD [um] 1.8 ±0.1 GSD 1.8 ±0.1 5 Table 23: Particle size distribution (2.5 mg dronabinol formulation) Batch: Oz220630 / DAL / A Mean DBN Metered Dose [pg] 2,494.0 ± 227.3 Delivered Dose [pg] 2,077.7 ± 192.6 Fine Particle Dose [pg] 887.2 ± 30.9 Fine Particle Fraction [%] 43.0 ± 4.4 MMAD [um] 2.7 ±0.1 The priming and tailing for the 0.5 mg dronabinol formulation are shown in Figure 11 and for the 2.5 mg dronabinol formulation in Figure 12. One priming dose to be fired before use of a new PMDI. For the 0.5 mg dronabinol formulation the mean shot weight 10 was 75 ± 2 mg (target 76.4 mg) and for the 2.5 mg dronabinol formulation it was 71.7 ± 1.1 mg (n = 52, doses 3-120) was 71.7 ± 1.1 mg (n = 52). Towards the end of the life of the can, tailing occurs over 2 doses well in excess of the target dose number of 120. A comparison of the particles generated with 0.5 mg and 2.5 mg formulations are represented in Table 24. 15 Table 24: Fine particle dose and fine particle fraction of dronabinol formulations 0.5 mg dronabinol formulation 2.5 mg dronabinol formulation Delivered dose [pg] 394 ±13 2077.7 ±192.6 Fine particle dose [pg] 323 ± 18 887.2 ±30.9 Fine particle fraction [%] 82 ±2 43.0 ±4.4 It was expected that the higher dosage formulation (2.5 mg) would deliver a larger particle dose. This was indeed the case, but the fine particle dose did not increase 5 proportionally to the increase in dronabinol concentration. Indeed, the fine particle fraction was approximately double in the 0.5 mg formulation compared to the 2.5 mg formulation. Example 3: Phase 1 clinical study to determine the pharmacokinetics of Dronabinol formulation 10 A clinical trial was conducted using the dosage device described in Example 1 and with the formulations described in Example 2. A schematic diagram of the study design for this example is shown in Figure 13. Figure 15 shows pictorial instructions for using the pDMI that was provided to the subjects. Study entry subjects satisfied all criteria set out in Table 25. Table 25: Inclusion criteria for study subjects 1. Aged > 18 to < 55 years (inclusive). 2. Subject is free from clinically significant (in the opinion of the Investigator) illness or disease as determined by their medical and surgical history, physical examination, 12-lead ECG, vital signs and clinical laboratory determinations. 3. BMI > 18 and < 32 kg / m^ at Screening. 4. Weight > 50.0 kg at Screening. 5. Adequate venous access in both arms for collection of a number of blood samples. 6. Capable of understanding the purposes and risks of the study and able to provide written informed consent before any study-specific screening procedures are performed. 7. Willing and able to adhere to all protocol requirements, including willingness to comply with scheduled visits, and tolerance to dosing using an inhaler. 8. The subject is able to perform deep inhalations with FEV1 more than 80%. Abbreviations: BMI=body mass index; ECG= electrocardiogram; FEV1=forced expiratory volume Individuals who fulfilled any criteria set out in Table 26 were excluded as study entry 5 subjects. Table 26: Exclusion criteria for study subjects 1. History of coronary disease, peripheral vascular disease, cerebrovascular accident, transient ischemic attack, uncontrolled hypertension or signs / symptoms of ischemic heart disease. 2. History of acute or severe bronchial asthma (excluding childhood or exercise induced asthma), diagnosed obstructive sleep apnea, hypoxia, hypoxemia, hypercarbia, or other obstructive airway disease or any condition that may increase the risk for respiratory depression. 3. History of neurologic conditions such as seizures (excluding single febrile seizures during childhood) or convulsive disorders (including epilepsy), severe head injury or increased intracranial pressure. 4. Presence of current psychiatric condition or psychiatric condition requiring pharmacological management within the last 6 months, presence of current or history of psychosis / schizophrenia and bipolar disorders. 5. A calculated creatinine clearance of < 80 mL / minute at Screening or Check-In (Day -1) according to the equation using Cockcroft and Gault. 6. Liver function tests showing values for ALT or AST > 1.5 times ULN at Screening. 7. Evidence or history of clinically relevant (in the opinion of the Investigator) other cardiovascular, pulmonary, neurologic or renal disorders or hepatic, gastrointestinal, oral (difficulty swallowing / taking oral medication), hematological, endocrine, or psychiatric impairment / disorders, making implementation of the protocol or interpretation of the study results difficult, or that would put the subject at risk by participating in the study in the opinion of the Investigator. 8. Have undergone surgery requiring or have received (for any reason) anesthetic within 30 days of Day 1. 9. Use of CNS depressants including: opioids, sedative, anxiolytics, hypnotics, neuroleptics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines or cimetidine within 30 days of Day 1. 10. Use of macrolide antibiotics (e.g., Erythromycin), azole antifungal agents (e.g., Ketoconazole) or protease inhibitors (e.g., Ritonavir) within 30 days of Day 1. 11. Use of any prescription medication within 14 days of Day 1 and for duration of study, unless approved by both the Investigator and the Medical Monitor (in writing). COVID-19 vaccine within 1 week of Day 1 may be administered. Paracetamol, ibuprofen, hormonal contraception may be administered. 12. Use of any over the counter product, herbal product, diet aid, or hormone supplement, with a particular regard to hemp or products containing cannabidiol, within 14 days of Day 1 and for duration of study, unless approved by both the Investigator and Medical Monitor (in writing). Vitamins and dietary supplements and topical preparations may be administered (other than those in the prohibited list). 13. History of severe allergic or anaphylactic reactions, known intolerance, allergy or hypersensitivity reactions to dronabinol. 14. Positive screening test for HIV antibodies, Hepatitis B surface antigen or Hepatitis C antibody. 15. Evidence or history of substance or alcohol abuse (drink more than 4 standard units of alcohol per day or >14 standard units per week), including positive results for the urine drugs of abuse test or a positive alcohol breath test at Screening or at Check- In (Day -1). 16. Unwilling or unable to abstain from recreational drug / substance use, alcohol, from 48 hours before check-in until discharge. 17. Unwilling or unable to abstain from caffeine or other xanthine-containing products from check-in until discharge. 18. Subjects who are smokers (within the last 3 months). 19. Consumption of grapefruit, grapefruit juice or any products containing CYP3A4 inhibitors and inducers within 14 days of Day 1 and through to completion of the study. 20. Female subject or female partner of male subject that is pregnant or lactating. 21. Treatment with another investigational drug, investigational device, or approved therapy for investigational use within 1 month or 5 half-lives prior to Day 1. 22. Donation or loss of more than 500 mL of blood within 1 month of Day 1 and / or plans to donate blood during the study. 23. Subject tests positive for COVID-19 at Day -1. 24. Other unspecified reasons that, in the opinion of the Investigator, make the subject unsuitable for enrolment. Abbreviations: ALT=alanine transaminase; AST=aspartate transaminase; CNS=central nervous system; COVID-19=disease resulting from SARS-CoV2 virus or variants thereof; CYP3A4= hepatic metabolic enzyme; FEV1=forced expiratory volume; HIV=human immunodeficiency virus 5 The IPs used in this study are presented in Table 27. IRX211 a (dronabinol PMDI 0.655% w / w) was supplied in a multi-dose container with a mean emitted dose of 0.5 mg / actuation. IRX211 m (dronabinol PMDI 3.42% w / w) was supplied in a multi-dose container with a mean emitted dose of 2.5 mg / actuation. Table 27: Investigational products administered Investigational Product Dose form Route of administration Dose (mg) per Actuation IRX211a Inhalation Aerosol Inhaled 0.5 mg IRX211m Inhalation Aerosol Inhaled 2.5 mg Placebo Inhalation Aerosol Inhaled 0 mg This study was a double-blind study and thus the investigator, site staff (other than pharmacy personnel), sponsor, sponsors delegates (if applicable) and subjects were all blinded to treatment. No individual-subject information that could potentially un-blind the investigator or subject was reported until the end of the study. The presentation of the 15 placebo was identical in appearance to the 0.5 mg and 2.5 mg dronabinol formulations. The investigator remained blinded, unless knowledge of the subjects’ treatment assignment was necessary for the clinical management or welfare of the subject. The reason for un-blinding would be clearly documented. A computer-generated randomization schedule was prepared by an unblinded statistician prior to the start of the study. At the time of randomization, the subject was assigned a unique randomization number, which was allocated sequentially based on the pre-determined randomization schedule, and according to their chronological order of inclusion in the study. For each dose cohort, subjects was randomized 3 active:1 placebo. For the first cohort, 2 sentinel subjects were dosed (1 dronabinol and 1 placebo) at least 24 hours prior to the remaining subjects in each cohort. Once safety to 24 hours post-dose was confirmed by the safety review committee (SRC) in the sentinel subjects, the remaining 6 subjects were dosed (5 dronabinol and 1 placebo). The SRC advised if sentinel dosing was required for subsequent cohorts. The first cohort included the initial dosing of a sentinel group (1 dronabinol and 1 placebo subject). The remaining 6 subjects in the cohort (5 dronabinol and 1 placebo) were dosed if, in the opinion of the investigator or delegate, there were no significant safety concerns identified in the sentinel subjects within the first 24 hours after administration of the dose (dronabinol or placebo). The SRC advised if sentinel dosing is required for subsequent cohorts. A COVID-19 rapid antigen test was performed. Subjects were treated with a single dose of dronabinol or placebo according to the dose level and randomization schedule on Day 1. Both the site staff treating subjects and the subjects themselves were blinded to the treatments being administered. The study consisted of a Screening Period, Dose Evaluation Period and Follow-up Period. Subjects undertook a screening visit between Day -28 and Day -2 to determine their eligibility to participate in the study. Those subjects that met the eligibility criteria were admitted to the study site on the evening prior to dosing (Day -1) when continued eligibility was assessed. Subjects completed at least a 10 hour fast prior to study drug administration on Day 1. On Day 1 prior to dosing, baseline assessments were performed, and a pre dose PK sample was collected. Subjects were then dosed according to the randomization schedule. Screening evaluations commenced once a subject signed electronic informed consent. Screening evaluations permitted review of baseline health status and to determine eligibility. A complete medical history included evaluation for past or present cardiovascular, respiratory, gastrointestinal, renal, hepatic, neurological, endocrine, metabolic, lymphatic, hematologic, immunologic, dermatologic, psychiatric, and genitourinary 5 disorders, medication and surgical history, and review of any other diseases or disorders. The study was designed as a dose escalation study. Dosing commenced with the lowest dose cohort. The study dose-ascended once safety data and PK data were reviewed by the Safety review Committee (SRC). Subjects remained at the study site 10 for observation through to 8 hours post-dose and completed an end of study Visit 7 ± 2 days after dosing. Enrolment to Cohorts 2, 3 and 4 did not begin without approval of the SRC. A SRC meeting took place prior to dose escalation to review safety and PK data. The SRC provided recommendations of doses for Cohorts 2 to 4. 15 Following dosing, PK, safety and tolerability assessments were performed according to the study schedule, represented in Table 28. Table 28: Schedule of Events STUDY DAY Days -28 to -2 Day -1 Day 1 Follow Up Day 7 ± 2 days Visit Screening Check-in Treatment Exit Confinement at Phase I unit V V Screening Informed consent V Assessment of eligibility V V Demographics V Height and weight V Medical and surgical history V Medication history V COVID-19 rapid antigen test V Inhaler education / tolerability1 V Safety Physical Examination V V2 V Vitals Signs V V V3 V ECG V V V4 V FEV1 V V5 Hematology / Biochemistry V V V Serology V Urinalysis V V V Drug and Alcohol Screen V V V6 Urine pregnancy test V V Serum pregnancy test V Adverse Events V V V Concomitant Medications V V V Discharge Checklist V6 Pharmacokinetic PK sampling IP Randomization V IP Administration V8 Abbreviations: ECG=electrocardiogram; FEV1= Forced Expiratory Volume; IP=investigational product; PK=pharmacokinetic 1. Education on inhaler use, assessment of tolerability to dosing using an inhaler. 2. Symptom directed. 5      3. Vital signs to be captured within 60 minutes pre-dose, and every 15 minutes (±5 minutes) post dose to 150 minutes post-dose, at 4 hours (±10 minutes) and at 8 hours (±10 minutes) post-dose. 4. ECG to be performed within 60 minutes pre-dose, and at 15 minutes (±5 minutes), 30 minutes (±5 minutes), 1 hour (±10 minutes), 2 hours (±10 minutes), 4 hours (±10 minutes), and 8 hours (±10 minutes) post-dose. 5. FEV1 to be performed within 60 minutes pre-dose, at 1 hour (±10 minutes) and 4 hours (±10 minutes) post-dose. 6. If the Day 7 drug screen is positive, participants need to return to the clinic for a follow-up drug test until they test negative, these visits will be called unscheduled visits. 7. To be completed after the 8 hours post dose assessments have been performed, prior to discharge. 8. PK sample collection: pre dose, and at 1,2, 3, 4, 5,10,15, 30, 60, 90, 120 and 150 minutes post-dose, at 4, and 8 hours post-dose. 9. IP will be administered to subjects on the morning after an overnight fast of at least 10 hours. An interim review of safety and PK data from the study was performed. At least 25 subjects were enrolled in this study to ensure that 20 complete. A review of prior medications was completed. Prior medications are those used within 30 days of Day 1. Pharmacokinetic Assessments Blood samples for the determination of plasma concentrations of A9-THC, 11 -OH-delta-9-tetrahydrocannabinol, and COOH-THC were collected from subjects at the time points listed in Table 29. Table 29: Time-points for PK assessments Day 1 Pre-dose (within 30 minutes prior to dosing) 1 minute post dose (±5 seconds) 2 minutes post dose (±10 seconds) 3 minutes post dose (±10 seconds) 4 minutes post dose (±10 seconds) 5 minutes post dose (±10 seconds) 10 minutes post dose (±30 seconds) 15 minutes post dose (±1 minute) 30 minutes post dose (±1 minute) 60 minutes post dose (±5 minutes) 90 minutes post dose (±5 minutes) 120 minutes post dose (±5 minutes) 150 minutes post dose (±5 minutes) 4 hours post dose (±10 minutes) 8 hours post dose (±10 minutes) Blood samples on Day 1 were collected via either the indwelling IV cannula to reduce the frequency of direct venipuncture (at the discretion of the investigator) or by direct venipuncture. 5 Example 4: Clinical study report of phase 1 study of the pharmacokinetics and safety of IRX211 in healthy volunteers Study patients Disposition of participants A total of 105 healthy volunteers were screened for the study (Part A). Of these, 28 10 were randomized, with 21 randomized to IRX211, and 7 randomized placebo overall. The breakdown by cohort is shown in Table 30. • One participant randomized in cohort 2 (IRX211a 1.0 mg) was discontinued by the medical monitor prior to treatment due to failing pre-dose spirometry. • Three participants were erroneously enrolled and dosed in the trial despite not 15            meeting all eligibility criteria (baseline spirometry requirements not met). As a result of these deviations, 3 additional participants were enrolled. A total of 27 participants were dosed. All 27 dosed participants were included in the safety population. All 27 dosed participants completed the study. Table 30: Summary of Randomized Treatment by Cohort IRX211  Placebo     Total    Number (n)       (n)    Randomized Treated _______________________________________on_______on___ Cohort 1                      8         3           11          11 (IRX211a0.5 mg) Cohort 2                    7        2           9          8 (IRX211a 1.0 mg) Cohort 3                    6        2           8          8 (IRX211m 2.5 mg) Total                       21        7           28         27 All participants who received IRX211 or placebo comprised the safety population (N=27). A further breakdown by Cohort is provided below in Figure 14. Protocol deviations 5 Overall, 23 (82.1%) of 28 randomized participants had at least one protocol deviation. A total of 88 deviations were reported, of which 18 (reported by 8 participants) were considered major and 70 (reported by 23 participants) were considered minor. The most frequent major deviations by category were “Missed trial procedures related to primary endpoint assessment”, reported by 4 (14.3%) participants overall (Table 31). 10 Table 31: Summary of Major Protocol Deviations by Category (Randomized Population) Severity Deviation type IRX211a Dose 0.5 mg N=8 n(%) IRX211a Dose 1.0 mg N=7 n(%) IRX211m Dose 2.5 mg N=6 n(%) All Placebo N=7 n(%) Overall N=28 n(%) Subjects with a protocol deviation 6(75.0) 6(85.7) 4(66.7) 7(100.0) 23(82.1) Major 2(25.0) 2(28.6) 2(33.3) 2(28.6) 8(23.5%) Missed trial procedures related to primary endpoint assessment 0(0.0) 1(14.3) 2(33.3) 1(14.3) 4(14.3) Participant enrolled without meeting all trial criteria 2(25.0) 0(0.0) 0(0.0) 1(14.3) 3(10.7) Missed laboratory collection or not within specific timepoint for PK lab only - trend 0(0.0) 0(0.0) 1(16.7) 1(14.3) 2(7.1) Missed laboratory collection- non safety related 0(0.0) 1(14.3) 0(0.0) 0(0.0) 1(3.6) A subject is counted only once within a severity term and deviation type. Percents are based on the number of randomized subjects by treatment group and cohort. Three participants (102-006 [IRX211 0.5 mg], 102-014 [IRX211 0.5 mg], and 102-002 [Placebo Cohort 1]) were erroneously enrolled and dosed in the trial despite not meeting all eligibility criteria (baseline spirometry requirements not met). These 3 participants were subsequently replaced with new participants. All 27 dosed participants were included in the safety population. The most frequent minor deviations by category were “Assessments not completed as per visit schedule or according to instructions in protocol / manuals”, reported by 15 (53.6%) participants overall. No treated participants were excluded from any analysis population as a result of recorded protocol deviation. (Participant 102-012 was excluded from the PK Concentration and PK Parameters Sets due to all plasma THC, COOHTHC and OHTHC concentrations being reported as below the limit of quantification, however this was not considered a protocol deviation). The PI and sponsor considered that the reported deviations were unlikely to have affected the overall results and conclusions of the study or the safety of study participants. Pharmacokinetic evaluation Data sets analyzed A total of 28 participants were enrolled in the study. 27 participants received at least one dose of study medication and comprised the safety population. All 27 treated participants were also included in the Pharmacokinetic Concentration and Pharmacokinetic Parameters sets. A further breakdown by treatment is presented in Table 32. Table 32: Data Sets Analyzed IRX211a IRX211a IRX211m All Placebo Total Dose 0.5 mg Dose 1.0 mg Dose 2.5 mg N=7 N= 28 N=8       N=7       N=6       n(%)     n(%) n(%)       n(%)       n(%) Randomized 8(100.0)     7(100.0)    6(100.0)     7(100.0)    28(100.0) T reated 8(100.0) 6(85.7) 6(100.0) 7(100.0) 27(96.4) Randomized 8(100.0) 7(100.0) 6(100.0) 7(100.0) 28(100.0) Population (Full Analysis Set) Safety Analysis Set 8(100.0) 6(85.7) 6(100.0) 7(100.0) 27(96.4) Pharmacokinetic 8(100.0) 6(85.7) 6(100.0) 7(100.0) 27(96.4) Concentration Set Pharmacokinetic 8(100.0) 6(85.7) 6(100.0) 7(100.0) 27(96.4) Parameters Set Percents are based on the number of randomized subjects by treatment group and cohort. Demographic and other baseline characteristics Demographic Characteristics Overall, the mean (SD) age of the population was 26.4 (7.8) years with range of 18 to 51 5 years. The population was just over half female (53.6%), and predominantly of white race (71.4%), and non-Hispanic or Latino ethnicity (78.6%). Most participants were never smokers (82.1%) and mean BMI was in the normal range (23.86 kg / m2). Demographic characteristics were reasonably similar across treatment groups. A summary of key demographics by treatment and overall is presented in Table 33. 10 Table 33: Summary of Key Demographics Randomized Population) IRX211a Dose 0.5 mg N=8 IRX211a Dose 1.0 mg N=7 IRX211m Dose 2.5 mg N=6 All Placebo N=7 Total N=28 Gender n(%) Female 3(37.5) 2(28.6) 5(83.3) 5(71.4) 15(53.6) Male 5(62.5) 5(71.4) 1(16.7) 2(28.6) 13(46.4) Age (years) Mean (SD) 4.9 (9.2) 24.9 (6.7) 26.7 (2.7) 29.3 (10.3) 26.4 (7.8) Range (min, max) 19, 47 18, 39 23, 31 20, 51 18, 51 Race (%) White 4(50.0) 7(100) 4(66.7) 5(71.4) 20(71.4) Asian 3(37.5) 0 1(16.7) 2(28.6) 6(21.4) American Indian or Alaska Native 1(12.5) 0 1(16.7) 0 2(7.1) Ethnicity n(%) Not Hispanic or Latino 5(62.5) 5(71.4) 5(83.3) 7(100) 22(78.6) Hispanic or Latino 2(25.0) 2(28.6) 1(16.7) 0 5(17.9) Not Reported 1(12.5) 0 0 0 1(3.6) Smoking status n(%) Former user 2(25.0) 2(28.6) 0 1(14.3) 5(17.9) Never user 6(75.0) 5(71.4) 6(100) 6(85.7) 23(82.1) BMI (kg / m2) Mean (SD) 23.69 (2.15) 24.50 (1.16) 24.29 (2.27) 23.02 (2.76) 23.86 (2.12) Denominators are the number of randomized subjects with data available for the given parameter by treatment group and cohort Denominators are the number of randomized subjects with data available for the given parameter by treatment group and cohort. Medical History and Concurrent Illnesses In line with the study inclusion criteria, participants were generally healthy. Medical history events were reported at Baseline by 26 out of 28 participants overall. The most frequently reported medical history events by SOC were Infections and infestations, reported by 17 participants overall; the most common of these by PT was Covid-19, reported by 14 participants. Surgical and medical procedures were the next most frequently reported medical history events by SOC (reported by 11 participants overall), with wisdom teeth removal being the most common by PT, reported by 8 participants overall. Prior and Concomitant Treatments Overall, 9 out of 28 randomized participants (32.1%) reported any prior medication use at Baseline. The most frequently used prior medications were Vitamins, used by 4 participants overall, and Mineral Supplements, used by 3 participants overall. Overall, 5 out of 28 randomized participants (17.9%) reported concomitant medication use during the study. Of these, 2 participants reported use of Vitamins, 1 participant reported use of Mineral supplements, 3 participants reported use of Sex hormones / contraceptives, and 1 participant used paracetamol for a medical history event. No concomitant medication use was reported for the treatment of adverse events. Baseline Laboratory Testing and Device Education Covid-19 testing was performed for all participants at Day -1. All Covid-19 test results were negative. Pregnancy testing was performed for all female participants at Screening, Day -1 and Day 8 (+ / - 2 Days). All pregnancy test results were negative. Serology testing was performed for all participants at Screening. All serology test results were negative. Drug Screening tests were performed for all participants at Screening, Day -1 and Day 8 (+ / - 2 Days). All drug screening test results were normal (Not detected). Alcohol breath testing was performed for all participants at Screening, Day -1 and Day 8 (+ / - 2 Days). All alcohol breath test results were negative. Education on use of the inhaler device, and testing of tolerability and technique, were performed for all participants at Screening. All participants passed testing of tolerability and technique. Measurements of treatment compliance Summary of pharmacokinetic results Blood PK samples were collected from a total of 27 subjects across the 3 cohorts, 20 of whom received IRX211 and 7 of whom received placebo, as described in Table 34. Subject assignment to the PK analysis sets and reasons for exclusion are summarized in Table 34. Table 34: Summary of Subject Dosing And Inclusion In Pharmacokinetic Analyses Sets Dose and Formulation Total Dosed PK Concentrations Analysis Set PK Parameter Analysis Set (n) (n (%)) (n (%)) 0.5 mg IRX211 via IRX211a 8 7 (87.5%) 7 (87.5%) 1.0 mg IRX211 via IRX211a 6 5 (83.3%) 5 (83.3%) 2.5 mg IRX211 via IRX211m 6 6 (100%) 6(100%) Placebo 7 0 (0.0%) 0 (0.0%) Plasma THC Concentrations Mean plasma THC concentration-time profiles by treatment are presented up to 2.5 hours and 24 hours (in linear and semi-log scales) post dose in Figure 15. Following inhaled administration of a single dose of IRX211 (via IRX211 a or IRX211 m) IRX211 was absorbed rapidly with peak mean plasma THC concentrations occurring at 3 minutes post dose for all 3 treatment groups. After reaching peak concentrations, THC appeared to decline rapidly in a bi-exponential manner, with plasma THC concentrations returning to below the limit of quantification by 4 to 8 hours post dose for the majority of subjects, with measurable plasma THC concentrations at 8 hours post dose for 1 subject treated with IRX211 a 1 mg and 1 subject treated with IRX211 m 2.5 mg. For subjects dosed with the IRX211a formulation, mean concentrations increased in an approximately dose-proportional manner between the 0.5 mg and 1 mg dosing groups. Mean concentrations after IRX211m 2.5 mg administration were greater than those for IRX211 a 0.5 mg group but less than those observed after IRX211 a 1 mg administration. Between subject variability in plasma THC concentrations was generally greater after IRX211 m dosing compared with both dose levels investigated using IRX211a. Plasma THC Pharmacokinetic Parameters A summary of plasma THC PK parameters is presented by treatment group in Table 35. Table 35: Summary of Plasma THC Pharmacokinetic Parameters By Treatment (PK Parameter Analysis Set) Analyte PK Parameter (unit) T reatment Cohort 1:           Cohort 2:           Cohort 3: IRX211a0.5mg    IRX211a1mg    IRX211m2.5mg Summary Statistics THC Cmax (ng / mL) 12.72 (44.1) [n=7] 26.58(18.4) [n=5] 12.75(133.7) [n=6] Tmax (h) 0.0500 (0.042 - 0.067) [n=7] 0.0500 (0.033 - 0.067) [n=5] 0.0667 (0.050 - 0.083) [n=6] AUCO-12 (h*ng / mL) 3.507 (22.9) [n=7] 8.453 (39.6) [n=5] 6.170 (104.4) [n=6] AUCO-last (h*ng / mL) 3.507 (22.9) [n=7] 8.453 (39.6) [n=5] 6.170 (104.4) [n=6] AUCO-inf (h*ng / mL) 3.811 (20.9) [n=7] 8.866 (38.6) [n=5] 8.796 (66.9) [n=5] kel (h1) 1.0798(16.1) [n=7] 1.1822 (32.8) [n=5] 1.6628(17.1) [n=5] t1 / 2 (h) 0.6565(16.2) [n=7] 0.6470 (37.0) [n=5] 0.4264(16.5) [n=5] Cl / F (L / h) 133.5(19.4) [n=7] 118.9(34.4) [n=5] 328.3(57.9) [n=5] Vz / F (L) 212.1 (32.5) [n=7] 189.7(28.4) [n=5] 794.2(64.8) [n=5] Note: AUC’s and Cmax are presented as: geometric mean (geometric CV%) [number of subjects] Note: Tmax is presented as: median (minimum - maximum) [number of subjects] Note: kel, t1 / 2. Cl / F and Vz / F are presented as the arithmetic mean (CV%) [number of subjects] IRX211 was absorbed rapidly with median plasma THC Tmax ranging between 3 minutes and 4 minutes over the treatment groups, with individual subject plasma THC Tmax ranging between 2 minutes and 5 minutes post-dose across all subjects included in the PK Parameter Analysis Set. Geometric mean (geometric CV%) plasma THC Cmax values ranged between 12.72 ng / mL (44.1%) for the IRX211a 0.5 mg treatment group to 26.58 ng / mL (18.4%) for the IRX211 a 1 mg group. The IRX211 m 2.5 mg group achieved a geometric mean (geometric CV%) plasma THC Cmax of 12.75 ng / mL (133.7%) which was similar to that observed for the IRX211 a 0.5 mg treatment group, although with substantially greater between subject variability. Geometric mean (geometric CV%) plasma THC AUCO-last values ranged between 3.507 h*ng / mL (22.9%) for the IRX211a 0.5 mg treatment group to 8.453 h*ng / mL (39.6%) for the IRX211 a 1 mg group. The IRX211 m 2.5 mg achieved a geometric mean (geometric CV%) plasma THC AUCO-last value of 6.170 h*ng / mL (104.4%), which was approximately mid-way between the IRX211a 0.5 mg and 1 mg treatment groups, again with substantially greater between subject variability compared with IRX211a dosing. Plasma THC arithmetic mean (CV%) t1 / 2 was short ranging between 1.0798 h (16.1%) for the IRX211a 0.5 mg treatment group and 1.7040 h (16.0%) for the IRX211 m 2.5 mg treatment group. Apparent clearance was approximately 2.5 to 2.7-fold greater after IRX211m 2.5 mg with a mean (CV%) Cl / F of 328.3 L / h (57.9%) for the IRX211 m 2.5 mg group compared with 133.5 L / h (19.4%) and 118.9 L / h (34.4%) for the IRX211a 0.5 mg and 1 mg treatment groups, respectively. This difference in Cl / F for IRX211m is likely to be predominantly due to reduced bioavailability for IRX211m compared with IRX211a and not due to a major difference in elimination mechanisms at higher doses. This correlates with non-clinical analysis of the device which indicated that despite the lower API dose, a higher proportion of the API dose inhaled via the IRX211 a (0.5 mg) device is dispersed as fine particle droplets (270 mcg; 54%) in the respirable range, compared with the IRX211 m (2.5 mg) device which emits a lower relative proportion (671 mcg; 27%) of fine particle droplets in the respirable range. This is consistent with the data summarised in Table 24. Dose normalized plasma Cmax AUCO-last and AUCO-inf values were comparable between the IRX211a 0.5 mg and 1 mg treatment groups indicating approximately dose-proportional increase in THC exposure over this dose range with IRX211a. Dose normalized plasma Cmax AUCO-last and AUCO-inf values for the IRX211 m 2.5 mg group were reduced compared to the IRX211a dosing groups indicating that systemic exposure is reduced on a dose-relative basis after administration with IRX211 m. This reduction in dose normalized exposure for IRX211m is likely due to differences in the administration formulations. Plasma COOHTHC Concentrations Mean plasma COOHTHC concentration-time profiles by treatment are presented on linear concentration scale up to 24 hours post dose in Figure 16. Following inhaled administration of a single dose of IRX211 via IRX211a THC was rapidly metabolised to COOHTHC with peak mean plasma COOHTHC concentrations occurring at 15 minutes post dose for both IRX211 a treatment groups. For the IRX211 m 2.5 mg group there was an increased duration of COOHTHC formation with peak mean plasma concentration occurring 2.5 hours post-dose. Mean plasma COOHTHC concentrations increased with increasing dose across the IRX211 dose range investigated, irrespective of formulation type, although between 10 minutes and 30 minutes post dose mean plasma COOHTHC concentrations were greater after IRX211 a 1 mg than after IRX211 m 2.5 mg. After IRX211 m dosing, between subject variability in plasma COOHTHC concentration was generally greater than for IRX211a dosing up to 1 hour post dose, and was similar to the variability observed for IRX211 a from 1 -hour postdose. Plasma COOHTHC Pharmacokinetic Parameters A summary of plasma COOHTHC PK parameters is presented by treatment group in Table 36. Table 36: Summary Of Plasma COOHTHC Pharmacokinetic Parameters By Treatment 5 (PK Parameter Analysis Set) Analyte PK Parameter (unit) T reatment Cohort 1: IRX211a0.5 mg Cohort 2: IRX211a 1 mg Cohort 3: IRX211m 2.5 mg Summary Statistics COOH T HC Cmax 1.925 (34.9) 3.228 (41.1) [n=5] 4.545 (50.9) [n=6] (ng / mL) [n=7] Tmax (h) 0.2833 (0.250 - 0.2500 (0.167- 1.5000 (1.500 - 1.500) [n=7] 0.333) [n=5] 4.217) [n=6] AUCO-12 (h*ng / mL) 3.926 (70.6) [n=7] 9.616(90.2) [n=5] 24.46 (84.7) [n=6] AUCO-last (h*ng / mL) 3.926 (70.6) [n=7] 10.52 (123.8) [n=5] 34.09 (127.9) [n=6] AUCO-inf (h*ng / mL) [n=0] [n=0] [n=0] kel (h1) [n=0] [n=0] [n=0] t1 / 2 (h) [n=0] [n=0] [n=0] Cl / F (L / h) [n=0] [n=0] [n=0] Vz / F (L) [n=0] [n=0] [n=0] Note: AUC’s and Cmax are presented as: geometric mean (geometric CV%) [number of subjects] Note: Tmax is presented as: median (minimum - maximum) [number of subjects] Note: kel, t1 / 2. Cl / F and Vz / F are presented as the arithmetic mean (CV%) [number of 10 subjects] After administration of IRX211a, COOHTHC was rapidly formed with median Tmax ranging between 15 minutes and 17 minutes post dose over the IRX211 a dose range, with individual subject Tmax ranging between 10 minutes and 1.5 hours post-dose across all IRX211 a subjects included in the PK Parameter Analysis Set. Compared with 15 IRX211a administration, formation of COOHTHC after 2.5 mg Dronabinol via IRX211m was prolonged, with Tmax ranging between 1.5 and 4.2 hours and a median value of 1.5 hours post dose. Geometric mean (geometric CV%) plasma COOHTHC Cmax values increased with increasing dose and ranged between 1.925 ng / mL (34.9%) for the IRX211a 0.5 mg treatment group to 4.545 (50.9%) for the IRX211m 2.5 mg group. Geometric mean (geometric CV%) plasma COOHTHC AUCO-last values increased with increasing dose and ranged between 3.926 h*ng / mL (70.6%) for the IRX211a 0.5 mg treatment group to 34.09 h*ng / mL (127.9%) for the IRX211m 2.5 mg group. Graphical evaluation of dose normalized plasma COOHTHC Cmax indicated a trend of non-dose proportionality with reduced dose-relative peak COOHTHC exposure with increasing dose amount. Plasma COOHTHC AUCO-last values were comparable between the IRX211a 0.5 mg and 1 mg treatment groups indicating approximately doseproportional increase in COOHTHC total exposure over this dose range with IRX211a. Dose normalized plasma COOHTHC AUCO-last values for the IRX211 m 2.5 mg group were increased compared to the IRX211a dosing groups indicating that formation, and thus total systemic exposure of COOHTHC may be greater on a dose-relative basis after administration with IRX211 m formulation and / or when doses above 1 mg are administered. Compared with THC, plasma COOHTHC Cmax was substantially lower, with geometric mean plasma COOHTHC Cmax values being approximately 15%, 12%, and 36% of that observed for THC after IRX211a0.5 mg, IRX211a 1 mg and IRX211m 2.5 mg administration, respectively. Conversely, plasma COOHTHC AUCO-last was similar to that observed for THC (112% and 124% for IRX211 a 0.5 mg and IRX211 a 1 mg, respectively) and substantially greater than that observed for THC (553%) after IRX211m 2.5 mg. Plasma OHTHC Concentrations Mean plasma OHTHC concentration-time profiles by treatment are presented on linear concentration scale up to 24 hours post dose in Figure 17. Following inhaled administration of a single dose of Dronabinol via IRX211a OHTHC was formed rapidly with peak mean plasma OHTHC concentrations occurring between 10 minutes and 15 minutes post dose for the IRX211 a treatment groups. For the IRX211m 2.5 mg group there was an increased duration of OHTHC formation with peak mean plasma concentration occurring 1 hour post-dose. Over the majority of the PK sampling period (i.e. between 1 hour and 24 hours post-dose) mean plasma OHTHC concentrations increased with increasing dose across the IRX211 dose range investigated, irrespective of formulation type. However, it was observed that IRX211 a 1 5 mg mean concentrations were greater than the IRX211 m 2.5 mg group at timepoints prior to 1 hour post dose and the IRX211 a 1 mg group had the greatest peak mean plasma OHTHC concentration. Between subject variability in plasma OHTHC concentrations was similar for all treatment groups. Plasma OHTHC Pharmacokinetic Parameters 10 A summary of plasma OHTHC PK parameters is presented by treatment group in Table 37. Table 37: Summary Of Plasma OHTHC Pharmacokinetic Parameters By Treatment (PK Parameter Analysis Set) Analyte PK Parameter (unit) T reatment Cohort 1: IRX211a0.5 mg Cohort 2: IRX211a 1 mg Cohort 3: IRX211m 2.5 mg Summary Statistics OHTHC Cmax (ng / mL) 0.2568 (72.7) [n=7] 0.3699 (120.4) [n=5] 0.5197 (48.5) [n=6] Tmax (h) 0.2500 (0.083 -0.283) [n=7] 0.5000 (0.083 - 0.567) [n=5] 1.3084 (0.167 2.550) [n=6] AUCO-12 (h*ng / mL) 0.1457 (269.3) [n=7] 0.7439 (92.8) [n=5] 1.633 (74.3) [n=6] AUCO-last (h*ng / mL) 0.1457 (269.3) [n=7] 0.7439 (92.8) [n=5] 1.633 (74.3) [n=6] AUCO-inf (h*ng / mL) [n=0] 3.274 [n=1] 3.453 (19.7) [n=2] kel (h1) [n=0] 1.7118 [n=1] 2.3569 (4.7) [n=2] t1 / 2 (h) [n=0] 0.4049 [n=1] 0.2944 (4.7) [n=2] Cl / F (L / h) [n=0] 305.5 [n=1] 731.0 (19.4) [n=2] Vz / F (L) >0] 754.4 [n=1] 2497 (24.0) [n=2] Note: AUC’s and Cmax are presented as: geometric mean (geometric CV%) [number o 15 subjects] Note: Tmax is presented as: median (minimum - maximum) [number of subjects] Note: kel, t1 / 2. Cl / F and Vz / F are presented as the arithmetic mean (CV%) [number of subjects] After administration via IRX211a, OHTHC was rapidly formed with median Tmax ranging between 15 minutes and 30 minutes post dose over the IRX211 a dose range, with individual subject Tmax ranging between 5 minutes and 35 minutes post-dose across all IRX211 asubjects included in the PK Parameter Analysis Set. Compared with IRX211 a administration, formation of COOHTHC after 2.5 mg IRX211 via IRX211 m was prolonged, ranging between 10 minutes and 2.6 hours with a median value of 1.3 hours post dose. Geometric mean (geometric CV%) plasma OHTHC Cmax values increased with increasing dose amount and ranged between 0.2568 ng / mL (72.7%) for the IRX211a 0.5 mg treatment group to 0.5197 ng / mL (48.5%) for the IRX211 m 2.5 mg group. Geometric mean (geometric CV%) plasma OHTHC AUCO-last values increased with increasing dose amount ranged between 0.1457 h*ng / mL (269.3%) for the IRX211a 0.5 mg treatment group to 1.633 h*ng / mL (74.3%) for the IRX211m 2.5 mg group. Graphical evaluation of dose-normalized plasma OHTHC Cmax indicated a possible trend of reduced dose-relative peak exposure with increasing dose amount. Plasma OHTHC AUCO-last values were comparable between the IRX211a 0.5 mg and 1 mg treatment groups and the IRX211 m 2.5 mg treatment group indicating approximately dose-proportional increase in OHTHC total exposure over this dose range regardless of formulation type. Compared with THC, plasma OHTHC Cmax was substantially lower, with geometric mean plasma OHTHC Cmax values being approximately 2%, 1%, and 4% of that observed for THC after IRX211a0.5 mg, IRX211a 1 mg and IRX211m 2.5 mg administration, respectively. Likewise, plasma OHTHC AUCO-last was also substantially reduced compared to that observed for THC, with AUCO-last values being approximately 4% and 9% of that observed for THC after IRX211a0.5 mg and IRX211a 1 mg, respectively and 26% of that observed for THC after IRX211 m 2.5 mg. Pharmacokinetic conclusions The objective of the PK analysis was to investigate the plasma PK of THC and its metabolites COOHTHC and OHTHC after single ascending inhaled doses of IRX211 via IRX211aand IRX211m. The following key observations were noted for plasma THC: • IRX211 was absorbed rapidly with median plasma THC Tmax ranging between 3 minutes and 4 minutes over all 3 treatment groups. • Plasma THC Cmax increased with increasing dose after IRX211 a administration over a 0.5 mg to 1 mg dosing range with geometric mean (geometric CV%) plasma THC Cmax values of 12.72 ng / mL (44.1%) for the IRX211 a 0.5 mg treatment group and 26.58 ng / mL (18.4%) for the IRX211a 1 mg group. The IRX211 m 2.5 mg group achieved a geometric mean plasma THC Cmax similar to that observed for the IRX211 a 0.5 mg treatment group (12.75 ng / mL), although with substantially greater between subject variability (geometric CV% of 133.7%). • Plasma THC AUCO-last increased with increasing dose after IRX211a administration over a 0.5 mg to 1 mg dosing range with geometric mean (geometric CV%) plasma THC AUCO-last values of 3.507 h*ng / mL (22.9%) for the IRX211a 0.5 mg treatment groupand 8.453 h*ng / mL (39.6%) for the IRX211a 1 mg group. The IRX211 m 2.5 mg achieved a geometric mean (geometric CV%) plasma THC AUCO-last value of 6.170 h*ng / mL (104.4%), which was approximately mid-way between the IRX211a 0.5 mg and 1 mg treatment groups, again with substantially greater between subject variability compared with IRX211a dosing. • Plasma THC arithmetic mean (CV%) t1 / 2 was short, ranging between 1.0798 h (16.1%) for the IRX211a 0.5 mg treatment group and 1.7040 h (16.0%) for the IRX211 m 2.5 mg treatment group. • Dose normalized plasma Cmax, AUCO-last and AUCO-inf values were comparable between the IRX211a 0.5 mg and 1 mg treatment groups indicating approximately dose- proportional increase in THC exposure over this dose range with IRX211a. Dose normalized plasma Cmax, AUCO-last and AUCO-inf values for the IRX211 m 2.5 mg group were reduced compared to the IRX211a dosing groups indicating that systemic exposure is reduced on a dose-relative basis after administration with IRX211 m and / or at doses above 1 mg. The following key observations were noted for plasma COOHTHC: • After administration with IRX211 a COOHTHC was rapidly formed with median Tmax ranging between 15 minutes and 17 minutes post dose over the IRX211a dose range. Compared with IRX211a administration, formation of COOHTHC after 2.5 mg IRX211 via IRX211 m was prolonged, with median Tmax of 1.5 hours post dose. • Plasma COOHTHC Cmax values increased with increasing dose with geometric mean (geometric CV%) values ranging between 1.925 ng / mL (34.9%) for the IRX211a 0.5 mg treatment group to 4.545 ng / mL (50.9%) for the IRX211 m 2.5 mg group. • Plasma COOHTHC AUCO-last values increased with increasing dose with geometric mean (geometric CV%) values ranging between 3.926 h*ng / mL (70.6%) for the IRX211 a 0.5 mg treatment group to 34.09 h*ng / mL (127.9%) for the IRX211m 2.5 mg group. • Dose normalized plasma COOHTHC Cmax indicated a trend of non-dose proportionality with reduced dose-relative peak exposure with increasing dose amount. • Dose normalized plasma COOHTHC AUCO-last values were comparable between the IRX211a 0.5 mg and 1 mg treatment groups indicating approximately doseproportional increase in COOHTHC total exposure over this dose range with IRX211a. However, dose normalized plasma COOHTHC AUCO-last values for the IRX211 m 2.5 mg group were increased compared to the IRX211 a dosing groups. • Compared with THC, plasma COOHTHC Cmax was substantially lower, with geometric mean plasma COOHTHC Cmax values being approximately 15%, 12%, and 36% of that observed for THC after IRX211a 0.5 mg, IRX211a 1 mg and IRX211m 2.5 mg administration, respectively. • Geometric mean plasma COOHTHC AUCO-last after IRX211 a administration was similar to that observed for THC (112% and 124% for IRX211a 0.5 mg and IRX211a 1 mg, respectively) and substantially greater than that observed for THC (553%) after IRX211 m 2.5 mg. The following key observations were noted for plasma OHTHC: • After administration via IRX211a, OHTHC was rapidly formed with median Tmax ranging between 15 minutes and 30 minutes post dose over the IRX211 a dose range. Compared with IRX211a administration, formation of OHTHC after 2.5 mg IRX211 via IRX211 m was prolonged, with a median Tmax value of 1.3 hours post dose. • Plasma OHTHC Cmax values increased with increasing dose with geometric mean (geometric CV%) plasma OHTHC Cmax values ranging between 0.2568 ng / mL (72.7%) for the IRX211a 0.5 mg treatment group to 0.5197 ng / mL (48.5%) for the IRX211 m 2.5 mg group. • Plasma OHTHC AUCO-last values increased with increasing dose with geometric mean (geometric CV%) plasma OHTHC AUCO-last values ranging between 0.1457 h*ng / mL (269.3%) for the IRX211a 0.5 mg treatment group to 1.633 h*ng / mL (74.3%) for the IRX211 m 2.5 mg group. • Dose normalized plasma OHTHC Cmax indicated a possible trend of reduced dose-relative peak exposure with increasing dose amount. • Dose normalized plasma OHTHC AUCO-last values were comparable between all treatment groups indicating approximately dose-proportional increase in OHTHC total exposure over the dose range investigated regardless of formulation type. • Compared with THC, plasma OHTHC Cmax and AUCO-last were substantially lower, with geometric mean plasma OHTHC Cmax values being approximately 2%, 1%, and 4% of that observed for THC and plasma COOHTHC AUCO-last values being approximately 4% and 9% and 26% of that observed for THC after IRX211 a 0.5 mg, IRX211 a 1 mg and IRX211 m 2.5 mg, respectively. Safety evaluation Extent OF EXPOSURE Overall, 20 participants were administered a single dose of IRX211, and 7 participants were administered placebo. A breakdown of the number of participants by treatment is provided in Table 38. Table 38: Summary of IP exposure Treatment Number of participants dosed (single dose) IRX211a0.5 mg 8* IRX211a 1.0 mg 6** IRX211m 2.5 mg 6 Placebo 7 *One participant (102-012) was excluded from the PK Concentrations Analysis Set and PK Parameter Analysis Set due to all plasma THC, COOHTHC and OHTHC concentrations being reported as BLQ. Post-dose weights were subsequently checked indicated that a full dose was delivered. It is therefore likely that this was due to poor inhalation technique rather than due to device failure. **One participant (102-024) attested to feeling the administration of both actuations, although device counter did not tick over correctly. Post-dose weight of the pMDI were subsequently checked, and it was confirmed that this was consistent with only one dose having been dispensed. Evaluation of Each Laboratory Parameter No clinically significant abnormal laboratory parameters were reported during the study. There were no clinically meaningful changes from baseline in any mean laboratory parameters in any treatment group at any timepoint. Vital Signs Participant 102-076 (IRX211 2.5 mg) had abnormal clinically significant vital signs recorded for systolic blood pressure, diastolic blood pressure, pulse rate, respiratory rate and oxygen saturation at several unscheduled post-dose timepoints. The participant had an associated TEAE, Presyncope, reported, which was moderate in severity and considered possibly related to study treatment. No other clinically significant abnormal vital signs were reported during the study. Physical Examinations Physical examinations were conducted at Screening, Baseline and Day 8. All physical examination findings for all participants at all timepoints were normal, with the exception of 5 abnormal physical examination findings, all related to minor findings on skin examination (4 findings in 3 participants who received IRX211, and 1 in 1 participant who received placebo). Only 1 was considered clinically significant, namely mild tenderness on palpation of the right cubital fossa (at site of venipuncture) (Participant 102-666, Day 7). Spirometry All participants had FEV1 >80% of predicted and FEV1 / FVC ratio >0.7 at all timepoints throughout the study. No concerning changes from baseline in spirometry parameters were observed for any participant. Lead ECG No clinically significant abnormal 12-lead electrocardiogram (ECG) findings were reported during the study. No concerning trends in shifts from baseline in ECG interpretation were observed in any treatment group at any timepoint. Safety conclusions The safety population comprised a total of 27 participants, of whom 20 received a single dose of IRX211 (IRX211 0.5 mg n=8; IRX211 1.0 mg n=6; IRX211 2.5 mg n=6), and 7 received a single dose of placebo, under fasted conditions. Overall, the mean (SD) age of the randomized population was 26.4 (7.8) years with range of 18 to 51 years. The population was 53.6% female, and predominantly of white race (71.4%), and non-Hispanic or Latino ethnicity (78.6%). No safety concerns were identified during the study. There were no severe TEAEs, no AEs leading to study discontinuation, and no serious adverse events (SAEs). Discussion This was a Phase 1 study designed to investigate the safety, tolerability and pharmacokinetics of single escalating doses of IRX211 (a dronabinol Pressurized Metered Dose Inhaler) in Healthy Volunteers. A total of 27 participants received a single inhaled dose of study treatment, 20 of whom received IRX211 and 7 who received placebo. The primary objective of the study was to assess the safety and tolerability of escalating doses of IRX211 administered as a single inhaled dose via dispensing pMDI units filled with either 0.655% and emitting 0.5mg per actuation (IRX211a) or 2.5mg (IRX211 m) per actuation. No safety concerns were identified during the study. There were no severe TEAEs, no AEs leading to study discontinuation, and no serious adverse events (SAEs). Adverse events were reported by just over half (55.6%) of participants who received study drug, and in similar proportions to those who received IRX211 (55%) and those who received placebo (57.1%). There was no trend towards increasing frequency of TEAEs with increasing dose of IRX211. The majority (76.5%) of adverse events were mild in severity, with the remainder all moderate in severity. The secondary objectives of the study were to determine the systemic exposure of escalating doses of IRX211 administered as a single inhaled dose in healthy volunteers, including the plasma PK of THC and its metabolites COOHTHC and OHTHC. IRX211 was found to be rapidly absorbed with median Tmax for THC of between 3-4 minutes for all treatment groups. Peak concentration (Cmax) and overall systemic exposure (AUCO-last) increased approximately dose proportionally between exposures of 0.5 mg and 1 mg of IRX211, but did not increase further with an IRX211 m dose of 2.5 mg, with dose normalized exposure reduced in this group. Compared with THC, plasma COOHTHC Cmax was substantially lower, with geometric mean plasma COOHTHC Cmax values being approximately 15%, 12%, and 36% of that observed for THC after IRX211 a 0.5 mg, IRX211 a 1 mg and IRX211 m 2.5 mg administration, respectively. After administration with IRX211a COOHTHC was rapidly formed with median Tmax ranging between 15 minutes and 17 minutes post dose over the IRX211 a dose range. Compared with IRX211a administration, formation of COOHTHC after 2.5 mg IRX211 via IRX211 m was prolonged, with median Tmax of 1.5 hours post dose. Geometric mean plasma COOHTHC AUCO-last after IRX211 a administration was similar to that observed for THC (112% and 124% for IRX211 a 0.5 mg and IRX211 a 1 mg, respectively) and substantially greater than that observed for THC (553%) after IRX211 m 2.5 mg. After administration via IRX211 a, OHTHC was rapidly formed with median Tmax ranging between 15 minutes and 30 minutes post dose over the IRX211a dose range. Compared with IRX211a administration, formation of OHTHC after 2.5 mg IRX211 via IRX211m was prolonged, with a median Tmax value of 1.3 hours post dose. Compared with THC, plasma OHTHC Cmax and AUCO-last were substantially lower, with geometric mean plasma OHTHC Cmax values being approximately 2%, 1%, and 4% of that observed for THC and plasma COOHTHC AUCO-last values being approximately 4% and 9% and 26% of that observed for THC after IRX211a 0.5 mg, IRX211a 1 mg and IRX211m 2.5 mg, respectively. Overall conclusions Overall, a single inhaled dose of IRX211 at 0.5 mg, 1.0 mg, and 2.5 mg was well-tolerated, with no concerning safety signals identified. Approximately dose-proportional increase in systemic exposure to THC was observed with inhalation of 0.5 mg and 1.0 mg of IRX211 a, but did not increase further with an IRX211m dose of 2.5 mg, with dose normalized exposure reduced in this treatment group. It is likely that the reduction in dose-normalized exposure seen with IRX211 m (2.5 mg / actuation) dosing was due to the higher API load in the drug suspension, which produced an aerosol with a lower proportion of inhalable (<5pm) API-containing particles. Example 5: Phase 2 clinical study to determine the safety and efficacy of Dronabinol formulation in patients with Breakthrough cancer pain (BTcP) A list of abbreviations is provided in Table 39. Table 39: List of Abbreviations Abbreviation or Specialist Term Explanation AE Adverse Event AIDS Acquired Immune Deficiency Syndrome ALP Alkaline Phosphatase ALT Alanine Aminotransferase ANOVA Analysis of Variance AST Aspartate Transaminase AUCO-inf Area under the plasma concentration-time curve from time zero to time infinity AUCO-t Area under the plasma concentration-time curve from time zero to time t BDI Beck Depression Inventory BMI Body Mass Index BT Body temperature BTcP Breakthrough Cancer Pain BTP Breakthrough Pain BP Blood Pressure BUN Blood Urea Nitrogen CL Chloride CFR Code of Federal Regulations CNS Central Nervous System Clast Concentration at Last Sample Cmax Maximum Concentration CRF Case Report Form CRO Clinical research organization CRPS Complex regional pain syndrome C-SSRS Columbia Suicide Severity Rating Scale CTU Clinical trial unit CYP Cytochrome P450 ECG Electrocardiogram ECS Endocannabinoid system EENT Eyes, Ears, Nose, and Throat EOS End-of-study-visit ET Early termination FDA Food and Drug Administration FSH Follicle Stimulating Hormone FU Follow-up GCP Good Clinical Practice HBsAg Hepatitis B Virus surface Antigen HIV Human Immunodeficiency Virus HR Heart rate ICD-11 International Classification of Diseases ICF Informed Consent Form ICH International Conference on Harmonization HD Inactive Ingredient Database IP Investigational Product ITT Intent-to-treat K+ Potassium LDH Lactate Dehydrogenase LOQ Limit of Quantification LSM Least-Squares Mean MAOI Monoamine Oxidase inhibitor MHRD Maximum human recommended dose mmHG Millimeter of Mercury Na+ Sodium NICU Neonatal intensive care unit QC Quality control OTC Over-the-counter pDMI Pressurized metered-dose inhaler PK Pharmacokinetic PR Pain Relief PRO Patient reported outcome PT Preferred term RBC Red blood cell RR Respiratory rate SAE Serious Adverse Event SOC System organ class SPID Sum of differences in pain intensity t1 / 2 Elimination Half-life TEAE Treatment-emergent Adverse Event tMDI Thermal-metered-dose inhaler △9- THC Tetrahydrocannabidiol Tmax Time of Maximum Concentration USP United States Pharmacopoeia AZ Elimination Rate Constant Phase 1 (pharmacokinetics trial) First-in-human study of IRX211a (IRX211-001) was performed as described in Examples 3 and 4. PK parameters were identified following administration of escalating doses of IRX211 at 0.5, 1, and 2.5 mg dose levels or matching placebo by inhalation via pMDI. In this study, IRX211 was found to be rapidly absorbed with median Tmax for THC of between 3-4 minutes for all treatment groups. Peak concentration (Cmax) and overall systemic exposure (AUCo-iast) increased approximately dose proportionally between exposures of 0.5 mg and 1 mg of IRX211 but did not increase further with an IRX211 m dose of 2.5 mg, with dose normalized exposure reduced in this group. Compared with THC, plasma COOHTHC Cmax was substantially lower, with geometric mean plasma COOHTHC Cmax values being approximately 15%, 12%, and 36% of that observed for THC after IRX211a 0.5 mg, IRX211a 1 mg and IRX211m 2.5 mg administration, respectively. After administration with IRX211a COOHTHC was rapidly formed with median Tmax ranging between 15 minutes and 17 minutes post-dose over the IRX211 a dose range. Compared with IRX211a administration, formation of COOHTHC after 2.5 mg IRX211 via IRX211 m was prolonged, with median Tmax of 1.5 hours post-dose. Geometric mean plasma COOHTHC AUCo-last after IRX211a administration was similar to that observed for THC (112% and 124% for IRX211a 0.5 mg and IRX211a 1 mg, respectively) and substantially greater than that observed for THC (553%) after IRX211 m 2.5 mg. After administration via IRX211a, OHTHC was rapidly formed with median Tmax ranging between 15 minutes and 30 minutes post-dose over the IRX211 a dose range. Compared with IRX211a administration, formation of OHTHC after 2.5 mg IRX211 via IRX211m was prolonged, with a median Tmax value of 1.3 hours post-dose. Compared with THC, plasma OHTHC Cmax and AUCO-last were substantially lower, with geometric mean plasma OHTHC Cmax values being approximately 2%, 1%, and 4% of that observed for THC and plasma COOHTHC AUCO-last values being approximately 4% and 9% and 26% of that observed for THC after IRX211a 0.5 mg, IRX211a 1 mg and IRX211m 2.5 mg, respectively. Overall Study Design This is a multicenter, Phase 2, randomized, double-blind, placebo-controlled, cross-over comparative study with titration period in patients with BTcP using stable around-the-clock opioid therapy who required add-on therapy for BTcP episodes. Figure 18 is a schematic showing the Phase 2 study design. The trial will consist of two phases: an open-label titration phase (Part A), during which patients will have up to 14 days to determine a single effective dose of IRX211a for adequate treatment of BTcP episodes (titration period), followed by a double-blind, randomized, placebo-controlled phase (Part B), during which 10 episodes of BTcP will be treated with individual single effective dose of IRX211a or placebo in double-blind manner. It is planned to enrol 60 patients diagnosed with BTcP who are using stable around-the-clock opioid therapy and who required add-on therapy for BTcP episodes. During each BTcP episode treated with the study medication, patients will log in their electronic diary the dose level administered (Part A; 0.5 mg to 2 mg) or the designated number of the study medication (Part B, no. 1-10). In addition, patients will independently document information related to pain and the effectiveness of the treatment at specific timepoints. This documentation will involve pain scales and relevant questions as described herein. Study and Design Rationale The inventors have developed a device-drug combination containing Dronabinol as its API for delivery via pDMI to maximize Dronabinol bioavailability and achieve a shorter rapid onset action to manage BTcP in patients using stable around-the-clock opioid therapy who required add-on therapy for BTcP episodes. This study is a multicenter, Phase 2, randomized, double-blind, placebo-controlled, cross-over comparative study with titration period to evaluate the effectivity of IRX211a to treat BTcP. The study baseline observation periods permit subjects to become familiar with monitoring and recording their daily BTcP period details and relevant patient reported questionnaire (PRO) questionnaires in an electronic diary. Titration phase permits to identify the single effective dose level to maintain their BTcP for each patient, while patients who will not be able to achieve sufficient pain relief for at least two consecutive BTcP episodes will be discontinued. Part B permits controlled evaluation of IRX211a (at individual dose levels deemed efficient in Part B) vs. placebo with the collection of safety and efficacy data. Dosing in this study will be standardised through the inhalation of IRX211a for patient’s first BTcP episode in the day, experienced between 7 am and 7 pm, in order to ensure administration during the daytime. In addition, participants must ensure the study medication will be used for BTcP period happening at least 4 hours post-last rescue medication administration to maintain adequate washing out period. Dosage of 7 active vs placebo for study part to permits access to IRX211a to as time as possible while maintaining a placebo presence for comparative purposes. Dose Selection Rationale In this multi-center, Phase 2 study of IRX211 a for BTcP in patients using stable opioid therapy, dose selection is crucial for balancing efficacy and safety. The two-phase trial design, with an open-label titration (Part A) and a double-blind, placebo-controlled, cross-over phase (Part B), supports a patient-centric approach to dose optimization. The dose selection for the Phase 2 study of IRX211a is derived from a thorough consideration of safety, efficacy, and tolerability data from previous studies. The starting dose of 0.5 mg is based on the lowest dose administered in the Phase I first-in-human study (IRX211-001), which demonstrated an acceptable safety profile across escalating doses of 0.5, 1, and 2.5 mg. In this Phase I trial, the majority of AEs were mild, with the most frequent being mouth / throat symptoms and presyncope, indicating a favorable safety margin for initiating treatment. During the open-label titration phase (Part A), patients are allowed to self-up-titrate to achieve effective pain relief without exceeding the maximum tested dose of 2.0 mg, which aligns with the highest dose from the Phase I study that did not produce severe or unexpected AEs. This approach ensures that each patient's dosage is tailored to their analgesic needs while maintaining a well-established safety threshold. Patients experiencing intolerable side effects at the first dose of 0.5 mg administered under clinical monitoring will discontinue. Patients will be self-titrated the dose until a single administration of IRX211a can be used to treat at least two consecutive BTcP episodes without exceeding 7 actuation per 24 hours period. The cross-over phase (Part B) employs the individualized single effective dose determined during titration, reinforcing the dose's relevance to the patient's pain management, ensuring safety of participant and direct comparison between the therapeutic and placebo effects. Rationale for the Study Population Breakthrough cancer pain (BTcP), characterized by its sudden onset and severe intensity, significantly affects the quality of life in cancer patients. Despite being on stable around-the-clock opioid therapy, a substantial subset of these patients experience frequent BTcP episodes that current treatment regimens fail to adequately control. This study focuses on this specific patient population, who present a unique challenge and opportunity for assessing the efficacy of additional pain management strategies. The inclusion criteria for this study are chosen to target cancer patients who are already on a stable opioid regimen. This stability is crucial for isolating the effects of the inhalation IRX211a, ensuring that observed pain relief can be confidently attributed to the study drug. Patients with unstable or poorly managed pain are excluded to minimize confounding factors and ensure patient safety. This study is poised to fill a significant gap in the management of BTcP. For patients who are already on a full opioid regimen, the addition of an inhalation Dronabinol product - IRX211 a could offer a much-needed alternative for pain control. The expected outcomes of this study, including reduced pain intensity and improved overall quality of life, are highly relevant for this population. These outcomes could provide critical insights into the efficacy and safety of IRX211 a as an adjunct therapy in BTcP management. Risk Assessment To enhance the monitoring and management of potential risks, this study will implement a dual approach combining technology and traditional clinical oversight. Participants will be provided with a study-specific mobile application, designed to facilitate real-time monitoring and reporting of any AEs or changes in their condition. This app will enable patients to log their symptoms, medication usage, and any other relevant health information promptly and conveniently. It serves as a tool for both patients and clinical staff to track the treatment's effects closely and to identify any concerns early. Additionally, regular generic and / or outpatient visits will be scheduled throughout the duration of the study. These visits are crucial for thorough clinical assessments, including physical examinations and laboratory tests, to monitor the patients' overall health and the treatment's impact. They also provide an opportunity for face-to-face interactions between the participants and the study team, allowing for a more in-depth evaluation of the patient's condition and the treatment's efficacy and safety. The combination of digital monitoring through the Study App and regular generic visits ensures a comprehensive and dynamic approach to patient care and safety monitoring. This integrated strategy not only enhances the quality of data collected but also ensures that participants receive timely and appropriate care throughout the study period. Notably, the study will be overseen by SRC to ensure the utmost safety of the study patients. The SRC will regularly review and evaluate study data, ensuring that any safety concerns are promptly identified and addressed. Aims of study This Phase 2 study will evaluate the efficacy of IRX211 a in treating breakthrough pain episodes in opioid tolerant cancer patients using stable doses of opioid medication. This study will also evaluate the safety and tolerability of IRX211a in patients with Breakthrough Cancer Pain (BTcP), and the efficacy of IRX211a in reducing opioid usage for pain management in patients with BTcP. Primary Endpoints: • Sum of differences in pain intensity (PIDs) scores at 15 and 30 minutes from baseline (SPID15 and 30) • Total Pain Relief (TOT PAR) scores at 15 and 30 minutes compared to baseline. Secondary Endpoints: • The percentage reduction in daily opioid dosage required for pain management following treatment with IRX211a compared to baseline • Sum of differences in pain intensity (PIDs) scores at 5, 10 and 60 minutes from baseline (SPID15, 30, and 60) • Time to onset of pain relief • PIDs and pain relief (PR) measured from 5 minutes through 60 minutes compared to placebo • Overall responder rate defined as greater than 33% reduction in PI from baseline and greater than 50% reduction in PI from baseline • Use of the rescue medication Screening and Baseline Observation Period: The study will begin once the patient signs the informed consent at the clinical site or via an electronic system. Once informed consent has been signed, patient will undergo on-site screening visit (Visit 1). The screening visit will take place on any day within 28 days prior to the first dose is administered (Visit 2, Day 0) and must occur before the patient enters the baseline observation period. During the screening visit, responsible study personnel will perform eligibility assessments and provide support and training to the patient on the use of the inhaler, Study App and completion of the e-Diary. Patients who satisfy all inclusion and none of the exclusion criteria will be assigned a unique patient number and start a 14-day baseline observation period (as part of the screening period - at least 14-days prior to the first dose is administered), during which they will monitor and record: • Number of BTcP episodes per 24 hours for the whole baseline observation period. • Details of Rescue Medication* used to treat BTcP episodes (if occurs) throughout the whole baseline observation period. Patients will record details (drug’s name, frequency, dose level) once a day for a 24-hour interval. *Rescue medication = previously prescribed breakthrough pain medication and / or immediate release oxycodone 5 mg to 20 mg titrated to the discretion of Investigator. • Pain Intensity Recording for at least one BTcP episode per day (if occurs) at immediately before and 5-, 10-, 15-, 30-, and 60-minutes post-dose previously prescribed breakthrough pain medication. Patients will be required to record the requested details as close to the specified timepoints as possible. • Pain relief of the actual pain for at least one BTcP episode per day (if occurs) at 5, 10-, 15-, 30-, and 60-minutes post-dose of previously prescribed breakthrough pain medication compared to immediately prior to taking the medication. Patients 86 will be required to record the requested details as close to the specified timepoints as possible. After 28 (±5) days post Visit 1, patients will return to the clinic to assess the number of BTcP episodes from the baseline observation period data recorded in the diary to re- 5 confirm their eligibility. Patients must have recorded 1 or more BTcP episode(s) on at least 7 separate (or consecutive) days of the 14-day baseline observation period (i.e. experience a BTcP episode during a minimum of 50% of the days of the baseline observation period). Following confirmation of eligibility, patients will enter Part A and receive the first dose of allocated treatment (Day 0) under medical supervision as 10 described below. Table 40: Schedule of assessments Study Stage Screening visits and Baseline observation period Baseline visit Treatment Period Part A Treatment Period Part B EOS / ET Study Day(s) / Duration Day -28-to Day-1 Day 0 Week 1 (Day 1 to Day 7± 3 days) Week 2 (Day 8 to Day14± 3 days) 10 days up to maximum of 4 weeks Visit number q Visit 1 q Visit 2 Visit 31 Visit 41 Visit 5 up to 2 visit 8 N / A Informed consent X Eligibility _ .     . 3 Criteria X Reconfirmation of eligibility x3 Demographic data X Medical and medication history X Body Weight and BMI 4 calculation X Serology tests5 X FSH (PostMenopausal Females only) X Spirometry (FEV1 / FVC) X x36,37 x1 x1 X Inhaler education / tolerability6 X X36 Baseline observation X period e-Diary recording7 Randomization8 X Study drug administration x9 X10 x1 x11 Site visit X X x12 X13 Generic safety visits / outpatient ■ -X 14 visits X15’1 X15’1 X16 Physical ■     X-     17 examination X X36 x1 x1 X X 1    •         18 Vital signs X x36,37 x1 x1 X X 19 12-lead ECG X x36,37 x1 x1 X X 20 C-SSRS X X36 x1 x1 X X SBT X 21 BDI-II X X36 x1 x1 X X DEQ X36 x1 x1 X X Clinical laboratory x x 22 tests X X36 x1 x1 X X Study Stage Screening visits and Baseline observation period Baseline visit Treatment Period Part A Treatment Period Part B EOS / ET Study Day(s) / Duration Day -28-to Day-1 Day 0 Week 1 (Day 1 to Day 7± 3 ,             x 1 days) Week 2 (Day 8 to Day14± 3 ,             x 1 days) 10 days up to maximum of 4 weeks Visit number q Visit 1 q Visit 2 Visit 31 Visit 41 Visit 5 up to 2 visit 8 N / A Urine drug of .       23 abuse X x36 x1 x1 X X Pregnancy x .24 test X x36 X Alcohol Breath Test25 X x36 x1 x1 X X Urine Cotinine t x26 Test X x36 x1 x1 X X Pain Intensity Recording x27 x28 X28 x28 X28 Pain Relief Recording X29 X30 X30 x30 X30 Rescue Medication Recording X31 X32 X32 X32 X32 Monitoring and recording of AEs and W                                                                          F concomitant 33 Medications Abbreviations: AE = adverse event; BDI-II = Beck’s Depression Inventory; BMI = body mass index; C-SSRS = Columbia suicidality severity rating scale; DEQ = Drug Effects Questionnaire; ECG = electrocardiogram; EOS = end of study; ET = early termination; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; QIDS = The Quick Inventory of Depressive Symptomatology; SBT = Short Blessed Test 1. If applicable. The open-label titration phase has a minimum duration of 1 day and a maximum duration of 2 weeks. Visit 3 and Visit 4 may not be performed if the patient achieves effective pain relief for at least two consecutive BTcP episodes prior to the visits. In that case, the patient undergoes the safety assessments before the commencement of Part B. 2. Number of visits will be based on the length of Part B. Visits will be performed by the study nurse at the participant’s home or at site (if requested by Investigator) every 7±3 days until 10 BTcP are treated with the study medication. Following the completion of 10 BTcP episodes, patients will undergo EOS within 48 hours. 3. Eligibility to be confirmed at screening and re-confirmed at admission on Day 0 and prior to entering of Phase B. 4. BMI to be calculated using the height values recorded on screening. 5. Serology tests include HBsAg, HCV antibody, and HIV antibody. 6. Patients will undergo the tolerability assessment and will receive education on the proper use of an inhaler, which includes instructions on correct inhalation techniques and device maintenance during the screening visit. Patients will be reeducated on inhalation use and maintenance at baseline visit (Day 0). 7. Patients will use the e-Diary to record number of their BTcP episodes and details (name of drug, frequency, dose level) of rescue medication (immediate release oxycodone and / or previously prescribed breakthrough pain medication) used to treat BTcP throughout the baseline observation period (14 days) and Pain Intensity and relief Recording for at least one BTcP episode per day during the whole baseline observation period to capture baseline data, and to ensure good compliance with the e-Diary. 8. Eligible patients who enter Part B will be randomized to undergo 10 period crossover. 9. The first dose of the study drug will be administered for the first episode of BTcP at clinical site, followed by a 4-hour safety observation period before they discharged. 10. Patients will self-up-titrate by increments of 1 actuation per titration step to a maximum dose of 2.0 mg (4 actuations) of IRX211a or until effective pain relief is achieved for at least two consecutive BTcP episodes. At least 4 hours between treating BTcP episodes, with no more than 4 BTcP episodes treated with IRX211a or a total of 7 actuations of IRX211 a per 24 hours, whichever comes first. 11. Patients will self-administer the allocated study drug to treat their first BTcP episode every day between 7 am to 7 pm (maximum of 1 BTcP episode treated with study drug per day) until 10 BTcP episodes are treated with the study medication or till the maximum duration of 4 weeks. In addition, participants must ensure the study medication will be used for BTcP period happening at least 4 hours post-last rescue medication administration 12. Patients eligible for Part B attend a clinical site following the completion of Part A to receive 10 pre-numbered pMDI units. 13. The End of Study (EOS) assessment will be conducted at the clinical site as long as the patient's health condition permits. If required, the study nurse will conduct the EOS assessment at the patient's home. 14. Patients will undergo safety assessments visits performed by the study nurse at their home or a during outpatient visits at site (if requested by Investigator). 15. Patients will undergo generic safety visits performed by the study nurse at home or return to outpatient visits at site (if requested by Investigator) every 7±3 days until a single administration of up to 2 mg of IRX211a can be used to treat at two consecutive BTcP episodes. 16. Patients will undergo generic safety visits performed by the study nurse at their home or return to outpatient visits at site (if requested by Investigator) every 7±3 days until 10 BTcP episodes are treated with the study medication or till the maximum duration of 4 weeks. 17. A full physical examination will be performed at screening and at admission on Day 0 and EOS. A symptom directed physical examination will be performed at each generic safety / outpatient visits. Additional symptom directed physical examinations may also be performed at any time through the study as clinically indicated. 18. Vital signs will be collected with the participant supine and after they have been resting for 5 minutes. Vital signs will be taken at screening, Day 0 at admission, Days 0 post-dose at 10 minutes (± 2 min), 30 minutes (± 5 min), 1 hour (± 10 min) and 4 hours (± 10 min), during each generic safety / outpatient visit and EOS. Additional vital signs may be taken at any time during study as needed. 19. Twelve-lead ECGs will be performed in triplicate, approximately 1 minute apart (a maximum of 2 minutes between traces is acceptable) after the participant has rested comfortably in the supine position for 5 minutes at screening, Day 0 at admission and 15 minutes (± 2 min), 2 hrs (± 10 min), and 4 hrs (± 10 min) post-dose, each genetic safety / outpatient visit and EOS. Testing for any out-of-range values may be repeated once at the discretion of the Investigator. Otherwise, assessments may be performed on the scheduled day, at any time. 20. A suicide risk assessment will be performed using the screening version of C-SSRS questionnaire at screening. Subsequent C-SSRS assessments will be performed using the ‘since last visit’ version of C-SSRS on Day 0 at admission, and at each generic safety / outpatient visit and EOS. 21. A BDI assessment will be performed using the screening version of BDI questionnaire at screening. Subsequent BDI assessments will be performed using the ‘since last visit’ version of BDI on Day 0 at admission, and at each generic safety / outpatient visit and EOS. 22. Laboratory assessments include hematology, biochemistry, coagulation and urinalysis and will be performed at screening, Day 0 at admission, and at each generic safety / outpatient visit and EOS. 23. Urine drug of abuse test at screening, on Day 0 at admission, each generic safety / outpatient visit and EOS. 24. Serum pregnancy test at screening, urine pregnancy test on Day 0 at admission and EOS. 25. Alcohol breath test at screening, on Day 0 at admission, each generic safety / outpatient visit and EOS. 26. Urine cotinine test at screening, on Day 0 at admission, each generic safety / outpatient visit and EOS. 27. Pain Intensity Recording for at least one BTcP episode per day (if occurs), during 14 days of baseline observational period, at immediately before and 5-. 10-, 15-, 30-, and 60-minutes post-dose of rescue medication (immediate release oxycodone and / or previously prescribed drug of breakthrough medication). Patients will be required to record the requested details as close to the specified timepoints as possible, contingent upon their pain levels and overall health status. 28. Pain Intensity Recording for at all BTcP episodes treated with study medication (IRX211a or placebo [if applicable]) at immediately before and 5-, 10-, 15-, 30-, and 60-minutes post-dose. Patients will be required to record the requested details as close to the specified timepoints as possible, contingent upon their pain levels and overall health status. 29. Pain relief of the actual pain for at least one BTcP episode per day (if occurs) at 5-, 10-, 15-, 30-, and 60-minutes post-dose of rescue medication (immediate release oxycodone and / or previously prescribed drug of breakthrough medication), compared to immediately prior to taking the medication. Patients will be required to record the requested details as close to the specified timepoints as possible, contingent upon their pain levels and overall health status. 30. Pain relief of the actual pain for at all BTcP episodes treated with study medication (IRX211 a or placebo [if applicable]) at 5-, 10-, 15-, 30-, and 60-minutes postdose. Patients will be required to record the requested details as close to the specified timepoints as possible, contingent upon their pain levels and overall health status. 31. Patients will be required to record the date, time and use of Rescue Medication (immediate release oxycodone and / or previously prescribed breakthrough pain medication) used to maintain BTcP throughout the 24 hours for the whole baseline observation period. 32. Patients will be required to record the date, time and use of Rescue Medication (immediate release oxycodone and / or previously prescribed breakthrough pain medication) used to maintain BTcP throughout the 24 hours for the whole Part A and Part B period. 33. Adverse events are collected upon signing the ICF through the last study visit; those that occur before dosing will be recorded as medical history instead of as an AE, however, if their condition deteriorates at any time during the study, it will be recorded as an AE. 34. Following the completion of 10th BTcP treatment with study medication (or at the end of the 4th week - whichever occurs first), patients will return to the clinical site for the EOS visit within 48 hours. In the case of early termination EOS procedures will be performed as soon as possible. 35. The baseline observation period will begin after the patient's eligibility is confirmed and will occur during the 14 days leading up to Day 0. 36. Assessment to be performed prior to study drug administration 37. Assessment(s) to be performed at specified timepoint post study drug administration Study Part A: A total of 60 patients diagnosed with cancer and experiencing 1 or more BTcP episode(s) on at least 7 separate (or consecutive) days of the 14-day baseline observation period (14 days period prior to baseline visit on Day 0) will be enrolled in the open-label titration period - Part A. Table 41: Titration schedule - Study Part A Titration Dronabinol IRX211a Formulation No. actuation(s)2 Step1 Dose Level 1 0.5 mg IRX211 a aerosol for oral 1 actuation 2 1.0 mg inhalation, Dronabinol 2 actuations 3 1.5 mg content of 0.655% w / w; 3 actuations 4 2.0 mg 0.5 mg / actuation 4 actuations 1lf no sufficient pain relief if achieved after 30 minutes, subsequent BTcP episode will be treated with next titration dose level. If AEs occur subsequent BTcP episode will be treated with previous titration dose level. Maximum of 4 BTcP episodes at least 3 hours apart treated with IRX211 a in 24 hours period 2 Maximum of 7 actuations administered per 24 hours Patients will also be required to record into their e-Diary following details: • Specific dose level of the study medication (i.e. number of actuations) administered for each BTcP episode treated with the study medication. • Number of BTcP episodes per 24 hours for the whole Part A period. • Details of BTcP rescue medication used to maintain BTcP throughout the whole Part A period. Patients will record details once a day for a 24-hour interval. • Pain Intensity Recording for all BTcP episodes when study medication was used at immediately before and 5-, 10-, 15-, 30-, and 60-minutes post-dose. Patients will be required to record the requested details as close to the specified timepoints as possible, contingent upon their pain levels and overall health status. • Pain relief achieved for each BTcP episodes treated with study medication at the following time points: immediately before and 5-, 10-, 15-, 30-, and 60-minutes post-dose. Patients will be required to record the requested details as close to the specified timepoints as possible, contingent upon their pain levels and overall health status. At the start of the titration phase, all patients will be administered 0.5 mg of IRX211a (1 actuation) for the first episode of BTcP at clinical site, followed by a 4-hour safety observation period before they are discharged. If pain relief is insufficient after 30 minutes, rescue medication (immediate release oxycodone and / or previously prescribed breakthrough pain medication) may be used, and the IRX211a dose used for the subsequent BTcP episode will be increased as per titration schedule. If a patient experiences intolerable side effects after a 0.5 mg dose of IRX211a, they will be discontinued from the study. After 4 hours of a safety observational period where vital signs and ECG measurements will be performed at specified time points, patients will receive IRX211 a (120 doses per unit, 0.5 mg Dronabinol per dose) before they are released home and will be instructed to self-administer IRX211a as per the titration schedule below. In addition, participants will be provided with necessary study instructions post-discharge and access to medical care and site contact details. • Dose level will be increased by 1 actuation per each titration step in subsequent BTcP episodes, if pain relief is insufficient 30 minutes after administration of the most recent IRX211a dose in response to a BTcP episode. • Dose level will be reduced by 1 actuation if patient experiences AEs (at doses > 1 mg IRX211a). In addition, following restriction apply: • Patient must wait at least 4 hours before treating another BTcP episode with IRX211a. • Patient must not treat more than 4 BTcP episodes or use a total of 7 actuation administered per 24 hours, whichever comes first. Patients who were not be able to treat BTcP episodes with a single administration of up to 2 mg of IRX211 a (equivalent to 4 actuations) by the end of 2nd week will be discontinued from the study. Patients who achieve effective pain relief (defined as a reduction by at least 3 points in SPID15 or SPID30 score) for at least two consecutive BTcP episodes will enter the double-blind, randomized, placebo-controlled, cross-over phase (Part B). Study Part B After the identification of each participant's effective IRX211 a dose in Part A they will be immediately entered into a 10-period cross-over study consisting of 10 BTcP episodes treated with the IRX211a or placebo in double blind manner. Each patient will receive 10 pre-numbered pMDI units, comprising 7 active IRX211a-containing and 3 matching placebo pMDIs. The patients will be instructed to administer the single effective dose -i.e. the number of actuations of each pMDI that correspond to the single effective dose identified during the titration period. At least 45 eligible patients are planned to be randomized and entered into Part B. The randomization scheme determines the order in which each patient administers the study medication. The exact order will be specified on the study medication packaging. Patients will be randomized 1:1 to sequence A or B, respectively. The order of study medication within each sequence will be pre-determined with 7:3, IRX211 -a to placebo ratio. Patients will be instructed to use one dose of study medication per day, specifically for their first BTcP episode in the day, experienced between 7 am and 7 pm. In addition, participants must ensure the study medication will be used for BTcP period happening at least 4 hours post-last rescue medication administration. In that case, 4-hours washing out period will be maintained. If pain relief is insufficient after 30 minutes, rescue medication (immediate release oxycodone and / or previously prescribed drug of breakthrough pain medication) may be used. Patients will be required to record into their e-Diary the following details: • Unit number corresponding to the number printed on the label of the study medications (numbered from 1 to 10) upon each administration of the study medication for BTcP episode. • Number of BTcP episodes per 24 hours for the duration of Part B. • Details of BTcP Rescue Medication used to maintain BTcP throughout the whole Part B period. Patients will record details once a day for a 24-hour interval. • Pain Intensity Recording of the BTcP episode for which the study medication was administered at immediately before and 5-, 10-, 15-, 30-, and 60-minutes postdose. Patients will be required to record the requested details as close to the specified timepoints as possible. • Pain relief of the actual pain of the BTcP episode for which the study medication was administered at immediately before and 5-, 10-, 15-, 30-, and 60-minutes post-dose compared to immediately prior to taking the medication. Patients will be required to record the requested details as close to the specified timepoints as possible. Timeline and Visits Schedule The study will include a screening visit from Day -28 to Day -1. Eligible patients will be admitted to the clinical site on Day 0, with dosing occurring on Day 0 once the first BTcP episode occurs. Patients will be confined until the completion of the safety assessments at the end of the 4-hour safety observation period at the clinical site and will be discharged at the Investigator's discretion. Eligible participants (anyone who did not experience AEs following IRX211a administration) will continue with the outpatient portion of Part A for up to 14 days. Patients will undergo generic safety visits to ensure patients safety performed by the study nurse at home or return to outpatient visits at the site (if requested by the Investigator) every 7±3 days from entering the Part A until a single dose of up to 2 mg of IRX211a can be used to treat at least two consecutive BTcP episodes. If the patient achieves sufficient pain relief before the first generic safety visit planned (7±3), in that case, the patient undergoes identical assessments prior to entering Part B. The open-label titration phase, therefore, has a minimum duration of 1 day (and a maximum duration of 2 weeks). Patients must be able to treat at least two consecutive BTcP episodes with a single administration of up to 2 mg of IRX211a by the end of 2nd week to be able to continue with the study. After identification of a single effective IRX211a dose, patients will enter a 10-period cross-over, where they will self-administer the allocated study drug to treat their BTcP episodes until 10 BTcP episodes are treated as per treatment schedule or till maximum duration of 4 weeks in double blind manner. Patients will undergo generic safety visits performed by the study nurse at their home or outpatient visits at site (if requested by Investigator) every 7±3 days after entering the Part B, until 10 BTcP episodes are treated with the study medication or till the maximum duration of 4 weeks. Following the completion of 10th BTcP treatment with study medication, patients will undergo EOS visit at study site within 48 hours. Patients who were not able to treat 10 BTcP episodes by the end of Week 4 will be required to attend study site for the EOS visit. The doubleblind randomized phase has a minimum duration of 10 days and a maximum duration of 4 weeks. The total duration of study participation for each patient deemed eligible for both Study Part A and B is anticipated to be up to approximately 10-11 weeks. This includes about 6 to 7 weeks for screening and Part A, in addition to up to 4 weeks for Study Part B. Number of Patients A total of 60 adult patients will be enrolled for participation in the titration phase (period A) in order to have at least 45 eligible patients who achieve effective pain relief following administration up to 2 mg of IRX211a (equivalent to 4 actuations) and thus become eligible to enter Phase B (double-blind, cross-over phase). The sample size was determined via a power analysis to ensure that the efficacy and safety of IRX211 a are adequately assessed while minimizing unnecessary participant exposure. Inclusion Criteria To be enrolled in the study, patients must meet the following criteria: 1. Male or female, aged >24 and <84 years (inclusive), non-smokers. 2. Patients must have a current diagnosis of cancer. 3. Eastern Cooperative Oncology Group (ECOG) status of 0 to 3. (with Principal Investigator discretion based on the participant's ability to reliably use the pMDI). 4. Life expectancy should be longer than 3 months. 5. If currently receiving chemotherapy and / or radiotherapy treatment, patients must be on a stable regimen for at least one month (30 days ± 2 days) prior to screening and the treatment(s) is expected to remain stable thoughout the clinical trial. 6. Participants must experience 1 or more BTcP* episode(s) on at least 7 separate (or consecutive) days of the 14-day baseline observation period (i.e. experience a BTcP episode during a minimum of 50% of the days of the baseline observation period). *Defined as transitory flair of moderate to severe pain that occurs against a background of persistent pain controlled to moderate intensity or less by the opioid regiment that required additional opioids from pain control. 7. Background stable cancer pain (pain <4 / 10 on numeric rating scale) and adequately controlled with use of long-acting oral morphine or oral morphine equivalent (OME) 8. Patients must be opioid-tolerant - taking at least 60 mg of oral morphine / day, at least 25 mcg of transdermal fentanyl / hour, at least 30 mg of oxycodone / day, at least 8 mg of hydromorphone / day, of an equianalgesic dose of another opioid for relief of chronic pain management. 9. Add-on therapy for pain such as physical therapy, biofeedback therapy, acupuncture therapy or herbal remedies, should remain unchanged throughout the duration of trial. 10. No known history or family history of schizophrenia or other psychotic illness; history or presence of severe personality disorder or other significant psychiatric history or mental illness (in the opinion the Investigator). 11. No known allergic reaction to cannabis products (including THC, CBD, marijuana, and hashish), Marinol®and Epidiolex®; 12. The patient is able to perform deep inhalations with forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) to be > 80% of predicted value and FEV1 / FVC ratio of > 0.7 at screening. 13. Must not be pregnant, breastfeeding (non-lactating), or planning pregnancy. 14. Female patients must have negative serum hCG pregnancy test at screening and negative urine test a check-in. 15. Females of childbearing potential who are sexually active with a non-sterile male partner (sterile male partners are defined as men vasectomised at least 3 months prior to the first study drug administration) must be willing to use one of the following acceptable contraceptive methods throughout the study and for at least 3 months after the last study drug administration: a. Simultaneous use of intrauterine contraceptive device (without hormone release system) placed at least 4 weeks prior to the first study drug administration, and condom for the male partner. 16. Females of non-childbearing potential must be: a. Post-menopausal (absence of menses for at least 12 months prior to the first study drug administration) with confirmation of the post-menopausal status by documented FSH level > 40 mlll / mL; or b. Surgically sterile (complete hysterectomy, bilateral oophorectomy or tubal ligation at least 3 months prior to the first study drug administration). 17. Male patients who are not vasectomised for at least 3 months prior to dosing and who are sexually active with a female partner of childbearing potential must be willing to use one of the following acceptable contraceptive methods from the first dose and for 90 days after the last dose: a. simultaneous use of condom and hormonal contraceptive (e.g., oral, patch, depot injection, implant, vaginal ring, intrauterine device) or non-hormonal intrauterine device used for at least 4 weeks prior to sexual intercourse for the female partner; 18. Male patients (including men who have had a vasectomy) with female (not postmenopausal, not surgically sterile) partner must agree to use a condom from the first dose and for 90 days after the last dose. 19. Male patients must be willing not to donate sperm for 90 days after the last dose. 20. Willing and able to adhere to all study requirements, including willingness to remain in the study unit for the entire duration of the confinement period. 21 .Able to understand the study procedures and provide signed and dated patient informed consent form (ICF) to participate in the study prior to screening. Exclusion Criteria Patient who meets any of the following criteria will not be eligible for participation in this study: 1. History of any clinically significant cardiopulmonary disease, including but not limited to moderate to severe Chronic Obstructive Pulmonary Disease (COPD) (GOLD stages 2-4 requiring daily use of bronchodilators or steroids), Congestive Heart Failure (NYHA Class III or IV), significant Coronary Artery Disease (CAD) (previous myocardial infarction, coronary artery bypass grafting, or percutaneous coronary intervention within the last 6 months), Pulmonary Hypertension (mean pulmonary artery pressure > 25 mmHg at rest or > 30 mmHg during exercise), or uncontrolled symptomatic arrhythmias (such as atrial fibrillation with rapid ventricular response or ventricular tachycardia), or any other condition which, in the opinion of the Investigator, would jeopardize participant safety or impact the validity of study results. 2. History (1 month prior screening) or presence of active unstable lung disease (e.g. asthma, chronic obstructive pulmonary disease [COPD], pulmonary fibrosis, hemoptysis, bronchiectasis) or prior intubation for respiratory illness, as per Investigator discretion. Patients with active infective exacerbation will be excluded. 3. Neurologic or psychological disease that would compromise data collection. This includes patients with cognitive impairment as determined by a Short Blessed Test score >10 or those with acute delirium within 30 days prior to screening. 4. Any laboratory test results deemed clinically significant by the Investigator. 5. Patients with uncontrolled or rapidly escalating pain as determined by the Investigator. 6. Patients with a score > 10 Columbia Suicide Severity Rating Scale (C-SSRS) 7. The patient is expected to have surgery during the study. 8. Known allergic reactions to any excipient in the formulations 9. History of substance use disorder, as defined by DSM-5 criteria, such as cocaine, phencyclidine (PCP), crack, opioid derivatives including heroin, and amphetamine derivatives within 1 year prior to screening. 10. Use of marijuana within 1 month prior to the screening. 11 .Current (< 1 year) alcohol as identified during screening in accordance with Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria. 12. Use of medications for the timeframes specified below, with the exception of medications exempted by the Investigator on a case-by-case basis: a. Monoamine oxidase inhibitors (MAOIs) within 14 days prior to dosing; b. Marinol®, Sativex, Epidiolex® or Medical Cannabis therapy c. Any investigational drug (non-approved) within the previous 30 days or during the course of the study. For concomitant medication details, refer to the study restriction. 13. Any reason which, in the opinion of the Investigator, would prevent the patient from participating in the study. Study restriction • The following medications and therapies must remain at a stable dose / regimen (if possible) throughout the titration and double-blind periods: tranquilizers, muscle relaxants, sedatives, antidepressants, anticonvulsants, benzodiazepines, physical therapy, biofeedback therapy, acupuncture therapy and herbal remedies. In addition, if dexamethasone is administered, participants must notify the clinical staff immediately and document the use, including the dose level. The medical monitor must be notified in advance of (or as soon as possible after) any instances in which changes in current therapies being administered. • Food containing poppy seeds from 24 hours prior to screening until EOS. • Abstain from alcohol for 72 hours prior to admision on Day 0 and 24 hours prior to each outpatient visit and screening • Patients must not drive 24 hours post study drug administration Patient Withdrawal and Replacement Patients who withdraw following the screening procedures but before receiving the study medication will not be considered a dropout and will not be included in the database. Patients will be informed that they have the right to withdraw from the study at any time for any reason, without prejudice to their medical care. Over the course of the study, the Investigator also has the right to withdraw any patient from the study for any one of the reasons described below: • Intercurrent illness, AE, or surgery as determined by the physician in charge if not specified in the protocol; • Symptoms or signs indicating possible toxicity; • Needs for medication which may interfere with study measurements; • Noncompliance with protocol requirements or non-adherence to study drug; • Significant protocol deviation; • Unwillingness to continue in the study; • Any other reason based upon the medical judgment of the Investigator. If a patient is withdrawn from the Study Part A (titration phase) or Part B (double-blind, cross-over phase) for any reason, whether related to the study drug or not, or if a patient voluntarily withdraws before or after receiving the study drug, such patient will be considered an early termination patient. The reason for study withdrawal is to be documented in the patient’s source documents and electronic case report form (eCRF). Patients who withdraw prior to dosing may be replaced. In the event that the number of drop-outs exceeds initial expectations, patients who withdraw or are withdrawn from the Study Part A after dosing for reasons other than safety and tolerability may be replaced after consultation between the Investigator and the Sponsor. Patients who withdraw or are withdrawn from the study after dosing during the Phase B, for any reason will not be replaced. Identification of Study Drugs The IPs to be used in this study are presented in Table 43. 5      • IRX211a (Dronabinol pMDI) 0.5 mg / dose is a clear, colourless pressurized solution having a A9-THC concentration of 0.655% w / w. All excipient levels for once-daily (QD) dosing are below the maximum daily exposure levels as detailed in the United States FDA Inactive Ingredient Database (HD). All excipients are United States Pharmacopoeia (USP) grade or equivalent. 10      • Matching placebo (pMDI) Placebo aerosol for oral inhalation is provided in the identical pMDI device to IRX211a, containing the same excipients but no API. Table 42: Investigational Products Details Study Drug Dronabinol Dose Form Route of Administration Dronabinol (mg) per Actuation Inactive Ingredients / Excipients IRX211a 0.655% w / w; 0.5 mg / actuation pulmonary 0.5 Dehydrated Ethanol, HFA 134a (1,1,1,2 Tetrafluoroet hane) Placebo N / A pulmonary 0.5 Dehydrated Ethanol, HFA 134a (1,1,1,2 Tetrafluoroet hane) Table 43: IRX211a Formulation Component Amount Per Actuation MPD / MDE Route Purpose Dronabinol 0.5 mg N / A Inhalation API Dehydrated Ethanol 1.528 mg 52 mg (MDE) Inhalation Co-solvent HFA134a (1,1,1,2-Tetrafluoroethane) 74.354 mg 685 mg (MDE) Inhalation Propellant 15 Abbreviations: API = active pharmaceutical ingredient; MPD = maximum potency per unit dose; MDE = maximum daily exposure; N / A = not available IRX211a is supplied in a multi-dose canister. The container closure / delivery system comprises a 14 mL aluminum fluorocarbon polymerization plasma-treated canister, a metering valve and a mouthpiece. The dosing device (inhaler) is a non-electronic, pressurized, metered, multi-dose inhaler that is designed to deliver Dronabinol aerosol via oral inhalation. The product consists of a canister filled with the product formulation, a metering valve, and an actuator, which doubles as a mouthpiece. The patient self-administers a dose of the medication, by closing their mouth tightly around the plastic mouthpiece. Pressing down on the canister triggers the release of a specific dose of the drug through the metering valve into the mouthpiece of the inhaler, which is to be drawn into the lungs via a deep concurrent inhalation. The inhaler has a counter to indicate the number of remaining actuations. The counter commences at 124 and decreases with each actuation to a minimum of 000. Packaging, Labelling and Storage Conditions The labels for the IPs will contain the information as per local regulatory requirements. For Study Part A, one Dronabinol-containing inhalation aerosol device will be used per patient. Each inhaler will contain 120 doses of 0.5 mg Dronabinol. For Study Part B, each patient will receive ten inhalers, of which seven will have canisters filled with the Dronabinol-containing formulation and three with the placebo formulation. Each inhaler will be labelled in accordance with double-blind requirements with device identification numbers from 1 to 10. The study drug will be stored in upright position in controlled temperature from 20°C to 25°C. Based on the real-time stability data on the research and development batch, the product is stable for at least 5 months when stored valve-up at controlled room temperature. Drug Supply and Accountability IRX211a will be manufactured, packaged and labelled by Ab-Initio, in accordance with Good Manufacturing Process (GMP) for Medicinal Products for use in human clinical trials. IRX211 a will be supplied to the Pharmacy in a multi-dose container. Likewise, placebo will be manufactured, packaged and labelled by Ab-Initio, in accordance with GMP for Medicinal Products for use in human clinical trials and must be provided with a certificate of analysis and supplied to the Pharmacy in a multi-dose container. The IPs will be stored at the central pharmacy in a secure location in accordance with federal regulations and requirements from the Therapeutic Goods Administration adhering to local state and federal laws associated with a Schedule 8 drug. The Pharmacy will dispense the first dose of IRX211 a and provide the study drug for the titration period (Part A; IRX211 a pMDI; 120 doses), and in a blinded fashion in accordance with the randomization schedule IPs for study cross-over phase (Part B; IRX211 a and placebo - 10 pMDIs). Patients will be provided IP with device and dosing instructions before discharge on Day 0 for Study Part A, at the beginning of Part B, if deemed eligible. Investigational Product Education Instructions regarding IP use will be provided to the patient during the first study site visit, with a first dose administration done under the control of site staff. Such instructions are shown in Figure 19. This will be reinforced by the site staff at each visit. Contact information and availability of study staff will be provided to patients. Blinding Study Part B is a double-blind study and thus the Investigator, site staff (other than pharmacists), Sponsor, sponsors delegates (if applicable) and patients are all blinded to treatment. No individual patient information that can potentially unblind the Investigator or patient will be reported until the end of the study. The presentation of the placebo will be identical in appearance to IRX211a. Randomization This study consists of two study parts. Part A is an open-label study due to the objective nature of the data. Patients eligible for the study will self-administer IRX211 a drugs according to titration scheme for up to 2 weeks. Patients who achieve effective pain relief for at two consecutive BTcP episodes will enter Part B. Part B is double-blind, randomized, placebo-controlled, cross-over phase. Following confirmation of eligibility for Study Part B, patients will be randomized to a treatment sequence of seven doses of IRX211a at individually pre-determined dose level and three doses of matching placebo. At the time of randomization, patients will be assigned a unique randomization number, allocated sequentially based on the pre-determined randomization schedule and according to their chronological order of inclusion in the study. Confirmation of the treatment number allocated will be documented in the drug accountability records and recorded in the eCRF. Both the screening and randomization numbers will be used to identify the patient throughout the study period and on all study-related documentation. A computer-generated randomization schedule will be prepared by an experienced statistician prior to the start of the Study Part B. Investigational products will be prepared in accordance with the randomization list. After signing the ICF, each patient will be given a screening number according to the screening order. Throughout the study, individuals participating in the study and clinical staff responsible for activities related to AE collection, monitoring, review, or assessment, as well as those who could influence the study outcome will be blinded (Part B) with respect to the participant’s treatment assignment (IRX211a or placebo). This blinding part (Part B) will be maintained until the clinical phase of the study concludes, signified by the completion of AE reporting and evaluation for all cohorts. The designated pharmacy personnel who are not directly engaged in clinical aspects of the trial will be responsible for the preparation and dispensation of the study medication and will be aware of the randomization code. To ensure blinding integrity, both the study drug and placebo will share identical visual appearances and taste. In the event of an emergency for an individual participant in which knowledge of the study treatment is critical to the participant’s medical management or for the decision of dose escalation, the Investigator may break the blind for that participant and the treatment / placebo group will be revealed. The Investigator or other attending study physician will make every effort to contact the Sponsor prior to unblinding a participant’s treatment assignment and will record the date and reason for unblinding in the study source documents. Study Drug Administration Upon admission to the clinical trial, patients will receive comprehensive training on how to use the pMDI. In Study Part A, patients will be instructed to inhale a single dose (one puff) of IRX211a using a pMDI as soon as a BTcP episode begins on Day 0. During the dosing process, clinic staff will be available to provide assistance. After completing the 4-hour safety observation period, patients will be discharged and sent home at the discretion of the Investigator. They will be guided to continue self-administering IRX211a, with the dosage adjusted up to a maximum of 2 mg per single episode of BTcP. Patients are advised to wait at least 4 hours before using IRX211 a to treat another BTcP episode. Additionally, they should not exceed treating more than 4 BTcP episodes with IRX211 a or use more than a total of 7 puffs (actuations) within any 24-hour period, adhering to whichever of these limits is reached first. In Part B, patients will be instructed to use the single effective dose - i.e. the number of actuations of each pMDI that correspond to the single effective dose identified during the titration period, per day, specifically for their first BTcP episode on that day experienced between 7 am and 7 pm. In addition, participants must ensure the study treatment will be used for BTcP period happening at least 4 hours post-last rescue medication administration. Prior and Concomitant Medications Patients with cancer and BTcP are expected to continue taking any stable medications with the approval of the Investigator, and breakthrough pain medications where required. Patients will be required to avoid taking monoamine oxidase inhibitors (MAOIs), Marinol® or Sativex within 14 days prior to the commencement of the study dosing and throughout the study. In addition, patients will be notified that participation in other clinical trials involving investigational (non-approved) drugs or medical device is not permitted within 30 days or 5 half-lives prior to the start of this study or at any time during its course. Any medication or vaccine that the patient is receiving at the time of enrolment (within 14 days before the time of randomization) or any medication, except the study drug, used after the first treatment period until the end of the study will be recorded on the eCRF along with the following: • Reason for use; • Dates of administration, including start and end dates; • Dosage information, including dose and frequency. Medications taken by patients before dosing will be documented as prior medications, and medications taken by patients after dosing through the last study day will be documented as concomitant medications. Drugs, Nicotine and Alcohol Patient must have a negative drug of abuse, alcohol breath test at timepoints specified in Table 40. Patients will be required to abstain from: • Use of marijuana (directly or indirectly) within 30 days prior to screening and throughout the study • Alcohol-based products from 72 hours prior to admission on Day 0, and 24 hours prior to each outpatient visit and screening visit • Patients should be non-smokers and non-vapers Additional Restrictions • Patients must refrain from getting any new piercings on their nose or nasal cavity. • Patients must not drive 24 hours post study drug administration Participants will be offered taxi vouchers or equivalent to support them for transport post-drug administration. These measures are designed to ensure participant safety. Legal compliance with driving restrictions is to be managed by the participant following all reasonable measures to support them during the study dosing period. Study Procedures The following procedures and assessments from screening through the EOS will be performed at pre-defined times as specified in Table 40. There will be a combination of on-site visits, nurse home visits and telehealth appointments. Every effort will be made to perform the assessments at the nominated timepoints within the time windows (if applicable), and actual times of procedures will be recorded in eCRF. In the event multiple post-dose procedures are required to be conducted at the same nominal time point the following order is recommended: 1. ECG recording; 2. Vital signs assessments; 3. Physical examination; 4. Clinical laboratory tests sampling; 5. C-SRRS, BDI and DEQ score; 6. Patient Reported Outcomes (PROs) and Questionnaires Generic Study Visits A mobile nurse will visit a patient at their home during the trial (unless outpatient study site visit is requested by Investigator) and will perform the assessments as detailed in Table 40 (Generic Study Visits). These visits are important for training patients on study procedures and the Study App, monitoring patient’s health status and study compliance. All nurse home visits will be scheduled through the Study App. The mobile nurse will have access to the Study App through their mobile to schedule all home visits. Study Add The Study App will be used to: • Obtain electronic informed consent (if preferred by patient); • Facilitate communication between the enrolled study patients and the study team; • Record responses to e-Diary questionnaires and electronic patient report outcome (ePRO) assessments; • Collect information on change in health status, concomitant medication use, and AEs; • Capture data by the mobile nurse during home visits and visits performed by the Investigator. All patients will be given instructions on how to download the app and use the app. Screening Evaluations The study will begin once the patient signs the informed consent on the clinical site or via an electronic system. Once informed consent has been signed, will undergo on-site screening visit (Visit 1). The screening visit will take place on any day within 28 days before the first dose is administered (Visit 2, Day 0) and must occur before patients enter the baseline observation period. During the screening visit, responsible study personnel will perform eligibility assessments and provide support and training to the patient on the use of the inhaler, Study App and completion of the e-Diary. Patients who satisfy all inclusion and none of the exclusion criteria will be assigned a unique patient number and start a 14-day baseline observation period (as part of the screening period -at least 14-days prior to the first dose is administered), during which they will monitor and record specific information as described herein. Baseline Demographics Patient demographics will be recorded, including year of birth, sex, race and ethnicity, smoking status, and for females only, childbearing potential status. Medical, Surgical and Medication History A complete medical history will include evaluation for past or present cardiovascular, respiratory, gastrointestinal, renal, hepatic, neurological, endocrine, metabolic, lymphatic, hematologic, immunologic, dermatologic, psychiatric, and genitourinary disorders, medication and surgical history and review of any other pre-existing conditions. All medical history relevant to chronic cancer pain and BTcP should be documented in detail. A precise location of the BTcP, consistent with the location of signs and symptoms, must be documented. Medical history will also include alcohol and caffeine consumption and smoking history. A review of prior medications will be completed. Prior medications are those used within 30 days of Day 0. Medications that the patient is currently taking for cancer treatment, including those for BTcP management will be documented. Body weight (kilograms) and height (centimeters), wearing light clothes, but no shoes, will be measured to allow the calculation of body mass index (rounded to one decimal place). Viral Serology Human Immunodeficiency Virus (HIV) antibodies, hepatitis B surface antigen or hepatitis C antibody will be measured at screening. Spirometry (FEV1 & FVC) Spirometry will be performed as a screening evaluation. Forced expiratory volume in the first second (FEV1) is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Forced vital capacity (FVC) is the amount of air that can be forcibly exhaled from the lungs after taking the deepest breath possible. FEV1% is a measure of lung function and is defined as the proportion of a person's FVC that can be expired in the first second of forced expiration. Measurements of both FEV1 and FVC will be taken electronically by spirometry and the ratio FEV1 / FVC (FEV1%) calculated. The values recorded will be the mean of 3 assessments (expirations) made at least 5 minutes apart. Testing for any out-of-range values may be repeated at the discretion of the Investigator. Inhaler Education and Tolerability Patients will receive counselling on taking IP including correct inhaler technique. One dose of placebo will be administered under the supervision of the Investigator or qualified designee at the screening visit to ensure that the patient can use the correct technique. The Investigator or qualified designee will record an assessment of the patient’s technique and delivery of IP. Patients who are unable to demonstrate that they can tolerate inhaled delivery of placebo or who are unable to demonstrate appropriate technique will not be enrolled. Columbia Suicide Severity Rating Scale (C-SSRS) A suicide risk assessment will be performed using the screening version of C-SSRS questionnaire at screening visit. This scale will be administered by a member of the medical team. If the Investigator determines that a patient is at risk of suicide or selfharm, he / she will not be enrolled and referred to support services (e.g. Lifeline). Subsequent C-SSRS assessments will be performed using the ‘since last visit’ version of C-SSRS. This scale will be administered by a member of the medical team, If the Investigator determines that a patient is at risk of suicide or self-harm, he / she must immediately be discontinued from the study and appropriate measures to ensure the patient’s safety and obtain mental health evaluation must be implemented. The Beck Depression Inventory (BPI) The Beck Depression Inventory (BDI) is a widely used, standardized self-report questionnaire designed to assess the presence and severity of depressive symptoms. Comprising 21 multiple-choice questions, the BDI evaluates a range of symptoms associated with depression, including mood, cognitive disturbances, behavioral changes, and physical symptoms. Each item is scored on a scale from 0 to 3, with higher total scores indicating more severe depressive symptoms. To evaluate depressive symptoms in study patients, an initial BDI using the screening version questionnaire at screening visit will be performed. To evaluate depressive symptoms in study patients through the study, an BDI using the “since last visit” version questionnaire will be performed at multiple timepoints throughout the duration of study. A member of the medical team will administer this scale and will assess various aspects of depression, such as mood, sleep, and thoughts of death / suicide. The Short Blessed Test The Short Blessed Test (SBT) is a brief, six-item cognitive screening tool used to assess orientation, memory, and concentration. It is commonly employed in clinical trials to identify potential cognitive impairment, particularly in populations at risk for dementia. The test involves tasks such as recalling the current year, month, and repeating a short list of items, with the total score indicating the level of cognitive dysfunction. The SBT is quick to administer (taking around 5-10 minutes) and is a validated measure for detecting early cognitive decline. Safety and Tolerability Assessments Safety and tolerability will be evaluated by performing physical examinations, vital signs measurements, ECG measurements, clinical laboratory safety tests, concomitant medication, C-SSRS assessment, BDI assessment, DEQ assessment and AEs monitoring. Physical Examination A physical examination will be performed at screening and EOS / early withdrawal visit. The physical examination will include examination of the following: general appearance, head, ears, eyes, nose, throat, neck (including thyroid), skin, cardiovascular system, respiratory system, gastrointestinal system, musculoskeletal system, lymph nodes and nervous system. Any findings made during the physical examination must be noted regardless of whether they are part of the patient’s medical history. A brief physical examination will be performed at generic / outpatient study visits. Additional symptom directed physical examinations may also be performed at any time through the study as clinically indicated. Vital Signs Measurements Vital signs measurements will include systolic and diastolic blood pressure (mmHg), radial pulse rate (beats / minute), respiratory rate (breaths / minute), body temperature (tympanic; °C) and pulse oximetry. Wherever possible, vital signs will be recorded after the patient has rested comfortably (supine position) for at least 3 minutes and using consistent methods between patients. The Investigator (or a qualified observer at the investigational site) will interpret the vital signs using one of the following categories: within normal limits, abnormal not clinically significant (NCS), or abnormal clinically significant (CS). The following normal ranges for vital sign parameters will be applied: • Systolic BP: 90 to 140 mmHg; • Diastolic BP: 40 to 90 mmHg; • Heart rate: 40 to 100 beats / minute; • Respiratory rate: 10 to 20 breaths / minute; • Temperature: 35.5 to 37.5 °C; • Oxygen saturation: 95% to 100% (pulse oximetry). 12-lead Electrocardiogram A 12-lead ECGs will be performed in triplicates, approximately 1 minute apart (a maximum of 2 minutes between traces is acceptable) after the patient has rested comfortably in the supine position for 5 minutes. The following ECG parameters will be assessed: heart rate, PR interval, RR interval, QRS duration, QT interval and QTcF. The mean value for the triplicate will be utilized. Testing for any out-of-range values may be repeated once at the discretion of the Investigator. The Investigator (or a qualified observer at the investigational site) will interpret the ECG using one of the following categories: within normal limits, abnormal NCS, or abnormal CS. The following ranges for normal 12-lead ECG parameters will be applied: • Heart rate: 40 to 100 beats / minute; • PR interval: 120 to 220 msec; • QRS duration: <120 msec; • QTcF interval: <470 msec (female) or <450 msec (male). Clinical Laboratory Safety Tests The following safety clinical laboratory samples will be analyzed at the site, or by the site’s local laboratory: Blood samples to be collected for the following tests: • Biochemistry [following an 8 hour fast] (9 mL blood sample): albumin, total protein, blood glucose, sodium, potassium, urea, creatinine, creatinine clearance (Cockcroft-Gault formula), aspartate transaminase, alanine transaminase, alkaline phosphatase, gamma glutamyl transferase, total bilirubin, triglyceride, total cholesterol, lactate dehydrogenase, calcium, and uric acid; • Hematology (4 mL blood sample): Hemoglobin, hematocrit, red blood cell count, white blood cell (WBC), platelet count, WBC subset count (neutrophils, eosinophils, basophils, lymphocytes, and monocytes), mean corpuscular volume, mean corpuscular hemoglobin, mean cell hemoglobin concentration and coagulations; • Viral Serology (9 mL blood sample): hepatitis B surface antigen, hepatitis C virus and human immunodeficiency virus; • Pregnancy Screen: Females of childbearing potential will be screened for pregnancy. To be performed per the Schedule of Events: blood sample to detect the presence of [3-HCG (collected as part of biochemistry sample). Urine samples to be collected for the following tests: • Urinalysis (10 mL fresh urine sample): Urine specific gravity, pH, protein, glucose, ketones, urobilinogen, bilirubin and blood. Urine microscopy, if required, will be performed at Investigator’s discretion; • Urine Drugs Screen (10 mL fresh urine sample): a screen for amphetamines, methamphetamines, methadone, barbiturates, benzodiazepines, cocaine, opiates, methyl enedioxy methamphetamine, phencyclidine, tetrahydrocannabidiol. Upon consultation with the Investigator, patients on stable doses of prescribed medications containing amphetamines, benzodiazepines, or opioids may be permitted to participate even if the test is positive; • Pregnancy Screen: Females of childbearing potential will be screened for pregnancy. To be performed per the Schedule of Events: urine dipstick. Alcohol Screen: The presence of alcohol will be detected using a breath test. Drug Effects Questionnaire (DEQ) To evaluate the abuse potential, the participative effects before and after dosing will be self-reported using the DEQ. The DEQ is a validated instrument commonly used in psychoactive drug research consisting of 20 items that are each rated using a unipolar 100 mm visual analog scale, with anchors of “not at all” on one end and “extremely” on the other. Participants are instructed to rate how they were feeling “right now” on six items related to the investigational study product: feeling the effect, liking any of the effects, disliking any of the effects, feeling any good effects, feeling any bad effects and likelihood of taking the study product again. Additionally, participants rate how much they are experiencing the following 14 adjectives: “sick,” “heart racing,” “anxious,” “relaxed,” “paranoid,” “tired / drowsy,” “alert,” “irritable,” “energetic,” “restless,” “hungry,” “dazed,” “distracted” and “euphoric / happy.” Efficacy Assessments Pain Intensity Assessment This assessment measures the intensity of a patient's pain. Patients will be asked to rate their current pain level immediately before and at specific time intervals post-dose. Patients will be required to record the requested details as close to the specified timepoints as possible, contingent upon their pain levels and overall health status. • Timepoints: Ratings will be recorded at baseline (immediately before dose), and at 5, 10-, 15, 30-, and 60-minutes post-dose. • Scale: An 11 -point scale will be used, ranging from 0 (no pain) to 10 (pain as bad as you can imagine). Pain Relief Assessment This assessment evaluates the effectiveness of the study medication in providing pain relief. Patients will compare the intensity of their pain relief at various timepoints postdose to their pain level immediately prior to taking the medication. Patients will be required to record the requested details as close to the specified timepoints as possible, contingent upon their pain levels and overall health status. • Timepoints: Evaluations will be made at 5, 10-, 15-, 30-, and 60-minutes postdose. • Scale: A 5-point scale will be utilized, with 0 indicating no relief, and 4 indicating complete relief. Rescue Medication Usage This section documents the use of rescue medication by patients following the administration of the study drug. It aims to track additional pain management requirements. Rescue medication is defined as immediate release oxycodone 5mg to 20mg titrated to the discretion of the investigator and / or previously prescribed breakthrough medications. Upon signing the consent form, patients who was not prescribed with immediate release oxycodone prior, will be prescribed with Oxycodone as a Rescue Medication during screening visit. The cost of Oxycodone supply will be borne by the sponsor, InhaleRx Ltd. • Record Keeping: Patients will record the date, time, and specifics of any rescue medication used for each BTcP episode after study drug administration. Statistics Analytical Methodology The primary efficacy analysis will be based on the ITT population using the primary endpoint. The primary efficacy endpoint, i.e., SPID at 30 minutes after dosing will be analyzed using a mixed analysis of variance (ANOVA) model with repeated measures with fixed effects for treatment, center, and random effect for patient. Least squares mean, standard error, p-values and 95% confidence intervals of the treatment difference will be calculated. To avoid multiple comparisons, other primary endpoints, i.e. SPID at 15 mins and TOT PAR scores at 15 and 30 minutes comparted to baseline, will be analysed in the same manner as SPID at 30 minutes without the generation of a p-value. The supportive analyses include analyses of secondary endpoints based on the ITT population and all endpoints on the per-protocol population. All secondary parameters, including PID and PR scores at all time points, SPID at 60 minutes after dosing, will be analysed in the same manner as the primary endpoint. The percentage reduction in daily opioid dosage required for pain management will be summarized between the two treatment groups and will be analysed in the same manner as the primary endpoint. The percentage of treated breakthrough pain episodes that required the use of rescue medication between the two treatment groups will be summarized. The episodes with rescue medication will be analyzed using a logistic regression with repeated measure. Odds ratios and their 95% confidence intervals will be calculated. The percentage of responders between the two treatment groups will be summarized. Responders will be analyzed using a logistic regression with repeated measure. Odds ratios and their 95% confidence intervals will be calculated. Unless otherwise specified, all statistical tests will be two-sided with a significance level of a = 0.05. Safety Endpoints Safety and tolerability of IRX211 a will be evaluated through the assessment of TEAEs (i.e., seriousness, severity, relationship to the study drug, outcome, duration, and management), vital signs, 12-lead ECGs, physical examinations, C-SSRI, DEQ and BDI assessment. Sample Size Determination A sample size of 29 will enable the detection of effect sizes above .25 where we assume an a of .05 with an approximate power of 80% under an ANOVA repeated measures model. A total of 60 patients with BTcP will be enrolled for participation in Study Part A with at least 45 patients to be enrolled for participation for Study Part B, which assumes a 26% discontinuation rate within Part B and a 25% discontinuation rate within Part A. Analysis Populations The following patient populations will be used for analysis: all treated (titration and double-blind phases), intent-to-treat, and per-protocol. The definitions of these datasets follow: • All Treated patients (titration phase): All patients who received at least one dose of the open-label titration medication. Safety data from the open-label titration phase will be summarized using this population. • All Treated patients (double-blind phase): All patients who received at least one dose of double-blind medication. Safety data in the double-blind phase will be summarized using this population. • Intent-to-Treat (ITT) Population: All randomized patients who received at least one dose of double-blind study medication and provided baseline and at least one post-baseline pain intensity score. All efficacy analyses will be performed using this population. • Per-protocol Population: All ITT patients with evaluable episodes that are compliant with the protocol. Unevaluable episodes will be excluded for reasons such as: pain treated not target breakthrough pain, change to current pain medication, incomplete episodes, etc. Statistical Analyses This section describes the general framework to be used for the analysis and presentation of data in this study. A complete description of the statistical analyses to be performed on efficacy as well as safety and tolerability data will be presented in a separate statistical analysis plan. Safety and Tolerability Analysis Safety and tolerability of IRX211 a will be evaluated primarily through the frequency and percentages of TEAEs for all treated patients. TEAE summaries will be summarized by primary system organ class (SOC) and preferred term (PT). TEAE summaries will be presented by dosages for Part A, if applicable. Cumulative AE summaries for both Part A and Part B will also be presented. Additional details will be provided through listings. Additional safety summaries will include vital signs, 12-lead ECGs, physical examinations, C-SSRI and BDI assessment and labs. All analyses include cumulative summaries for both Part A and Part B will be presented where necessary for all treated patients. The summary of laboratory evaluations will be presented for hematology, chemistry, and urinalysis. Laboratory data will be summarized by presenting summary statistics of raw data and change from baseline values by visit. Raw data for vital sign measurements and their change from baseline will be summarized with descriptive statistics by visit. The number and percentage of patients with clinically notable vital signs will be presented. ECG interval will be summarized by presenting summary statistics for change from baseline values. Incidence rates of clinically notable ECG abnormalities will be summarized with counts and percentages. Demographics and Other Baseline Characteristics Demographics and baseline characteristics will be summarized for all within the ITT population using frequency and percentages for categorical variables and descriptive statistics for continuous variables. Listings will be provided when necessary. Efficacy Analysis All efficacy analyses will be based on the ITT set. Selected efficacy analyses will also be repeated based on the PP set as a supporting analysis to the ITT analysis. The aim of this study is to estimate the treatment effect of the study drug IRX211 compared to placebo for the target population on the primary pain parameter. Summary statistics by treatment and pain episode will be provided for the primary and efficacy variable. The primary estimation method for both the primary and several secondary efficacy variables will be based on a mixed ANOVA repeated measures model including site and treatment as fixed factors with subject as a random effect. The primary objective will be achieved if IRX211 is statistically significant versus placebo in terms of the primary efficacy variable (e.g. p-value < .05). 5 This study will estimate the treatment effect of the study drug IRX211 compared to placebo for the target population on the primary pain parameter. It is expected that administration of the study drug IRX211 will result in improvement in the primary pain parameter compared to baseline for BTcP patients.

Claims

1. A method of treating breakthrough cancer pain (BTcP), the method comprising:aerosolising a composition comprising not more than about 3% (w / w) tetrahydrocannabinol (THC), a co-solvent, and a propellant to produce an aerosol comprising liquid particles comprising THC, andadministering by inhalation to a subject in need thereof a therapeutically effective amount of the aerosol.

2. The method according to claim 1, wherein the composition comprises about 0.6% to about 0.7% (w / w) THC.

3. The method according to claim 1 or 2, wherein the tetrahydrocannabinol is administered to the subject at the onset of BTcP.

4. The method according to claim 1 -3, wherein the tetrahydrocannabinol reduces the number of occurrences of pain, prevents recurrence of pain, relieves the severity of pain, reduces the number of BTcP episodes per 24 hours, reduces pain intensity for at least one BTcP episode per day, provides pain relief for at leat one BTcP episode per day, and / or provides pain relief such that the dose of a previously prescribed medication to treat BTcP is reduced.

5. The method according to any one of claims 1 to 4, wherein the tetrahydrocannabinol is a synthetic tetrahydrocannabinol.

6. The method according to any one of claims 1 -5, wherein the THC is administered to the subject in the form of a unit dose.7 The method according to claim 6, wherein the unit dose comprises about 0.5 mg of THC.

8. The method according to claim 7, wherein the unit dose comprises about 0.5 mg dronabinol, about 1.5 mg ethanol and about 743 mg 1,1,1,2-tetrafluoroethane.

9. The method according to any one of claims 6 to 8, wherein at least 1 unit dose is administered to the subject.

10. The method according to any one of claims 6 to 9, wherein 2 to 7 unit doses are administered to the subject in succession.

11. The method according to claim 10, wherein each successive unit dose is administered at least 30 min after administration of the previous dose.

12. The method according to any one of claims 1 to 11, wherein the method comprises administering by inhalation to the subject with cancer a unit dose consisting of THC, ethanol and a propellent, via a pressurised metered dosage inhaler, to thereby treat BTcP.

13. The method according to any one of claims 1 to 12, wherein the subject receives or has received opioid therapy for BTcP, and wherein administering the THC via inhalation allows for a reduction in dose of opioid for BTcP or replaces opioid therapy for BTcP.

14. A pharmaceutical composition for inhalation comprising a synthetic THC, a cosolvent and a propellant, wherein the composition comprises less than about 3.5% (w / w) THC.

15. The pharmaceutical composition according to claim 14, wherein the composition comprises about 0.6% to about 0.7% (w / w) THC.

16. The composition according to claim 14 or 15, wherein the composition comprises not more than about 5% (w / w) co-solvent.

17. The composition according to any one of claims 14 to 16, wherein the composition comprises about 0.655% w / w of dronabinol, about 2% w / w of ethanol and about 97.3% w / w of 1,1,1,2 tetrafluoroethane.

18. The composition of any one of claims 14-17 consisting of the synthetic THC, the co-solvent and the propellant.

19. An inhaler system comprising an actuator and an interchangeable canister, wherein the canister contains the pharmaceutical composition of any one of claims 14 to 18.

20. The inhaler system according to claim 19 adapted to dispense about 0.5 mg of synthetic THC with each actuation.

21. A kit comprising the inhaler system according to claim 19 or 20 and instructions for use.

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